www.arquivosonline.com.br
Sociedade Brasileira de Cardiologia • ISSN-0066-782X • Volume 105, Nº 2, August 2015
Right Kidney
Left Kidney
Figure 1 – Renal Denervation Procedure. Selective angiography performed with a 7-F Renal Double
Curve guide catheter in the left anterior oblique 10° projection. Note that a single renal artery supplies
each kidney and that the caliber and length of the main renal artery prior to bifurcation is ideally suited
to denervation. Page 203
Editorial
Role Of MMP-2 and MMP-9 in Resistance to Drug Therapy in Patients
Editorial Considerations on the New Clinical and Surgical Perspectives
with Resistant Hypertension
of Brazilian Cardiology
Reduced Progression of Cardiac Allograft Vasculopathy with Routine
Special Article
Use of Induction Therapy with Basiliximab
Executive Summary – Guideline on Telecardiology in the Care of
Brief Communication
Patients with Acute Coronary Syndrome and Other Cardiac Diseases
Original Articles
Myocardial Scintigraphy in the Evaluation of Cardiac Events in
Patients without Typical Symptoms
New Exercise-Dipyridamole Combined Test for Nuclear Cardiology
in Insufficient Effort: Appropriate Diagnostic Sensitivity Keeping
Diastolic Function in Paced Children with Cardiac Defects: Septum vs Apex
Review Article
Nobel Prizes: Contributions to Cardiology
Viewpoint
Sudden Death in Brazil: Epilepsy Should be in Horizon
Exercise Prognosis
Clinicoradiological Session
Cardiac Surgery Costs According to the Preoperative Risk in the
Pulmonary Valve Lesion after Double Valvotomy in Childhood
Brazilian Public Health System
Case 6 / 2015 – A 27-Year-Old Male Patient with Double Aortic and
Case Report
Screening for Fabry Disease in Left Ventricular Hypertrophy:
Profound Sustained Hypotension Following Renal Denervation:
Documentation of a Novel Mutation
A Dramatic Success?
Heart Failure with Preserved Left Ventricular Ejection Fraction in
Image
Patients with Acute Myocardial Infarction
Giant Right Atrial Mass Following Surgical AorticValve Replacement
Tramadol Alleviates Myocardial Injury Induced by Acute Hindlimb
Letter to the Editor
Ischemia Reperfusion in Rats
Subclinical Ventricular Dysfunction Detected by Speckle-Tracking Two
Effects of One Resistance Exercise Session on Vascular Smooth
Muscle of Hypertensive Rats
Years after Use of Anthracycline
Erratum
A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948
Contents
Editorial
Editorial Considerations on the New Clinical and Surgical Perspectives of Brazilian Cardiology
Paulo Roberto B. Evora and Alfredo J. Rodrigues
.....................................................................................................................................................................page 103
Special Article
Executive Summary – Guideline on Telecardiology in the Care of Patients with Acute Coronary
Syndrome and Other Cardiac Diseases
Mucio Tavares de Oliveira Jr., Leonardo Jorge de Paula, Milena Soriano Marcolino, Manoel Fernandes Canesin
.....................................................................................................................................................................page 105
Original Articles
Nuclear Cardiology and PET
Myocardial Scintigraphy in the Evaluation of Cardiac Events in Patients without Typical Symptoms
Paola Emanuela Poggio Smanio, Juliana Horie Silva, João Vitor Holtz, Leandro Ueda, Marilia Abreu, Carlindo
Marques, Leonardo Machado
.....................................................................................................................................................................page 112
New Exercise-Dipyridamole Combined Test for Nuclear Cardiology in Insufficient Effort:
Appropriate Diagnostic Sensitivity Keeping Exercise Prognosis
Inés Vidal Cortinas, Mario Beretta, Omar Alonso, Fernando Mut
.....................................................................................................................................................................page 123
Cardiac Surgery - Adults
Cardiac Surgery Costs According to the Preoperative Risk in the Brazilian Public Health System
David Provenzale Titinger, Luiz Augusto Ferreira Lisboa, Bruna La Regina Matrangolo, Luis Roberto Palma
Dallan, Luis Alberto Oliveira Dallan, Evelinda Marramon Trindade, Ivone Eckl, Roberto Kalil Filho, Omar
Asdrúbal Vilca Mejía, Fabio Biscegli Jatene
.....................................................................................................................................................................page 130
Epidemiology
Screening for Fabry Disease in Left Ventricular Hypertrophy: Documentation of a Novel Mutation
Ana Baptista, Pedro Magalhães, Sílvia Leão, Sofia Carvalho, Pedro Mateus, Ilídio Moreira
.....................................................................................................................................................................page 139
Arquivos Brasileiros de Cardiologia - Volume 105, Nº 2, August 2015
Ischemia/Myocardial Infarction
Heart Failure with Preserved Left Ventricular Ejection Fraction in Patients with Acute
Myocardial Infarction
Lucas Antonelli, Marcelo Katz, Fernando Bacal, Marcia Regina Pinho Makdisse, Alessandra Graça Correa,
Carolina Pereira, Marcelo Franken, Anderson Nunes Fava, Carlos Vicente Serrano Junior, Antonio Eduardo
Pereira Pesaro
.....................................................................................................................................................................page 145
Tramadol Alleviates Myocardial Injury Induced by Acute Hindlimb Ischemia Reperfusion in Rats
Hamed Ashrafzadeh Takhtfooladi, Adel Haghighi Khiabanian Asl, Mehran Shahzamani, Mohammad
Ashrafzadeh Takhtfooladi, Amin Allahverdi, Mohammadreza Khansari
.....................................................................................................................................................................page 151
Exercising
Effects of One Resistance Exercise Session on Vascular Smooth Muscle of Hypertensive Rats
Tharciano Luiz Teixeira Braga da Silva, Marcelo Mendonça Mota, Milene Tavares Fontes, João Eliakim dos
Santos Araújo, Vitor Oliveira Carvalho, Leonardo Rigoldi Bonjardim, Márcio Roberto Viana Santos
.....................................................................................................................................................................page 160
Hypertension
Role Of MMP-2 and MMP-9 in Resistance to Drug Therapy in Patients with Resistant Hypertension
Leandro Lacerda, Ana Paula de Faria, Vanessa Fontana, Heitor Moreno, Valéria Sandrim
.....................................................................................................................................................................page 168
Heart Transplantation - Clinical
Reduced Progression of Cardiac Allograft Vasculopathy with Routine Use of Induction Therapy
with Basiliximab
Ricardo Wang, Lidia Ana Zytynski Moura, Sergio Veiga Lopes, Francisco Diniz Affonso da Costa, Newton
Fernando Stadler Souza Filho, Tiago Luiz Fernandes, Natália Boing Salvatti, José Rocha Faria-Neto
.....................................................................................................................................................................page 176
Brief Communication
Diastolic Function in Paced Children with Cardiac Defects: Septum vs Apex
Michel Cabrera Ortega, Adel Eladio Gonzalez Morejon, Giselle Ricardo Serrano, Dunia Barbara Benitez Ramos
.....................................................................................................................................................................page 184
Review Article
Nobel Prizes: Contributions to Cardiology
Evandro Tinoco Mesquita, Luana de Decco Marchese, Danielle Warol Dias, Andressa Brasil Barbeito, Jonathan
Costa Gomes, Maria Clara Soares Muradas, Pedro Gemal Lanzieri, Ronaldo Altenburg Gismondi
.....................................................................................................................................................................page 188
Viewpoint
Sudden Death in Brazil: Epilepsy Should be in Horizon
Fulvio Scorza and Paulo José Ferreira Tucci
.....................................................................................................................................................................page 197
Arquivos Brasileiros de Cardiologia - Volume 105, Nº 2, August 2015
Clinicoradiological Session
Case 6 / 2015 – A 27-Year-Old Male Patient with Double Aortic and Pulmonary Valve Lesion
after Double Valvotomy in Childhood
Edmar Atik
.....................................................................................................................................................................page 199
Case Report
Profound Sustained Hypotension Following Renal Denervation: A Dramatic Success?
Ganiga Srinivasaiah Sridhar, Timothy Watson, Chee Kok Han, Wan Azman Wan Ahmad
.....................................................................................................................................................................page 202
Image
Giant Right Atrial Mass Following Surgical AorticValve Replacement
Teresa Bastante and Fernando Alfonso
.....................................................................................................................................................................page 205
Letter to the Editor
Subclinical Ventricular Dysfunction Detected by Speckle-Tracking Two Years after Use of Anthracycline
Aguinaldo Figueiredo Freitas Jr., Raquel Oliveira Santos, Salvador Rassi
.....................................................................................................................................................................page 206
Erratum
.....................................................................................................................................................................page 208
Arquivos Brasileiros de Cardiologia - Volume 105, Nº 2, August 2015
www.arquivosonline.com.br
A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948
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Back to the Cover
Editorial
Editorial Considerations on the New Clinical and Surgical Perspectives
of Brazilian Cardiology
Paulo Roberto B. Evora and Alfredo J. Rodrigues
Departamento de Cirurgia e Anatomia da Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, SP – Brazil
The Arquivos Brasileiros de Cardiologia (ABC) has been the
official publication of the Brazilian Society of Cardiology for
more than 60 years, and has proved to be one of the most
prestigious scientific journals in Latin America, approaching
all aspects of cardiology, including the surgical ones. In August
1986, the Revista Brasileira de Cirurgia Cardiovascular
(RBCCV), specifically directed to the surgical aspects of heart
diseases, began to be published. Thus, the editorial policy of
the ABC has progressively privileged publications focused on
the clinical treatment of cardiovascular diseases over surgical
publications of common interest to cardiologists and cardiac
surgeons1. Despite the substantial changes in the treatment of
heart diseases, deriving from the appearance of new drugs and
percutaneous devices, cardiac surgeries are still the treatment
of choice to a substantial number of heart diseases, mainly the
congenital, valvular and even coronary ones, whose onus of
surgery indication is invariably on cardiologists. Thus, those
specialists should be aware of several aspects of cardiac
surgery, mainly those concerning their risks and results, so that
they can base their indications on evidence.
The great majority of cardiologists might know that the
use of bilateral internal thoracic arteries (BITA) for coronary
artery bypass grafting improves survival as compared to the
use of only one single internal thoracic artery (ITA)2. Thus, the
optimization of arterial grafts has been widespread with the use
of the radial artery (RA) and composite grafts. However, only
few professionals are aware of the controversies involving risky
situations, possible limitations to the use of BITA3, the patency
index of RA grafts and their influencing factors. The RA was
the second arterial graft introduced in the clinical practice for
coronary artery bypass grafting, and has drawn the interest
of Brazilian surgeons since the 1990s4. Skeletonization of the
left ITA (LITA) can favorably change the flow capacity of the
graft, leading to the assumption that the behavior of the RA,
as a coronary graft, is similar to that of the skeletonized LITA.
Considering the potential role of the RA as a second option
of coronary grafting and the concept of complete coronary
artery bypass grafting with the exclusive use of arterial grafts,
Keywords
Cardiology/trends; Case-Control Studies; Cardiovascular
Surgical Procedures/trends; Evidence Based Practice/trends.
Mailing Address: Paulo Roberto B. Evora •
Faculdade de Medicina de Ribeirão Preto – USP. Rua Rui Barbosa 367/15,
Centro. Postal Code 14015-120, Ribeirão Preto, SP – Brazil
E-mail: [email protected]; [email protected]
Manuscript received July 06, 2015; revised manuscript July 08, 2015;
accepted July 08, 2015.
DOI: 10.5935/abc.20150094
103
Bonini et al5 have carried out a prospective randomized study
comparing 40 patients distributed into two groups. In group I,
skeletonized RA was used in 20 patients, and, in group II, RA
with adjacent tissues was used in 20 patients. After the surgical
procedure, flow velocity was measured. The results showed
that the morphological and pathological characteristics, as
well as the hemodynamic performance of the free RA grafts,
regardless of being skeletonized or having adjacent tissues,
were similar. However, a larger number of non-obstructive
lesions was observed in the group with the RA graft preserving
the adjacent tissues5.
In addition, small is the number of cardiologists aware of
the models to calculate the perioperative risk for morbidity
and mortality available and popular among cardiac surgeons6,
as well as of their limitations, mainly regarding the most recent
options of percutaneous therapies6,7. The applicability of risk
scores to cardiac surgery is another relevant international
matter, but not well defined in centers outside North America
and Europe. Garoffalo et al8 have assessed the ability of the
Parsonnet-Bernstein 2000 score and EuroSCORE to predict
the in-hospital mortality of patients undergoing cardiac
surgery at a reference hospital in Brazil, and have identified
risk predictors. The use of those scores has underestimated
in-hospital mortality, suggesting inadequate preoperative
assessment of the patients undergoing cardiac surgery.
That study has stressed the need to develop local scores based
on the reality of the populations to better assess the risk of
cardiac surgery3.
Considering the controversies about the ideal method of
coronary artery bypass grafting for patients on dialysis, Herzog
et al9, in the United States, have compared long-term survival
of patients on dialysis after angioplasty, coronary stenting
and coronary artery bypass grafting. That retrospective study
has reported better long-term survival of patients on dialysis
after coronary artery bypass grafting than after percutaneous
coronary intervention and coronary stenting, emphasizing the
relatively poorer results of patients with diabetes. That study
has supported the need to develop large clinical registries and
prospective studies on coronary revascularization procedures
for patients on dialysis9. Miranda et al10 have approached that
important question, analyzing retrospectively 50 consecutive
and non-selected patients on dialysis, undergoing coronary
artery bypass grafting at a tertiary university-affiliated hospital
between 2007 and 2012. Those authors have shown that
coronary artery bypass grafting is feasible in patients on dialysis,
although followed by high morbidity and in-hospital mortality.
In addition, they have emphasized the frequent exclusion of
that group of patients from large cardiac studies. That detail
might even contribute to the difficulty in selecting a better
approach and to the still modest surgical results as compared
to those of patients with preserved kidney function10.
Evora & Rodrigues
Brazilian clinical and surgical perspectives
Editorial
It is therefore evident that, although the ABC prioritizes
articles on clinical therapies and their guidelines, the
restriction upon articles with a surgical bias can deprive
cardiologists from essential information to support their
clinical decision-making, especially regarding the case-
to-case analysis in daily practice. It is worth noting the
publication in the ABC of several articles of common interest
to both cardiac surgeons and cardiologists in recent years,
therefore providing a relevant service to cardiology and
cardiovascular surgery.
References
1. Evora PR. Cardiac surgery, the Brazilian Archives of Cardiology and the
Brazilian Journal of Cardiovascular Surgery. Rev Bras Cir Cardiovasc.
2012;27(4):VIII-XI.
2. Lytle BW, Blackstone EH, Sabik JF, Houghtaling P, Loop FD, Cosgrove DM.
The effect of bilateral internal thoracic artery grafting on survival during 20
postoperative years. Ann Thorac Surg. 2004;78(6):2005-12; discussion
2012-4.
3.
Gatti G, Dell’Angela L, Benussi B, Dreas L, Forti G, Gabrielli M, et al. Bilateral
internal thoracic artery grafting in octogenarians: where are the benefits?
Heart Vessels. 2015. [Epub ahead of print]
4. Dallan LA, Oliveira SA, Jatene FB, Corso R, Iglesias JCR, Prates N,
et al. Radial artery for a wider arterial myocardial revascularization:
microscopical anatomy and surgical technique. Rev Bras Cir Cardiovasc.
1996; 11(2): 75-81.
5. Bonini RC, Staico R, Issa M, Arnoni AS, Chaccur P, Abdulmassih Neto C,et
al. Effects of skeletonized versus pedicled radial artery on postoperative graft
patency and flow. Arq Bras Cardiol. 2014;102(5):441-8.
6.
Head SJI, Osnabrugge RL, Howell NJ, Freemantle N, Bridgewater B, Pagano
D, et al. A systematic review of risk prediction in adult cardiac surgery:
considerations for future model development. Eur J Cardiothorac Surg.
2013;43(5):e121-9
7. Thalji NM, Suri RM, Greason KL, Schaff HV. Risk assessment methods for
cardiac surgery and intervention. Nat Rev Cardiol. 2014;11(12):704-14.
8.
Garofallo SB, Machado DP, Rodrigues CG, Bordim O Jr, Kalil RA, Portal VL.
Applicability of two international risk scores in cardiac surgery in a reference
center in Brazil. Arq Bras Cardiol. 2014;102(6):539-48.
9. Herzog CA, Ma JZ, Collins AJ. Comparative survival of dialysis patients
in the United States after coronary angioplasty, coronary artery stenting,
and coronary artery bypass surgery and impact of diabetes. Circulation.
2002;106(17):2207-11.
10. Miranda M, Hossne NA Jr, Rodrigues Branco JN, Vargas GF, Almeida Palma da
Fonseca JH, Medina de Abreu Pestana JO, et al. Myocardial revascularization
in dyalitic patients: in-hospital period evaluation. Arq Bras Cardiol.
2014;102(2):128-33.
Arq Bras Cardiol. 2015; 105(2):103-104
104
Back to the Cover
Special Article
Executive Summary – Guideline on Telecardiology in the Care of
Patients with Acute Coronary Syndrome and Other Cardiac Diseases
Mucio Tavares de Oliveira Jr.1, Leonardo Jorge Cordeiro de Paula1, Milena Soriano Marcolino2, Manoel Fernandes
Canesin3
Instituto do Coração, HCFMUSP1, São Paulo, SP; Universidade Federal de Minas Gerais2, Belo Horizonte, MG; Universidade Estadual de
Londrina3, Londrina, PR – Brazil
Cardiology is a very promising field in telemedicine.
The transmission of electrocardiograms (ECG) from remote
health services or ambulances to a central for analysis
is already routine in the approach to acute coronary
syndromes (ACS). This approach allows the obtention of
expert guidance and referral to appropriate health units,
with the potential of saving lives. This impact may be seen in
acute myocardial infarction (MI), in which telemedicine has
reduced intra-hospital mortality rates from 12.3% to 7.1%1-4.
Basic concepts
In a health system geographically distributed like the
Brazilian system, in which Basic Health Units (Unidades
Básicas de Saúde, UBSs), Emergency Care Units (Unidades
de Pronto Atendimento, UPAs), secondary hospitals, and
ambulances are scattered throughout the country (often in
remote locations), and specialized centers are located in
advanced care units in large cities (such as tertiary hospitals),
telemedicine offers the opportunity to improve the treatment
of emergencies. The clinical ability of specialists in tertiary
hospitals may be used to improve the care in Remote Care
Units (Unidades Remotas de Atendimento, URAs), offering
support for early diagnosis and therapy guidance for
non‑specialist medical practitioners providing medical care
to patients in URAs5,6.
Communication channels in telemedicine include
telephone lines for voice communication and connection
to the internet, and for transmission of test results, ECG
tracings, and images. Optionally, a video link may be used
for visualization of the patient.
Telemedicine in the approach to ACS7,8
Situation A: A patient goes by himself to the nearest URA,
or calls the prehospital care service and is taken to the URA
in a standard ambulance without an electrocardiograph.
Keywords
Heart Failure / mortality; Myocardial Infarction / mortality;
Telemedicine / utilization; Electrocardiography; Mobile
Health Units.
Mailing Address: Mucio Tavares de Oliveira Jr. •
Av. Dr. Eneas de Carvalho Aguiar, 44 - Unidade de Emergência.
Postal Code 05403-900, São Paulo, SP – Brazil
E-mail [email protected]
Manuscript received July 10, 2015; revised manuscript July 10, 2015;
accepted July 10, 2015.
DOI: 10.5935/abc.20150104
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Arq Bras Cardiol. 2015; [online].ahead print, PP.0-0
The professionals at the URA take the clinical history, examine,
and obtain serial ECGs from the patient. The ECG tracings are
transmitted along with the clinical history to the telecardiology
hub where they are interpreted by cardiologists who quickly
prepare and send a report, and guide the professionals at the
URA on the appropriate therapy.
Situation B: A patient connects with the prehospital care
service and an ambulance with an electrocardiograph and
without a physician answers the call. Based on the patient's
history and interpretation of the ECG, if the cardiologist at
the telecardiology hub diagnoses the patient as having an
ST‑segment elevation MI (STEMI), he guides the medical
team to administer the standard therapy (for example,
aspirin and other medications) and transport the patient to
a hospital that offers percutaneous coronary intervention
(PCI) or to administer fibrinolytic treatment. Even if the
diagnosis of STEMI is excluded, the ambulance team is
oriented to follow the cardiologist’s instructions about the
path to be followed for that patient.
Situation C: A patient calls the prehospital care service,
an ambulance with a physician and an electrocardiograph
answers the call, and the team obtains an ECG that is
transmitted to the telecardiology hub. Based on the clinical
history and interpretation of the ECG, if the cardiologist
at the telecardiology hub determines that the patient has
STEMI, he guides the physician to administer treatment for
STEMI, such as antiplatelet and anticoagulant agents, and
to follow one of these options:
• If the STEMI patient can be transported to a hospital
with PCI capability and the PCI can be performed within
120 minutes, or if the patient has contraindication to
fibrinolytic treatment, the patient must be transported
to the hospital with PCI. The ambulance physician
also alerts the hospital to prepare the catheterization
laboratory to treat a STEMI patient with primary PCI.
• If the PCI cannot be performed within 120 minutes,
the ambulance physician is instructed to first administer
fibrinolytic agents, preferably within 30 minutes, and
then transport the patient to the nearest hospital
equipped with a catheterization laboratory to continue
the therapy.
• If the cardiologist in the telecardiology hub confirms that
STEMI is not the diagnosis and the ambulance physician
determines that the patient has ACS, after receiving
the initial therapy the patient should be transferred
preferably to a hospital equipped with a catheterization
laboratory. If that is not possible, the patient should be
transferred to the nearest hospital equipped with an
intensive cardiac care unit. If the cardiologist determines
Oliveira Jr. et al
Guideline on Telecardiology in ACS and Other Cardiopathies
Special Article
that the chest pain protocol should be initiated for the
patient, he or she may direct the ambulance team
to transport the patient to the nearest hospital, even
if the hospital is not equipped with a catheterization
laboratory, for monitoring of clinical parameters, ECG,
and markers of myocardial necrosis (Figure 1).
• Third "D": if the ECG does not show signs of ischemia,
assess the probability of the patient having coronary artery
disease (CAD) based on the presence of risk factors: age
(above 45 years in men and 55 years in women), smoking,
diabetes, hypertension, and family history of early CAD
(below the age of 55 years in men and 65 years in women).
To ensure that the transmitted information has good
quality and the interaction is valuable, the patient with
chest pain should receive a systematic approach, which
can be achieved with several methodologies. One of these
methodologies takes into account the "4D" for systematization
of the diagnosis of ACS (Figure 2)9:
• Fourth "D": the diagnosis of ACS must be confirmed or
excluded, or the chest pain protocol should be initiated.
Requirements in telemedicine for adequate diagnosis
and treatment of ACS and other acute cardiac diseases
(Figure 3)10.
• First "D": classify the chest pain (discomfort) into types
A (definitely anginal), B (probably anginal), C (probably
not anginal), or D (definitely not anginal).
Financial requirements, procedures, and clinical and
team protocols for deployment of telemedicine for adequate
diagnosis and treatment of ACS and other acute cardiac
diseases (Figure 4)10.
• Second "D": define whether an ST-segment elevation is
present or not in the ECG.
Medical equipment, information technology, and services
(Figures 5 and 6)10.
Figure 1 – Schematic representation of telemedicine for acute emergency therapy. Treatment strategies using telemedicine are shown for acute coronary syndrome
(ACS). ECG: surface electrocardiogram.
Arq Bras Cardiol. 2015; 105(2):105-111
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Chest pain (Discomfort): screen the patient and classify the pain into types A, B, C, or D
Define the ECG: presence of ST-segment elevation or signs of ischemia
CAD: low, intermediate, or high probability
Diagnosis: confirm/exclude ACS or initiate the chest pain protocol
Figure 2 – Care systematization for the establishment of the diagnosis in patients with chest pain. ECG: electrocardiogram; CAD: coronary artery disease; ACS: acute
coronary syndrome.
Investigation of the patient, including the type of pain and the
likelihood of coronary artery disease, and acquisition of an
electrocardiogram for detection of ST-segment elevation myocardial
infarction and coronary syndrome without ST-segment elevation in
patients with suspected acute coronary syndrome treated in mobile
and fixed emergency units before the teleconsultation.
Distant specialized support for electrocardiogram interpretation for
detection of ST-segment elevation myocardial infarction and coronary
syndrome without ST-segment elevation in patients treated in mobile
and fixed emergency units.
Distant specialized support for guidance on the management of
patients with suspected acute coronary syndrome treated in mobile
and fixed emergency units.
Acquisition of a prehospital electrocardiogram to refine the
management and reduce the time to reperfusion in patients presenting
with ST-segment elevation myocardial infarction.
Acquisition of a prehospital electrocardiogram for the diagnosis of STsegment elevation myocardial infarction and acute coronary syndrome
without ST-segment elevation to reduce mortality in these patients.
Recommendation Grade
Level of Evidence
I
A
Recommendation Grade
Level of Evidence
I
B
Recommendation Grade
Level of Evidence
IIa
A
Recommendation Grade
Level of Evidence
I
B
Recommendation Grade
Level of Evidence
I
B
Figure 3 – Recommendation grades and levels of evidence of the procedures for management of patients with ACS.
Telecardiology in remote routine diagnosis
One of the most common applications of telecardiology
in remote areas is in the analysis of diagnostic tests, such
as ECG, Holter, ambulatory monitoring of blood pressure
(AMBP), and echocardiography. Other applications include
synchronous or asynchronous teleconsulting systems or
second opinions, teleauscultation, remote monitoring of
blood pressure, vital signs and implantable electronic devices,
and educational activities. In addition, telecardiology
107
Arq Bras Cardiol. 2015; 105(2):105-111
has important applications in the penitentiary system, in
pediatrics, and in fetal cardiology.
Cardiac arrhythmias and syncope11-13
Since several types of cardiac arrhythmia occur in short
and unexpected episodes, its diagnosis depends on an
ECG recorded during the paroxysmal episode. A standard
10-second surface ECG may not be able to detect the
abnormality in the heart rhythm. In this case, long-term
Oliveira Jr. et al
Guideline on Telecardiology in ACS and Other Cardiopathies
Special Article
Adequate support from financial resources to establish the
infrastructure of the telecardiology hub and assembly of the
organizational structure for operation of the telecardiology service.
In the telecardiology hub and in the Remote Care Unit, the clinical
protocols for diagnosis and treatment must be written in easy
language and have simple application. The processes and work pace
for each step must be documented and communicated to the team.
The team of cardiologists at the telecardiology hub for emergency
consultations, such as interpretation of electrocardiograms,
conference calls, web conferences, videoconferences, or telephone
calls, must be adequate to the number of calls and the number of
units connected to the hub.
Technical support and management professionals must be part of the
team, and everyone should be trained, including users of the system
at the mobile and fixed Remote Care Units.
Recommendation Grade
Level of Evidence
I
C
Recommendation Grade
Level of Evidence
I
C
Recommendation Grade
Level of Evidence
I
C
Recommendation Grade
Level of Evidence
I
C
Figure 4 – Recommendation grades and levels of evidence for the financial requirements, procedures, and clinical and team protocols in telemedicine for adequate
diagnosis and treatment of ACS and other acute cardiac diseases.
monitoring is recommended, such as 24-hour Holter
monitoring or event recording for 2 to 4 weeks. For selected,
more difficult cases, an implantable monitoring device named
loop recorder may be used to record the ECG patterns during
occasional but significant symptoms like syncope.
patient and offer specialized treatment to HF patients, has
been shown to reduce the mortality and hospitalizations due
to HF, improve quality of life, reduce the cost of treatment of
prescriptions based on evidence, and improve the patients’
knowledge and their knowledge about self-treatment.
The system may be useful in several situations, among others:
• Detection of asymptomatic episodes of atrial fibrillation,
which may require anticoagulation therapy to reduce
the risk of stroke.
• Quick recognition of electrode lead failure, allowing
fast intervention and avoiding inappropriate shocks.
• Reduction in the number of outpatient visits during
long-term follow-up of patients with a pacemaker or
implanted defibrillator.
Heart failure (HF)14,15
Distant monitoring, or telemonitoring, is a promising strategy
to improve the outcomes of HF treatment, allowing remote
monitoring of patients so physicians can intervene early when
evidence of clinical deterioration is present. The approaches
vary from computerized systems for decision support to
programs managed by nurses or physicians. A dedicated
hardware or a smartphone may be used to transmit the patient's
data (for example, symptoms, weight, blood pressure, and heart
rate). A structured phone support, which can better guide the
Author contributions
Conception and design of the research, Acquisition of
data, Writing of the manuscript and Critical revision of the
manuscript for intellectual content: Oliveira Jr. MT, Paula LJC,
Marcolino MS, Canesin MF; Analysis and interpretation of the
data and Obtaining financing: Oliveira Jr. MT.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
This study was partially funded by Philips Healthcare.
Study Association
This study is not associated with any thesis or dissertation work.
Arq Bras Cardiol. 2015; 105(2):105-111
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In the Remote Care Unit, all patients with chest pain must have a
12‑lead electrocardiogram performed, which should be interpreted in
less than 10 minutes from the first medical contact (FMC).
Availability of a 12-lead electrocardiograph with a capability to
transmit the tracing to the telecardiology hub, preferably with an
option to print the tracing.
Use of photographic reproduction or low-quality scanning to
transmit the electrocardiogram to the telecardiology hub for
preparation of the report.
Use of software for electrocardiogram interpretation validated for
emergency situations.
In remote locations in which the results of the markers are not
available within 60 minutes, the local availability of point-of-care
equipment should be evaluated.
Wait for the results of myocardial necrosis markers to start
therapy in patients with a diagnosis of ST-segment elevation
myocardial infarction.
Availability of cardiac markers assessment by a point-of-care
methodology in remote fixed areas where a central laboratory is
not available.
Recommendation Grade
Level of Evidence
I
A
Recommendation Grade
Level of Evidence
I
C
Recommendation Grade
Level of Evidence
III
C
Recommendation Grade
Level of Evidence
IIb
C
Recommendation Grade
Level of Evidence
I
A
Recommendation Grade
Level of Evidence
III
A
Recommendation Grade
Level of Evidence
IIa
B
Figure 5 – Recommendation grades and levels of evidence for the medical equipment in telemedicine for adequate diagnosis and treatment of ACS and other acute
cardiac diseases.
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Arq Bras Cardiol. 2015; 105(2):105-111
Oliveira Jr. et al
Guideline on Telecardiology in ACS and Other Cardiopathies
Special Article
Internet availability for wired or wireless transmission of patients’ data,
electrocardiogram, and other tests.
Presence of equipment for patient monitoring in the Remote Care Unit
and in the mobile unit for all patients with suspected acute coronary
syndrome.
Presence of telephone equipment for routine transmissions or to allow
communication during network downtime, or failure in the equipment
or transmission system.
Presence of internet connection with adequate bandwidth in
the Remote Care Unit and in the telecardiology hub adapted for
transmission of electrocardiograms and other additional resources,
such as data and image.
Presence of wired or wireless hardware for work and communication,
suitable for the demand of both the telecardiology hub and Remote
Care Unit.
In services that choose to transmit videos, or still or dynamic images,
the wired or wireless hardware for work and communication should be
suitable for this purpose.
Presence of a protection system, security of local data and data to
be transmitted, as well as an up-to-date anti-virus program in the
telecardiology hub and Remote Care Unit.
Recording of all the communication involving orientation or
exchange of information between the telecardiology hub and the
Remote Care Unit.
Presence in the Remote Care Unit of electrocardiogram equipment
compatible with the system used in the telecardiology hub and
technical stock in sufficient amount to replace and maintain the
system operative.
Recommendation Grade
Level of Evidence
I
C
Recommendation Grade
Level of Evidence
I
A
Recommendation Grade
Level of Evidence
I
C
Recommendation Grade
Level of Evidence
I
C
Recommendation Grade
Level of Evidence
I
B
Recommendation Grade
Level of Evidence
I
A
Recommendation Grade
Level of Evidence
I
C
Recommendation Grade
Level of Evidence
I
C
Recommendation Grade
Level of Evidence
I
C
Figure 6 – Recommendation grades and levels of evidence for the information technology equipment and services in telemedicine for adequate diagnosis and treatment
of ACS and other acute cardiac diseases.
Arq Bras Cardiol. 2015; 105(2):105-111
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Back to the Cover
Original Article
Myocardial Scintigraphy in the Evaluation of Cardiac Events in
Patients without Typical Symptoms
Paola Emanuela Poggio Smanio, Juliana Horie Silva, João Vitor Holtz, Leandro Ueda, Marilia Abreu, Carlindo
Marques, Leonardo Machado
Instituto Dante Pazzanese de Cardiologia, São Paulo, SP – Brazil
Abstract
Background: Cardiovascular disease is a leading cause of death in the world and in Brazil. Myocardial scintigraphy is
an important noninvasive method for detecting ischemia in symptomatic patients, but its use in asymptomatic ones or
those with atypical symptoms is yet to be defined.
Objective: To verify the presence of major cardiac events in asymptomatic patients or those with atypical symptoms
(atypical chest pain or dyspnea) that underwent myocardial scintigraphy (MS), over a period of 8 years. Secondary
objectives were to identify cardiac risk factors associated with myocardial scintigraphy abnormalities and possible
predictors for major cardiac events in this group.
Methods: This was a retrospective, observational study using the medical records of 892 patients that underwent myocardial
scintigraphy between 2005 and 2011 and who were followed until 2013 for assessment of major cardiac events and risk
factors associated with myocardial scintigraphy abnormalities. Statistical analysis was performed by Fisher’s exact test,
logistic regression and Kaplan-Meyer survival curves, with statistical significance being set at p ≤ 0.05.
Results: Of the total sample, 52.1% were men, 86.9% were hypertensive, 72.4% had hyperlipidemia, 33.6% were diabetic,
and 12.2% were smokers; 44.5% had known coronary artery disease; and 70% had high Framingham score, 21.8% had
moderate and 8% had low risk. Of the myocardial scintigraphies, 58.6% were normal, 26.1% suggestive of fibrosis and
15.3% suggestive of ischemia. At evolution, 13 patients (1.5%) had non-fatal myocardial infarction and six individuals (0.7%)
died. The group with normal myocardial scintigraphy showed longer period of time free of major cardiac events, non-fatal
myocardial infarction (p = 0.036) and death. Fibrosis in the myocardial scintigraphy determined a 2.4-fold increased risk of
non-fatal myocardial infarction and five-fold higher risk of death (odds ratio: 2.4 and 5.7, respectively; p = 0.043).
Conclusion: The occurrence of major cardiac events in 8 years was small. Patients with fibrosis at MS had more major
events, whereas patients with normal MS result had fewer major cardiac events, with higher survival. (Arq Bras Cardiol.
2015; [online].ahead print, PP.0-0)
Keywords: Myocardial Scintigraphy; Ischemia; Atypical Symptoms; Hard events.
Introduction
Cardiovascular diseases are the leading cause of death
worldwide, with ischemic heart disease and cerebrovascular
accident (CVA) being the most frequent1.
The incidence of coronary artery disease (CAD) is increasing
worldwide, being the second leading cause of death in Brazil,
with a mean of 80,000 deaths per year. Its prevalence in
the adult population is estimated at 5-8%2. According to the
Department Informatics of the Brazilian Unified Health System
(DATASUS), in 2010, ischemic heart disease accounted for
210,046 hospital admissions in Brazil and 29% of deaths
Mailing Address: Paola Emanuela Poggio Smanio •
João Lourenço,763 Vila Nova Conceição. Postal Code 045080-31.
São Paulo, SP – Brazil.
E-mail: [email protected]
Manuscript received February 18, 2014; revised manuscript December 08,
2014; accepted December 08, 2014.
DOI: 10.5935/abc.20150074
112
(99,408 deaths or 55.11 deaths/100,000 inhabitants)3,4,
corresponding to a burden of R$ $ 1.9 billion, or 19% of the
total cost with hospitalizations5.
Due to the epidemiological importance of CAD,
appropriate risk stratification strategies are needed to establish
better cost-effectiveness and safety of preventive treatments,
as well as request for additional tests.
The clinical manifestation of coronary heart disease is the
result of the imbalance between myocardial oxygen supply
and consumption. The subjective description of angina may
make symptom interpretation difficult and, therefore, the
clinical diagnosis. Thus, objective ischemia tests can confirm
the diagnostic hypothesis and assess CAD severity6.
Myocardial scintigraphy (MS) is a cornerstone in the
evaluation of patients with suspected CAD due to its high
diagnostic accuracy, as well as being able to define the extent,
severity and location of myocardial perfusion abnormalities,
greatly assisting in clinical management7.
The technique uses electromagnetic gamma radiation
to obtain images. Radioactive isotopes are injected into the
Smanio et al.
Myocardial perfusion without typical symptoms events
Original Article
patient and, due to affinity for the myocardium, they bring
perfusion and/or metabolic information. After the radiotracer
injection, it is possible to indirectly assess blood flow and
myocardial flow reserve in a non-invasive manner8,9.
patient had creatinine clearance < 90 mL/min; LVEF
was determined by Doppler echocardiogram performed
at most three months before the MS with no procedures
between the methods.
Currently, there is strong evidence for using MS in the
diagnosis, follow-up, risk stratification and prognosis of
symptomatic patients with known or suspected CAD.
However, MS indication in asymptomatic patients or patients
with atypical symptoms, even with known CAD, is yet to
be defined, since in addition to the fact that benefits in this
population are not fully established, the examination involves
the inherent risks of physical or pharmacological stress, as well
as exposure to ionizing radiation10,11.
MS was performed using 99mTc-sestamibi as the radiotracer
and according to the standard protocol of 1 or 2 days,
with the stress test (exercise or pharmacological test) being
the basal stage, being performed on the same day or on
subsequent days.
The objective of this study was to identify, in asymptomatic
patients or patients with atypical symptoms submitted to
MS, the occurrence of events such as death and acute
myocardial infarction (AMI), occurring in up to 8 years.
Secondary objectives were to define the time free of events
such as death and AMI after normal MS in asymptomatic
patients or patients with atypical symptoms; to identify risk
factors associated with alterations in myocardial perfusion
scintigraphy; to identify risk factors that are independent
predictors of death and nonfatal AMI in this group of patients.
Methods
Retrospective, observational study carried out by the
data analysis of medical records in a group of asymptomatic
patients with cardiovascular symptoms or those considered to
be atypical, with previously known CAD or not.
All patients underwent MS at Instituto Dante Pazzanese
de Cardiologia from December 2005 to June 2011.
Patients were followed for the period from the date of the
examination until July 2013, to verify the occurrence of
nonfatal myocardial infarction or death. All patients were
analyzed for the presence of systemic arterial hypertension
(SAH), dyslipidemia, smoking status, occlusive peripheral
arterial disease (OPAD) and / or carotid disease, diabetes
mellitus, chronic renal failure (CRF), ischemic cerebrovascular
accident (iCVA), previously known CAD, Left Ventricular
Ejection Fraction (LVEF) < 50%, family history of coronary
heart disease, type of stress used at the MS (exercise stress
or pharmacological stress test with dipyridamole), and
presence of alteration suggestive of ischemia in the exercise
test performed prior to the MS.
Patients were also classified as having high, intermediate
and low cardiovascular risk, according to the Framingham
score. A patient was considered hypertensive if he/she
required the use of one or more antihypertensive drugs
and through the criteria used in the VI Brazilian Guidelines
on Hypertension of the Brazilian Society of Cardiology11;
and was considered dyslipidemic according to the
criteria of the IV Brazilian Guidelines on Dyslipidemia
and Atherosclerosis Prevention of the Department of
Atherosclerosis of the Brazilian Society of Cardiology 12.
A patient was considered diabetic when he or she required
the use of one or more oral hypoglycemic agents and/or
insulin and no patients with metabolic syndrome were
included. The presence of CRF was defined if the
Inclusion criteria were patients submitted to MS that
did not show any cardiac symptom from the date of the
examination request by the requesting clinician to the date
when the MS was performed; and those with symptoms
considered atypical by the clinician that requested the
examination, as they did not meet the classic characteristics
described, such as angina (retrosternal pain, triggered by
exertional or emotional stress, with relief at rest or nitrate)
or that had symptoms suggestive of ischemic equivalent
(dyspnea). Most of the patients had other cardiac symptoms
that were poorly characterized and uncharacteristic for
ischemic heart disease.
Exclusion criteria were patients with chest pain suggestive
of ischemic heart disease, dyspnea or symptoms suggestive
of ischemic equivalent, or electrocardiogram suggestive
of ischemia from the date of the MS request until its
performance; and patients with incomplete data during the
review of medical records.
The MS were analyzed by two specialists in nuclear medicine
and a third expert was called in to analyze the images, when
there was disagreement. The images were analyzed qualitatively
only by the presence or absence of low radiotracer uptake in
the myocardium in the 17 analyzed segments.
The equipment used for image acquisition was the
Millennium VG gamma camera (GE Medical Systems,
Milwaukee, United States), with two scintillation detectors,
angled at 90°, with parallel hole collimators, high resolution
and low energy. Information acquired was processed in a
Xeleris workstation.
MS was performed associated with physical exertion with
exercise testing or pharmacological stimulation through
dipyridamole infusion, according to clinical indication.
Bruce and modified Bruce protocols were used at the
exercise testing, with anti-ischemic medications being
withdrawn according to standardized recommendations
from the nuclear medicine department.
The clinicians of the institution were aware of the
drug withdrawal for the test and, when they did not wish
the medication to be withdrawn they requested that the
evaluation should be performed while on medication, in
the medical request form. The following were considered
as ischemic myocardial response criteria to the physical
stress test, as standardized in the literature: the presence
of ST‑segment depression ≥ 1.5 mm during or after
exercise, when compared to baseline, with slow ascending
morphologies (analyzed at point Y), horizontal (analyzed at
point J) or descending (analyzed at point J), or the presence
of clinical signs/symptoms suggestive of ischemia, according
to the known classical and standardized criteria13.
Arq Bras Cardiol. 2015; 105(2):112-122
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Original Article
For the pharmacological test, dipyridamole was infused at
a dose of 0.56 mg /kg/ min during a total time of 4 minutes.
A dose of 20 mCi or 740 MBq of 99mTc-MIBI was administered
in the second minute after the dipyridamole infusion was
finished, considered as the moment of maximum hyperemia.
As interpretation criteria of electrocardiographic response
to dipyridamole, used for the characterization of the
ischemic response, the presence of horizontal depression,
slowly ascending or descending ST segment ≥ 1.0 mm (or
intensification of depression = 1.0 mm) was considered
suggestive of ischemia, measured at the J point in the horizontal
and descending morphologies, and at the Y point, in the slow
ascending morphology. Typical chest pain and/or other clinical
manifestations suggestive of coronary heart disease were also
considered suggestive of ischemia, according to known classical
and standardized criteria13.
being set at p < 0.05. Moreover, logistic regression analysis
of the clinical and epidemiological characteristics and
risk factors was performed and the event-free survival
Kaplan‑Meier curve was constructed.
The present study only analyzed the presence or absence
of alterations in the functional tests that were suggestive of
ischemia and prognostic scores were not calculated.
Of patients without known CAD (483 patients),
449 patients were completely asymptomatic since the
consultation when MS was requested and 34 patients had
symptoms considered atypical for CAD. Of the patients with
known CAD (388 patients), 368 were totally asymptomatic
since the consultation when MS was requested and 20 had
atypical symptoms (p = 0.059).
The images were processed using the dedicated software
QGS, also known as Cedars-Sinai software, obtaining
tomographic cuts in the vertical plane, according to the
smallest cardiac axis, in the vertical plane, according to the
greatest axis and in the horizontal plane, according to the
greatest axis. The cuts of the two phases were paired to allow
a cut-to-cut comparison of the radioactive concentration at
stress and at baseline.
Image processing synchronized with the ECG provided
the reproduction of cardiac wall contractions, in addition
to indices of systolic and diastolic volumes and LVEF;
it was possible to visualize the heart dynamics in both
views, as well as of a three-dimensional representation
of the left ventricle.
According to the department routine, the criteria for the
analysis of myocardial perfusion images were visual and
qualitative evaluations of the radiotracer concentration
in the different myocardial segments (17 segments),
comparing cut‑by-cut the images of the stress phase with
the corresponding baseline ones. The following factors
were considered in the qualitative analysis of myocardial
perfusion: homogeneity or heterogeneity of the radiotracer
concentration in myocardial segments; extension of
radiotracer concentration defects in the myocardial
segments; and intensity of the relative low uptake of the
radiotracer in the myocardial segments. However, for this
study, we took into account only the presence or absence
of perfusion abnormalities.
MS was considered normal if the radiotracer concentration
was homogeneous in both phases (basal and stress);
suggestive of ischemia, if the low uptake was reversible after
stress; suggestive of fibrosis, if the low uptake was fixed after
the stress phase in relation to baseline; and suggestive of
ischemia and fibrosis, if there was fixed and reversible low
uptake of the radiotracer in one or more myocardial segments
at the baseline and stress phases.
Statistical analysis was performed using the Statistical
Package for Social Sciences (SPSS), and Pearson’s chi-square
test and Fisher’s test were used, with statistical significance
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Arq Bras Cardiol. 2015; 105(2):112-122
This study was submitted to the Research Ethics Committee,
with Certificate Presentation for Ethics Appreciation (CAAE:
20702313500005462).
Results
A total of 892 patients were analyzed, characterized
as asymptomatic or with atypical cardiac symptoms, who
were submitted to MS from December 2005 to June 2011.
Twenty-one patients were excluded due to inconclusive
information in medical records or loss to follow-up during
the study period, thus totaling 871 patients.
After statistical analysis of the collected data, it was
observed equivalence between the genders, with a prevalence
of 454 (52.1%) male patients.
The Framingham score was applied to all assessed
patients, with 611 (70.1%) being classified as having high
cardiovascular risk, 190 (21.8%) as intermediate risk and
70 (8%) as low risk.
The prevalence of all analyzed variables with their respective
percentages is shown in Table 1, depicting a large number of
hypertensive (86.9%) and dyslipidemic (72.4%) patients.
When evaluating the MS characteristics, it was observed that
of the examinations performed, 385 (44.2%) were submitted
to physical stress through exercise test and 486 (55.8%)
Table 1 – Prevalence of cardiovascular risk factors
Variables
Yes
n (%)
Systemic arterial hypertension
757 (86.9)
Dyslipidemia
631 (72.4)
Smoking
106 (12.2)
OPAD/ carotid disease
Diabetes mellitus
58 (6.7)
293 (33.6)
CRF
37 (4.2)
iCVA
48 (5.5)
Previous CAD
388 (44.5)
LVEF < 50%
86 (9.9)
Family history of CAD
101 (11.6)
OPAD: Occlusive peripheral arterial disease; CRF: Chronic renal failure;
iCVA: Ischemic cerebrovascular accident; CAD: Coronary artery disease;
LVEF: Left ventricular ejection fraction.
Smanio et al.
Myocardial perfusion without typical symptoms events
Original Article
were performed with pharmacological stimulation, through
dipyridamole administration. At the ischemia-inducing tests
for the MS, of the 871 tests analyzed, 189 (21.7%) showed
abnormalities suggestive of ischemia due to the presence of ECG
alterations and / or symptoms suggestive of ischemia.
The prevalence of normal MS, fixed low uptake
suggestive of fibrosis and reversible low uptake suggestive
of ischemia in the assessed patients was 511 individuals
(58.6%), 227 (26.1%) and 133 (15.3%), respectively.
Table 2 shows the prevalence of the results obtained by
scintigraphy, including the ischemia-inducing test.
Statistical analysis of the association between the
clinical and epidemiological variables and the result of
the MS was performed, which were described as normal,
with fixed or reversible low uptake. The results are shown
in Tables 3 to 5.
Patients with CRF, ischemic CVA, previous known CAD and
LVEF < 50% showed a greater association with MS suggestive
of fibrosis, with statistical significance (Table 4).
Table 2 – Analysis of the results of altered ischemia-inducing tests
and results of myocardial scintigraphy (MS)
Yes
n (%)
Result
Altered ischemia-inducing test
189 (21.7)
Normal MS
511 (58.6)
Fixed low uptake
227 (26.1)
Reversible low uptake
133 (15.3)
Altered ischemia-inducing test: suggestive of ischemia.
When assessing the primary endpoint, patients with fixed
low uptake had an increased chance of developing AMI
during the analyzed period that was 2.4-fold higher than
patients with normal MS, but without statistical significance.
When evaluating the occurrence of death, of the six recorded
deaths, four had MS with fixed low uptake, with a more than
5-fold higher chance of having this outcome, with statistical
significance (odds ratio - OR: 5.958; 95% confidence interval
- 95%CI: 1.047 to 31.651; p = 0.043) (Table 4).
In the group of patients that had MS with reversible low
uptake suggestive of ischemia, the analysis of the variables
showed that diabetes mellitus, previous known CAD and
altered ischemia-inducing test (suggestive of ischemia)
were associated with the development of reversible low
uptake, which was statistically significant, with p < 0.05.
The incidence of death and AMI was not statistically
significant for this group of patients (Table 5).
In the independent analysis of variables, for the
occurrence of death and AMI it was observed that CRF and
LVEF < 50% were predictors for the occurrence of death
was statistically significant, with p = 0.001 and 0.031,
respectively. The presence of factors such as smoking
and LVEF < 50% was an independent predictor for the
occurrence of AMI, with p = 0.037 and 0.039, respectively.
Figure 1 shows the Kaplan-Meier curve for the presence of CRF
and LVEF < 50% for the outcome of death. Figure 2 shows the
Kaplan-Meier curve for the presence of smoking and LVEF < 50%
for the occurrence of AMI.
During the study period, 13 cases of AMI were obtained,
of which four (30.8%) in the normal MS group, six (46.2%) in
the MS group with fixed low uptake and three (23.1%) in MS
group with reversible low uptake.
Table 3 – Analysis on the association between clinical variables, risk factors, functional test results, events at the follow-up and normal
myocardial scintigraphy (MS)
Variables
Normal MS
n (%)
p value
OR
95%CI
Systemic arterial hypertension
463 (86.5)
0.757
0.919
0.611-1.381
Dyslipidemia
377 (70.5)
0.102
0.770
0.565-1.051
Smoking
61 (11.4)
0.396
0.832
0.551-1.256
35 (6.5)
0.889
0.953
0.553-1.642
173 (32.3)
0.338
0.860
0.649-1.147
0.238-0.899
OPAD/ carotid disease
Diabetes mellitus
CRF
16 (3)
0.250
0.462
iCVA
13 (2.4)
< 0.0001
0.214
0.112-0.411
147 (27.5)
< 0.0001
0.149
0.110-0.202
LVEF < 50%
15 (2.8)
< 0.0001
0.108
0.061-0.192
Family history of CAD
74 (13.9)
0.009
1.841
1.158-2.927
Altered ischemia-inducing test
Previous CAD
102 (19.1)
0.018
0.674
0.487-0.934
AMI
4 (0.7)
0.04
0.274
0.840-0.896
Death
1 (0.2)
0.034
0.124
0.014-1.066
OR: Odds ratio; 95% CI: 95% confidence interval; OPAD: Occlusive peripheral arterial disease; CRF: Chronic renal failure; iCVA: Ischemic cerebrovascular accident;
CAD: Coronary artery disease; LVEF: Left ventricular ejection fraction; AMI: Acute myocardial infarction.
Arq Bras Cardiol. 2015; 105(2):112-122
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Table 4 – Analysis of association between clinical variables, risk factors, functional test result, events at the follow-up and myocardial
scintigraphy (MS) with fixed low uptake suggestive of fibrosis
Variables
Systemic arterial hypertension
MS fibrosis
n (%)
p value
OR
95%CI
194 (85.5)
0.492
0.846
0.547-1.309
Dyslipidemia
168 (74)
0.604
1.113
0.790-1.568
Smoking
30 (13.2)
0.557
1.138
0.724-1.790
OPAD/ carotid disease
20 (8.8)
0.162
1.541
0.877-2.208
Diabetes mellitus
75 (33)
0.870
0.964
0.699-1.329
CRF
17 (7.5)
0.007
2.526
1.299-4.912
iCVA
29 (12.8)
< 0.001
4.818
2.644-8.786
Previous CAD
181 (79.7)
< 0.001
8.307
5.776-11.947
LVEF < 50%
60 (26.4)
< 0.001
8.540
5.227-13.952
Family history of CAD
17 (7.5)
0.0290
0.539
0.312-0.929
Altered ischemia-inducing test
40 (17.6)
0.092
0.771
0.482-1.047
AMI
6 (2.6)
0.113
2.471
0.821-7.430
Death
4 (1.8)
0.043
5.758
1.047-31.651
OR: Odds ratio; 95% CI: 95% confidence interval; OPAD: Occlusive peripheral arterial disease; CRF: Chronic renal failure; iCVA: Ischemic cerebrovascular accident;
CAD: Coronary artery disease; LVEF: Left ventricular ejection fraction; AMI: Acute myocardial infarction.
Table 5 – Analysis of the association between clinical variables, risk factors, functional test result, events in the follow-up and myocardial
scintigraphy (MS) with reversible low uptake suggestive of ischemia
Ischemia MS
n (%)
p value
OR
95%CI
Systemic arterial hypertension
122 (91.7)
0.093
1.799
0.938-3.450
Dyslipidemia
103 (77.4)
0.172
1.366
0.882-2.114
Smoking
16 (12)
1.000
0.985
0.558-1.736
OPAD/ carotid disease
7 (5.3)
0.574
0.748
0.332-1.686
55 (41.4)
0.046
1.481
1.015-2.162
7 (5.3)
0.487
1.311
0.564-3.050
Variables
Diabetes mellitus
CRF
iCVA
9 (6.8)
0.534
1.303
0.615-2.2753
Previous CAD
84 (63.2)
< 0.001
2.447
1.671-3.584
LVEF < 50%
18 (13.5)
0.153
1.542
0.885-2.689
Family history of CAD
13 (9.8)
0.557
0.799
0.432-1.476
Altered ischemia-inducing test
51 (38.3)
< 0.001
2.704
1.821-4.016
AMI
3 (2.3)
0.432
1.680
0.456-6.187
Death
1 (0.8)
1.000
1.111
0.124-9.582
OR: Odds ratio; 95% CI: 95% confidence interval; OPAD: Occlusive peripheral arterial disease; CRF: Chronic renal failure; iCVA: Ischemic cerebrovascular accident;
CAD: Coronary artery disease; LVEF: Left ventricular ejection fraction; AMI: Acute myocardial infarction.
Six deaths were recorded, of which three were of cardiac origin.
Of these three, two (33.3%) belonged to the fixed low uptake and
one (16.7%) to the reversible low uptake group. The other three
deaths were of noncardiac origin, with two (33.3%) in the fixed low
uptake group and one (16.7%) in the normal scintigraphy group.
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Arq Bras Cardiol. 2015; 105(2):112-122
During the mean follow-up of nearly 8 years, patients with
normal MS showed better survival rates free of events such
as death and AMI, when compared to that of patients with
altered MS, with statistical significance, as demonstrated by
the Kaplan-Meier curves (Figure 3).
Smanio et al.
Myocardial perfusion without typical symptoms events
Original Article
Event-free survival curve
1.0
0 No CRF
1 CRF
0.8
p = 0.001
0.6
0.4
0.2
0.0
0
500
1000
1500
2000
2500
3000
Cumulative survival x time
Event-free survival curve
1.0
0 LVEF > 50%
1 LVEF < 50%
0.8
p = 0.031
0.6
0.4
0.2
0.0
0
500
1000
1500
2000
2500
3000
Cumulative survival x time
Figure 1 – Kaplan-Meier curves for the occurrence of death vs. chronic renal failure (CRF) and vs. left ventricular ejection fraction (LVEF) < 50%.
Discussion
Recent publications have sought to identify subgroups
of asymptomatic patients that could benefit from the MS
for the detection of ischemia, such as those with early
CAD family history and patients with anginal equivalent,
OPAD, erectile dysfunction, chronic renal failure and type 2
diabetes. However, the evidence for MS indication in these
subgroups is still scarce10.
The American Society of Nuclear Cardiology (ASCN)9
recommends the performance of MS when screening for
coronary disease in the following asymptomatic patient
subgroups: those with high cardiovascular risk by the ATP III
Arq Bras Cardiol. 2015; 105(2):112-122
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Smanio et al.
Myocardial perfusion without typical symptoms events
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Event-free survival curve
1.00
0 No SMK
1 SMK
0.98
p = 0.037
0.96
0.94
0.92
0.90
0
500
1000
1500
2000
2500
3000
Cumulative survival x time
Event-free survival curve
1.00
0 LVEF > 50%
1 FEVE < 50%
0.95
p = 0.039
0.90
0.85
0.80
0
500
1000
1500
2000
2500
3000
Cumulative survival x time
Figure 2 – Kaplan-Meier curves for the occurrence of acute myocardial infarction (AMI) and vs. smoking (SMK) vs. left ventricular ejection fraction (LVEF) <50%.
criteria; those with Agatston calcium score > 400; diabetics;
patients with CRF; patients with incomplete myocardial
revascularization; and as follow-up in patients with myocardial
revascularization, 5 years after the surgery.
The results obtained in our study showed that MS should
be performed in patients with high pretest probability, even
without symptoms considered typical of ischemia, whether
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Arq Bras Cardiol. 2015; 105(2):112-122
they have known coronary disease or not, as their outcome,
when normal, is associated with low prevalence of major
events in the follow-up.
The safety period after the performance of MS with normal
result was well evaluated in a meta-analysis that included 17 studies
with 8,008 patients, which showed that a normal MS result had
a high negative predictive value for cardiac events for 3 years14.
Smanio et al.
Myocardial perfusion without typical symptoms events
Original Article
Event-free survival curve
1.00
0 Abnormal MS
1 Normal MS
0.8
0.6
p = 0.036
0.4
0.2
0.0
0
500
1000
1500
2000
2500
3000
Cumulative survival x time
Event-free survival curve
1.00
0 Abnormal MS
1 Normal MS
0.98
0.96
p = 0.019
0.94
0.92
0.90
0
500
1000
1500
2000
2500
3000
Cumulative survival x time
Figure 3 – Event curves (acute myocardial infarction and death) in patients with normal or abnormal myocardial scintigraphy (MS).
A study published by Ottenhouf et al. 15 evaluated
261 patients with known CAD and normal myocardial
perfusion scintigraphy, who were followed for a mean period
of 12 years, assessing as primary endpoint of death from all
causes, cardiac death and AMI and / or cardiac death. They
also analyzed independent predictors for the occurrence
of events during this period. The results showed 94 (36%)
deaths, 26 (10%) due to cardiac causes and 15 (6%) due to
AMI; of the risk factors, age and diabetes were predictors for
the event death from all causes, with statistical significance
Arq Bras Cardiol. 2015; 105(2):112-122
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Smanio et al.
Myocardial perfusion without typical symptoms events
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(OR: 1.05; 95% CI: 1.03 to 1.07; p < 0.05; and OR: 2.13;
95%CI: 1.23 to 3.71; p < 0.05, respectively).
Age and male gender were predictors for cardiac death,
also with statistical significance (OR: 1.05; 95% CI: 1.01-1.10;
p < 0.05; and OR: 2.45; 95% CI: 1.07 to 5.64; p < 0.05,
respectively). Diabetes was associated with the occurrence of
cardiac death and / or AMI, also with statistical significance (OR:
2.34; 95% CI: 1.03 to 5.30; p < 0.05). In the same study, the
normal MS was associated with a lower probability of death
from all causes, cardiac death and AMI and/or cardiac death,
with annual event rates of 3.2, 0.9 and 1.2%, respectively.
Schinkel et al. 16, in another recent study, evaluated
233 patients with suspected or known CAD who underwent
MS with 99m Tc-setamibi and had normal myocardial
perfusion. They were followed for a mean of 15.5 years
for the occurrence of death from all causes, cardiac death,
AMI, and major cardiac events, defined as the occurrence
of cardiac death, myocardial infarction and need for
myocardial revascularization. Among the 233 patients, there
were 41 (18%) deaths from all causes, of which 13 were
cardiac deaths; 18 (8%) had AMI; and 47 (20%) required
myocardial revascularization, of which 7% were submitted
to cardiac surgery and 13% to PCI. The event annual rates
for death from all causes, cardiac death and / or AMI and
the presence of major cardiac events were 1.1, 0.3, 0.7 and
1.8%, respectively.
Factors such as age, male gender and diabetes were
independent predictors for the occurrence of death
from all causes, with statistical significance (OR: 1.06;
95% CI: 1.04‑1.09; p < 0.001; OR; 2.70; 95% CI: 1.45 to 5.03;
p = 0.002; and OR: 3.06; 95% CI, 1.22 to 7.65; p = 0.02,
respectively). Factors such as male gender and diabetes were
also independent predictors for the occurrence of major cardiac
events with statistical significance (OR: 2.61; 95% CI: 1.11
to 6.14; p = 0.03; and OR: 6.93; 95% CI: 2.18 to 22.04,
p = 0.01, respectively). It was concluded that patients with
known or suspected CAD showed a favorable outcome during
the analyzed period, especially during the first 5 years.
In comparison, this study showed normal MS in 511 patients
(58.6%); 388 (44.5%) of them had known CAD, 293 (33.6%)
patients had diabetes mellitus and 611 (70%) were classified
as high risk by the Framingham score. Nevertheless, the group
with normal MS showed lower probability of events such as
death (p = 0.019) and AMI (p = 0.036) during the analyzed
period with statistical significance, suggesting that patients
with normal MS, even though they are at high cardiovascular
risk, are less likely to have major events in the follow-up over
a mean period up to 8 years.
In this study, when analyzing which variables were
independent predictors of events such as death and AMI,
it was verified that the presence of CRF and LVEF < 50%
were risk factors associated with death, with statistical
significance, with p = 0.001 and p = 0.031, respectively.
For the occurrence of AMI, risk factors such as smoking and
LVEF < 50% were associated with higher probability of this
event, also with statistical significance, with p = 0.037 and
0.039, respectively.
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Arq Bras Cardiol. 2015; 105(2):112-122
It was also observed that patients with fixed low uptake
in the MS showed higher probability of death outcome, with
p = 0.043. Risk factors such as CRF, previous CVA, known
CAD and LVEF < 50%, were, in turn, associated with the
occurrence of fixed low uptake, suggestive of fibrosis.
Study limitations
In this group of patients that was totally asymptomatic
or without typical symptoms of ischemia since the medical
consultation when the scintigraphy was requested, 44.5%
had known coronary disease. In fact, the aim of this study
was to evaluate events in patients without typical symptoms,
and not in individuals without typical symptoms and without
known CAD; therefore, the group with known CAD was
not excluded. The idea for this study appeared when
we discovered that, unlike what is recommended by the
appropriate use criteria, many patients in our institution
undergo scintigraphy even when they are asymptomatic and
we tried to retrospectively determine whether the method
discriminated events in asymptomatic patients, with most
of them being considered as high risk according to the
Framingham score. We observed that the method is of great
value to discriminate major events in the follow-up.
Scintigraphy was analyzed qualitatively and magnitude
(intensity and extent of perfusion findings) was not evaluated.
The exercise test was interpreted as suggestive of ischemia
due to the presence of suggestive clinical signs and symptoms
and the presence of ECG alterations, whereas prognostic
scores, such as the Duke score, was not analyzed.
Conclusion
The results obtained suggest that in the group of patients
without typical symptoms (asymptomatic or with atypical
symptoms), submitted to myocardial scintigraphy, the
occurrence of major cardiac events such as death and acute
myocardial infarction was small. The event-free period after
normal myocardial scintigraphy in this group was 7.5 years.
The presence of perfusion alterations suggestive of fibrosis in
the myocardial scintigraphy was associated with an increased
number of deaths at follow-up and might, therefore, be
considered an adjunctive risk factor for more detailed patient
assessment and monitoring. The occurrence of acute nonfatal
myocardial infarction showed no statistically significant
difference between the groups of patients with normal
perfusion, suggestive of fibrosis or ischemia.
Risk factors associated with perfusion abnormalities
suggestive of fibrosis in the assessed group were chronic
renal failure, ischemic stroke, known prior coronary
artery disease and left ventricular ejection fraction
< 50%. Diabetes, previous coronary artery disease and
ischemic test (exercise or dipyridamole test) showed to
be associated with myocardial scintigraphy suggestive of
ischemia, but patients with this alteration in the myocardial
scintigraphy showed no statistical significance for death or
acute myocardial infarction, probably because they were
submitted to therapeutic optimization and/or some type
of therapeutic intervention.
Smanio et al.
Myocardial perfusion without typical symptoms events
Original Article
Risk factors considered to be independent predictors of death
were chronic renal failure and left ventricular ejection fraction
< 50%. Smoking and left ventricular ejection fraction < 50%
were independent predictors of nonfatal acute myocardial
infarction, regardless of the myocardial scintigraphy result.
Author contributions
Conception and design of the research:Smanio PEP. Acquisition
of data:Smanio PEP, Silva JH, Holtz JV, Ueda L, Abreu M, Marques
C. Analysis and interpretation of the data: Silva JH, Holtz JV,
Machado L. Writing of the manuscript:Smanio PEP. Critical
revision of the manuscript for intellectual content: Smanio PEP.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation work.
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Smanio et al.
Myocardial perfusion without typical symptoms events
Original Article
122
Arq Bras Cardiol. 2015; 105(2):112-122
Back to the Cover
Original Article
New Exercise-Dipyridamole Combined Test for Nuclear Cardiology
in Insufficient Effort: Appropriate Diagnostic Sensitivity Keeping
Exercise Prognosis
Inés Vidal Cortinas, Mario Beretta, Omar Alonso, Fernando Mut
Departamento de Medicina Nuclear do Hospital ‘Asociación Española’, Br. Artigas 1515, Montevideo – Uruguay
Abstract
Background: Myocardial perfusion scintigraphy (MPS) in patients not reaching 85% of the maximum predicted heart
rate (MPHR) has reduced sensitivity.
Objectives: In an attempt to maintain diagnostic sensitivity without losing functional exercise data, a new exercise
and dipyridamole combined protocol (EDCP) was developed. Our aim was to evaluate the feasibility and safety of this
protocol and to compare its diagnostic sensitivity against standard exercise and dipyridamole protocols.
Methods: In patients not reaching a sufficient exercise (SE) test and with no contraindications, 0.56 mg/kg of dipyridamole
were IV administered over 1 minute simultaneously with exercise, followed by 99mTc-MIBI injection.
Results: Of 155 patients, 41 had MPS with EDCP, 47 had a SE test (≥ 85% MPHR) and 67 underwent the dipyridamole alone
test (DIP). They all underwent coronary angiography within 3 months. The three stress methods for diagnosis of coronary
lesions had their sensitivity compared. For stenosis ≥ 70%, EDCP yielded 97% sensitivity, SE 90% and DIP 95% (p = 0.43).
For lesions ≥ 50%, the sensitivities were 94%, 88% and 95%, respectively (p = 0.35). Side effects of EDCP were present in
only 12% of the patients, significantly less than with DIP (p < 0.001).
Conclusions: The proposed combined protocol is a valid and safe method that yields adequate diagnostic sensitivity,
keeping exercise prognostic information in patients unable to reach target heart rate, with fewer side effects than the DIP.
(Arq Bras Cardiol. 2015; 105(2):123-129)
Keywords: Coronary Artery Disease; Exercise Test; Myocardial Perfusion Imaging/methods; Dipyridamole/diagnostic use.
Introduction
The reduced diagnostic sensitivity of myocardial
perfusion scintigraphy (MPS) in patients not achieving
a sufficient exercise (SE) test is well recognized 1-4 .
Many laboratories, in the absence of contraindications,
usually perform a vasodilator test in these patients, either
on the same session or on a separate one. However, this
procedure is time consuming and cost-inefficient, since the
stress laboratory personnel needs to perform and monitor
a full second stress test.
Knowing the functional capacity is important for
prognosis in patients evaluated for coronary artery disease
(CAD) 5-9 . The same can be said of the chronotropic
response to exercise and the speed of heart rate
recovery10,11. Therefore, in order to improve diagnostic
sensitivity without losing functional ergometric data,
patients with insufficient exercise tests could benefit from
a combined protocol that uses vasodilators in addition to
physical stress. Another advantage would be the fact that
patients would not be transferred from the treadmill or
bicycle to a stretcher, where they would wait for recovery
before receiving the pharmacologic stimulus.
Adequate diagnostic sensitivity has been reported in
patients with insufficient exercise tests and limited exercise
capacity by using a combined protocol of exercise and
dipyridamole12. Also, the side effects of dipyridamole are
less serious in patients who exercise at the same time13‑16.
Further consideration must be given to the improved
diagnostic quality of the scintigraphic images achieved
with the simultaneous injection of the vasodilator. This is
due to a diminished hepatic and intestinal uptake of the
radiotracer, which is usually high after dipyridamole13-16.
The objectives of our investigation were:
Mailing Address: Inés Vidal Cortinas •
Presidente Giró, 2540, La Blanqueada. Postal Code 11600,
Montevideo – Uruguay
E-mail: [email protected], [email protected]
Manuscript received June 06,2014; revised manuscript January 01,2015;
accepted January 01,2015.
DOI: 10.5935/abc.20150051
123
1) To establish the safety and sensitivity for CAD diagnosis
of a new protocol combining exercise and dipyridamole
given over the course of 1 minute;
2)To validate that protocol use for patients performing
insufficient exercise test by comparing its diagnostic
sensitivity with those of conventional tests: SE test and
dipyridamole alone test (DIP).
Vidal et al.
Combined Diagnostic Test in Insufficient Exercise
Original Article
Methods
Since March 2004, every patient submitted to stress
MPS, who performed an insufficient exercise test [who did
not reach at least 85% of the maximum predicted heart rate
(MPHR) for their age, calculated as 220 - age in years] and
had no contraindication for vasodilators, was injected with
0.56 mg/kg of dipyridamole over 1 minute while maintaining
the physical stress. One minute after the completion of
dipyridamole infusion, 99mTc-methoxy-isobutyl-isonitrile
(99mTc-MIBI) was intravenously (IV) administered at the dose
of 14 MBq/kg. If the patient was unable to keep exercising
at the maximum effort achieved, the workload was lowered
during the dipyridamole infusion. This allowed all patients
to keep at least some level of exercise until test completion.
One minute after the tracer injection, 240 mg of aminophylline
were IV administered, and upon completion, exercise was
stopped (Figure 1).
Due to the incorporation of this protocol, all patients
were instructed to fast for at least 2 hours prior to the
test and to abstain from caffeine and other xanthines
for at least 24 hours. Informed consent was obtained in
all cases. Exercise was performed on a cycle-ergometer
placed vertically, adding weights of 150 or 300 kgm/min
at each stage.
The protocol included the acquisition of a post-stress
gated SPECT scan, approximately 30‑45 minutes after the
injection of the radiotracer, and of a rest gated SPECT on a
separate day. Studies were obtained using a dual-head camera
equipped with high-resolution collimators, 180° rotation,
32 projections, 40 s/projection, 8 frames/cycle, no arrhythmia
rejection and a 64×64 matrix with 1.5 zoom. These studies
were reconstructed using iterative algorithm (OSEM) without
attenuation or scatter correction, and realigned along the heart
axis. Image interpretation was performed by one or more
members of our medical staff. Diagnostic criteria were based
on the presence of reversible perfusion defects (considered as
ischemia), fixed perfusion defects (considered as infarction),
or partially reversible defects (considered as infarction plus
ischemia). No quantitative analysis was used, but rather the
visual analysis of experienced observers.
We included patients studied with MPS using our
exercise-dipyridamole combined protocol (EDCP), patients
having SE tests, and patients undergoing conventional DIP
(0.56 mg/kg over 4 minutes). All patients included in this
investigation were studied during the first half of 2012, and
the selection criterion was that they should have a coronary
angiography performed no later than 3 months after the MPS.
Side effects of the new protocol were recorded and
compared with those of the conventional DIP.
The diagnostic sensitivity of the proposed protocol for severe
coronary lesions (stenosis of ≥ 70%, and ≥ 50% in case of left
main coronary artery involvement) as well as for moderate ones
(stenosis of ≥ 50%) was determined. Sensitivity was calculated
with the 95% confidence interval (95% CI). The Student’s t
Test was used for the comparison of sample means, and the
Chi‑square Test was used for categorical data comparison among
different subsamples. Group differences were considered
significant at p < 0.05, and calculations were performed using
GraphPad Prism software, version 6.00 for Windows (GraphPad
Software, La Jolla, California, USA).
Results
Of 155 patients recruited, the EDCP was followed in 41
[73% male, mean age 62.26 (SD = 9.4) years]. Forty-seven
patients [72% male, mean age 59.8 (SD = 9.2) years] underwent
a SE test, while the DIP was performed in 67 patients [51% male,
mean age 64 (SD = 9.2) years]. There were no significant
Exercise/dipyridamole protocol
Dipyridamole
0.56 mg/kg
99 mTc-MIBI
25 mCi
Aminophylline
240 mg
Exercise
Vital signs supervsion
Figure 1 – Schematic representation of the proposed combined protocol.
Arq Bras Cardiol. 2015; 105(2):123-129
124
Vidal et al.
Combined Diagnostic Test in Insufficient Exercise
Original Article
differences in the mean age of the three groups of patients.
Risk factors resulted similar among groups, except for overweight,
which was less prevalent in the SE group (Table 1). There were
no significant differences regarding the presence of previous
myocardial infarction: 15 patients in the EDCP group; 14 patients
in the SE group; and 22 patients in the DIP group (p = 0.79).
groups (p < 0.001). Dizziness was present in 5 patients
(12%) of the EDCP and in 4 patients of the DIP group (6%)
(p = 0.25). A mean drop of 26 (SD = 13.6) mm Hg in systolic
blood pressure was found in patients who did not experience
symptoms, while the decrease was 37 (SD = 15) mm Hg in
patients with dizziness (p = 0.14).
Patients undergoing SE test reached a higher mean heart
rate and developed a higher metabolic output than those
following the combined protocol: 87% vs. 70% of MPHR, and
5.8 (SD = 1.56) vs. 5.1 (SD = 1.57) METs, respectively, each
with p = 0.03. In patients undergoing EDCP, mean systolic
blood pressure was 180 (SD = 27) mm Hg at maximum effort
and decreased to 152 (SD = 24) mm Hg after dipyridamole
injection (p < 0.001), while mean diastolic blood pressure
values were 103 (SD = 13) mm Hg and 88 (SD = 13) mm
Hg, respectively (p < 0.001).
No change in the PR interval was found with either the
DIP protocol or the EDCP.
There were no significant differences in CAD prevalence
among the three groups of patients, either regarding the
severity of the lesions or the number of affected vessels
(Table 2). In 83% of the patients, severe coronary lesions
were found (76% of those following the EDCP, 83% with
SE, and 87% with DIP). In 42%, one vessel was affected, in
24%, two vessels, and in 17%, three vessels or its equivalent
(left main and right coronary artery). The combined protocol
had 97% diagnostic sensitivity for severe coronary lesions
(95% CI: 83.2% to 99.5%), while the SE test showed 90%
(95% CI: 75.8% to 97.1%) and the DIP protocol, 95% (95%
CI: 85.8% to 98.9%), with no significant difference among
them (p = 0.43) (Figure 2). At least moderate coronary
lesions were present in 88% of the total population (85% of
patients following the EDCP, 87% of those with SE test, and
91% of those with DIP). The EDCP showed 94% sensitivity
for moderate coronary lesions (95% CI: 80.8% to 99.1%); the
ES test showed 88% (95% CI: 73.8% to 95.9%), and the DIP
protocol, 95% (95% CI: 86.3% to 98.9%). These differences
in sensitivity between the different types of protocols showed
no statistical significance (p = 0.35) (Figure 2).
Regarding side effects, 49 patients in the DIP group (73%)
showed one or more. Headache was present in 40% of the
patients, flushing in 30%, weakness in 22%, gastric discomfort
in 10%, and dizziness in 6%. Conversely, dizziness was the
only side effect present with the EDCP (5 patients), usually
in connection to a drop in blood pressure. These results
establish a difference of statistical significance between both
Discussion
The idea of combining an insufficient exercise test with a
dipyridamole stimulus in order to reach adequate diagnostic
sensitivity without losing functional capacity data seems
to be theoretically correct and to have achieved positive
practical results. Candell-Riera et al.12 have shown that
the diagnostic sensitivity for 50% coronary stenosis of their
combined protocol (89%) was significantly higher than that
of the insufficient effort test (71%) and comparable to that of
the SE test (93%). We achieved similar results: the difference
between the diagnostic sensitivity of our combined protocol
and that of the SE for coronary lesions ≥ 50% was not
significant. We also compared it to the DIP protocol alone
and found no diagnostic difference either. However, we
made no comparison with the diagnostic sensitivity of the
insufficient exercise test alone. As a rule, no insufficient
effort scintigraphy is performed in our laboratory except
when it is specifically required by the attending physician.
Before the EDCP was adopted, any patient who failed to
reach at least 85% of the MPHR was laid in a stretcher and,
after 10-15 minutes, underwent conventional dipyridamole
test. With EDCP, adequate diagnostic sensitivity is
achieved without losing information from the exercise
test about functional capacity and chronotropic response.
Furthermore, the total time required for completion of the
full procedure is shortened.
Candell-Riera et al.12 have administered IV 0.56 mg/kg
of dipyridamole over 4 minutes during the exercise test.
The major differences with our protocol are that we give the
dose in only 1 minute and that it is used in all patients not
reaching sufficient effort, not only those achieving less than
5 METs. We chose to shorten the infusion time because most
patients with insufficient exercise tests showed difficulties
in maintaining the effort further. Unlike the investigation by
the abovementioned authors, heart rate alone was taken
Table 1 – Risk factors in the three groups of patients
Risk factor
EDCP (n = 41)
SE (n = 47)
DIP (n = 67)
p value
Diabetes
13 (32%)
9 (19%)
19 (28%)
0.36
Hypertension
27 (66%)
31 (66%)
52 (78%)
0.28
Dyslipidemia
26 (63%)
27 (57%)
35 (52%)
0.52
Smoking
12 (29%)
9 (19%)
17 (25%)
0.53
BMI ≥ 25
25 (61%)
16 (34%)
40 (60%)
0.01
Family history
15 (37%)
24 (51%)
34 (51%)
0.29
EDCP: Exercise-dipyridamole combined protocol; SE: Sufficient exercise test; DIP: Dipyridamole only; BMI: Body mass index.
125
Arq Bras Cardiol. 2015; 105(2):123-129
Vidal et al.
Combined Diagnostic Test in Insufficient Exercise
Original Article
Table 2 – Prevalence of CAD among the three groups
Angiography
EDCP (n = 41)
SE (n = 47)
DIP (n = 67)
Total (n = 155)
p value
Lesions ≥ 70%
31(76%)
39(83%)
58(87%)
128(83%)
0.45
3V
8(20%)
6(15%)
12(18%)
26(17%)
0.66
2V
8(20%)
10(21%)
19(28%)
37(24%)
0.51
1V
15(37%)
23(49%)
27(40%)
65(42%)
0.47
Lesions ≥ 50%
35(85%)
41(87%)
61(91%)
137(88%)
0.19
3V
12(29%)
11(23%)
15(22%)
38(25%)
0.71
2V
9(22%)
8(17%)
18(27%)
35(23%)
0.46
14(34%)
22(47%)
28(42%)
64(41%)
0.48
1V
EDCP: Exercise-Dipyridamole Combined Protocol; SE: Sufficient exercise test; DIP: Dipyridamole only; V: Vessel.
Diagnostic sensitivity
100
97
94
90
95
90
95
88
80
70
60
50
40
30
20
10
0
EDCP (n = 41)
SE (n = 47)
Stenosis ≥ 70%
DIP (n = 67)
Stenosis ≥ 50%
Figure 2 – Comparison of diagnostic sensitivity of the three protocols for coronary stenosis ≥ 70% and ≥ 50%.
EDCP: Exercise-Dipyridamole Combined Protocol; SE: Sufficient exercise test; DIP: Dipyridamole only.
into account and not METs; whenever 85% of MPHR was
not reached – and no contraindications were present –
dipyridamole was always administered. Our results seem to
validate the followed criteria, since the diagnostic sensitivity
of the EDCP was not significantly different from that of the
SE test, even though some patients with a mean metabolic
output higher than 5 METs (5.1, SD = 1.57) were included.
It could be argued that full vasodilation effect of
dipyridamole might not have been reached in every case
at the time of the radiotracer injection due to the short
time allowed for the pharmacologic action. However, no
difference in sensitivity was demonstrated compared to
conventional protocols. This fact permits the assumption
that vasodilation was adequate enough for diagnostic
purposes. Furthermore, even if pharmacologic vasodilation
was not optimal, it should be taken into account that some
vasodilation was already present with exercise, and that
myocardial extraction of the radiotracer is not linear with
flow, especially at high values17, so a marginal increase with
time might not be reflected in imaging.
We also confirmed the previously demonstrated fact
that the combination of exercise with dipyridamole
produces fewer side effects than the use of dipyridamole
alone. Patients studied with the new combined protocol
only presented dizziness in 12%, which can be associated
with a decrease in blood pressure. This decline (rapidly
compensated laying the patient down) could be explained
by the vasodilatation effect of dipyridamole, as well as by
the physiologic decrease resulting from exercise cessation or
reduction. In fact, patients presenting dizziness underwent
Arq Bras Cardiol. 2015; 105(2):123-129
126
Vidal et al.
Combined Diagnostic Test in Insufficient Exercise
Original Article
a more pronounced yet non-significant decrease in systolic
blood pressure. Conversely, most patients (73%) studied
with the DIP protocol experienced some kind of discomfort,
mostly headache. The usual supine position during
conventional pharmacologic stress allows better tolerance
to hypotension than the upright position. Nevertheless, we
did not find a statistical significant difference regarding the
presence of dizziness for both groups.
At the beginning of the implementation of the
combined protocol, we usually asked the patient to stop
exercising after MIBI injection. Afterwards, aminophylline
administration was started. We frequently observed a
sudden drop in blood pressure, caused by the vasodilatation
effect of dipyridamole added to the abrupt cessation of the
physical effort. This was resolved by quickly positioning
the patient in the decubitus position. In consequence, we
decided thereafter to ask the patients to keep pedaling at a
lower level until the aminophylline infusion was completed.
As a result, the prevalence of dizziness as a side effect was
reduced significantly, as described in the study.
The association of exercise with dipyridamole has also
proved to increase image quality13-16. Even though image
characteristics in the various protocols considered in our
investigation were not specifically evaluated, all the images
were adequate for diagnostic purposes according to standard
criteria of interpretation.
To our knowledge, with the exception of our protocol and
of that described by Candell-Riera et al.12, all others combining
exercise with dipyridamole start first with the vasodilator drug,
being then complemented with exercise, either at a low‑level
or limited by symptoms13,16,18. However, this sequence does
not allow clinical monitoring, which is more relevant in
patients with exercise-related symptoms, or proper evaluation
of functional capacity.
Ahlberg et al.18 reported that almost one third of patients
referred for MPS reached 85% of their MPHR. If this had
been known in advance, the stimulation with dipyridamole
before the exercise would have been unnecessary.
These authors proved the prognostic value of their protocol
combining dipyridamole with symptom-limited exercise,
but they recognized limitations by not comparing with
a similar group of patients reaching suboptimal effort or
using dipyridamole alone. An editorial 19 written about
their work mentions the need of a control group, such
as dipyridamole with low-level exercise, dipyridamole
alone, or exercise alone. In addition, the lack of coronary
angiography to evaluate the sensitivity and specificity of the
test is highlighted. Therefore, it is not known whether the
dipyridamole/exercise test limited by symptoms improves
the diagnostic sensitivity for CAD when compared to other
protocols. The same conclusions could be drawn from the
analysis of adenosine/exercise protocols.
An approach similar to ours has been possible with
regadenoson, a vasodilating drug , which specifically
stimulates the A2a receptors. In recent works by Parker et
al.20 and Ross et al.21, regadenoson was administered at peak
exercise in bolus injection if the patient had not reached 85%
of the MPHR. However, the subjects studied were submitted
127
Arq Bras Cardiol. 2015; 105(2):123-129
to a pharmacologic stress and agreed to undergo an exercise
test as an additional procedure. They were not patients
directly assigned to an exercise MPS who did not reach the
target heart rate. Parker et al.20 reported that 50% of their
patients were able to reach 85% of the target heart rate, while
this was the case in 62.5% of the patients in the series by Ross
et al.21. Hence, at least half of their patients did not formally
require the administration of a vasodilator stimulus since the
exercise was adequate. This highlights a frequently mistaken
medical perception of the patient’s exercise capacity when
perfusion tests are indicated. It also supports the design of
a protocol geared towards complementing an insufficient
exercise test while at the same time saving the prognostic
functional data of physical stress.
Therefore, every patient referred to our department for
an exercise MPS is instructed to abstain from xanthines
for 24 hours previous to the test, just in case dipyridamole
has to be administered in a combined protocol. In regard
to this, we share the idea of administering a vasodilator
when necessary22. Both Parker et al.20 and Ross et al.21 have
demonstrated that their respective protocols are feasible and
safe, and are associated with fewer side effects compared
to the administration of regadenoson only. However, their
patients underwent no coronary angiography, so the diagnostic
sensitivity was not determined.
The current work proves that our EDCP is feasible, safe,
and, more importantly, has a diagnostic sensitivity at least
similar to that provided by a SE test or a DIP test alone.
Together with the evaluation of exercise-induced symptoms,
ECG changes, functional capacity and chronotropic
response, we could say that, paraphrasing Hendel and
Frost22, with our combined protocol, we work off-label, on
target and with diagnostic accuracy.
Limitations
The coronary anatomy of only a few dozens of the hundreds
of patients undergoing the EDCP was established, because the
indication of a coronary angiography depended mainly on a
positive nuclear test result, producing a strong referral bias
that explains the high prevalence of CAD. This was an obvious
obstacle to evaluate specificity, accuracy, as well as positive and
negative predictive values of the technique.
Conclusions
We demonstrated that our combined protocol for MPS is
well tolerated and yields at least similar diagnostic sensitivity
as compared to a SE test or a DIP test alone. It preserves
prognostic information from the exercise even when the test
is insufficient. Additionally, it can be safely completed in a
shorter time than other proposed combined protocols with
dipyridamole, and close to that using regadenoson.
Author contributions
Conception and design of the research: Vidal I.
Acquisition of data:Vidal I, Beretta M. Analysis and
interpretation of the data: Vidal I, Mut F. Statistical analysis:
Alonso O. Writing of the manuscript:Vidal I, Mut F. Critical
Vidal et al.
Combined Diagnostic Test in Insufficient Exercise
Original Article
revision of the manuscript for intellectual content: Mut F.
Supervision / as the major investigador:Vidal I.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation work.
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A strategy of symptom-limited exercises with regadenoson-as-needed for
stress myocardial perfusion imaging: a randomized controlled trial. J Nucl
Cardiol. 2013;20(2):185-96.
21. Ross MI, Wu E, Wilkins JT, Gupta D, Shen S, Aulwes D, et al. Safety and
feasibility of adjunctive regadenoson injection at peak exercise during
exercise myocardial perfusion imaging: the Both Exercise and Regadenoson
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22. Hendel RC, Frost L. Off-label, but on target: use of regadenoson with exercise
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Arq Bras Cardiol. 2015; 105(2):123-129
128
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Combined Diagnostic Test in Insufficient Exercise
Original Article
129
Arq Bras Cardiol. 2015; 105(2):123-129
Back to the Cover
Original Article
Cardiac Surgery Costs According to the Preoperative Risk in the
Brazilian Public Health System
David Provenzale Titinger, Luiz Augusto Ferreira Lisboa, Bruna La Regina Matrangolo, Luis Roberto Palma Dallan,
Luis Alberto Oliveira Dallan, Evelinda Marramon Trindade, Ivone Eckl, Roberto Kalil Filho, Omar Asdrúbal Vilca
Mejía, Fabio Biscegli Jatene
Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP – Brazil
Abstract
Background: Heart surgery has developed with increasing patient complexity.
Objective: To assess the use of resources and real costs stratified by risk factors of patients submitted to surgical cardiac
procedures and to compare them with the values reimbursed by the Brazilian Unified Health System (SUS).
Method: All cardiac surgery procedures performed between January and July 2013 in a tertiary referral center were
analyzed. Demographic and clinical data allowed the calculation of the value reimbursed by the Brazilian SUS.
Patients were stratified as low, intermediate and high-risk categories according to the EuroSCORE. Clinical outcomes,
use of resources and costs (real costs versus SUS) were compared between established risk groups.
Results: Postoperative mortality rates of low, intermediate and high-risk EuroSCORE risk strata showed a significant linear
positive correlation (EuroSCORE: 3.8%, 10%, and 25%; p < 0.0001), as well as occurrence of any postoperative complication
(EuroSCORE: 13.7%, 20.7%, and 30.8%, respectively; p = 0.006). Accordingly, length-of-stay increased from 20.9 days to
24.8 and 29.2 days (p < 0.001). The real cost was parallel to increased resource use according to EuroSCORE risk strata
(R$ 27.116,00 ± R$ 13.928,00 versus R$ 34.854,00 ± R$ 27.814,00 versus R$ 43.234,00 ± R$ 26.009,00, respectively;
p < 0.001). SUS reimbursement also increased (R$ 14.306,00 ± R$ 4.571,00 versus R$ 16.217,00 ± R$ 7.298,00
versus R$ 19.548,00 ± R$935,00; p < 0.001). However, as the EuroSCORE increased, there was significant difference
(p < 0.0001) between the real cost increasing slope and the SUS reimbursement elevation per EuroSCORE risk strata.
Conclusion: Higher EuroSCORE was related to higher postoperative mortality, complications, length of stay, and costs.
Although SUS reimbursement increased according to risk, it was not proportional to real costs. (Arq Bras Cardiol. 2015;
105(2):130-138)
Keywords: Cardiac Surgical Procedures/economics; Hospital Costs; Unified Health System; Risk Groups; Preoperative Care;
Hospital Mortality; Morbidity.
Introduction
During the last four decades, cardiac surgery has developed
with the increase in complex procedures in progressively
critically‑ill patients 1. Evidence shows that this scenario
proportionally increases with morbimortality and hospital costs2,3.
In Brazil, most of the highly complex procedures are
performed with funding from the Unified Health System
(SUS). This system is responsible for 80% of CABG
surgeries performed in the country4. The reimbursement for
hospitals that belong to SUS uses SUS own price list for the
hospitalization authorization (AIH). The payment of this value
is little yielding in its composition and may not reflect correct
Mailing Address: Omar Asdrúbal Vilca Mejía •
Instituto do Coração, Segundo Bloco, Segundo Andar, Sala 11. Avenida
Doutor Enéas de Carvalho Aguiar, 44 – Cerqueira César.
Postal Code 05403-900, São Paulo, SP – Brazil.
E-mail: [email protected]
Manuscript received October 30, 2014; revised manuscript March 23, 2015;
accepted March 24, 2015.
DOI: 10.5935/abc.20150068
130
fund allocation that correspond to the actual cost (AC) of the
procedure5. Thus, the AIH paid by SUS for the procedure may
have no direct association with patient severity.
An unequal association between the AC of these
procedures and SUS reimbursement may discourage hospital
care provided to high-risk surgical patients, which are the cases
that would benefit the most from these procedures6.
On the other hand, international guidelines advise about
the use of risk scores to identify patients at higher risk of
morbimortality7. In Brazil, the EuroSCORE is the most used model
and the only one that has been validated in significant samples8.
The objective of this study was to evaluate the use of
resources by risk group, comparing the AC of cardiovascular
procedures with SUS reimbursement in a hospital.
Methods
Sample
A prospective observational study carried out at the
Cardiovascular Surgery Division and SUS Billing Unit of
Instituto do Coração do Hospital das Clínicas da Faculdade de
Titinger et al.
Cardiac surgery costs according to the risk
Original Article
Medicina da Universidade de São Paulo (InCor-HC/FMUSP)
(Heart Institute of the Faculty of Medicine, University of São
Paulo (InCor-HC / USP)).
Data from consecutive patients were obtained from the
institution’s database (SI3). All demographic data that could
identify patients were removed. Clinical data and use of
resources were exported to an Excel spreadsheet for analysis.
By cross-checking patients’ data with the registry of the
participating units, it was verified that there were no errors
and no patients loss due to lack of data.
Inclusion and exclusion criteria
The inclusion criteria were: adult patients consecutively
operated between January and July 2013, in the elective,
urgent or emergency mode, at the Cardiovascular Surgery
Division of InCor-HC/FMUSP.
Patients not hospitalized by SUS were excluded from the study.
Data collection, definition and organization
Data were collected prospectively in the electronic medical
file system of InCor-HC/FMUSP (SI3). After exporting data to
a single worksheet in Excel and removal of demographic data
that could identify patients, this worksheet was adapted to take
into account all the variables described in the first EuroSCORE
model (additive version)9. All definitions assigned to variables
by EuroSCORE were accomplished, together with their values,
according to their relevance to the death event.
Therefore, after calculating the value of the variables in
each patient, the patients were classified according to the risk
groups established by the model. In addition to the clinical
and laboratory variables included in the EuroSCORE, the
economic variables were considered. The total value of AC
included fixed and variable costs per patient. The AC was
calculated by analysis of variable costs accounted by the
micro-costing methodology10 and by the full costing method
for the fixed costs. The mean unit cost of each material item
and medications was estimated from the purchases of these
items during this period, being considered, in each category,
the individual units costs. The mean unit cost of each
diagnostic service, daily hospital stay costs or therapy was
estimated by total inclusion of fixed costs (pro-rata of general
consumption fixed costs – water, electricity and telephone,
auxiliary services – maintenance contracts, cleaning services,
air conditioning, etc., and administrative services) from the
cost centers, divided by unit of produced outcome. Thus, we
considered the quantitative variables ICU length of stay (days),
hospitalization length of stay (days) and time of orotracheal
intubation (hours). Similarly, it was considered the total value
of SUS reimbursement, adding hospital service, professional
service, ICU and compatible materials.
The primary outcomes were in-hospital mortality and
morbidity (cerebrovascular accident, Renal Replacement
Therapy - RRT, pneumonia, atrial fibrillation, mediastinitis/
osteomyelitis and reoperation for bleeding). The definitions of
the study variables outside the EuroSCORE were taken from
the glossary of the American Heart Association11. All patients
were followed until hospital discharge.
Statistical analysis
Continuous variables were expressed as mean ± standard
deviation or median, and categorical variables as percentages.
Logistic regression analysis for the hospital morbidity and
mortality outcome was performed by using the value provided
by EuroSCORE for each patient. Patients were subdivided by
the EuroSCORE as low (1-4), intermediate (5-7), and high
(≥ 8) risk.
The three categories were analyzed to highlight the
differences related to the morbimortality, resource use, AC
and SUS reimbursement. Variable distribution was tested for
normality using the Kolmogorov-Smirnov test. Variables with
normal distribution were compared between the risk categories
using analysis of variance. Paired comparisons were corrected
using the Bonferroni-Dunn test.
Student’s t test was used for parametric distributions,
and the Mann-Whitney and Kruskal-Wallis tests were used
for non-parametric distributions. Categorical variables were
compared using Pearson’s chi-square test. The null hypothesis
was rejected when p < 5% (p < 0.05). This study made a
comparison, in the “real world”, between the mean costs of
the risk categories, reducing the possibility of bias in patient
selection12. The analysis was performed using the Statistical
Package for the Social Sciences (SPSS) software, version
20.0.0 (Chicago, IL).
Ethics and Consent Form
This study was approved by the Ethics Committee for
Analysis of Research Projects (CAPPesq) HC/FMUSP, under
number 1575, being exempt from the need to use the Free
and Informed Consent form, due to the use of analysis of
non-identified data only.
Results
Sample
The characteristics of patients in the different risk groups
are shown in Table 1. The low-risk group consisted of 131
(34%) patients, the intermediate risk group, of 150 (39%)
and the high-risk group of 104 (27%) patients. There were
significant differences in EuroSCORE means according to the
risk group: 2.91 ± 1.03, 5.89 ± 0.84 and 10.32 ± 2.6 in the
lower, intermediate and high-risk categories, respectively. The
mean age was 61 ± 12.29 years.
Clinical outcomes and resource use
The clinical outcomes and resource use are shown
in Table 2. The EuroSCORE was associated with death
(p < 0.0001) and showed good calibration (p = 0.9744) in
the Hosmer‑Lemeshow test. Nevertheless, this model was
associated with morbimortality (p < 0.0001) and also showed
good calibration (p = 0.2221) in the Hosmer‑Lemeshow
test. Mortality, morbidity and morbimortality of 11.26,
21.41 and 27.15% were observed, respectively. There was
3.82% of mortality in low risk, 10% in intermediate risk
and 25% in high risk (Figure 1). The low-risk group had
Arq Bras Cardiol. 2015; 105(2):130-138
131
Titinger et al.
Cardiac surgery costs according to the risk
Original Article
Table 1 – Patient characteristics
Characteristics
Sample (n = 385)
Low Risk (n = 131)
Intermediate Risk (n = 150)
High Risk (n = 104)
p
Age
61 ± 12.3
56.1 ± 10.3
61.2 ± 12.5
65.3 ± 12.5
< 0.001*
Female gender
160 (41.6)
48 (36.6)
69 (46)
43 (41.3)
0.28
EuroSCORE
6.1 ± 3.3
2.9 ± 1
5.9 ± 0.8
10.3 ± 2.6
< 0.001*
Creatinine > 2mg/dL
39 (10.1)
2 (1.5)
11 (7.3)
26 (25)
< 0.001‡
Ejection fraction < 30%
32 (8.3)
7 (5.3)
16 (10.7)
9 (8.7)
0.27
Recent Infarction
42 (10.9)
7 (5.3)
18 (12)
17 (16.3)
0.012†
Reoperation
68 (17.7)
5 (3.8)
25 (16.7)
38 (36.5)
< 0.001*
CABG
188 (48.8)
78 (59.5)
78 (52)
32 (30.8)
< 0.001‡
HVS
173 (44.9)
50 (38.2)
63 (42)
60 (57.7)
0.002‡
CABG + HVS
21 (5.5)
3 (2.3)
7 (4.7)
11 (10.6)
0.007‡
Others (Not CABG + HVS)
3 (0.8)
0
1 (0.7)
2 (1.9)
0.28
Urgency / Emergency
17 (4.4)
2 (1.5)
6 (4)
9 (8.7)
0.014‡
Events
38 (9.9)
0
4 (2.7)
34 (32.7)
< 0.001‡
The item “events” includes at least one of the following situations prior to surgery: intra-aortic balloon, cardiogenic shock, ventricular tachycardia or fibrillation,
orotracheal intubation, acute renal failure, use of inotropic drugs and cardiac massage. * Significant difference between all risk groups; † Significant difference
between the low/intermediate risk groups and the high-risk group; ‡ Significant difference between the low-risk group and the intermediate/high risk group.
CABG: Coronary‑artery bypass grafting; HVS: Heart valve surgery.
Table 2 – Clinical outcomes and resource utilization
Variable
Sample (n = 385)
Low risk (n = 131)
Intermediate risk (n = 150)
High risk (n = 104)
p
Mortality
56 (14.5)
5 (3.8)
15 (10)
26 (25)
< 0.001*
Morbidity
81 (21)
18 (13.7)
31 (20.7)
32 (30.8)
0.004*
CVA
1 (0.3)
1 (0.8)
0
0
0.61
Atrial fibrillation
30 (7.8)
6 (4.6)
15 (10)
9 (8.7)
0.22
RRT
15 (3.9)
4 (3.1)
2 (1.3)
9 (8.7)
0.003*
Pneumonia
12 (3.1)
4 (3.1)
3 (2)
5 (4.8)
0.46
Reoperation x Bleeding
17 (4.4)
5(3.8)
4 (2.7)
8 (7.7)
0.15
OTI > 24h
Time of ICU
Hospital length of stay
22 (5.7)
3 (2.3)
9 (6)
10 (9.6)
0.055
8.3 ± 10.1 days
5.6 ± 5.9 days
8.1 ± 10.4 days
11.9 ± 12.6 days
< 0.001‡
25 ± 17days
21 ± 13.2days
25 ± 13.25 days
29 ± 16.3days
< 0.001†
* Significant difference between low / intermediate risk and high risk groups. †Significant difference between the low risk and intermediate / high risk groups. ‡
Significant difference between all risk groups. CVA: Cerebrovascular accident; RRT: Renal replacement therapy; OTI: Orotracheal intubation; ICU: Intensive care unit.
the lowest percentage of deaths, which increased with the
risk increase (p < 0.0001). There was 13.74% of morbidity
in low risk, 20.67% in intermediate risk and 30.77% in
the high risk. The low-risk group had a lower percentage
of complications, which increased with the risk increase
(p = 0.0063). There was 3.1% of RST in the low-risk,
1.3% in intermediate‑risk and 8.7% in the high-risk group.
The low‑risk and intermediate‑risk groups had the lowest
percentage of RST, and the high-risk group had the highest
percentage (p = 0.003). While one can observe that,
regarding the length of stay, the high-risk group showed no
132
Arq Bras Cardiol. 2015; 105(2):130-138
significant difference compared to the intermediate risk, the
low-risk group had a significantly lower value than the groups
at high and intermediate risk. In the analysis of ICU length
of stay, we observed that the low‑risk group had significantly
lower value than the groups with intermediate and high risk,
and the group with intermediate risk had a significantly lower
value than the high-risk group.
SUS reimbursement and actual cost
Risk groups differed in relation to the total value of the
SUS reimbursement (low risk: R$ 14.306,00 ± R$ 4.571,00;
Titinger et al.
Cardiac surgery costs according to the risk
Original Article
40
35
30
p = 0.002
p < 0.001
p < 0.001
p = 0.155
25
%
p = 0.052
Low
20
15
p < 0.001
p = 0.111
Moderate
High
p = 0.003
10
p = 0.457
5
0
Mortality
Morbidity
RRT
Figure 1 – In-hospital outcomes of morbidity, mortality and renal replacement therapy (RRT) by risk groups, according to the EuroSCORE.
intermediate risk: R$ 16.115,00 ± R$ 7.381,00, and high
risk: R$ 19.548,00 ± R$ 9.355,00, p < 0.001), being
higher in higher risk categories. Still, regarding the AC, the
low risk group (R$ 27.116,00 ± R$ 13.928,00) showed
a significantly lower value than the other groups, and the
intermediate risk group had a significantly lower value
than the high group risk (R$ 34,854.00 ± R$ 27,814.00 &
R$ 43.234,00 ± R$ 26.009,00 ± R) (Figure 2).
However, when we analyze the risk groups for specific values
of SUS reimbursement, we found some discrepancies not
demonstrated in the total sample (Figure 3). In reimbursement
for hospital services, even if the high-risk group had significantly
higher value than the low and intermediate‑risk groups, the
low‑risk group showed no significant difference in relation to the
intermediate risk group. Similarly, in relation to reimbursement
for professional services, the low-risk group showed no
significant difference in relation to the intermediate-risk group,
although there was a lower significant difference in relation to
the high-risk group.
In this item, the intermediate and high-risk groups were not
significantly different. Similarly, on the reimbursement for the
cost of materials, even if the high-risk group had significantly
higher value than the low and intermediate-risk groups, the
low risk group showed no significant difference in relation to
the intermediate risk. Only in the reimbursement assessment
for the ICU costs, the low-risk group had significantly lower
value than the groups with intermediate and high risk, and the
group with intermediate risk had a significantly lower value
than the high-risk group.
However, when we discriminately analyze the items
established for the AC calculation (Figure 4), we can observe
a significant difference as the risk increases by EuroSCORE.
To confirm this, a logistic regression model was created for
the SUS reimbursement value versus EuroSCORE (p < 0.0001):
11371 + 839.14*EuroSCORE
It was also a model for the AC value versus EuroSCORE
(p < 0.0001):
18831 + 2577.69*EuroSCORE
Thus, with the estimates obtained from EuroSCORE (Table 3),
the greater the patient risk, the greater the difference between
the AC and the SUS reimbursement value.
Discussion
Being a reference only in simple procedures should not give
credit to an institution that does not make any effort to treat
critically-ill patients that need complex surgeries. With an aging
population and increasing life expectancy13, a larger population
of frail patients is referred for cardiovascular procedures and
improved quality of life. Evidence shows that critical patients
are those that benefit the most from cardiovascular procedures,
even if they have higher cost and morbimortality risk14.
This would explain why surgeons and hospitals that accept
to operate more severe patients can have higher costs and
greater morbimortality15,16. The use of risk scores allows the
correction of the results according to patient severity for a
more stringent cost-effectiveness analysis17. In Brazil, the most
widely used risk model in cardiovascular surgery for outcome
adjustment is the EuroSCORE18-22. Our study confirmed the
direct association of the EuroSCORE with increased mortality
and morbimortality.
Arq Bras Cardiol. 2015; 105(2):130-138
133
Titinger et al.
Cardiac surgery costs according to the risk
Original Article
90000
p < 0.05
p < 0.05
80000
p < 0.05
70000
60000
p < 0.05
Low
R$
50000
p < 0.05
40000
p < 0.05
30000
Moderate
High
20000
10000
0
Actual Cost
SUS Reimbursement
Figure 2 – Total value of actual costs and the Unified Health System (SUS) reimbursement for risk groups, according to EuroSCORE.
p < 0.05
25.000,00
p < 0.05
20.000,00
19.548,19
16.217,49
13.305,69
15.000,00
R$
3.463,34
3.415,11
2.518,95
2.278,78
10.000,00
p < 0.05
4.679,40
6.543,72
4.064,69
4.205,75
4.378,11
4.498,87
4.813,39
5.211,25
Low (n = 131)
Moderate (n = 150)
High (n = 104)
5.000,00
Materials
ICU costs
Prof Serv
Hosp Serv
Risk
Figure 3 – Detailed values of the of the Unified Health System (SUS) reimbursement for cardiovascular procedures by risk groups, according to EuroSCORE. Materials:
reimbursement for cost of materials (excluding drugs); ICU costs: reimbursement for the intensive care unit services; Prof Serv: reimbursement for professional services;
Hosp Serv: reimbursement for hospital services.
134
Arq Bras Cardiol. 2015; 105(2):130-138
Titinger et al.
Cardiac surgery costs according to the risk
Original Article
p < 0.05
60.000,00
p < 0.05
50.000,00
p < 0.05
43.234,33
R$
40.000,00
30.000,00
20.000,00
10.000,00
34.854,16
23.819,97
27.115,63
19.065,86
Items
Surgery Fees
13.944,62
3.386,62
3.441,44
ICU Daily Fee
9.370,58
Floor Daily Fee
3.244,73
4.403,53
6.418,15
5.522,75
6.002,94
6.602,34
Low (n = 131)
Moderate (n = 150)
High (n = 104)
Risk
Figure 4 – Detailed values of the actual costs for cardiovascular procedures by risk groups, according to the EuroSCORE. Items: Includes the actual value of the
materials and drugs; ICU: Intensive care unit.
Table 3 – Estimates obtained from the regression models for reimbursement by the Unified Health System (SUS) and the actual cost (AC),
according to the EuroSCORE value.
EuroSCORE
SUS (R$)
AC (R$)
Difference (R$)
0
11371,00
18831,00
-7460,00
2
13049,28
23986,38
-10937,10
4
14727,56
29141,76
-14414,20
6
16405,84
34297,14
-17891,30
8
18084,12
39452,52
-21368,40
10
19762,40
44607,90
-24845,50
12
21440,68
49763,28
-28322,60
14
23118,96
54918,66
-31799,70
16
24797,24
60074,04
-35276,80
26475,52
65229,42
-38753,90
18
(R$) Values in Brazilian reais.
SUS performs the majority of cardiovascular surgeries
in Brazil, treating primarily patients with more unfavorable
socioeconomic conditions. At InCor-HC/FMUSP, the
number of cardiovascular surgeries by SUS corresponds to
approximately 80% of the total. It is important to mention
that the government allocates to the public health in Brazil
a total of US$ 157.00 per inhabitant/year (I/Y). This is in
sharp contrast with public health spending in Germany
(US$ 3.521,00 I/Y), Canada (US$ 2.823,00 I/Y), United
States (US$ 2.725,00 I/Y), Portugal (US$ 1,850,00 I/Y),
Chile (US$ 720,00 I/Y), Argentina (US$ 380,00 I/Y)
and Costa Rica (US$ 378,00 I/Y) 6. We know that the
value of public spending in the US is an emblematic
example of a system segmented for the poor (Medicaid),
elderly (Medicare) and war veterans (about 66 million
of inhabitants), while Brazil is the source of funding for
approximately 160 million of inhabitants23.
A publication on patients undergoing aortic valve
replacement in the United States showed a direct correlation
between the risk increase of patients and increased
morbimortality and costs14. In Brazil, a study published by
Instituto Dante Pazzanese de Cardiologia5 (Dante Pazzanese
Institute of Cardiology) showed that the cost of coronary artery
bypass surgery (primary, isolated and elective) is lower than
Arq Bras Cardiol. 2015; 105(2):130-138
135
Titinger et al.
Cardiac surgery costs according to the risk
Original Article
Study limitations
the reimbursement supplied by SUS, showing that the mean
cost of surgery was R$ 6.990,00 and the amount paid was
R$ 5.551.41. These values are different from those found in
our analysis, upon which the variety of procedures performed,
including emergency care, the progressive worsening of the
patients over time, and the current adjustment of costs and
SUS reimbursement may have influenced.
There are several limitations in this study. First, no
follow‑up was performed for long-term analysis, although
a recent study showed that, in a follow-up of five years
after aortic valve replacement, there was a higher cost for
high-risk patients24. Second, a multicenter analysis could
have found differences related to specific patterns of SUS
reimbursement between hospital categories. Third, the
sample size may have influenced some analyses, especially
among the categories of intermediate and high risk. Fourth,
some risk factors, such as frailty, were excluded from the
study. However, this could increase differences in the highrisk patient group25.
This cost discrepancy has made university and
philanthropic hospitals, and even private hospitals with
social security-funded care suspend medical care due to
accumulated debt. All this can worsen considering the
global trend of increased high-risk patients referred to
undergo cardiovascular procedures.
In this study, it was shown that AC increases progressively
when the preoperative risk of the patient increases. Although
the SUS reimbursement also increases with the patient’s risk, it
is disproportionate to the AC, and this increases as the patient’s
risk increases. This scenario could influence the selection of
patients operated in SUS-funded hospitals. Unquestionably,
the ideal would be that SUS-funded hospitals be reimbursed
by an amount equivalent to the AC. However, the minimum
to be done is a reimbursement proportional to the AC. In the
current context and for the same budget, that would be to pay
less for low-risk surgeries and more for higher-risk surgeries,
according to what we call risk adjusted reimbursement
(Figure 5). Therefore, for each EuroSCORE unit increase, there
will be a fairer amount to be reimbursed by SUS.
In short, high-risk patients referred for cardiovascular
surgery, in addition to the fact that they have higher cost, also
show higher risk of morbimortality. Analyses in larger samples
are needed to justify the cost-effectiveness of the procedures,
to support SUS sustainability and funding, and improve the
quality of outcomes and safety for patients.
Conclusions
Although the SUS reimbursement increases with the
increase in patient risk, it is disproportionate to the real cost.
Future directions in SUS reimbursement should be adopted so
that care of an increasing number of high-risk surgical patients
is not discouraged.
Risk adjusted reimbursement
160000
140000
120000
R$
100000
80000
y = 2538x + 18449
60000
40000
20000
0
y = 831.31x + 11246
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
EuroSCORE
SUS reimbursement
Actual cost
SUS
Actual cost
Risk adjusted reimbursement
Figure 5 – Unified Health System (SUS) reimbursement increase, actual cost (AC) and risk adjusted reimbursement, according to the EuroSCORE value.
136
Arq Bras Cardiol. 2015; 105(2):130-138
Titinger et al.
Cardiac surgery costs according to the risk
Original Article
Acknowledgments
To FAFESP, for the limitless support in carrying out the
present study.
Lisboa LAF, Dallan LAO, Trindade EM, Kalil Filho R, Mejia
OAV, Jatene FB.
Potential Conflict of Interest
Author contributions
Conception and design of the research:Titinger DP, Trindade
EM, Mejia OAV, Jatene FB. Acquisition of data:Titinger DP,
Matrangolo BR, Eckl I, Mejia OAV. Analysis and interpretation
of the data:Titinger DP, Lisboa LAF, Dallan LAO, Trindade EM,
Mejia OAV. Statistical analysis: Titinger DP, Trindade EM, Mejia
OAV, Jatene FB. Writing of the manuscript:Titinger DP, Lisboa
LAF, Matrangolo BR, Dallan LRP, Dallan LAO, Mejia OAV.
Critical revision of the manuscript for intellectual content:
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation work.
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Cardiac surgery costs according to the risk
Original Article
138
Arq Bras Cardiol. 2015; 105(2):130-138
Back to the Cover
Original Article
Screening for Fabry Disease in Left Ventricular Hypertrophy:
Documentation of a Novel Mutation
Ana Baptista, Pedro Magalhães, Sílvia Leão, Sofia Carvalho, Pedro Mateus, Ilídio Moreira
Centro Hospitalar de Trás-os-Montes e Alto Douro, Unidade de Vila Real – Portugal
Abstract
Background: Fabry disease is a lysosomal storage disease caused by enzyme α-galactosidase A deficiency as a result
of mutations in the GLA gene. Cardiac involvement is characterized by progressive left ventricular hypertrophy.
Objective: To estimate the prevalence of Fabry disease in a population with left ventricular hypertrophy.
Methods: The patients were assessed for the presence of left ventricular hypertrophy defined as a left ventricular
mass index ≥ 96 g/m2 for women or ≥ 116 g/m2 for men. Severe aortic stenosis and arterial hypertension with mild
left ventricular hypertrophy were exclusion criteria. All patients included were assessed for enzyme α-galactosidase A
activity using dry spot testing. Genetic study was performed whenever the enzyme activity was decreased.
Results: A total of 47 patients with a mean left ventricular mass index of 141.1 g/m2 (± 28.5; 99.2 to 228.5 g/m2] were
included. Most of the patients were females (51.1%). Nine (19.1%) showed decreased α-galactosidase A activity, but only
one positive genetic test − [GLA] c.785G>T; p.W262L (exon 5), a mutation not previously described in the literature.
This clinical investigation was able to establish the association between the mutation and the clinical presentation.
Conclusion: In a population of patients with left ventricular hypertrophy, we documented a Fabry disease prevalence
of 2.1%. This novel case was defined in the sequence of a mutation of unknown meaning in the GLA gene with further
pathogenicity study. Thus, this study permitted the definition of a novel causal mutation for Fabry disease – [GLA]
c.785G>T; p.W262L (exon 5). (Arq Bras Cardiol. 2015; 105(2):139-144)
Keywords: Fabry disease/complications; Hypertrophy, left ventricular; Alpha-Galactosidase/genetics.
Introduction
Establishing the cause of left ventricular hypertrophy (LVH)
is a common challenge in clinical practice, given its high
prevalence and the variety of diseases with which it may
be associated. This is particularly relevant from the clinical
standpoint because of the therapeutic implications regarding
the different differential diagnoses.
Fabry disease (FD) is a rare X-linked disease caused by
enzyme α-Galactosidase A (Gal A) deficiency as a result of
GLA gene mutations. Most families present with a “private”
mutation found only in that family and, thus, hundreds
of causal mutations are currently known. This multiplicity
of mutations may contribute to variations in the residual
enzyme activity and the different clinical presentations.
Enzyme Gal-A deficiency leads to a progressive tissue
accumulation of glycosphingolipids, especially of
globotriaosylceramide (Gb3), resulting in organ failure.
Mailing Address: Ana Baptista •
CHTMAD. Avenida da Noruega, Vila Real. Postal Code 5000, Vila Real – Portugal
E-mail: [email protected]
Manuscript received November 17, 2014; revised manuscript March 27, 2015;
accepted April 17, 2015.
DOI: 10.5935/abc.20150090
139
The organs more frequently involved are the kidneys,
heart, skin, central and autonomic nervous systems, eyes
and auditory system. As regards the cardiac manifestations,
Gb3 accumulation leads to LVH, whose etiology is
difficult to distinguish from others using the common
cardiac imaging methods, especially echocardiography.
Currently, suspecting lysosomal storage diseases, namely
FD, is key given the availability of enzyme replacement
therapy, which brings an impact on disease progression.
Thus, innumerable studies have been conducted to assess
the prevalence of FD in risk populations. The objective
of this study was to evaluate the prevalence of FD in a
population of patients with LVH.
Methods
The study was conducted between October 2010
and February 2011 in a hospital center in the region
of Tras‑os‑Montes and Alto Douro, northern Portugal,
after approval of the Institutional Ethics Committee.
All patients with age > 18 years referred for transthoracic
echocardiography (TTE) were considered eligible for the FD
screening program. They were included if there was evidence
of LVH, defined as a left ventricular (LV) mass / body surface
area (BSA) ≥ 96 g/m2, for women, and ≥ 116 g/m2, for men.
LV mass was calculated using the formula:
Baptista et al.
Fabry disease – description of a novel mutation
Original Article
LV mass = 0.8 x (1.04 [(LV internal diameter + posterior
wall + septum)3 – (LV internal diameter)3]) + 0.6
Linear measurements during diastole obtained from
two‑dimensional echocardiography were used for the
calculation. The exclusion criteria were presence of severe
aortic stenosis and arterial hypertension when associated
with mild LVH – LV mass/BSA < 109 g/m2 (women) and
< 132 g/m2 (men), regardless of the hypertension stage.
All patients enrolled gave written informed consent prior to
undergoing clinical assessment, investigation of multiorgan
involvement, and determination of enzyme Gal-A activity.
Clinical assessment
After the inclusion criteria were defined, brief history
taking focused on the investigation of symptoms suggestive
of FD and multiorgan involvement, especially cardiac,
was performed. Thus, the questionnaire included the
assessment of history of bouts of pain in extremities;
gastrointestinal transit or sweating abnormalities; history of
stroke; and presence of shortness of breath/orthopnea or
chest pain. Next, blood pressure (BP), height and weight
measurements were taken, and angiokeratomas were
investigated. Clinical assessment did not include family
history for cardiovascular or renal diseases.
Investigation of multiorgan involvement
The cardiac investigation was complemented by
electrocardiogram (ECG) – assessment of rhythm, heart
rate (HR), PR interval, conduction disturbances, and
voltage criteria for LHV (Sokolow-Lyon criteria). For the
investigation of renal involvement, BUN and serum
creatinine levels were determined, with further estimate of
the glomerular filtration rate (GFR) using the MDRD formula
(Modification of Diet in Renal Disease). Random urine
specimens were also collected to rule out albuminuria,
using the microalbuminuria/urine creatinine ratio.
Enzyme Gal-A activity determination
Screening for FD was based on the dried blood spot (DBS)
test, with four blood spots placed in a filter paper and allowed
to dry at room temperature. Enzyme Gal-A activity was
determined in an outside laboratory (laboratory of metabolism,
Hamburg University Medical Center). Values between 200 and
2000 pmol/spot*20 h were considered normal.
Genetic screening
Whenever enzyme Gal-A activity was reduced, genetic
screening was performed using 10 mL of blood collected in
an EDTA tube with further GLA gene sequencing in the Center
of Medical Genetics Doctor Jacinto de Magalhaes.
Data were submitted to descriptive analysis using the
Statistical Package for the Social Sciences (SPSS) program,
version 19.0 (SPSS Statistics IBM®), and were expressed
as numbers or percentages or mean values ± standard
deviation (SD). 95% confidence intervals (95% CI) were
used when applicable.
Results
During the study period, 75 patients had inclusion criteria;
of these, 28 (37.3%) were excluded for showing arterial
hypertension with mild LVH (21 patients), or severe aortic
stenosis (7 patients). Screening for FD was then performed in
47 patients, of whom 24 were women (51.1%). The mean age
of patients was 65.6 ± 14.5 years (ranging from 25 to 90 years).
As regards their ventricular mass, the mean LV mass/BSA was
141.1 ± 28.5 g/m2 (99.2 to 228.5 g/m2) and the mean septal
and posterior wall thickness was 15.3 ± 3.4 mm (10 to 24 mm)
and 12.9 ± 2.1 mm (9 to 20 mm), respectively.
Clinical characterization of the study population
Most of the study population assessed had a known history
of arterial hypertension (n = 35; 74.5%), with a mean systolic
BP recorded on the day of assessment of 144.2 ± 30.3 mmHg
(96 to 216 mmHg). The summary review of the clinical history
suggested the presence of bouts of pain in the extremities
in 27.7% of patients, sweating abnormalities in 4.3%, and
gastrointestinal transit abnormalities in 29.8%. No skin lesions
suggestive of angiokeratoma were found in any of the patients.
Eight patients (17%) had history of stroke, 66% presented with
dyspnea, and 40.4% with chest pain.
Of the patients assessed, three (6.4%) were on a regular
dialysis program, with the population showing a mean GFR of
81.7 ± 50.2 mL/min/1.73m2 (3.9 to 232.6 mL/min/1.73m2),
as estimated from mean creatinine values of 1.4 ± 2.1 mg/dL
(0.4 to 14.6 mg/dL). The prevalences of microalbuminuria
and proteinuria were of 25.5% and 55.4%, respectively.
Electrocardiographic assessment showed normal sinus rhythm
in most of the patients (63.8%), with the remaining showing
atrial fibrillation (19.1%) or pacemaker rhythm (17.1%).
Their mean HR was 71 ± 15 bpm (45 to 110 bpm), PR interval
of 169 ± 34 miliseconds (108 to 250 miliseconds), prevalence
of atrioventricular and intraventricular conduction disturbance
of 8.5% and 23.4%, respectively, with 40.4% of patients with
criteria for LVH.
Nine patients, all females, showed reduced enzyme
Gal-A activity (19.1%), and were therefore referred for
genetic screening. Only one of the genetic studies was able
to document a GLA gene mutation. Thus, the incidence of
false positives using the enzymatic test with DBS was 88.9%.
Description of the case showing GLA gene mutation
The single positive genetic test showed heterozygosis
for [GLA] c.785G>T; p.W262L (exon 5) mutation, which
had never been previously described in the literature as the
cause of FD. The patient was a 46-year-old female recently
diagnosed with arterial hypertension, who had been referred
for TTE because of a brain stem stroke. In the clinical
assessment, she had history of frequent episodes of bouts of
pain in the extremities, especially in hands, and gastrointestinal
transit abnormalities, but no angiokeratoma. The ECG revealed
normal sinus rhythm, HR of 76 bpm and voltage criteria for
LVH with an overload pattern. The echocardiogram showed
moderate concentric LVH with grade-II diastolic dysfunction.
Renal assessment revealed the presence of microalbuminuria
with preserved renal function (creatinine level of 0.6 mg/dL).
Arq Bras Cardiol. 2015; 105(2):139-144
140
Baptista et al.
Fabry disease – description of a novel mutation
Original Article
Although the manifestations were suggestive of FD
(microalbuminuria and LVH), they could also be explained by
the history of hypertension and, therefore, the pathogenicity
of this novel mutation had to be documented. This process
involved three key steps: genetic information, demonstration
of accumulation of Gb3 deposits, and family screening.
Regarding the study of the mutation, the bioinformatics
tools showed that it was causal, and the hypothesis of
polymorphism was ruled out when it was not found in
the study of 100 individuals from the population. Another
aspect corroborating causality was the fact that other causal
mutations had already been described in its proximity1,2.
Tissue accumulation of Gb3 was demonstrated by cutaneous
biopsy, which showed rare lysosomal inclusions with
characteristics typical of Gb3 deposits in smooth muscle
fibers and increased blood concentrations of lysoGb3.
As regards the family study (Figure 1), it was negative for all
her siblings, but positive for her daughter, who, at the age of
30 years, also presented with manifestations suggestive of FD:
cornea verticilatta, peripheral neuropathic pain, and slightly
increased proteins in the 24-hour urine, thus confirming
the association of the mutation with the manifestations
suggestive of FD. The investigation also included ruling
out the involvement of other organs not defined by the
study algorithm (dermatological, ophthalmological, ENT
and pulmonary assessments were normal) and additional
characterization by MRI of cardiac involvement, which
demonstrated LVH with no late enhancement, and brain
involvement, which demonstrated white matter damage.
Blood pressure was also documented by ambulatory
BP monitoring under medication. Thus, in a study on
FD screening in patients with LVH, one case of FD was
documented in association with a causal mutation – [GLA]
c.785G>T; p.W262L (exon 5), which had not been
previously described in the literature and is associated with
80 years (?)
XY (?)
X– Y
40 years
(Accident)
X– Y
Figure 1 – Family tree.
141
Arq Bras Cardiol. 2015; 105(2):139-144
Discussion
In a population of patients with LVH, after exclusion of
cases with severe aortic stenosis and arterial hypertension
associated with mild LVH, we documented a FD prevalence
of 2.1% (95%CI: 0.1-11.3%). This prevalence is similar
to that found in other screening studies in high-risk
populations (populations selected with LVH, stroke and
patients undergoing dialysis)3, which reported prevalence
rates much higher than that estimated in the general
population of 0.02 to 0.09 per 10 thousand individuals4.
However, the prevalence found should be carefully
interpreted taking into consideration the small number of
patients analyzed in this study. The importance of screening
studies lies on two major factors. First, they seek to increase
awareness on FD in target groups, in which there is a higher
probability of detecting cases, and thus contribute for the
definition of disease prevalence. Second, these studies also
provide the opportunity to detect the disease at earlier stages,
at which enzyme replacement therapy is more effective.
The available studies on the prevalence of FD in populations
with LVH used different criteria for patient inclusion, whether
because of different forms of assessing LVH, or because of the
cutoff values defined. Most of the studies used the maximum
ventricular wall thickness threshold of 13 or 15mm4 as an
inclusion criterion, unlike in the present study, in which
patient selection was based on the ventricular mass index.
Although the typical manifestation of the cardiac involvement
in FD is concentric LVH, several cases of asymmetrical LVH have
already been documented5. To corroborate this fact, there are
studies demonstrating a FD incidence of approximately 1.0%
82 years (stroke)
XX (?)
X– Y
X– X–
neurological, cardiac and renal involvement. The Organizing
Committee of Treatment of Lysosomal Storage Disorders
approved enzyme replacement therapy for the patient.
X– X–
49 years
X+ X–
30 years
X+ X–
Baptista et al.
Fabry disease – description of a novel mutation
Original Article
in populations diagnosed with hypertrophic cardiomyopathy6,
in which asymmetrical LVH is the most frequent form of
presentation. Thus, in the present study, patients with possible
FD may have been excluded because increased thickness
of a single ventricular wall – usually the ventricular septum,
may be not associated with increased LV mass. However, this
variable –left ventricular mass index, is one of the main criteria
for monitoring the effectiveness of enzyme replacement
therapy in the reduction of LVH7, and this is why it was used
as a criterion for patient selection.
In this study, enzyme Gal-A activity as assessed by DBS
was the method used for FD screening, whose result may
be normal in up to 40% of women with FD8. Interpretation
of the enzymatic assay is more complicated in females,
because the enzyme activity may be normal or at borderline
lower limits because of the phenomenon of X-chromosome
inactivation (i.e., the permanent epigenetical silencing
of one X chromosome creating cellular mosaicism,
which explains the disease presentation in women – of
delayed onset and with a higher probability of a singleorgan involvement)9. This leads to a study limitation: the
possibility of underestimating FD prevalence because
of false negatives among women although, interestingly,
the only positive result occurred in a female patient.
The use of the DBS test was based on the fact that it is an
easily-accessible screening method in the clinical practice
and has advantages over enzyme activity assessment in
leukocytes or fibroblasts. First, it requires only a few blood
spots for dose determination and, second, it permits easy
and quick specimen shipping to specialized laboratories,
an important aspect in our study center, where there is
no laboratory dedicated to lysosomal storage diseases.
Thus, we were interested in analyzing the DBS behavior to
determine its further inclusion in the assessment of female
patients with suspected FD. In addition to the known false
negatives – a reality for which clinicians are aware of,
given documentation from multiple studies, as previously
mentioned, this screening showed another limitation of the
DBS test: a high incidence of false positives, which has been
infrequently reported in studies10. Only one in nine of the
patients with reduced enzyme activity (all females) had FD
confirmed by genetic testing, thus resulting in 88.9% of false
positives. Therefore, in the current scenario in which costs
are weighted in clinical investigation, this study questions
the usefulness of DBS in female patients with suspected FD
(high rate of false negatives and false positives).
We observed a low incidence of unspecific manifestations,
namely sweating disorders; however, gastrointestinal
abnormalities and bouts of pain had an incidence of
approximately 30%. This is probably explained by the fact
that these are common manifestations of more prevalent
diseases such as musculoskeletal and digestive disorders.
On the other hand, manifestations of possible multiorgan
involvement such as albuminuria had a high incidence, since
they are also possible manifestations of hypertensive disease
– a common finding in the study population. The assessment
of these clinical and laboratory factors, which are common
manifestations of FD, is a distinguishing feature of this study.
Its inclusion in the screening study, unlike the usual genetic
study alone in risk populations, was motivated by the interest
in the definition of associations of factors with a higher
probability of FD. Thus, the study results could be applied to
the clinical practice, such as in the integration of findings in
algorithms of etiologic studies on LVH. This way, we could limit
genetic studies to certain groups selected according to criteria
corroborated by a clinical trial. However, this was not possible
because the sample size and the low incidence of FD limited
the study power to draw conclusions on the improvement
of pre-test probability. These findings were ultimately useful
in the assessment of the significance of de novo mutations,
as explained bellow.
To date, more than 600 GLA gene variants have been
described and most of them is unique for each family.
However, as more studies on FD screening started to be
conducted, an unexpected high number of individuals with
mutations of unknown significance was observed, with a
prevalence rate estimated at 0.6% in high-risk populations,
although only 0.12% have typical clinical manifestations or
decreased enzyme activity11. Thus, the significance of these
mutations is not easy to define, because many of the screening
studies involve high-risk populations that express one single
specific symptom – the inclusion criteria, LVH in the case of
this study and, thus, the symptom may be not related to the
GLA gene variant detected or may be an FD manifestation
in its non-classic form. In this study on FD screening in a
predominantly hypertensive population (74.5%) with LVH,
this became a clear issue. We found a GLA gene mutation
not previously described in the literature - [GLA] c.785G>T;
p.W262L (exon 5), whose significance could not be defined
based on the finding of LVH on TTE. The patient had been
diagnosed with hypertension and, thus, the LVH findings
along with the presence of microalbuminuria and history
of stroke could be explained either by FD or by arterial
hypertension with target-organ involvement, given that the
manifestations can overlap in both situations. This led to a
clinical investigation focused on proving the pathogenicity
associated with the mutation, which involved three key steps:
bioinformatics techniques, histological diagnosis, and family
screening. The assessment of the occasional pathogenicity of
the mutation involved the documentation of its absence in
the study of 100 chromosomes of individuals from the general
population, thus excluding the hypothesis of polymorphism.
Then, we proceeded to a literature review in the search for
mutations described in its proximity, which also increases
the probability of pathogenicity, and found the p. W262C
(c.786G>C) mutation documented by Schafer et al.12, and
the p. W262X (c.785G>A) mutation described by Shabbeer
et al.13. The use of bioinformatics tools defined the mutation as
causal. We used the PolyPhen-2® (Polymorphism Phenotyping
v2) program, which predicts the possible impact of the
replacement of one amino acid on the structure and function
of human proteins (Figure 2). Accumulation of Gb3 deposits –
histological diagnosis of FD, was demonstrated by cutaneous
biopsy, which showed sparse lysosomal inclusions with
characteristics typical of Gb3 deposits exclusively in smooth
muscle fibers thus corroborating the relationship between
genotype and phenotype. The process was concluded with
family screening focused on confirming the association of
Arq Bras Cardiol. 2015; 105(2):139-144
142
Baptista et al.
Fabry disease – description of a novel mutation
Original Article
PolyPhen-2 report for P06280 W262L
Query
Protein Acc
P06280
Position
262
AA1
AA2
W
L
Descrição
Canonical; RecName: Full=Alphagalactosidase A; EC=3.2.1.22;
AltName: Full=Alpha-D-galactosidase
A; AltName: Full=Alpha-Dgalactoside galactohydrolase;
AltName: Full=Melibiase; AltName:
INN=Agalsidase; Flags: Precursor;
Length: 429
Results
Prediction/Confidence
PolyPhen-2 v2.2.2r398
HumDiv
This mutation is predicted to be PROBABLY DAMAGING
(sensitivity: 0.00; specificity: 1.00)
0.00
0.20
0.40
0.60
With a score of 1.000
0.80
1.00
HumDiv
Details
Multiple sequence alignment
UniProt/UniRef 2011-12 (14-dez-2011)
3D Visualization
PDB/DSSP Snapshot 03-Jan-2012 (78304 Structures)
Figure 2 – Use of bioinformatics tools to estimate the causality of the mutation.
the mutation with clinical manifestations in multiple patients.
Documentation of the mutation in a normotensive first-degree
relative (daughter) associated with early manifestations of FD
(cornea verticillata, peripheral neuropathic pain, and increased
24-hour urine proteins) also helped to establish a causal
relationship between the mutation found - [GLA] c.785G>T;
p.W262L (exon 5), and FD.
Conclusions
In a population of patients with left ventricular
hypertrophy, after exclusion of severe aortic stenosis and
arterial hypertension associated with mild left ventricular
hypertrophy, we documented a Fabry disease prevalence
of 2.1%. This stresses the importance of including this
disease among the differential diagnoses of left ventricular
hypertrophy. This screening study also documented
an issue regarding these research methods that is not
related to Fabry disease – the occurrence of a mutation of
unknown significance in GLA gene, and showed the clinical
management required to define the role of the mutation on
the development of the clinical presentation. Thus, this study
143
Arq Bras Cardiol. 2015; 105(2):139-144
allowed the definition of a novel causal mutation for Fabry
disease – [GLA] c.785G>T; p.W262L (exon 5).
Author contributions
Conception and design of the research and Writing of the
manuscript: Baptista A, Mateus P; Acquisition of data and
Critical revision of the manuscript for intellectual content:
Baptista A, Magalhães P, Leão S, Carvalho S, Mateus P; Analysis
and interpretation of the data: Baptista A, Magalhães P;
Statistical analysis: Baptista A, Leão S.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation work.
Baptista et al.
Fabry disease – description of a novel mutation
Original Article
References
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Schäfer E, Baron K, Widmer U, Deegan P, Neumann HP, Sunder-Plassmann
G, et al. Thirty-four novel mutations of the GLA gene in 121 patients with
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2. Shabbeer J, Yasuda M, Benson SD, Desnick RJ. Fabry disease:
Identification of 50 novel α-galactosidase A mutations causing the classic
phenotype and three-dimensional structural analysis of 29 missense
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2014;37(6):969-78.
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Linthorst GE, Bouwman MG, Wijburg FA, Aerts JM, Poorthuis BJ, Hollak CE.
Screening for Fabry disease in high-risk populations: a systematic review.
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9. Yousef Z, Elliott PM, Cecchi F, Escoubet B, Linhart A, Monserrat L, et al.
Left ventricular hypertrophy in Fabry disease: a practical approach to
diagnosis. Eur Heart J. 2013;34(11):802-8.
4. Terryn W, Deschoenmakere G, Keyser JD, Meersseman W, Van Biesen
W, Wuyts B, et al. Prevalence of Fabry disease in a predominantly
hypertensive population with left ventricular hypertrophy. Int J Cardiol.
2013;167(6):2555-60.
10. Caudron E, Germain DP, Prognon P. [Fabry disease: enzymatic screening using
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5. Elliott P, Baker R, Pasquale F, Quarta G, Ebrahim H, Mehta AB, et al.
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6. H a g è g e A A , C a u d r o n E , D a m y T, R o u d a u t R , M i l l a i r e A ,
Etchecopar‑Chevreuil C, et al; FOCUS study investigators. Screening patients
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the FOCUS study. Heart. 2011;97(2):131-6.
11. Tol LV, Smid BE, Poorthuis JH, Biegstraaten M, Deprez RH, Linthorst GE, et al.
A systematic review on screening for Fabry disease: prevalence of individuals
with genetic variants of unknown significance. J Med Genet. 2014;51(1):1-9.
12. Schäfer E, Baron K, Widmer U, Deegan P, Neumann HP, Sunder-Plassmann
G, et al. Thirty-four novel mutations of the GLA gene in 121 patients with
Fabry disease. Hum Mutat. 2005;25(4):412.
13. Shabbeer J, Yasuda M, Benson SD, Desnick RJ. Fabry disease:
identification of 50 novel alpha-galactosidase A mutations causing
the classic phenotype and three-dimensional structural analysis of 29
missense mutations. Hum Genomics. 2006;2(5):297-309.
Arq Bras Cardiol. 2015; 105(2):139-144
144
Back to the Cover
Original Article
Heart Failure with Preserved Left Ventricular Ejection Fraction in
Patients with Acute Myocardial Infarction
Lucas Antonelli, Marcelo Katz, Fernando Bacal, Marcia Regina Pinho Makdisse, Alessandra Graça Correa, Carolina
Pereira, Marcelo Franken, Anderson Nunes Fava, Carlos Vicente Serrano Junior, Antonio Eduardo Pereira Pesaro
Hospital Israelita Albert Einstein (HIAE), São Paulo, SP – Brazil
Abstract
Background: The prevalence and clinical outcomes of heart failure with preserved left ventricular ejection fraction after acute
myocardial infarction have not been well elucidated.
Objective: To analyze the prevalence of heart failure with preserved left ventricular ejection fraction in acute myocardial
infarction and its association with mortality.
Methods: Patients with acute myocardial infarction (n = 1,474) were prospectively included. Patients without heart failure
(Killip score = 1), with heart failure with preserved left ventricular ejection fraction (Killip score > 1 and left ventricle ejection
fraction ≥ 50%), and with systolic dysfunction (Killip score > 1 and left ventricle ejection fraction < 50%) on admission
were compared. The association between systolic dysfunction with preserved left ventricular ejection fraction and in-hospital
mortality was tested in adjusted models.
Results: Among the patients included, 1,256 (85.2%) were admitted without heart failure (72% men, 67 ± 15 years),
78 (5.3%) with heart failure with preserved left ventricular ejection fraction (59% men, 76 ± 14 years), and 140 (9.5%) with
systolic dysfunction (69% men, 76 ± 14 years), with mortality rates of 4.3%, 17.9%, and 27.1%, respectively (p < 0.001).
Logistic regression (adjusted for sex, age, troponin, diabetes, and body mass index) demonstrated that heart failure with
preserved left ventricular ejection fraction (OR 2.91; 95% CI 1.35–6.27; p = 0.006) and systolic dysfunction (OR 5.38; 95% CI
3.10 to 9.32; p < 0.001) were associated with in-hospital mortality.
Conclusion: One-third of patients with acute myocardial infarction admitted with heart failure had preserved left ventricular
ejection fraction. Although this subgroup exhibited more favorable outcomes than those with systolic dysfunction, this condition
presented a three-fold higher risk of death than the group without heart failure. Patients with acute myocardial infarction and
heart failure with preserved left ventricular ejection fraction encounter elevated short-term risk and require special attention
and monitoring during hospitalization. (Arq Bras Cardiol. 2015; 105(2):145-150)
Keywords: Heart Failure; Myocardial Infarction; Stroke Volume; Prevalence.
Introduction
Diastolic heart failure (HF) is a clinical syndrome defined by
the presence of signs and symptoms of HF, preserved left ventricle
ejection fraction (LVEF), and abnormal diastolic function1.
It is characterized by an abnormality in ventricular distensibility,
relaxation, and filling, all of which can be indirectly measured
by echocardiography2. In the absence of echocardiographic
assessment of diastolic function, HF with LVEF ≥ 50% can be
termed only “HF with preserved LVEF.” Although patients with HF
with preserved LVEF generally present a more favorable prognosis
than those with systolic dysfunction, there is increasing morbidity
related to HF with preserved LVEF due to population aging and
therapeutic limitations associated with this pathology.
Mailing Address: Antonio Eduardo Pereira Pesaro •
Hospital Israelita Albert Einstein. Avenida Albert Einstein, 627/701, Pavilhão Vicky
e Joseph Safra, Bloco A1, 4º andar, Postal Code 05652‑901, São Paulo, SP - Brazil.
E-mail: [email protected].
Manuscript received November 18, 2014; revised manuscript February 20,
2015; accepted March 4, 2015
DOI: 10.5935/abc.20150055
145
In particular, systolic dysfunction is an important marker
of poor prognosis in acute myocardial infarction (AMI)3,4.
Conversely, the presence of diastolic dysfunction, whether
associated with systolic dysfunction, is an aggravating factor
that is associated with poor prognosis in this situation5,6.
Previous studies have suggested that the development of HF
after AMI is related to the infarction size, coronary multivessel
disease, reperfusion efficiency, and adjuvant medication
use 7-9. Despite the increasing use of early myocardial
revascularization8, the prevalence of post-AMI HF is still high
(20%–30%), representing the leading cause of in-hospital
mortality6,10. Systolic ventricular dysfunction after AMI in
relation to the development of HF and increased mortality
has been extensively studied. Moreover, data relating to
the prevalence and prognosis of patients with post-AMI HF
with preserved LVEF are still limited11. A few registries have
specifically evaluated post-AMI HF with preserved LVEF;
however, they generally have not simultaneously assessed
AMI patients with and without ST-segment elevation (STEMI
and NSTEMI, respectively) and have used heterogenous LVEF
cut-off points to establish the diagnosis of HF with preserved
LVEF12-14. Here we aim to evaluate the prevalence, clinical
Antonelli et al.
Diastolic heart failure in myocardial infarction
Original Article
characteristics, and clinical outcomes of patients admitted
with post-AMI HF with preserved LVEF.
Methods
Between January 2005 and December 2012, 1,474 patients
with AMI (71% men, 73 ± 14 years, 39% with STEMI) were
consecutively included in a single-center registry of a tertiary
hospital. Details regarding the registry design, methods, and
quality control have been previously published15. AMI was
defined according to the criteria set by international guidelines16.
LVEF was measured throughout hospitalization at the discretion
of the healthcare team. For this analysis, the worst LVEF of each
patient during hospitalization was selected. Baseline clinical
characteristics and in-hospital outcomes (length of stay and inhospital mortality) were compared among the three groups of
patients: those without HF at admission (Killip score = 1), those
with HF with preserved LVEF at admission (Killip score > 1 and
LVEF ≥ 50%), and those with systolic dysfunction at admission
(Killip score > 1 and LVEF < 50%). The diagnosis of AMI and
all decisions regarding the treatment administered were made
by the responsible medical team based on the institution’s
current guidelines and routine practices. Specific nursing staff
was assigned to collect all the variables included in this registry.
The Research Ethics Committee of Hospital Israelita Albert
Einstein approved the present study.
Statistical analyses
The numerical variables with normal distribution were
expressed as mean ± standard deviation or as median and
interquartile range when the distribution was not normal.
Categorical variables were presented as absolute and relative
frequencies. The comparison between numerical variables was
performed using analysis of variance or the Kruskal–Wallis test,
followed by the Bonferroni–Dunn multiple comparisons test,
when required. The chi-squared test was used for categorical
variables; Bonferroni multiple comparisons via generalized linear
models with logit link function were used when the differences
between the groups were significant. A logistic regression
model adjusted for sex, age, troponin, diabetes mellitus, body
mass index, type of AMI, and history of prior stroke/transient
ischemic attack was used to test the association between HF
and in-hospital mortality. A p-value < 0.05 was considered to
be statistically significant. All statistical analyses were performed
using STATA 11 Special Edition (Stata Corp LP, College Station,
Texas, United States).
Results
Among the 1,474 patients included in the study, 1,256
(85.2%) did not have HF (72% men, 67 ± 15 years), 78 (5.3%)
had HF with preserved LVEF (59% men, 76 ± 14 years), and 140
(9.5%) had systolic HF (69% men, 76 ± 14 years). The baseline
clinical characteristics of the three groups are shown in Table 1.
It was observed that HF patients with preserved LVEF and those
with systolic HF were older and had higher risk for thrombolysis
in myocardial infarction (TIMI) than patients without HF.
Compared with patients with systolic HF, HF patients with
preserved LVEF had higher LVEF and often exhibited NSTEMI.
Patients without HF, with HF with preserved LVEF, and with
systolic HF presented mortality rates of 4.3%, 17.9%, and
27.1%, respectively (p < 0.001), and hospital stay (standard
deviation) of 6 (5), 9 (14), and 10 (12.5) days, respectively
(p < 0.001). Logistic regression revealed that HF with preserved
LVEF [odds ratio (OR) = 2.91, 95% confidence interval (95% CI)
1.35–6.27, p = 0.006] and systolic dysfunction (OR = 5.38,
95% CI 3.10–9.32, p < 0.001) were notably and independently
associated with in-hospital mortality (Table 2).
Discussion
One-third of patients with AMI who had HF at admission
presented preserved LVEF (≥ 50%). Nevertheless, this
subgroup had an extended hospital stay and an almost
three-fold higher risk of in-hospital death than those without
HF. Patients admitted with systolic HF exhibited even higher
mortality rates, with a five-fold greater risk of in-hospital death
when compared with patients without HF.
Diastolic HF is a clinical syndrome characterized by the
presence of signs and symptoms of HF, preserved LVEF, and
abnormal diastolic function. The pathophysiology of diastolic
HF comprises ventricular relaxation deficit and intraventricular
pressure increase, with a consequent increase in pulmonary
capillary wedge pressure1. In general, post-AMI HF is a
result of complex and unbalanced structural, hemodynamic,
and neurohumoral interactions17. Ischemia and myocardial
necrosis promote systolic and diastolic contractile dysfunction
because ventricular diastole is an active physiological process
that consumes oxygen and glucose18. Even without extensive
necrosis, a stunned or hibernating myocardium also presents
contractile and relaxation dysfunction, although this may
be transitory19.
Echocardiographic assessment of diastolic function and
filling pressures requires careful data acquisition and proper
interpretation by the operating technician. Decreases in the
magnitude of the early to late diastolic filling ratio, increases
in the deceleration time of early diastolic filling, or increases
in the isovolumetric relaxation time indicate worsened
ventricular relaxation19. These echocardiographic parameters
can aid in diagnosis and assessment of the severity of diastolic
dysfunction. A 2007 European consensus suggested that,
in addition to the clinical characteristics of HF and LVEF,
echocardiographic parameters such as ventricular filling time,
diastolic volume, and ventricular mass should be included
among the diagnostic criteria for diastolic HF20. Data on these
parameters were not available in our registry; nevertheless, as
in the present study, the majority of clinical studies on post-AMI
diastolic dysfunction have used only clinical HF associated
with preserved LVEF to establish the diagnosis12,21.
In patients with acute coronary syndromes (ACS), the
presence of HF is an important marker for risk of death.
Stege et al. evaluated the characteristics and prognosis of
post-ACS HF based on the GRACE registry13. They observed
a 2.2-fold higher risk of death for patients with HF than those
without HF. Notably, the GRACE registry did not differentiate
according to patients the type of HF (systolic or diastolic) but
classified them only based on the Killip score at admission.
In addition, patients with Killip class IV AMI were excluded
Arq Bras Cardiol. 2015; 105(2):145-150
146
Antonelli et al.
Diastolic heart failure in myocardial infarction
Original Article
Table 1 – Clinical characteristics of the three groups of patients
Without HF
(n = 1,256)
HF with preserved LVEF
(n = 78)
Systolic HF
(n = 140)
p-value
Male, n (%)
910 (72)
46 (59)
96 (69)
0,028*
Age (±SD)
67 ± 15**,***
76 ± 14****
76 ± 14****
< 0,001
BMI (kg/m²) (±SD)
27 ± 4***
26 ± 5****
26 ± 5****
0,015
Diabetes, n (%)
370 (30)
30 (39)
50 (36)
0,130
SAH, n (%)
700 (58)
52 (67)
86 (63)
0,157
Stroke/TIA, n (%)
Previous AMI, n (%)
LVEF (±SD)
TIMI risk (P25/P75)
Troponin ng/mL (P25/P75)
NSTEMI, n (%)
48 (4)***
4 (5)
15 (11)****
0,005
195 (16)***
8 (11)
31 (23)****
0,050
0,54 ± 0,12**,***
0,59 ±0,07***,****
0,34 ±0,09**,****
< 0,001
2 (1/4)**,***
3 (2/6)****
4 (3/6,75)****
< 0,001
3.460 (580/16.100)
3.160 (450/21.200)
3.300 (420/21.500)
0,940
790 (63)***
47 (60)***
60 (43)**,****
< 0.001
* It was not possible to identify the groups in which the differences occurred. ** Statistically significant differences compared with HF patients with preserved LVEF. ***
Statistically significant differences compared with systolic HF patients. **** Statistically significant differences compared with patients without HF.
HF: Heart failure. LVEF: Left ventricular ejection fraction. SD: Standard deviation. BMI: Body mass index. SAH: Systemic arterial hypertension. TIA: Transient
ischemic attack. AMI: Acute myocardial infarction. TIMI: Thrombolysis in myocardial infarction. NSTEMI: Acute myocardial infarction without ST-segment elevation.
Table 2 – Multivariate logistic regression
Variable
OR
HF with preserved LVEF
95% CI
p-value
Lowest
Highest
2,91
1,35
6,27
0,006
Systolic HF
5,38
3,10
9,32
< 0,001
Age (years)
1,02
1,01
1,03
0,003
BMI (kg/m²)
0,84
0,81
0,88
< 0,001
Female sex
1,44
0,87
2,41
0,160
Diabetes
0,88
0,53
1,45
0,615
Previous AMI
0,80
0,42
1,50
0,482
Previous stroke/TIA
2,02
0,91
4,48
0,085
Troponin
1,00
1,00
1,00
0,996
NSTEMI
0,66
0,40
1,07
0,092
OR: Odds ratio. 95% CI: 95% confidence interval. HF: heart failure. LVEF: Left ventricular ejection fraction. BMI: Body mass index. AMI: Acute myocardial infarction.
TIA: Transient ischemic attack. NSTEMI: Acute myocardial infarction without ST-segment elevation.
from the analysis, which may justify the lower mortality in these
patients compared with the results of our or other registries14,22.
Conversely, the data available on diastolic dysfunction in
patients with ACS are highly limited. Patients with ACS and HF
often have preserved LVEF; nevertheless, most clinical studies
have only analyzed the outcomes of patients with systolic HF.
Recently, an epidemiological study demonstrated that, despite
the prevalence of post-AMI systolic HF declining over the past two
decades, prevalence for HF with preserved LVEF has remained
147
Arq Bras Cardiol. 2015; 105(2):145-150
stable, reaching a rate comparable with systolic HF23. In general,
patients with HF with preserved LVEF are majorly women, the
elderly, hypertensive individuals, and those with lower prevalence
of diabetes mellitus compared with patients with post-ACS systolic
HF12. In the present study, compared with patients without HF,
patients with systolic HF or HF with preserved LVEF were older
and had a higher risk of AMI, as assessed by the TIMI score.
Compared with patients with systolic HF, HF patients with
preserved LVEF had higher LVEF and often exhibited NSTEMI.
Antonelli et al.
Diastolic heart failure in myocardial infarction
Original Article
In relation to clinical outcomes, some studies have
shown that patients with post-AMI HF and preserved
LVEF had higher risk of mortality compared with patients
without HF, despite not exhibiting systolic dysfunction.
Bennett et al. found results similar to the present study in the
CRUSADE registry, specifically in patients with NSTEMI12.
In that registry, over half the patients with post‑AMI HF
had preserved LVEF. However, the cut-off point used to
determine preserved LVEF was 40%. Therefore, patients
with mild systolic ventricular dysfunction were considered
to have diastolic HF, which may have worsened the
prognosis of this subset of patients. Nevertheless, in the
CRUSADE registry, mortality in patients with HF with
preserved LVEF was lower than that in patients with systolic
dysfunction12. Similarly to the present study, this rate was
more than twice the rate in patients without HF. In the same
registry, this behavior was also observed in the short- and
long-term sub-analysis in patients aged over 65 years 24.
Notably, the CRUSADE registry did not include patients
with STEMI, who represented 40% of HF patients with
preserved LVEF in the study.
Subsequently, Kim et al.22 assessed predictors of death
including NT-proBNP in 555 patients with AMI and preserved
LVEF. Age and NT-proBNP were independent predictors
of cardiovascular mortality and rehospitalization for HF.
Recently, in a large registry (ACTION) analyzed by Shah et al.,21
3.8% of patients with AMI admitted without HF developed
HF during hospitalization. In this subgroup, 35% of patients
exhibited NSTEMI and 22% of those exhibiting STEMI
developed HF with LVEF ≥ 50%. Despite mortality in patients
with post-AMI HF being approximately five times greater
than in those without HF, they did not observe differences
in mortality between patients with systolic HF and those
with HF with preserved LVEF. However, the study suggested
that preserved LVEF and absence of HF at admission did not
guarantee that patients with AMI were free from the risk of
developing HF during hospitalization.
The present study had several limitations because this
was a retrospective, observational, single-center study with a
relatively small population sample. Data on the patients’ Killip
score throughout hospitalization was not available but only
that upon admission was available; therefore, this study did
not include cases of HF that developed during hospitalization.
Echocardiographic measurements related to diastolic function
other than the LVEF score were also not available in the
present registry. Finally, complete data on the medical and
interventional treatment of the patients were not available,
and as a result, statistical adjustments related to therapeutic
aspects were not possible.
Thus, although post-AMI HF with preserved LVEF is
moderately prevalent and presents important prognostic
implications, few studies have specifically evaluated the clinical
outcomes and therapeutic needs of this subgroup of patients.
Despite its limitations, the objective of this study was to describe
the clinical features, prevalence, and prognosis of patients with
systolic HF or HF with preserved LVEF following AMI.
Conclusion
One-third of patients with AMI with HF at admission
presented preserved LVEF. Although outcomes for this
subgroup were more favorable than those for the patients
with systolic HF, the former had longer hospital stays and a
three-fold higher risk of death than the patients without HF.
Therefore, HF patients with preserved LVEF after AMI are a
subgroup encountering a short-term risk and require special
attention and monitoring during hospitalization.
Acknowledgements
The authors would like to thank Rogério Ruscitto Prado for
his support in the statistical analyses.
Author contributions
Conception and design of the research:Antonelli L, Katz
M, Bacal F, Makdisse MRP, Correa AG, Pereira C, Franken
M, Fava AN, Serrano Junior CV, Pesaro AEP. Acquisition
of data:Antonelli L, Fava AN, Pesaro AEP. Analysis and
interpretation of the data: Antonelli L, Katz M, Pesaro AEP.
Statistical analysis: Antonelli L, Katz M, Pesaro AEP. Writing of
the manuscript:Antonelli L, Katz M, Bacal F, Makdisse MRP,
Correa AG, Pereira C, Franken M, Serrano Junior CV, Pesaro
AEP. Critical revision of the manuscript for intellectual content:
Antonelli L, Katz M, Bacal F, Makdisse MRP, Correa AG, Pereira
C, Franken M, Fava AN, Serrano Junior CV, Pesaro AEP.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation work.
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fraction after myocardial infarction: a community study. Am J Epidemiol.
2013;178(8):1272-80.
24. van Diepen S, Chen AY, Wang TY, Alexander KP, Ezekowitz JA, Peterson
ED, et al. Influence of heart failure symptoms and ejection fraction on
short- and long-term outcomes for older patients with non-ST-segment
elevation myocardial infarction. Am Heart J. 2014;167(2):267-73.
Antonelli et al.
Diastolic heart failure in myocardial infarction
Original Article
Arq Bras Cardiol. 2015; 105(2):145-150
150
Back to the Cover
Original Article
Tramadol Alleviates Myocardial Injury Induced by Acute Hindlimb
Ischemia Reperfusion in Rats
Hamed Ashrafzadeh Takhtfooladi1, Adel Haghighi Khiabanian Asl1, Mehran Shahzamani2, Mohammad
Ashrafzadeh Takhtfooladi3, Amin Allahverdi4, Mohammadreza Khansari5
Department of Pathobiology, Science and Research Branch, Islamic Azad University1, Department of Cardiovascular Surgery, Isfahan University
of Medical Sciences2, Young Researchers and Elites Club, Science and Research Branch, Islamic Azad University3, Department of Surgery, Science
and Research Branch, Islamic Azad University4, Department of Physiology, Science and Research Branch, Islamic Azad University5, Tehran - Iran
Abstract
Background: Organ injury occurs not only during periods of ischemia but also during reperfusion. It is known that
ischemia reperfusion (IR) causes both remote organ and local injuries.
Objective: This study evaluated the effects of tramadol on the heart as a remote organ after acute hindlimb IR.
Methods: Thirty healthy mature male Wistar rats were allocated randomly into three groups: Group I (sham), Group II (IR),
and Group III (IR + tramadol). Ischemia was induced in anesthetized rats by left femoral artery clamping for 3 h, followed
by 3 h of reperfusion. Tramadol (20 mg/kg, intravenous) was administered immediately prior to reperfusion. At the end of
the reperfusion, animals were euthanized, and hearts were harvested for histological and biochemical examination.
Results: The levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were higher in
Groups I and III than those in Group II (p < 0.05). In comparison with other groups, tissue malondialdehyde (MDA)
levels in Group II were significantly increased (p < 0.05), and this increase was prevented by tramadol. Histopathological
changes, including microscopic bleeding, edema, neutrophil infiltration, and necrosis, were scored. The total injury
score in Group III was significantly decreased (p < 0.05) compared with Group II.
Conclusion: From the histological and biochemical perspectives, treatment with tramadol alleviated the myocardial
injuries induced by skeletal muscle IR in this experimental model. (Arq Bras Cardiol. 2015; 105(2):151-159)
Keywords: Tramadol/ therapeutic use; Heart Injuries; Heart/physiopathology; Reperfusion Injury; Rats.
Introduction
Restoration of blood flow after a period of ischemia causes
ischemia reperfusion (IR) injury. IR injury is a serious clinical
problem that occurs in many diseases and surgeries, such as limb
orthopedic surgery, organ transplantation, cardiopulmonary
bypass, and hypovolaemic shock1,2. During IR, tissues are
subjected to destructive proinflammatory cytokines and reactive
oxygen species released by inflammatory cells, leading to
inflammatory injury and cell apoptosis3,4. IR also affects the
secondary organs, including liver5, heart6, kidney7, lung8, and
even causes multiple organ failure, which is a common cause
of mortality. Therefore, antioxidative, anti-inflammatory, and
antiapoptotic agents to attenuate multiple organ injury induced
by IR are urgently required.
Various investigators have demonstrated that the opioid
pathway is involved in tissue preservation during hypoxia
Mailing Address: Mohammad Ashrafzadeh Takhtfooladi •
Young Researchers and Elites Club, Science and Research Branch, Islamic
Azad University. Postal Code 8177613343, Tehran, Iran.
E-mail: [email protected]
Manuscript received January 02, 2015; revised manuscript February 27,
2015; accepted March 11, 2015.
DOI: 10.5935/abc.20150059
151
or ischemia, and this protection is mediated via the delta
opioid receptor9,10. It has been shown that morphine has
cardioprotective effects during IR11,12. Factors, such as respiratory
depression and histamine release, are disadvantages of using
morphine in the postoperative period of open heart surgery13.
Tramadol is a narcotic-like pain reliever drug as it
has an unusual mechanism of action involving opioid,
noradrenaline, and serotonin (5-hydroxytryptamine)
systems of analgesia. It is certainly useful in the treatment
of chronic and acute pain. Although it does not cause
respiratory depression, the problems of nausea when
used in clinically effective analgesic doses for severe pain
and the risk of intra-operative awareness may represent
significant disadvantages of tramadol14. Recent research
discloses that tramadol decreases lipid peroxidation
and regulates noradrenalin uptake; therefore, these
therapeutic properties are used for the management of
myocardial ischemia15.
In the past few years, the administration of tramadol was
shown to protect against IR injuries in local and remote
organs15-18. However, the role of tramadol in reducing injury
in the myocardium after hindlimb IR has not been addressed
yet. In this study, the effect of tramadol on myocardial
injury after hindlimb IR was assessed by biochemical and
histological changes in rats.
Takhtfooladi et al.
Effects of Tramadol on Myocardial Remote Injury
Original Article
Methods
Thirty healthy mature male Wistar rats weighing
250–300 g were purchased from the Pasteur Institute of
Iran. All experimental procedures and protocols used in
this investigation were reviewed and approved by the
Committee of Ethics in Research with Animals at the Islamic
Azad University Faculty of Veterinary Medicine. They were
kept under constant room temperature of 20–22°C, relative
humidity of 50%–60%, 12 h/12 h light/dark cycle, with ad
libitum access to filtrated tap water and commercial food and
were placed in individual plastic cages with soft bedding.
Experimental groups
The rats were randomly divided into three experimental
groups of ten rats each (of these ten, five were used for
biochemical assays and five for histological analysis):
Group I (sham group) was subjected to all procedures,
except arterial occlusion. The animals received 2 mL
of 0.9% saline via the jugular vein. Group II (IR group)
was subjected to IR. Two milliliters of 0.9% saline was
administered immediately prior to the reperfusion period.
Group III (IR + tramadol group) was subjected to IR.
A solution of 20 mg/kg tramadol16 in 0.9% saline solution
was administered, with a total volume of 2 mL.
Anesthesia
The rats were weighed and anesthetized using an intramuscular
injection of ketamine hydrochloride 10% and xylazine
hydrochloride 2% (50 mg/kg and 10 mg/kg, respectively).
Surgery
After induction of anesthesia, the animals were placed
on a board, in a dorsal, recumbent position, with their
thoracic and pelvic limbs immobilized with adhesive tape.
The jugular vein was isolated and catheterized for the
administration of heparin, tramadol, and normal saline.
The left hindlimb was prepared for sterile surgery. A skin
incision was made on medial surface of the left hindlimb
and femoral artery was isolated and was clamped with
a non-traumatic clamp for 3 h and followed by 3 h of
reperfusion. Prior to the occlusion of the femoral artery,
250 IU heparin17 was administered via the jugular vein in
order to prevent clotting. Rats were maintained in a dorsal,
recumbent position and kept anesthetized (additional
doses were given in case of necessity) throughout the
duration of the ischemic period. Body temperature was
maintained with a heating pad and monitored using a rectal
thermometer. The vascular forceps was removed and the
surgical site was routinely closed with 3/0 polypropylene
sutures following the ischemic period. Subjects in Group I
underwent a surgical procedure similar to the other groups
but the femoral artery was not occluded.
Specimen collection
At the end of the trial, rats were euthanized with an overdose
of pentobarbital injection (300 mg/kg, intraperitoneal) and the
hearts were rapidly excised.
Histological analysis
For histological analysis, the hearts were fixed with 10%
formalin and then embedded in paraffin and sectioned into
5-μm thick sections and stained with hematoxylin and eosin
(H&E). The sections were examined in a semiquantitative
manner, using 250× and 400× magnifications under a light
microscope by a pathologist who was blinded to the experiment
and data. The histological parameters, such as microscopic
bleeding, edema, neutrophil infiltration, and necrosis, were
scored according to the classification of Papoutsidakis et al.19
as shown in Table 1. Approximately ten fields of view were
examined under each magnification. The total histological
score for each specimen was determined by the sum of all the
partial scores.
Biochemical assays
Evidence of oxidative stress was determined from heart
tissue homogenates using glutathione peroxidase (GPx),
catalase (CAT), and superoxide dismutase (SOD) activities
and the levels of malondialdehyde (MDA). Each heart was
stored separately at −80°C until analysis. The tissues were
homogenized in 0.1 M phospate buffer (pH 7.4) with an Ultra
Turrax homogenizer. The homogenates were centrifuged at
5000 rpm at 4°C for 10 min; the supernatants were removed
and assayed for MDA, GPx, and SOD activities. Tissue GPx and
SOD activities were measured with a Hitachi 917 autoanalyser
using commercial kits. SOD and GPx activities were expressed
as U/mg protein in tissue samples. Tissue MDA levels were
determined by the thiobarbituric acid method of Okhawa et
al.20 MDA levels were expressed as nmol/mg protein in tissue
samples. CAT activities were determined by measuring the
decrease in hydrogen peroxide concentration at 230 nm by
the method of Beutler21. CAT activity was expressed U/mg
protein in tissue samples.
Statistical analysis
Data were analyzed using SPSS statistical software package
(version 18). Distribution of the groups was analyzed with one
sample Kolmogorov–Smirnov test. The results were analyzed
using analysis of variance for comparing multiple means (ANOVA)
with post-hoc test analysis. Biochemical data were tested using
the Kruskal–Wallis nonparametric test. Data are shown as the
mean ± standard deviation and the significance level was 5%.
Results
The experimental procedure was well tolerated and no
animals died during the experiment.
Biochemical results
SOD, CAT, GPx, and MDA levels were measured in the
heart tissues after 3 h of reperfusion. The levels of SOD, CAT,
and GPx were significantly lower in Group II than those in
the other groups (Figures 1–3). The reductions in the levels
of these molecules were reversed by intravenous injection of
tramadol. In comparison with other groups, tissue MDA levels
in group II were significantly increased (Figure 4) and this was
prevented by tramadol.
Arq Bras Cardiol. 2015; 105(2):151-159
152
Takhtfooladi et al.
Effects of Tramadol on Myocardial Remote Injury
Original Article
Table 1 – Histological grading (Papoutsidakis et al.)
0
1
2
3
Magnification
None or 1–3
dead cells in < 3 FOV
≤ 3 dead cells per FOV in at
least 3 FOV or 4–6 cells in
no more than 3 FOV
4–6 dead cells per FOV in at
least 4 FOV or > 6 cells in no
more than 3 FOV
> 6 dead cells in at least
4 FOV
400×
Polymorphonuclear leucocytes
None or 1–3
cells in < 3 FOV
≤ 3 cells per FOV in at least
3 FOV or 4–6 cells in no
more than 3 FOV
4–6 cells per FOV in at least
4 FOV or > 6 cells in no more
than 3 FOV
> 6 cells in at least 4 FOV
400×
Eosinophils
None or 1–3
cells in < 3 FOV
≤ 3 cells per FOV in at least
3 FOV or 4–6 cells in no
more than 3 FOV
4–6 cells per FOV in at least
4 FOV or > 6 cells in no more
than 3 FOV
> 6 cells in at least 4 FOV
400×
Loss of striation
None or 1–5
cells in < 3 FOV
≤ 5 cells per FOV in at least
3 FOV or 5–10 cells in no
more than 3 FOV
5–10 cells per FOV in at least
4 FOV or > 6 cells in no more
than 3 FOV
> 10 cells in at least
4 FOV
400×
Edema
None
< 10% of FOV in at least
3 FOV or > 10% in < 3 FOV
10%–30% of FOV in at least
3 FOV or > 30% in < 3 FOV
> 30% of FOV in at least
3 FOV
250×
Microscopic bleeding
None
Present in < 10% of FOV in
at least 3 FOV or > 10% in
< 3 FOV
Present in 10%–30% of FOV
in at least 3 FOV or > 30% in
< 3 FOV
Present in > 30% of FOV
in at least 3 FOV
250×
Necrosis
FOV: Fields of view
Histological results
Histopathological changes, including microscopic
bleeding, edema, neutrophil infiltration, and coagulative
necrosis, were scored. The total injury score in Group III
was significantly decreased compared with Group II
(Figure 5). Representative H&E-stained microscopic images
of myocardial tissue from Groups II and III are presented in
Figures 6 and 7, respectively.
Discussion
The local and remote consequences of limb IR injury
continue to be a serious clinical problem for general
vascular surgeons, interventional radiologists, and
cardiologists. Reperfusion of the skeletal muscle causes
activation and adhesion of polymorphonuclear neutrophils,
with the release of proinflammatory substances and the
formation of free radicals, which include nitrogen-derived
reactive nitrogen species and oxygen-derived reactive
oxygen species, such as superoxide, peroxide, and hydroxyl
radicals22-24. In addition, the proinflammatory and injurious
factors activated in large amounts after skeletal muscle IR
injury circulate via both the venous and lymph systems
and induce distant organ injury 25. This distant organ
injury may be a component of systemic inflammatory
response syndrome, acute respiratory distress syndrome,
or multi‑organ dysfunction syndrome, which are initially
triggered by muscle-derived inflammatory mediators26.
As far as we know, there are only a few reports
demonstrating remote myocardial injury following skeletal
muscle IR injury.8 The results of Takhtfooladi et al.27 indicated
that hindlimb IR induces severe myocardial damage and that
N-acetylcysteine has protective effects on the myocardium
after hindlimb IR. Their data supported the concept
that temporary occlusion of the femoral artery induced
myocardial injury in rats27.
153
Arq Bras Cardiol. 2015; 105(2):151-159
Previous studies have shown that the use of tramadol
after IR in animals attenuated the oxidative injuries.
Nagakannan et al. 28 demonstrated the neuroprotective
effect of tramadol against transient forebrain ischemia in
rats. Tramadol provides a cardioprotective effect against
myocardial IR in isolated rat hearts 15. Wagner et al. 29
suggested that tramadol given to humans in high doses
actually caused myocardial injury, with increased troponin 1
and decreased inducible nitric oxide synthases expression,
possibly due to the systemic undesirable serotonergic effect
on diseased coronary arteries.
A recent study showed that ischemia for 2 h was sufficient
to obtain a considerable degree of injury in skeletal muscles
and the intravenous injection of 20 mg/kg tramadol prevented
this deleterious effect16. Similarly, tramadol at a similar dose
was found to be beneficial on lung injuries induced by skeletal
muscle IR when femoral artery clamping was applied 17.
Furthermore, tramadol (20 mg/kg) was determined to be
protective against cerebral injuries caused by hindlimb IR
in rats18. There is growing evidence regarding tramadol’s
beneficial effects in ameliorating IR; however, its role in
reducing the damage in heart tissue after skeletal muscle IR
has not been addressed yet.
In our study, the antioxidant potential of tramadol was
investigated using MDA, GPx, CAT, and SOD contents in
myocardial tissue following acute hindlimb IR. The MDA
level is a marker of tissue lipid peroxidation. The amount
of MDA accumulation in tissue is an index of the extent of
lipid peroxidation and oxidative stress15,30. The lower levels
of MDA observed in the group receiving tramadol compared
with the IR group supports the hypothesis that tramadol
may reduce oxidative stress by scavenging peroxyl radicals.
GPx activity is known to depend on reduced levels of
glutathione, glutathione transferase, and glutathione
reductase. Activities of these enzymes play an essential role
in the cellular defense against free radicals15,30. Data regarding
Takhtfooladi et al.
Effects of Tramadol on Myocardial Remote Injury
Original Article
7
SOD (U/mg protein)
6
5
4
3
2
1
0
Sham
IR*
IR + T
Figure 1 – Superoxide dismutase (SOD; U/mg protein) in heart tissue between the groups studied. IR: ischemia reperfusion; and IR + T: ischemia reperfusion + tramadol.
Data were expressed as mean ± SD. *: The significant digits in all group were p < 0.001.
500
CAT (U/mg protein)
400
300
200
100
0
Sham
IR*
IR + T
Figure 2 – Catalase (CAT; U/mg protein) in heart tissue between the groups studied. IR: ischemia reperfusion and IR + T: ischemia reperfusion + tramadol. Data were
expressed as mean ± SD. *: The significant digits in all group were p < 0.001.
Arq Bras Cardiol. 2015; 105(2):151-159
154
Takhtfooladi et al.
Effects of Tramadol on Myocardial Remote Injury
Original Article
0.05
GPX (U/mg protein)
0.04
0.03
0.02
0.01
0.00
Sham
IR*
IR + T
Figure 3 – Glutathione peroxidase (GPX; U/mg protein) in heart tissue between the groups studied. IR: ischemia reperfusion and IR + T: ischemia reperfusion + tramadol.
Data were expressed as mean ± SD. *: The significant digits in all group were p < 0.001.
6
MDA (nmol/protein)
5
4
3
2
1
0
Sham
IR*
IR + T
Figure 4 – Malendialdehyde (MDA; nmol/mg protein) in heart tissue between the groups studied. IR: ischemia reperfusion and IR + T: ischemia reperfusion + tramadol.
Data were expressed as mean ± SD. *: The significant digits in all group were p < 0.001.
155
Arq Bras Cardiol. 2015; 105(2):151-159
Takhtfooladi et al.
Effects of Tramadol on Myocardial Remote Injury
Original Article
5
Histological Grading
4
3
2
1
0
Sham
IR*
IR + T
Figure 5 – Histological grading between the groups studied. IR: ischemia reperfusion and IR + T: ischemia reperfusion + tramadol. Data were expressed as mean ± SD.
*: The significant digits in all group were p < 0.001.
Figure 6 – Photomicrograph of myocardium in the ischemia reperfusion group showing coagulative necrosis. Muscle cells with pyknotic nuclei were stained more deeply
with eosin in the area of coagulative necrosis (hematoxylin and eosin staining, bar = 100 μm).
SOD support a possible antioxidant effect of tramadol.
The decreased levels of MDA and elevated levels of SOD
activity in tissues may be evidence of decreased lipid
peroxidation and increased antioxidant capacity.
The analysis of the myocardium under light microscopy
revealed the presence of more edema, neutrophil infiltration,
and coagulative necrosis in Group II than in Group III; this
shows tramadol’s tendency to attenuate these injuries, a
Arq Bras Cardiol. 2015; 105(2):151-159
156
Takhtfooladi et al.
Effects of Tramadol on Myocardial Remote Injury
Original Article
Figure 7 – Representative photomicrograph of myocardium in the ischemia reperfusion + tramadol group showing nearly normal structure (hematoxylin and eosin
staining, bar = 100 μm).
trend that has statistical significance. This observation was
supported by Takhtfooladi et al.27, who demonstrated that
temporary occlusion of the femoral artery in rats resulted in
histological changes.
Conclusion
The results of this study confirmed that the administration
of tramadol significantly decreased myocardial injuries
induced by hindlimb IR. This protective effect of tramadol is
probably ascribed to anti-inflammatory activity. We underscore
the necessity of human studies with tramadol that may be
beneficial in preventing remote organ injury, particularly
during surgical interventions.
and interpretation of the data: Takhtfooladi HA, Allahverdi
A. Statistical analysis: Khansari M. Obtaining financing:
Takhtfooladi MA. Writing of the manuscript: Takhtfooladi MA.
Critical revision of the manuscript for intellectual content:
Khiabanian AH. Supervision / as the major investigador:
Shahzamani M. Histological Analysis: Khiabanian AH. Help
with technical procedures: Allahverdi A.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
There were no external funding sources for this study.
Author contributions
Study Association
Conception and design of the research: Takhtfooladi HA,
Shahzamani M. Acquisition of data: Takhtfooladi MA. Analysis
This study is not associated with any thesis or dissertation work.
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Back to the Cover
Original Article
Effects of One Resistance Exercise Session on Vascular Smooth
Muscle of Hypertensive Rats
Tharciano Luiz Teixeira Braga da Silva1, Marcelo Mendonça Mota1, Milene Tavares Fontes1, João Eliakim dos
Santos Araújo1, Vitor Oliveira Carvalho1, Leonardo Rigoldi Bonjardim2, Márcio Roberto Viana Santos1
Universidade Federal de Sergipe1, São Cristóvão, SE; Universidade de São Paulo2, São Paulo, SP – Brazil
Abstract
Background: Hypertension is a public health problem and increases the incidence of cardiovascular diseases.
Objective: To evaluate the effects of a resistance exercise session on the contractile and relaxing mechanisms of vascular
smooth muscle in mesenteric arteries of NG-nitro L-arginine methyl ester (L-NAME)-induced hypertensive rats.
Methods: Wistar rats were divided into three groups: control (C), hypertensive (H), and exercised hypertensive (EH).
Hypertension was induced by administration of 20 mg/kg of L-NAME for 7 days prior to experimental protocols. The resistance
exercise protocol consisted of 10 sets of 10 repetitions and intensity of 40% of one repetition maximum. The reactivity of
vascular smooth muscle was evaluated by concentration‑response curves to phenylephrine (PHEN), potassium chloride (KCl)
and sodium nitroprusside (SNP).
Results: Rats treated with L-NAME showed an increase (p < 0.001) in systolic blood pressure (SBP), diastolic blood pressure
(DBP) and mean arterial pressure (MAP) compared to the initial period of induction. No difference in PHEN sensitivity was
observed between groups H and EH. Acute resistance exercise reduced (p < 0.001) the contractile response induced by
KCl at concentrations of 40 and 60 mM in group EH. Greater (p < 0.01) smooth muscle sensitivity to NPS was observed
in group EH as compared to group H.
Conclusion: One resistance exercise session reduces the contractile response induced by KCl in addition to
increasing the sensitivity of smooth muscle to NO in mesenteric arteries of hypertensive rats. (Arq Bras Cardiol.
2015; 105(2):160-167)
Keywords: Hypertension; Exercise; Vasodilatation; Rats; Muscle, Smooth; Mesenteric, Artery.
Introduction
Hypertension is a public health problem worldwide, and
is associated with the increasing incidence of deaths due
to cardiovascular diseases1. Several hypertension models
have been developed within the basic sciences to mimic
the pathological effects of hypertension2,3. The experimental
hypertension model in rats using inhibition of nitric oxide
synthase (NOS) with NG-nitro-L-arginine-methyl-ester (L-NAME)
determines arterial hypertension, kidney injury, sympathetic
overactivity and endothelial dysfunction4-8.
It is worth noting that the induction of hypertensive rats
depends on the L-NAME dose administered, treatment
duration, target organ studied, age and type of the animal
used in the study. In association with that hypertension
Mailing Address: Marcio Roberto Viana Santos •
Universidade Federal de Sergipe. Departamento de Fisiologia,
Universidade Federal de Sergipe, Av. Marechal Rondon, S/N, Rosa Elze.
Postal Code 49100-000, São Cristóvão, SE – Brazil
E-mail: [email protected], [email protected]
Manuscript received November 16, 2014; revised manuscript March 12,
2015; accepted March 23, 2015.
DOI: 10.5935/abc.20150070
160
model, studies have shown that aerobic and resistance
exercises are beneficial regarding aspects related to blood
pressure and vascular function in rats9,10.
Nitric oxide synthase inhibition induces hypertension by
increasing blood pressure via an endothelium-dependent
response7. Our team has recently shown that submitting
L-NAME-induced rats to resistance exercise for four weeks
can reduce sensitivity to phenylephrine (PHEN) and increase
sensitivity to sodium nitroprusside (SNP) of the superior
mesenteric artery smooth muscle10.
The study of resistance exercise in animal models
mimicking hypertension provides relevant information for
clinical studies aimed at disease prevention, treatment and
control. Despite our team’s findings10, so far the effects
of resistance exercise on the contracting and relaxing
parameters related to vascular smooth muscle have not
been well established. A study has recently shown that
submitting spontaneously hypertensive rats (SHR) to one
session of resistance exercise does not change the vascular
function of the tail artery in relaxations induced by SNP, an
exogenous donor of nitric oxide (NO)11. Several variables,
such as disease animal model, type of artery studied, type
of resistance exercise, and volume, intensity and duration
of physical stimulus, can influence the benefits of resistance
exercise. The present study aimed at assessing the effects
Braga da Silva et al.
Acute Effects of Resistance Exercise on Smooth Muscle
Original Article
of one resistance exercise session on the contraction and
relaxation mechanisms of the mesenteric artery smooth
muscle of L-NAME-induced hypertensive rats.
Methods
Animals
Wistar rats (250-300 g) were used in all experiments.
The animals were maintained under controlled temperature
(22 ± 1°C) and 12-hour light-dark cycles, with water and
food ad libitum. All procedures described in the present
study were approved by the Ethics Committee in Research
with Animals of the Universidade Federal de Sergipe, Brazil
(Protocol 32/2013). The animals were divided into three
groups with ten animals each: sedentary control (C); sedentary
control with hypertension (H) and exercised hypertensive (EH).
The animals of groups C and H were maintained inside boxes
with no exposure to exercise, and only group EH animals
underwent one resistance exercise session.
Hypertension induction, and blood pressure and body
weight measurements
Before beginning the procedure of experimental
hypertension induction, blood pressure was measured by
using the non-invasive caudal method (LETICA, LE5002,
Barcelona, Spain). After that, only animals of groups H and
EH received orally L-NAME (20 mg/kg, daily), through gavage,
for seven days8. By the end of the induction period, blood
pressure was measured again in all groups. Animals with
mean arterial pressure (MAP) greater than 130 mm Hg were
categorized as hypertensive. Body weight was daily assessed
to adjust the L-NAME dosage.
Protocol of resistance exercise
Resistance exercise was performed in a squatting apparatus
according to the model by Tamaki et al.12. Initially, group EH
animals were acquainted with the exercise apparatus for three
days, and, then, the one repetition maximum (RM) test was
performed. One RM was determined as the maximum weight
lifted by each rat, using the exercise apparatus13. Two days after
the RM test, the animals underwent the resistance exercise
protocol adapted from Fontes et al.14. The rats underwent ten
sessions of ten repetitions, with 60-second rest intervals, and
intensity of 40% of the load established by using the RM test.
The parameters of electrical stimulation are similar to those
described by Barauna et al.15. The animals of groups C and
H underwent none of those procedures.
Assessing smooth muscle vascular reactivity
Immediately after the resistance exercise session, all rats
of all groups were sacrificed and superior mesenteric artery
rings, free from connective tissue, were sectioned (1-2 mm).
Endothelium‑independent relaxation was assessed by using
the superior mesenteric artery rings prepared according to the
description by Menezes et al.16. The presence or absence of
functional endothelium was assessed by the ability, measured
as percentage (%), of acetylcholine (ACh; 1 µM) to relax the
pre‑contracted rings with 1 µM of PHEN. Rings whose relaxations
were below 10% were considered not to have a functional
endothelium and automatically selected for this study17.
The changes in vascular reactivity due to the contracting
and relaxing agents were assessed through concentrationresponse curves of the superior mesenteric artery rings of the
rats of all groups. After the stabilization period of the isolated
rings, curves for the contracting agents were performed: PHEN
(10-9-10-4 M) (α-1 adrenergic agonist) and KCl (20-80 mM)
(unspecific contracting agent). In addition, experiments for the
relaxing agent were conducted: SNP (10-11-10-6 M), NO donor,
in pre-contracted rings with PHEN (1 µM). All experimental
protocols were conducted separately.
Data from the concentration-response curves were assessed
by using the adjustment of a logistic function: E = Rmax/
((1+(10c/10x)n) + Φ), where E is the response; Rmax is the
maximal response the agonist can produce; c is the logarithm
of EC50, which is the concentration at which the agonist
produces a response equal to 50% of the maximal response;
x is the logarithm of the concentration of the agonist; the
exponential term, n, is a parameter of adjustment of the curve
that defines the inclination of the concentration-response line;
and Φ is the response observed in the absence of the agonist.
Non-linear regression analyses were performed to determine
the parameters Rmax, EC 50 and n, with the restriction
Φ = zero. The sensitivity of the superior mesenteric artery rings
was assessed by determining the pD2 value of each agonist.
That corresponds to the negative logarithm of the molar
concentration of the agonist that determines a response equal
to 50% of the maximal response (EC50), in each experiment.
Drugs and reagents
NG-nitro-L-arginine-methyl-ester (L-NAME), acetylcholine
chloride (ACh), L-phenylephrine chloride (PHEN), sodium
nitroprusside (SNP), salts and reagents used in the present
study were obtained from Sigma (Sigma Chemical Co, St.
Louis, MO, USA).
Statistical analyses
The Kolmogorov-Smirnov test was used to determine
whether the probability distributions of the data were parametric
or non-parametric. All data had a normal distribution.
The values were expressed as mean ± standard error of
the mean (SEM). Student t tests paired and analysis of
variance (one-way and two-way ANOVA) followed by
Bonferroni post‑test were used when necessary to assess
the significance of the differences between the means.
The values were considered statistically significant when p < 0.05.
The GraphPad Prism program, version 3.02 (GraphPad
Software, San Diego-CA, USA), was used in all procedures.
Results
Body weight and blood pressure in response to
hypertension induction
We observed that in the beginning and end of the
hypertension induction period, the body weight of the rats
Arq Bras Cardiol. 2015; 105(2):160-167
161
Braga da Silva et al.
Acute Effects of Resistance Exercise on Smooth Muscle
Original Article
was similar in all groups. After seven days of induction, the
rats treated with L-NAME showed an increase (p < 0.001) in
the levels of MAP, systolic blood pressure (SBP) and diastolic
blood pressure (DBP). When the end of the induction period
between the groups was statistically assessed, L-NAME showed
to induce an increase in MAP, SBP and DBP (p < 0.001) in the
groups H and EH as compared to group C (Table 1).
Vascular smooth muscle constriction in response to PHEN
We observed that PHEN (10 -9 -10 -4 M) induced
concentration-dependent contraction of the isolated rings
of the superior mesenteric artery in all groups. However, the
maximal contraction response did not differ between the
groups (Figure 1A).
L-NAME could interfere with the arterial sensitivity of
PHEN‑induced contractions in hypertensive-induced rats,
because pD2 changed (p < 0.05) in group H as compared to
group C (Figure 1B). In addition, one resistance exercise session
did not interfere with arterial sensitivity, and pD2 remained
unaltered when comparing groups EH and H (Figure 1B).
Vascular smooth muscle constriction in response to KCl
We observed that the increase in extracellular KCl
(20‑80 mM) produced contractile tension in the isolated rings
of the superior mesenteric artery of the rats of all groups.
However, the maximal responses induced by KCl did not
differ between the groups (Figure 2). The animals induced
to hypertension with L-NAME had a higher percentage
contraction of vascular smooth muscle at the concentrations
of 40 and 60 mM of KCl (p < 0.01; p < 0.001, respectively)
(Figure 2). On the other hand, group EH animals had a lower
percentage contraction of vascular smooth muscle at the
concentrations of 40 and 60 mM (p < 0.001) (Figure 2).
Vascular smooth muscle dilation in response to SNP
We observed that SNP (10-11-10-6 M) induced endotheliumindependent relaxation in the isolated rings of the superior
mesenteric artery of the rats of all groups (Figure 3A).
The maximal vascular relaxation in response to SNP was similar
in the three groups studied (Figure 3A). L-NAME reduced
(p < 0.05) the arterial sensitivity to SNP in group H animals as
compared to those in group C (Figure 3B).
Inversely, we observed that resistance exercise could restore
arterial sensitivity to SNP by increasing (p < 0.01) pD2 of group
EH as compared to that of group H (Figure 3B).
Discussion
The results of this study show that one resistance exercise
session in L-NAME-induced hypertensive rats caused a
reduction in the KCl-induced contracting mechanisms by
increasing the vasodilating sensitivity of the mesenteric artery
smooth muscle.
There is evidence that the reduced levels of NO play
an important role in the development of hypertension4,18.
The experimental model of hypertension that mimics that
effect is the one induced by the inhibition of NOS with a
unspecific inhibitor, L-NAME4,19. Treatment with L-NAME
is associated with structural and functional changes in the
kidneys, changes in autonomic modulation and in peripheral
vascular resistance, and an increase in blood pressure4,6,8,20.
The present study showed a blood pressure increase of the
animals treated with L-NAME for seven days. The hypertensive
levels obtained are similar to those previously reported for rats
treated with L-NAME for seven days 6,8,20.
The literature describes that the transmission of the
signal originated in the plasma membrane for the receptors
of the smooth muscle contractile machinery is due to
pharmacomechanical and/or electromechanical stimuli 21.
Those mechanisms should not be understood as completely
separated systems, but understood as part of a network of
signals that interact to maintain vascular physiology. In our
study, the rats treated with L-NAME showed higher α-1
adrenergic sensitivity. The modulation of α-1 adrenergic
receptors and the reduction in NO production play an
important role in the cardiovascular changes of hypertensive
rats22. It has already been shown that a reduction in NO shifts
the contraction curve of PHEN to the left in the aorta of rats,
but not in the tail artery, confirming that the modulation of
receptors in response to NO seems to depend on the type of
the artery studied23. Heijenbrok et al.24 have treated Wistar
rats with L-NAME (15 mg/kg/day) for six weeks and have not
observed any change related to PHEN in the vascular reactivity
of the carotid and mesenteric arteries. The inconsistence
about the modulation of α-1 adrenergic receptors in animals
Table 1 – Body weight, mean arterial pressure (MAP), systolic blood pressure (SBP) and diastolic blood pressure (DBP) of rats at the
beginning and end of systemic hypertension induction
Groups
C (n = 10)
H (n = 10)
EH (n = 10)
Period
Weight (g)
MAP (mm Hg)
SBP (mm Hg)
DBP (mm Hg)
INITIAL
253 ± 12.0
101.6 ± 1.8
125.0 ± 1.6
90.0 ± 2.0
FINAL
258 ± 13.7
106.3 ± 2.1
129.0 ± 1.4
95.0 ± 2.2
INITIAL
257 ± 11.6
104.3 ± 1.4
121.0 ± 1.5
96.0 ± 2.1
FINAL
263 ± 13.6
134.3 ± 2.0***.C
147.0 ± 1.8***.C
128.0 ± 1.9***.C
INITIAL
252 ± 12.6
104.6 ± 1.7
128.0 ± 1.3
93.0 ± 2.3
FINAL
257 ± 14.6
131.9 ± 1.9***.C
145.0 ± 1.3***.C
124.0 ± 1.6***.C
C: Control group; H: Hypertensive group; EH: Exercised hypertensive group. Data are shown as means ± SEM. The statistical differences were determined by
Student t tests one-way ANOVA followed by Bonferroni post-test. ***p < 0.001 initial vs final period; Cp < 0.001 vs final period of the control group.
162
Arq Bras Cardiol. 2015; 105(2):160-167
Braga da Silva et al.
Acute Effects of Resistance Exercise on Smooth Muscle
Original Article
125
A
C
H
EH
75
8
50
B
7
25
pD2
% of contraction
100
6
0
5
-25
4
9
8
7
6
- Log [PHEN] M
5
4
*
C
H
HE
Figure 1 – Concentration-response curves for phenylephrine (PHEN: 10-9-10-4 M) in isolated superior mesenteric artery rings without functional endothelium (Figure 1A)
obtained from rats of the groups Control (C), Hypertensive (H) and Exercised Hypertensive (EH). Figure 1B indicates means ± standard error of the mean (SEM) of pD2
of the phenylephrine induced contractions (B). Data are expressed as means ± SEM for ten experiments in each group. The statistical differences between means were
determined by using two-way ANOVA followed by the Bonferroni post-test (Figure 1A) and one-way ANOVA followed by the Bonferroni post-test (Figure 1B). *p < 0.01 vs
C. pD2: negative logarithm of the molar concentration of the agonist that produces 50% of maximal response.
treated with L-NAME can be associated with the administration
route, the drug dose, the treatment length and the type of
artery studied.
α-1 adrenergic receptor level, but successive resistance
exercise sessions can cause a significant reduction in the
contractile sensitivity promoted by PHEN.
In our study, immediately after one low-intensity
resistance exercise session, there was no change in the
sensitivity of α-1 adrenergic receptors of rats treated with
L-NAME. In healthy rats, repeated strenuous swimming
sessions, rather than only one session, reduced α-1
adrenergic sensitivity in the mesenteric artery with injured
endothelium25. Our results differ from those by Faria et
al.11, who, after one resistance exercise session (20 x 15,
50% intensity), have shown greater attenuation of the
post-exercise responses to PHEN in the tail artery with
intact endothelium11. The differences in our results can
be attributed to the training protocol, the experimental
hypertension model, the type of artery studied and the
functional endothelium preservation to assess vascular
reactivity. On the other hand, a previous study of our group
has demonstrated that chronic low-intensity resistance
exercise (3 x 10, 50% intensity) controlled blood pressure
and reduced the α-1 adrenergic sensitivity of the mesenteric
artery without functional endothelium of L-NAME-induced
hypertensive rats 10. This shows that one low-intensity
resistance exercise session in L-NAME-induced hypertensive
rats does not seem to be sufficient to make a change at the
In addition, the present study assessed another
mechanism that modulates smooth muscle contraction,
the contractile coupling through depolarizing KCl solutions.
In general, KCl produces smooth muscle vascular
contraction via membrane depolarization, causing Ca 2+
inflow via voltage-dependent Ca2+ channels26. It has been
reported that depolarizing KCl concentrations mediate the
increase in intracellular Ca2+ concentration27. Our results
indicate that animals treated with L-NAME increased smooth
muscle contraction through membrane depolarization in
mesenteric artery rings. Other studies with chronically
L-NAME-induced animals have shown abnormal functioning
of the voltage-dependent Ca2+ channels5,28. Bank et al.28
have suggested that the L-NAME-induced hypertension
model increases the vascular smooth muscle tonus, and
such effect is due to the reduction in NOS availability, which
can lead to an increase in Ca2+ concentration or intracellular
sensitivity. These findings are in accordance with our results
that the increase in smooth muscle contractility found in
L-NAME-induced animals can be related to the KCl-induced
contractile mechanisms.
Arq Bras Cardiol. 2015; 105(2):160-167
163
Braga da Silva et al.
Acute Effects of Resistance Exercise on Smooth Muscle
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100
C
H
EH
% of contraction
75
***
**
50
25
###
0
###
-25
20
40
60
80
KCI (mM)
Figure 2 – Concentration-response curves for potassium chloride (KCl: 20-80 mM) in isolated superior mesenteric artery rings without functional endothelium obtained
from rats of the groups Control (C), Hypertensive (H) and Exercised Hypertensive (EH). Data are expressed as means ± standard error of the mean (SEM) for ten
experiments in each group. The statistical differences between means were determined by using two-way ANOVA followed by the Bonferroni post-test. **p < 0.01 and
***
p < 0.001 vs C; ###p < 0.001 vs H.
It is worth noting that, when the rats in our study underwent
one resistance exercise session, they had a reduction
in contraction in response to depolarizing KCl solutions
(20‑80 mM). That points to the possibility that resistance exercise
alters in a beneficial way the depolarization of the vascular
smooth muscle cells of L-NAME-induced hypertensive animals.
Similarly, Chen et al.29 have shown a reduction in the contractile
response to KCl (15-60 mM) in mesenteric artery rings of healthy
rats after eight weeks of running training. In addition, the aortic
rings of rats trained in running (10 to 12 weeks) have shown a
lower contractile response to depolarizing KCl concentrations
(10‑100 mM) by the end of the protocol30. So far, the effects of
resistance exercise on the contractile response of the smooth
muscle to depolarizing KCl solutions have not been described.
The present study is the first to show the efficacy of one resistance
exercise session on the decrease of smooth muscle contractility
via independent mechanisms of adrenergic receptors in
hypertensive rats. These results suggest that low-intensity
resistance exercise, when performed for a long period, can be
an important tool to fight cardiovascular disorders originating
from smooth muscle contractile mechanisms.
In addition, we observed that the rats treated with L-NAME
had lower vasodilating sensitivity to SNP. When submitted to one
resistance exercise session, they showed increased vasodilating
sensitivity to NO in the smooth muscle of mesenteric artery rings.
A recent study by our group has shown that the NO pathway
sensitivity was decreased in L-NAME-induced hypertensive
rats for eight weeks, and that chronic low-intensity resistance
164
Arq Bras Cardiol. 2015; 105(2):160-167
exercise could reverse that effect10. Acute and chronic effects of
resistance exercise on the endothelium-independent vasodilating
response are beneficial to vascular function in L‑NAMEinduced hypertensive rats. It is worth noting that, the study by
another group conducting one resistance exercise session in
spontaneously hypertensive animals has shown no changes in the
SNP-induced relaxations in the vascular bed of the tail artery25.
Those differences can result from the hypertension induction
model and the training protocol adopted.
The present study has some limitations. The first is
that the results obtained are specific to hypertensive rats.
The second is not having assessed the effect of resistance
exercise on other arteries because there already is functional
heterogeneity among the arteries of different vascular beds.
The third is the lack of a healthy group undergoing exercise,
which limits data extrapolation. Another point to be noted is
that the resistance exercise protocol adopted in the present
study has the characteristic of high volume and low intensity.
That exercise characteristic is similar to aerobic exercise
protocols indicated to control blood pressure1,13. Some studies
have shown that moderate-intensity resistance exercise can
reduce blood pressure and improve vascular function1,11,31,32.
Despite those advantages, a recent meta‑analysis has
indicated that high-intensity resistance exercise is associated
with increased arterial stiffness in health young individuals33.
In addition, the physiological mechanisms responsible for the
advantages and/or disadvantages of resistance exercise on the
vascular health of animals and humans are yet to be established.
Braga da Silva et al.
Acute Effects of Resistance Exercise on Smooth Muscle
Original Article
A
0
B
9
50
##
8
***
75
pD2
% of relaxation
25
100
C
H
11
7
6
5
EH
125
*
10
9
8
7
- Log [SNP] M
6
4
H
C
HE
Figure 3 – Concentration-response curves for sodium nitroprusside (SNP: 10-11-10-6 M) in isolated superior mesenteric artery rings without functional endothelium and
pre-contracted with phenylephrine (1 µM) (Figure 3A). The rings were obtained from rats of the groups Control (C), Hypertensive (H) and Exercised Hypertensive (EH).
Figure 3B indicates means ± standard error of the mean (SEM) of pD2 of the SNP-induced relaxations. Data are expressed as means ± SEM for ten experiments in
each group. The statistical differences between means were determined by using two-way ANOVA followed by the Bonferroni post-test (Figure 3A) and one-way ANOVA
followed by the Bonferroni post-test (Figure 1B). *p < 0.05 vs C; ***p < 0.001 vs H; ##p < 0.01 vs H. pD2: negative logarithm of the molar concentration of the agonist that
produces 50% of maximal response.
Conclusion
The pharmacological evidence of this study showed
that one resistance exercise session caused benefits to the
vascular function of L-NAME-induced hypertensive animals.
Those benefits involve a reduction in the contractile responses
via KCl-induced cell depolarization, independent of α-1
adrenergic receptors, and higher vasodilating sensitivity to NO
of the mesenteric artery smooth muscle in L-NAME-induced
hypertensive rats. The vascular smooth muscle adjustments
resulting from one resistance exercise session seem beneficial
to control vascular tonus in hypertension.
Acknowledgements
We thank the Brazilian Board of Research and Technological
Development (CNPq), the Coordination for the Improvement of
Higher-Level-Education Personnel (Capes) and the Foundation
of Support to Research and Technological Innovation of the
State of Sergipe (Fapitec-SE) for financial support.
Author contributions
Conception and design of the research: Silva TLTB, Mota
MM, Fontes MT, Bonjardim LR, Santos MRV. Acquisition
of data: Silva TLTB, Araújo JES. Analysis and interpretation
of the data: Silva TLTB, Mota MM, Fontes MT, Carvalho
VO. Statistical analysis: Silva TLTB, Mota MM. Obtaining
financing: Santos MRV. Writing of the manuscript: Silva
TLTB, Mota MM, Fontes MT, Carvalho VO. Critical revision
of the manuscript for intellectual content: Silva TLTB, Mota
MM, Fontes MT, Bonjardim LR, Santos MRV. Supervision /
as the major investigador: Silva TLTB.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
This study was funded by Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq),
Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior (Capes) e Fundação de Apoio à Pesquisa e à Inovação
Tecnológica do Estado de Sergipe (Fapitec-SE).
Study Association
This article is part of the thesis of Doctoral submitted
by Tharciano Luiz Teixeira Braga da Silva from Programa
de Pós‑Graduação em Ciências da Saúde da Universidade
Federal de Sergipe (UFS).
Arq Bras Cardiol. 2015; 105(2):160-167
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Acute Effects of Resistance Exercise on Smooth Muscle
Original Article
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Braga da Silva et al.
Acute Effects of Resistance Exercise on Smooth Muscle
Original Article
Arq Bras Cardiol. 2015; 105(2):160-167
167
Back to the Cover
Original Article
Role Of MMP-2 and MMP-9 in Resistance to Drug Therapy in Patients
with Resistant Hypertension
Leandro Lacerda1, Ana Paula de Faria2, Vanessa Fontana2, Heitor Moreno2, Valéria Sandrim1
Núcleo de Pós-Graduação e Pesquisa - Santa Casa de Belo Horizonte1, Belo Horizonte, MG; Faculdade de Ciências Médicas da UNICAMP2,
Campinas, SP – Brazil
Abstract
Background: Despite the increased evidence of the important role of matrix metalloproteinases (MMP-9 and
MMP‑2) in the pathophysiology of hypertension, the profile of these molecules in resistant hypertension (RHTN)
remains unknown.
Objectives: To compare the plasma levels of MMP-9 and MMP-2 and of their tissue inhibitors (TIMP-1 and TIMP-2,
respectively), as well as their MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios, between patients with controlled RHTN
(CRHTN, n = 41) and uncontrolled RHTN (UCRHTN, n = 35). In addition, the association of those parameters with
clinical characteristics, office blood pressure (BP) and arterial stiffness (determined by pulse wave velocity) was
evaluate in those subgroups.
Methods: This study included 76 individuals diagnosed with RHTN and submitted to physical examination, electrocardiogram,
and laboratory tests to assess biochemical parameters.
Results: Similar values of MMP-9, MMP-2, TIMP-1, TIMP-2, and MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios were found
in the UCRHTN and CRHTN subgroups (p > 0.05). A significant correlation was found between diastolic BP (DBP) and
MMP-9/TIMP-1 ratio (r = 0.37; p = 0.02) and DPB and MMP-2 (r = -0.40; p = 0.02) in the UCRHTN subgroup. On the
other hand, no correlation was observed in the CRHTN subgroup. Logistic regression models demonstrated that MMP-9,
MMP-2, TIMP-1, TIMP-2 and their ratios were not associated with the lack of BP control.
Conclusion: These findings suggest that neither MMP-2 nor MMP-9 affect BP control in RHTN subjects. (Arq Bras
Cardiol. 2015; 105(2):168-175)
Keywords: Matrix Metalllooproteinases; Hypertension/physiopathology; Endopeptidases; Hyperaldosteronism/physiopathology.
Introduction
Resistant hypertension (RHTN) is a clinical condition
characterized by maintenance of blood pressure (BP) levels
above goal (140/90 mm Hg), despite the concurrent use of
three or more antihypertensive agents of different classes.
Ideally, one of these drugs should be a diuretic, and all agents
should be prescribed at optimal doses [subgroup called
uncontrolled RHTN (UCRHTN)]. The subgroup of resistant
hypertensive patients whose BP is controlled using four or
more drugs is known as controlled RHTN (CRHTN)1.
Matrix metalloproteinases (MMPs), a group of zinc- and
calcium-dependent endopeptidases, and their endogenous
tissue inhibitors (TIMPs) are primarily responsible for stromal
matrix remodeling2. Currently, some evidence has also suggested
that those molecules play a role in hypertensive processes3.
Mailing Address: Leandro Heleno Guimaraes Lacerda •
Universidade Federal de Minas Gerais – UFMG. Rua Santa Rita do Sapucaí, 70,
Vale das Palmeiras. Postal Code 35701168, Sete Lagoas, MG – Brazil
E-mail: [email protected]
Manuscript received September 17, 2014; revised manuscript January 21,
2015; accepted January 22, 2015.
DOI: 10.5935/abc.20150060
168
Experimental hypertension studies have reported that
the intima and media thickness of conduct vessels was
associated with increased expression of MMP-9 and MMP‑2,
and this event could be prevented with non-selective
MMP inhibitor (doxycycline) treatment4,5. Previous studies
have found that MMP-2 is upregulated in response to
high intra-luminal pressure6, and its increased levels have
been reported in the mammary arteries of hypertensive
subjects7. Evidence has suggested that MMP-2 can degrade
big endothelin-1, thus promoting vasoconstrictor effect8.
Matrix metalloproteinases have been shown to suppress
the vasodilation induced by β-agonists in hypertensive rats9.
In hypertensive patients, increased MMP-9 activity may lead
to degradation of elastin, while reduced TIMP-1 activity can
lead to accumulation of fibrin degradation products, resulting
in misdirected deposition of collagen10.
These experimental studies have stimulated further
investigation of MMPs and TIMPs as potential biomarkers
in hypertension. The circulating concentration of
these molecules may be associated with hypertension
complications and prognosis, being therefore useful in
clinical practice11. In addition, MMP-2, MMP-9, TIMP-1
and TIMP-2 may be directly associated with RHTN, playing
a role in BP control in those patients12.
Lacerda et al.
Gelatinases in resistant hypertension
Original Article
Although plasma MMP-9, MMP-2, TIMP-1 and TIMP‑2
levels have been measured in hypertensive subjects13, these
concentrations in RHTN patients are unknown. The present
study is the first to compare the plasma levels of those
molecules, as well as their ratios (MMP-9/TIMP-1 and
MMP‑2/TIMP-2) between CRHTN and UCRHTN patients.
Methods
Patient population
This cross-sectional study included all 76 individuals
diagnosed with RHTN on regular follow-up at the Resistant
Hypertension Outpatient Clinic, University of Campinas,
Campinas, Brazil. Patients were classified into two subgroups,
UCRHTN (n = 35) and CRHTN (n = 41), in accordance with
the guidelines established by the American Heart Association14.
All patients underwent physical examination,
electrocardiogram, and laboratory tests to assess biochemical
parameters. Patients with secondary forms of hypertension
as well as renal failure, ischemic heart, liver and peripheral
vascular diseases, stroke, smoking or any other serious
disease were properly identified and excluded from
the study. Ambulatory BP monitoring was performed
(Spacelabs 90207, Spacelabs Inc, Redmond, WA, USA) to
exclude pseudo‑resistant hypertension and to characterize
CRHTN and UCRHTN patients. Treatment adherence was
determined by pill counting (threshold of 80% or greater of
the prescribed medication).
This study was approved by the Research Ethics Committee
at the Medical Sciences School, University of Campinas,
Campinas, Brazil, and was performed in accordance with the
Declaration of Helsinki. All participants were aware of the
nature of the research study and signed an informed consent
before enrolling in the study.
The following patients’ parameters were evaluated: office
BP; pulse wave velocity (PWV); plasma concentrations of
MMP-9, MMP-2, TIMP-1 and TIMP-2; plasma aldosterone
concentration (PAC); and plasma renin activity (PRA).
Office BP measurements
Systolic and diastolic BP (SBP and DBP, respectively) levels
were assessed three times, using a digital sphygmomanometer
(Omron HEM-711DLX, OMRON Healthcare Inc.,
Bannockburn, IL, USA) on the right upper arm, in the sitting
position, after a 10-minute rest. The mean of two consecutive
measurements was used, with a variation lower than 5 mmHg.
Pulse wave velocity assessment
Pulse wave velocity was measured by using the
Sphygmocor System (Atcor Medical, Sydney, Australia)
with the patient in the supine position15. The PWVs of
the right carotid and femoral arteries were analyzed,
estimating the delay with respect to the electrocardiogram
wave. Distance measurements were taken between
the femoral recording site and the supra-sternal notch
minus the distance from the supra-sternal notch to
the carotid recording site. Carotid-femoral PWV was
calculated by dividing the traveled distance by transit time
[PWV = distance(m)/time(s)]. At least two measurements
were performed; if they differed by more than 0.5 m/s,
a third measurement was taken.
Laboratory assessments
Blood samples for biochemical assessment were collected at
8 AM, after an overnight fasting. PAC and PRA were measured
by using radioimmunoassay, with standard techniques.
Plasma levels of biomarkers MMP-9 and TIMP-1 were measured
by using enzyme-linked immunosorbent assay (ELISA) (R&D
System®, Minneapolis, USA). Similarly, the plasma biomarkers
MMP-2 and TIMP-2 were measured by using ELISA, following
the manufacturer´s instructions (RayBiotech®, Georgia, USA).
Statistical analyses
The Statistical Analysis System, version 3.02 (GraphPad
Prism Inc., 2000), and SigmaPlot version 12.0 (Systat software,
Inc.) were used for all statistical analyses of the study.
All values were expressed as mean ± standard deviation.
The normality of distribution was assessed by using
Kolmogorov–Smirnov test. The subgroups were compared by
using Student´s t test or Mann-Whitney test, according to data
distribution. Chi-square test was used for categorical variables.
The correlation of biomarkers with clinical parameters
was evaluated by using Pearson’s or Spearman´s test.
Regression models were performed to test the association
of variables apart from potential confounders. The level of
significance accepted was 0.05.
Results
Table 1 shows the clinical and laboratory data of
both subgroups, and Table 2 shows the plasma levels of
biomarkers. As expected, increased values of SBP, DBP
and PWV were found in UCRHTN as compared to CRHTN
patients. No significant differences were observed regarding
age, sex, body mass index (BMI) and biochemical parameters.
Similar values of MMP-9, TIMP-1, MMP-2, TIMP-2, and of
MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios were found in
the UCRHTN and CRHTN subgroups (p > 0.05; Table 2).
Regarding antihypertensive medication, UCRHTN patients
were taking a significantly higher number of anti-hypertensive
drugs, demonstrated by the use of calcium channel blockers,
as compared to controlled subjects (Table 1).
Correlation analyses for the UCRHTN subgroup indicated
that DBP correlated with MMP-9/TIMP-1 ratio (r = 0.37;
p = 0.02); however, DBP was inversely correlated with
MMP‑2 levels (r = -0.40; p = 0.02). In that subgroup, PAC
and age also correlated with MMP-9/TIMP-1 ratio (r = 0.57,
p < 0.001 and r = -0.37, p = 0.02, respectively), and, only
in that subgroup, MMP-2 correlated with age (r = 0.42,
p = 0.01). In addition, these associations remained significant
after adjusting for sex and BMI included in the linear regression
model [beta coefficient = 11.5, standard error (SE) = 5.5,
p = 0.04; beta coefficient = -0.08, SE = 0.04, p = 0.04,
respectively]. Finally, the plasma levels of the biomarkers
Arq Bras Cardiol. 2015; 105(2):168-175
169
Lacerda et al.
Gelatinases in resistant hypertension
Original Article
mentioned above did not correlate with any clinical parameter
in CRHTN subjects (Table 3 and 4). Considering the entire
RHTN group (n = 76), we found that (i) the MMP-9/TIMP-1
ratio was inversely associated with BMI (r = -0.25, p = 0.03),
but positively with aldosterone levels (r = 0.24, p = 0.04);
and (ii) MMP-2 was inversely associated with DBP (r = -0.26,
p = 0.02), but positively with age (r = 0.40, p < 0.001).
Finally, logistic regression models demonstrated that MMP-9
and MMP-2, their tissue inhibitors-1 and -2 and ratios were
not associated with the lack of BP control (data not shown)
in RHTN when adjusting for sex, age and BMI.
the RHTN population. Interestingly, correlations of DBP
and age with the MMP-9/TIMP-1 ratio and DBP and
MMP-2 were observed only in the UCRHTN subgroup.
Plasma aldosterone levels and age also correlated with
the MMP‑9/TIMP-1 ratio in UCRHTN. In this context,
as previously demonstrated 1,16,17 , the idea of several
important differences in the pathophysiology of the RHTN
subgroups should be reinforced. However, no association
of the biomarkers with SBP was found, probably because
DBP is a more stable variable than the systolic component.
Under physiological conditions, balance between MMPs
and TIMPs exists. On the other hand, in pathological processes,
such as hypertension, an MMPs/TIMPs ratio imbalance
contributes to the excessive degradation of extracellular
matrix (ECM) proteins18, and results in pathological vascular
Discussion
This is the first study to analyze the association of
the biomarkers MMP-2 and MMP-9 with BP levels in
Table 1 – General characteristics of the resistant hypertension (RHTN) subgroups
Female gender (%)
UCRHTN (n = 35)
CRHTN (n = 41)
63
66
Age (years)*
57 ± 11
61 ± 9
BMI (Kg/m2)
30.0 ± 4.4
30.1 ± 4.4
SBP (mm Hg)*
158 ± 20
136 ± 14
DBP (mm Hg)*
91 ± 14
80 ± 7
PWV (m/s) *
11.9 ± 1.8
10.6 ± 1.3
Total cholesterol (mg/dL)
203 ± 50
202 ± 39
LDL (mg/dL)
126 ± 38
125 ± 35
HDL (mg/dL)
44 ± 12
48 ± 14
Triglycerides (mg/dL)
Urea (mg/dL)
Creatinine (mg/dL)
Fasting glucose (mg/dL)
Uric acid (mg/dL)
160 ± 96
149 ± 66
38.1 ± 11.8
35.9 ± 7.5
1.0 ± 0.2
0.9 ± 0.2
125.4 ± 54.1
106.7 ± 34.2
5.9 ± 1.6
5.8 ± 1.5
Aldosterone (pg/mL) *
109.7 ± 82.0
101.1 ± 70.5
Renin (pg/mL)
22.4 ± 19.6
21.2 ± 18.2
4.6 ± 0.9
4.2 ± 0.9
Antihypertensive drugs
Total number (daily) *
Spironolactone (%)
43
37
Diuretics (%)
100
100
Beta-blockers (%)
69
68
ACEI (%)
46
29
ARB (%)
54
51
CCB (%)*
97
68
Centrally acting anti-hypertensive (%)
37
17
UCRHTN: Uncontrolled resistant hypertension; CRHTN: Controlled resistant hypertension; BMI: Body mass index; SBP: Systolic blood pressure; DBP: Diastolic blood
pressure; PWV: Pulse wave velocity; LDL: Low density lipoprotein; HDL: High density lipoprotein; ACEI: Angiotensin-converting-enzyme inhibitors; ARB: Angiotensin II receptor
blockers; CCB: Calcium channel blockers. Values are expressed as mean ± SD or percentage. * p < 0.05 between groups.
170
Arq Bras Cardiol. 2015; 105(2):168-175
Lacerda et al.
Gelatinases in resistant hypertension
Original Article
Table 2 – Characteristics of biomarkers in resistant hypertension (RHTN) subgroups
UCRHTN (n = 35)
CRHTN (n = 41)
MMP-9 (ng/mL)
253 ± 134
225 ± 121
TIMP-1 (ng/mL)
499 ± 406
407 ± 249
MMP-9/TIMP-1 Ratio
0.68 ± 0.45
0.77 ± 0.59
330 ± 71
312 ± 69
Biomarkers
MMP-2 (ng/mL)
TIMP-2 (ng/mL)
306 ± 132
339 ± 184
MMP-2/TIMP-2 Ratio
1.31 ± 0.79
1.24 ± 0.78
UCRHTN: Uncontrolled resistant hypertension; CRHTN: Controlled resistant hypertension; MMP-9: Matrix metalloproteinase-9; TIMP-1: Tissue inhibitor MMP-1; MMP‑2: Matrix
metalloproteinase-2; TIMP-2: Tissue inhibitor MMP-2. Values are expressed as mean ± SD or percentage. * p < 0.05 between groups.
Table 3 – Correlation among clinical parameters and MMP-9, TIMP-1 and MMP-9/TIMP-1
Groups
CRHTN
Biomarkers
SBP
DBP
PWV
MMP-9
0.23 (0.14)
0.06 (0.67)
0.06 (0.66)
TIMP-1
0.03 (0.85)
0.12 (0.44)
-0.06 (0.67)
r (p-value)
MMP-9/TIMP-1 Ratio
0.07 (0.64)
-0.12 (0.42)
-0.02 (0.86)
MMP-9
0.04 (0.82)
0.14 (0.41)
-0.03 (0.82)
UCRHTN
TIMP-1
-0.23 (0.17)
-0.33 (0.05)
-0.07 (0.68)
r (p-value)
MMP-9/TIMP-1 Ratio
0.15 (0.38)
0.37 (0.02*)
0.02 (0.91)
Data are expressed as correlation coefficient (p-value). CRHTN: Controlled resistant hypertension; UCRHTN: Uncontrolled resistant hypertension; SBP: Systolic
blood pressure; DBP: Diastolic blood pressure, PWV: Pulse wave velocity. *p < 0.05.
Table 4 – Correlation among clinical parameters and MMP-2, TIMP-2 and MMP-2/TIMP-2
Groups
CRHTN
Biomarkers
SBP
DBP
PWV
MMP-2
-0.01 (0.93)
0.02 (0.88)
-0.09 (0.54)
TIMP-2
-0.14 0.25)
-0.03 (0.83)
0.04 (0.77)
r (p-value)
MMP-2/TIMP-2 Ratio
0.23 (0.13)
0.04 (0.75)
-0.24 (0.12)
MMP-2
-0.21 (0.20)
-0.40 (0.02*)
0.18 (0.29)
UCRHTN
TIMP-2
0.21 (0.21)
-0.01 (0.97)
0.03 (0.85)
r (p-value)
MMP-2/TIMP-2 Ratio
-0.26 (0.11)
-0.28 (0.09)
0.06 (0.72)
Data are expressed as correlation coefficient (p-value). CRHTN: Controlled resistant hypertension; UCRHTN: Uncontrolled resistant hypertension; SBP: Systolic
blood pressure; DBP: Diastolic blood pressure, PWV: Pulse wave velocity. *p < 0.05.
remodeling19. Therefore, the MMP-9/TIMP-1 ratio might
be a better indicator of that process. Taken together,
MMP-9/TIMP-1 ratio in association with DBP levels in
UCRHTN could strengthen the importance of some different
phenotypes in the pathophysiology of uncontrolled patients.
Inconsistent results have been found about the levels of
gelatinases (MMP-2 and MMP-9) in essential hypertension3.
However, our study differs from this previous finding in
evaluating gelatinases and their inhibitors in RHTN. It is well
known that RHTN is associated with increased cardiovascular
risk20, but uncontrolled hypertensive patients are probably
exposed to increased cardiovascular risk, which may reflect
in a worse prognosis as compared to controlled subjects.
Moreover, our study found an inverse correlation between
MMP-2 and DBP in the UCRHTN subgroup, suggesting no
association between MMP-2 and BP control in that subgroup.
Matrix metalloproteinases are zinc- dependent
endopeptidases, with that ion in the active site. Likewise,
the angiotensin‑ converting ‑ enzyme (ACE) is also
zinc‑dependent and inhibited by ACE inhibitors, which
are widely used in current antihypertensive treatment.
Given this, MMP-9 may also be inhibited by ACE inhibitors
by binding with zinc in the active site21; this suggests that
treatment with ACE inhibitors may inhibit MMP-9 activity22.
Arq Bras Cardiol. 2015; 105(2):168-175
171
Lacerda et al.
Gelatinases in resistant hypertension
Original Article
Although high MMP-9 levels were expected in the
UCRHTN subgroup, this negative finding may be explained
by the fact that all RHTN individuals have the hypertensive
disease for a long time and take a great number of
antihypertensive drugs, which could cause the decrease
in MMP-9 activity, particularly related to the use of ACE
inhibitors, as evidenced by several studies21,22.
For example, some studies have evaluated the
relationship between MMP-9 and TIMP-1 in patients
with essential hypertension, and have shown that, after
antihypertensive treatment, the circulating levels of
those molecules were significantly higher in subjects with
hypertension than in normotensive controls. In some
cases, a reduction in plasma levels of MMP-9 and
consequent increased levels of TIMP-1 have occurred
after antihypertensive treatment 23. Other findings are
as follows: MMP changes in TIMP profile, which favor
decreased ECM degradation (decreased MMP-2, MMP-9
and MMP-13 and increased TIMP-1), are associated with
left ventricular hypertrophy and diastolic dysfunction;
and increased TIMP-1 predicted the presence of chronic
heart failure11.
In addition, significantly higher TIMP-1 levels have been
reported in hypertensive individuals as compared with
normotensive individuals; however, TIMP-1 levels are not
elevated in hypertension alone, but only in patients with
diastolic dysfunction and fibrosis. This suggests that TIMP-1
synthesis and release are independent of BP and probably
dependent on a variety of neurohormonal factors, being a
TIMP-1 level higher than 500 ng/mL an accurate indicator of
dysfunction diastolic and damage to target organs24.
One hypothesis to be raised about the increase of plasma
levels of TIMP-1 is to generate a response to modulate or limit
collagen degradation, thus contributing to the development
of arterial stiffness. Unlike MMP-9, some studies indicate an
increase of TIMP-1 after antihypertensive treatment10,23,24.
In contrast, some studies have reported that increased
TIMP-1 levels were associated with an increased incidence of
hypertension and risk of BP progression25. Other studies have
shown the increase of TIMP-1 in normotensive vs. hypertensive
subjects26, as well as unchanged27 or decreased TIMP-128.
In addition, TIMPs play an important role in cardiovascular
remodeling processes, regardless of their MMP inhibitory
activity, ie, such inhibitors may play an important role in BP,
irrespective of the action of MMPs23.
Pulse wave velocity is widely used as an arterial elasticity
and stiffness index, and the arterial wall properties, such
as thickness and lumen diameter, are the factors that most
influence PWV29. Pulse wave velocity is the gold standard
method to measure arterial stiffness, plays an essential role in
the pathophysiology of hypertension and predicts mortality
in patients with hypertension30. The mechanisms involved
in arterial stiffness are not completely understood; however,
evidence has shown that this process is accompanied by
complex mechanisms, including structural alterations of the
ECM, including the participation of MMPs. In our study, the
levels of gelatinases and TIMPs were not correlated with
PWV values. These negative findings may be related to
172
Arq Bras Cardiol. 2015; 105(2):168-175
vascular stiffness in RHTN, as previously shown31. In addition,
the stiffness of great arteries appears to be an inevitable
consequence of aging, ie, this process becomes more
pronounced at older ages, which, according to the authors,
is the most important determinant of arterial stiffness1. In this
study, the arterial stiffness process may have been completed
or lost, because the individuals were in advanced age,
which is directly related to the increase in PWV and pulse
pressure (PP), especially in the UCRHTN group. This may be
an explanation for the lack of correlation of the biomarkers
studied with PWV and PP.
Primary aldosteronism is the second most common
cause of RHTN 32 . This condition is characterized by
excessive secretion of aldosterone by the adrenal gland,
the major forms being the production of adenomas and
idiopathic hyperaldosteronism33,34.
It is noteworthy that patients with RHTN have increased
aldosterone levels, but that is not due to primary aldosteronism.
Previous works have shown that UCRHTN individuals have
higher PAC as compared to CRHTN individuals1. A study
of 88 consecutive patients with RHTN has reported a 20%
incidence of primary aldosteronism, defined by measuring
two parameters: PRA and urinary aldosterone concentration35.
Consistent with these findings, other medical centers have
reported a 17%–22% prevalence of primary aldosteronism in
RHTN patients36,37. High PAC leads to the remodeling of small
and large arteries, causing collagen synthesis, which results in
increased arterial stiffness and BP elevation38.
Although we found a positive correlation between PAC
and MMP-9/TIMP-1 ratio, hyperaldosteronism is known to be
an independent risk factor in arterial hypertension and, thus,
in the process of arterial stiffening32.
The main limitation of this study was the small number of
UCRHTN and CRHTN patients enrolled. This study’s sample
size was not calculated, because all 76 subjects on regular
follow-up at the Resistant Hypertension Outpatient Clinic
were included. Similarly, recent studies have demonstrated
important findings, including in CRHTN and UCRHTN, with
such a small population16,17,39. On the other hand, the lack
of association in the main findings may be attributed to low
statistical power or type II error. Moreover, antihypertensive
drugs can influence the levels of MMP-9, as demonstrated
by Fontana et al. 13 and other studies previously cited.
Multiple linear regression analyses was performed to predict
biomarkers (MMP-2, MMP-9, TIMP-1, TIMP-2, and their ratios)
adjusted for antihypertensive drugs. These regression models
indicated that only the beta-blocker use was a predictor of
TIMP-1 levels and of MMP-9/TIMP-1 ratio in all RHTN subjects.
However, this potential confounding factor did not affect our
findings, because both controlled and uncontrolled subgroups
had a similar proportion of beta-blocker use. Because of ethical
concerns, antihypertensive drugs could not be withdrawn
in the RHTN subjects to exclude the influence of those
medications on the plasma levels of biomarkers.
Conclusion
Briefly, although MMP-9/TIMP-1 ratio and MMP-2 were
associated with DBP levels, aldosterone and age in the
Lacerda et al.
Gelatinases in resistant hypertension
Original Article
UCRHTN subgroup, this does not seem to influence resistance
to antihypertensive therapy, because the biomarkers did not
predict the lack of BP control in RHTN. Future prospective
studies with a larger RHTN population should be carried out
to confirm the present study’s findings.
Acknowledgements
This study was supported by the State of Minas Gerais
Research Foundation (FAPEMIG), the State of São Paulo
Research Foundation (FAPESP) and the Brazilian National
Council for Scientific and Technological Development (CNPq).
Author contributions
Conception and design of the research:Moreno Júnior H,
Sandrim VC. Acquisition of data:Lacerda LHG, Sandrim VC.
Analysis and interpretation of the data: Faria AP, Moreno Júnior
H, Sandrim VC. Statistical analysis: Faria AP, Sandrim VC.
Obtaining financing: Moreno Júnior H, Sandrim VC. Writing
of the manuscript:Lacerda LHG, Faria AP, Sandrim VC. Critical
revision of the manuscript for intellectual content: Lacerda
LHG, Faria AP, Fontana V, Moreno Júnior H, Sandrim VC.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
This study was funded by FAPEMIG, FAPESP e CNPq.
Study Association
This article is part of the thesis of master submitted by
Leandro Heleno Guimarães Lacerda, from Instituto de Ensino
e Pesquisa da Santa Casa de Belo Horizonte.
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Lacerda et al.
Gelatinases in resistant hypertension
Original Article
Arq Bras Cardiol. 2015; 105(2):168-175
175
Back to the Cover
Original Article
Reduced Progression of Cardiac Allograft Vasculopathy with Routine
Use of Induction Therapy with Basiliximab
Ricardo Wang1,2, Lidia Ana Zytynski Moura1,2, Sergio Veiga Lopes2, Francisco Diniz Affonso da Costa1,2, Newton
Fernando Stadler Souza Filho1, Tiago Luiz Fernandes1, Natália Boing Salvatti1, José Rocha Faria-Neto2
Santa Casa de Curitiba1; Pontifícia Universidade Católica do Paraná2, Curitiba, PR - Brazil
Abstract
Background: Cardiac allograft vasculopathy (CAV) is a major limitation for long-term survival of patients undergoing
heart transplantation (HT). Some immunosuppressants can reduce the risk of CAV.
Objectives: The primary objective was to evaluate the variation in the volumetric growth of the intimal layer measured by
intracoronary ultrasound (IVUS) after 1 year in patients who received basiliximab compared with that in a control group.
Methods: Thirteen patients treated at a single center between 2007 and 2009 were analyzed retrospectively.
Evaluations were performed with IVUS, measuring the volume of a coronary segment within the first 30 days and
1 year after HT. Vasculopathy was characterized by the volume of the intima of the vessel.
Results: Thirteen patients included (7 in the basiliximab group and 6 in the control group). On IVUS assessment, the
control group was found to have greater vessel volume (120–185.43 mm3 vs. 127.77–131.32 mm3; p = 0.051). Intimal layer
growth (i.e., CAV) was also higher in the control group (27.30–49.15 mm3 [Δ80%] vs. 20.23–26.69 mm3 [Δ33%]; p = 0.015).
Univariate regression analysis revealed that plaque volume and prior atherosclerosis of the donor were not related to intima
growth (r = 0.15, p = 0.96), whereas positive remodeling was directly proportional to the volumetric growth of the intima
(r = 0.85, p < 0.001).
Conclusion: Routine induction therapy with basiliximab was associated with reduced growth of the intima of the vessel
during the first year after HT. (Arq Bras Cardiol. 2015; 105(2):176-183)
Keywords: Vascular Diseases/physiopathology; Heart Transplantation; Antibodies, Monoclonal, Murine-Derived/admininstration
& dosage; Immunosuppressive Agents.
Introduction
With increased survival among heart transplantation (HT)
patients, mainly due to improvements in immunosuppression,
the incidence of late complications, including cardiac allograft
vasculopathy (CAV)1, has increased. CAV is characterized by
progressive obliteration of vessels due to intimal proliferation and
is considered a major cause of graft dysfunction in the first year
after HT and the second most common cause of long-term death2.
Lymphocytes play an important role in both acute and chronic
graft rejection. The immunological and non‑immunological
factors implicated in the pathogenesis of CAV converge by
activating T lymphocytes (TL)3, as demonstrated by Nagano et
al.4. Animal models in which these cells were blocked did not
develop vasculopathy5. Thus, T lymphocyte blockade has been
the objective of therapies for the prevention of CAV6.
Mailing Address: Ricardo Wang •
Avenida Francisco Sales 1111, Santa Efigênia, Postal Code 30150-221,
Belo Horizonte, MG - Brazil.
E-mail: [email protected]; [email protected]
Manuscript received September 29, 2014; revised manuscript January 28,
2015; accepted January 29, 2015
DOI: 10.5935/abc.20150063
176
Basiliximab is a chimeric antibody receptor antagonist
of interleukin 2 (IL-2) and is indicated in induction
therapy for patients at high risk of rejection after organ
transplantation7. IL-2 is a potent immunomodulator that
plays an important role in the activation and maintenance
of the immune response and lymphocyte proliferation8;
furthermore, it is a key step in the development of acute
rejection9. Blockage of TL proliferation and reduced acute
rejection can delay the onset of CAV10. The aim of this
study was to determine whether blockage of IL-2 with
basiliximab early in the transplantation process has an
effect superior to placebo in decreasing the growth of the
vessel intima during the first year following HT.
Methods
We conducted a retrospective analysis of the database
from a single center, including patients who underwent HT
from September 2007 through March 2009. The patients
were separated in two groups according to the induction
therapy: those treated with basiliximab (Simulect®;
Novartis, NJ, USA) and those who received no induction
therapy (control group). In our institution the use of
basiliximab became routine in July 2008; therefore, a
comparison was made to a series of cases before and after
Wang et al.
Basiliximab and graft vasculopathy
Original Article
this period. In this period, there was no difference regarding
surgical technique, preservation, or other adjuvant
medications. We included only patients who had clinical
and ultrasound follow-up for at least 1 year. We excluded
patients who did not comply with intravascular ultrasound
(IVUS) follow-up or whose images in the database were
inadequate to allow such analysis. The study was approved
by local Ethics Committee (protocol 0005154/11).
Endpoints
The primary objective was to compare the two groups
with regard to volumetric growth of the intimal layer
measured by IVUS after 1 year. The secondary objective
was to evaluate the remodeling of the vessel and lumen
volume and donor atherosclerosis.
Immunosuppression protocol
Immunosuppression was performed in the basiliximab group
at a dose of 20 mg IV, together with 500 mg methylprednisolone
in three daily doses and 150 mg mycophenolate mofetil
(MMF) in two doses on the day of transplantation; on the fifth
day, another dose of 20 mg IV basiliximab was administered;
on that day, therapy with cyclosporine was initiated. In the
control group, immunosuppression was conducted with
methylprednisolone and MMF at the same dosage; in addition,
cyclosporine was initiated on the day of transplantation at the
same dosage.
Evaluation of vasculopathy
As part of the HT protocol, patients are routinely evaluated
with angiography and intracoronary ultrasound (IVUS) only
at the left anterior descending (LAD) artery. This evaluation
is performed 30 days after HT and then repeated annually.
Coronary angiography and IUVS were performed
concurrently with an endomyocardial biopsy. To perform
the procedure, a 6F introducer was introduced into the
femoral artery, followed by catheterization of the left
coronary artery. Unfractionated heparin (100 IU/kg) was
instilled intravenously together with an intracoronary dose of
isosorbide mononitrate (10 mg). The ultrasound examination
was performed with an Atlantis® catheter (Boston Scientific
Scimed Inc., Maple Grove, Minn.) and a 4.3 Fr catheter with
a 40-MHz transducer. The IVUS catheter was positioned in
the distal LAD artery; automatic pullback was performed with
a velocity of 1 mm/s and an acquisition rate of 30 frames/s.
The images were stored on a compact disk and analyzed
using ILab® software (Boston Scientific Scimed, Inc.).
IVUS Analysis
To provide monitoring of the same segment, a 10-mm
segment was selected just after the output of the first diagonal.
Segment analysis was methodologically validated in a manner
similar to that previously described11,12. Analysis was performed
on the first computed tomography (CT) slice after the departure
of the diagonal branch, marking the beginning of the segment;
then each image is evaluated every 30 cuts (1-mm interval
between analyses), until 10 segment images (10 mm) are
completed. The analysis consists of a manual outlining of the
lumen and external elastic membrane (EEM), calculating the
lumen area and EEM area. Measurements were performed as
standardized by the American College of Cardiology/European
Society of Cardiology13. The intimal area was calculated by
subtracting the area of the lumen minus EEM. Calculation of the
volume of the vessel lumen and intima was carried out using
the method described by Simpson11. The volume percent was
calculated according the following formula: {∑ (EEM area −
lumen area)/∑ EEem area × 100.
Statistical Analysis
Continuous data were expressed as median plus 25th and
75 percentiles. Categorical data were expressed as absolute
numbers. Nonparametric tests were used to evaluate differences
in continuous data, and due to the small sample size, we used
Mann–Whitney test for evaluation of the differences in IVUS
findings. A simple linear regression model was used to assess
the relationship between previous atherosclerosis and intimal
growth as well as the relationship between intimal and vessel
growth after 1 year, using Pearson correlation coefficients.
For categorical data, the differences were evaluated using
Fisher's exact test. A two sided p-value < 0.05 was required
for statistical significance. Analyses were performed with SPSS
12.0 software (Chicago, IL, USA).
th
Results
In the period from 2007–2009, 23 HTs were performed in
our institution. Two patients died during the perioperative period,
and three during the first year of follow-up. Two patients were
excluded from the present study due to inadequate IVUS images,
and 3 patients only underwent IVUS study beyond 13 months
of follow-up. We evaluated 13 patients, of whom 7 received
basiliximab (basiliximab group) and 6 did not (control group).
Demographic data are listed in Table 1. The patients were
predominantly male (n = 10); the median age was 55 years
in the basiliximab group and 47.5 years in the control group.
Three patients in the control group developed acute renal failure
in the postoperative period, characterized by a serum creatinine
> 0.5 mg/dL, whereas no patients in the basiliximab group
developed this complication. The levels of total cholesterol,
triglycerides, and angiotensin receptors were similar between
the groups (p = NS), and creatinine levels were somewhat
higher in the control group. The use of inhibitors and statins was
higher in the basiliximab group. Only a few patients received
everolimus/sirolimus during follow‑up: one in the basiliximab
group and two in the control group. However, all patients
received mycophenolate mofetil. No patient received a diagnosis
of cytomegalovirus confirmed by serology. The number of
rejection episodes was similar in both groups. Two patients in
the basiliximab group and three in the control group underwent
a biopsy with 2R; they required hospitalization and underwent
pulse therapy with intravenous corticosteroids.
Coronary angiography performed during the first year
following HT did not detect the presence of significant
vascular disease (e.g., CAV), based on the new classification
of the International Society of Heart and Lung Transplantation
(ISHLT)14. The data obtained by IVUS are presented in Table 2
Arq Bras Cardiol. 2015; 105(2):176-183
177
Wang et al.
Basiliximab and graft vasculopathy
Original Article
Table 1 – Patient demographics
Basiliximab group (n = 7)
Control group (n = 6)
p value
Male sex (n)
4
6
N.S. *
Age (years)
55 [40-65]
47.5 [40-59]
N.S.
Diabetes mellitus
3
2
N.S.
Renal failure after transplantation
0
3
N.S.
Rejection
6
6
N.S.
0R
2
1
N.S.
1R
3
2
N.S.
2R
2
3
N.S.
7
6
N.S.
Biopsy (during first year after transplantation)
Coronary angiography
ISHLT CAV0 †
Total cholesterol (mg/dL)
229 [179-243]
180 [152-249]
N.S.
Triglycerides (mg/dL)
223 [176-450]
150 [129.2-232]
N.S.
HDL (md/dL)
48 [36-52]
38 [28-44]
N.S.
Glucose
85 [83-98]
93 [82-105]
N.S.
1.2 [1.2-1.4]
1.6 [1.4-1.6]
N.S.
Prednisone
6
5
N.S.
MMF
7
6
N.S.
Cyclosporine
6
5
N.S.
Everolimus/rapamicin
1
2
N.S.
Statin
4
1
N.S.
Angiotensin converting enzyme inhibitor
6
4
N.S.
Insulin
0
1
N.S.
Creatinine
Imunossupressor:
N.S.
Other medications
* N.S.: Not significant; † ISHLT CAV0: International Society of Heart Lung Transplantation definition of cardiac allograft vasculopathy (reference: JHLT 2010;29(7):717‑727.);
MMF: Mycophenolate mofetil.
Table 2 – Analysis of volumes obtained with IVUS
Vessel Previous
Vessel after
Lumen previous
Intima previous
Intima after
Basiliximab group
131.32 [101.69;202.06]
127.77 [110.39;174.05]
113.22 [82.67;144.70]
99.23 [87.86;123.36]
20.23 [9.65;29.11]
26.69 [14.65;39.24]
Control group
120.77 [111.92;191.57]
185.43 [142.23;229.76]
103.31 [86.52;149.16]
134.96 [105.50;158.79]
27.30 [13.65;42.41]
4915 [39.76;82.89]
1.00
0.042
1.00
0.05
0.62
0.05
p value
and Graph 1. In the control group, vessel volume (delineated
by the EEM) exhibited positive remodeling (increase in volume
growth of 49.39 mm3), whereas in the basiliximab group, the
effect was reversed (negative remodeling: –4.17 mm3), with a
trend toward statistical significance (p = 0.051). The findings
were similar with regard to luminal volume (-11.53 × 17.3 mm3;
p = 0.051). Regarding the intimal layer (plate), a higher rate
of growth (follow-up volume minus baseline volume) occurred
in the control group (baseline value: 27.3 mm3; control group:
49.15 mm3; basiliximab group: 20.23–26.69 mm3; p = 0.015;
Graphs 2 and 3).
178
Lumen after
Arq Bras Cardiol. 2015; 105(2):176-183
In simple linear regression analysis assessment (Graph 4B),
previous atherosclerosis was not associated with increased
growth of the intima (r = 0.15; p = 0.96). Positive remodeling
(increase in EEM) was associated with a greater increase in
intimal volume (r = 0.85; p < 0.001; Graph 4A).
Discussion
This study revealed the following findings. (1) The use of
induction therapy with basiliximab was associated with less
intimal tissue growth in the first year after HT. (2) In the control
Wang et al.
Basiliximab and graft vasculopathy
Original Article
p = 0.051
80.00
30.00
0.00
40.0
20.0
100.00
B
Volumetric Growth of the Plaque
90.00
A
Volumetric Growth of the Lumen
Volumetric growth of the artery (EEM)
120.00
p = 0.051
8
0.0
-20.0
Não
Sim
C
2
p = 0.051
60.00
40.00
20.00
0.00
-40.0
-30.00
80.00
Não
Sim
Baxilicimab
Baxilicimab
Não
Sim
Baxilicimab
Graph 1 – Analysis of the volume change at 1 year after transplantation. A: Variation in the vessel. B: Variation in the lumen. C: Variation in the intima.
120
100
1
80
2
3
60
4
5
40
6
7
20
0
Previous Volume
After Volume
Graph 2 – Growth of plaque volume in patients undergoing induction therapy with basiliximab.
group, we observed greater positive remodeling, which was
probably related to increased intimal growth observed in this
group. (3) With simple linear regression analysis, vessel growth
was proportional to the increase of the plaque regardless of
induction therapy. (4) Atherosclerosis in the donor was not
associated with increased growth of the intima.
Graft vascular disease begins with endothelial injury,
followed by a repair process, cell proliferation, and
accumulation of extracellular matrix3,6. The degree of organ
preservation, ischemia/reperfusion injury, acute rejection,
and viral infection (particularly cytomegalovirus) are cited
as the main non-immunological factors that affect the
endothelium in the first year after HT. In response to injury,
endothelial cells express cell adhesion molecules (vascular
cell adhesion molecule, intercellular cell adhesion molecule,
and selectins); furthermore, recruitment of inflammatory cells
and release of proinflammatory cytokines occur. This results
in a vicious cycle of chronic inflammation, culminating in
the obliteration of the lumen15-17.
Growth inhibition by basiliximab, which exhibits its action
4–6 weeks after infusion9, reinforces the relationship between
early recruitment of lymphocytes and the appearance of
CAV6. Tori et al.18 and Young et al. 19 observed that the
infiltration and activation of lymphocytes in the first days
after HT are already sufficient for the appearance of CAV.
The specific activation pathway of major histocompatibility
complex II and proliferation of Th1 lymphocytes are
considered to be the primary route of CAV formation20.
Blocking various parts of this pathway has been proven
effective in reducing the appearance of CAV21. IL-2 also
plays a major role in the activation pathway of T helper 1
(Th1) lymphocytes, and this could explain the benefit of the
Arq Bras Cardiol. 2015; 105(2):176-183
179
Wang et al.
Basiliximab and graft vasculopathy
Original Article
140
120
100
1
2
80
3
60
4
5
40
6
20
0
After Volume
Previous Volume
Graph 3 – Plaque volume in patients who received no induction therapy.
Vessel growth
120.00
Plaque growth
100.00
A
B
80.00
90.00
60.00
60.00
r = 0.85
p < 0.001
30.00
40.00
0.00
20.00
-30.00
0.00
0.00
20.00
40.00
60.00
Intimal growth
80.00
r = 0.15
p < 0.096
100.00
0.00
20.00
40.00
60.00
Previous plaque volume
80.00
Graph 4 – A. Vessel growth according to intimal growth. B. Impact of previous plaque atherosclerosis on CAV growth.
use of basiliximab in the first weeks after HT to interrupt
the cycle of injury and repair, thus preventing the chronic
inflammatory process.
The reduction of intimal growth induction therapy is not a
new finding22. Zhang et al.22 observed that induction therapy
with antithymocyte antibody (antithymocyte globulin, ATG)
delays the onset of CAV. However, the effect did not translate
180
Arq Bras Cardiol. 2015; 105(2):176-183
into increased long-term survival. In addition, a higher
incidence of cancer is observed in patients treated with
ATG, which may explain the higher late mortality rate in this
group. Long-term follow-up is indicated to determine the
benefit and/or clinical harm of this therapy. As basiliximab is
not associated with increased infection or neoplasia9,23, we
expect a clinical benefit.
Wang et al.
Basiliximab and graft vasculopathy
Original Article
In the global registry of the ISHLT, the use of basiliximab
for induction therapy has a neutral effect on CAV (relative
risk [RR]: 1.16; confidence interval [CI]: 0.99–1.37);
however, CAV increased with the use of muromonab-CD3
(OKT3; RR: 1.17; p = 0.038)2. This effect is probably due to
selection bias. Patients with a higher risk of acute rejection in
the post-transplantation period and those who have higher
levels of a reactor panel of antibodies (PRA) are at greatest
risk of developing CAV24,25. Another example of selection
bias occurs with induction therapy, correlates with IL-2
receptor antagonists, and a risk of renal dysfunction, and
this medication is indicated for patients at high risk for renal
failure after transplantation26.
As in atherosclerosis27, we observed positive remodeling
to accommodate the increase of the intima, thus avoiding
involvement of the arterial lumen. In previous studies, most
intimal tissue growth and positive remodeling occurred
during the first year post-HT28,29. From the second year
onward, despite a lower growth of the intima, there is greater
involvement of the arterial lumen due to negative vessel
remodeling28. We found variation in the natural history of the
process in patients treated with basiliximab. We also found
a slight decrease in vessel remodeling and luminal volume
reduction; however, to date, we do not know how it will
progress following the second year.
In our institution, induction therapy with basiliximab
is routinely performed with the goal of delaying the onset
of the need for caucineurin inhibitors and minimizing the
nephrotoxic effects of cyclosporin26,30. Candidates for HT have
a high prevalence of renal dysfunction; furthermore, after HT,
renal function may deteriorate, particularly because of the
use of nephrotoxic drugs, low cardiac output, and impaired
cardiopulmonary bypass. Moreover, acute renal failure is
associated with a poor outcome2.
Due to low sensitivity of coronary angiography in
detecting early CAV, IVUS is used in our institution for
CAV research, because its high sensitivity and specificity
provide an earlier diagnosis of CAV14,31. Clinically, IVUS
has a good correlation with angiography; thus, it is a good
prognostic tool32. Some evidence exists that early diagnosis
of CAV, together with the adjustment of immunosuppressive
therapy is associated with growth control. Furthermore,
some studies have reported regression of CAV 21,33,34 .
The volumetric measurement of the plate by IVUS has
been previously validated by experimental11 and clinical
studies12. This methodology has a strong correlation with
histomorphometry. Moreover, it is a robust method and
requires a smaller sample to demonstrate the effectiveness
of strategies that have an impact on reducing the intima11.
The major limitation of this study is its small sample size,
possible bias in patient selection, and retrospective nature.
Thus, a prospective, multicenter, randomized study with
a larger sample size, which extends clinical follow-up to
assess the long-term benefit, is indicated. Furthermore, our
control group had greater plaque volume, probably due
to atherosclerosis of the donor; this may have affected the
outcome, as suggested by a recent study by Yamasaki et al.35.
However, in our study, plaque volume did not correlate with
higher growth of the intima (r = 0,24; p = 0.94), a finding
that is consistent with those of previous studies36,37.
Conclusion
In this retrospective analysis, induction therapy with
basiliximab was associated with less volumetric growth of
intimal tissue (graft vasculopathy) in the first year after HT.
Author contributions
Conception and design of the research:Wang R, Moura
LAZ, Costa FA, Souza Filho NS, Faria-Neto JR. Acquisition of
data:Wang R, Moura LAZ, Lopes SV, Costa FA, Fernandes TL,
Salvatti NB, Faria-Neto JR. Analysis and interpretation of the
data: Wang R, Moura LAZ, Lopes SV, Costa FA, Souza Filho
NS, Fernandes TL, Salvatti NB, Faria-Neto JR. Statistical analysis:
Wang R, Faria-Neto JR. Obtaining financing: Wang R, Lopes SV,
Souza Filho NS, Faria-Neto JR. Writing of the manuscript:Wang
R, Moura LAZ, Faria-Neto JR. Critical revision of the manuscript
for intellectual content: Wang R, Moura LAZ, Lopes SV, Costa
FA, Souza Filho NS, Fernandes TL, Salvatti NB, Faria-Neto JR.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This article is part of the thesis of master submitted by Ricardo
Wang, from Pontífica Universidade Católica do Paraná.
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2006;38(10):3169-71.
6. Valantine HA. Cardiac allograft vasculopathy: central role of endothelial
injury leading to transplant “atheroma”. Transplantation. 2003;76(6):891-9.
7. Bacal F, Souza-Neto J, Fiorelli A, Mejia J, Marcondes-Braga FG, Mangini S,
et al. II Brazilian Guidelines for cardiac transplantation. Arq Bras Cardiol.
2010;941 Suppl):e16-76.
8. Church AC. Clinical advances in therapies targeting the interleukin-2
receptor. QJM. 2003;96(2):91-102.
9.
Onrust SV, Wiseman LR. Basiliximab. Drugs. 1999;57(2):207-13.
10. Young JB, Lloyd KS, Windsor NT, Cocanougher B, Weilbaecher DG,
Kleiman NS, et al. Elevated soluble interleukin-2 receptor levels early after
heart transplantation and long-term survival and development of coronary
arteriopathy. J Heart Lung Transplant. 1991;10(2):243-50.
11. Mehran R, Mintz GS, Hong MK, Tio FO, Bramwell O, Brahimi A, et al.
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13. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, et al. American
College of Cardiology Clinical Expert Consensus Document on Standards for
Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies
(IVUS). A report of the American College of Cardiology Task Force on Clinical Expert
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14. Mehra MR, Crespo-Leiro MG, Dipchand A, Ensminger SM, Hiemann NE,
Kobashigawa JA, et al. International Society for Heart and Lung Transplantation
working formulation of a standardized nomenclature for cardiac allograft
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15. Yamani MH, Haji SA, Starling RC, Tuzcu EM, Ratliff NB, Cook DJ, et al.
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Wang et al.
Basiliximab and graft vasculopathy
Original Article
Arq Bras Cardiol. 2015; 105(2):176-183
183
Back to the Cover
Brief Communication
Diastolic Function in Paced Children with Cardiac Defects: Septum
vs Apex
Michel Cabrera Ortega, Adel Eladio Gonzalez Morejon, Giselle Ricardo Serrano, Dunia Barbara Benitez Ramos
Cardiocentro Pediatrico William Soler, La Habana - Cuba
Abstract
In children with structural congenital heart disease
(CHD), the effects of chronic ventricular pacing on diastolic
function are not well known. On the other hand, the
beneficial effect of septal pacing over apical pacing is still
controversial.
The aim of this study was to evaluate the influence of
different right ventricular (RV) pacing site on left ventricular
(LV) diastolic function in children with cardiac defects.
Twenty-nine pediatric patients with complete
atrioventricular block (CAVB) and CHD undergoing permanent
pacing were prospectively studied. Pacing sites were RV
apex (n = 16) and RV septum (n = 13). Echocardiographic
assessment was performed before pacemaker implantation
and after it, during a mean follow‑up of 4.9 years.
Compared to RV septum, transmitral E-wave was
significantly affected in RV apical pacing (95.38 ± 9.19
vs 83 ± 18.75, p = 0.038). Likewise, parameters at
the lateral annular tissue Doppler imaging (TDI) were
significantly affected in children paced at the RV apex.
The E´ wave correlated inversely with TDI lateral myocardial
performance index (Tei index) (R2 = 0.9849, p ≤ 0.001).
RV apex pacing (Odds ratio, 0.648; confidence interval,
0.067-0.652; p = 0.003) and TDI lateral Tei index (Odds
ratio, 31.21; confidence interval, 54.6-177.4; p = 0.025)
predicted significantly decreased LV diastolic function.
Of the two sites studied, RV septum prevents pacinginduced reduction of LV diastolic function.
Introduction
RV apical pacing is conventionally performed in pediatric
patients with CAVB. However, ventricular pacing induces
an abnormal electrical activation pattern, which causes
mechanical dyssynchrony, LV structural remodeling and
increased risk of heart failure1-3. Most pediatric studies
published1,2 have focused on ventricular systolic function
Keywords
Heart Defects, Congenital; Ventricular Function, Right;
Ventricular Function, Left; Child; Pacemaker, Artificial.
Mailing Address: Michel Cabrera •
Cardiocentro Pediatrico William Soler. 100 y perla, Boyeros.
Postal Code 10800, La Habana – Cuba
E-mail: [email protected], [email protected]
Manuscript received December 09, 2014; revised manuscript April 22,
2015; accepted manuscript April 30, 2015.
DOI: 10.5935/abc.20150077
184
assessment; therefore, the effects of chronic ventricular
pacing on diastolic function are not well known, even less
in children with CHD.
Moreover, the benefit of RV septal stimulation is still
controversial, with clinical studies 4 showing promising
results, while a recent research did not demonstrate any
superiority over RV apical pacing in children1; none of
these studies1,2,4 reported the effects on LV relaxation phase.
With the hypothetical premise that there are differences
between RV septal and RV apical pacing in terms of dynamic
alterations in LV filling, we performed the current study.
Methods
The study included all children with CHD and CAVB that
underwent pacemaker implantation in a single tertiary pediatric
cardiology center, paced from RV septum (n = 13) and from
RV apex (n = 16). Patients with clinical or anamnestic evidence
of heart failure were excluded. None of the patients were
older than 18 years at pacemaker implantation, had ≤ 95% of
ventricular pacing or ≤ 1 year of permanent cardiac pacing.
The study protocol was approved by the institutional research
ethics committee and parental written consent was obtained.
Two experienced observers, blinded for the ventricular pacing
site, performed prospective echocardiographic evaluations
(Aloka α-10) before pacemaker implantation, immediately
after and regularly during a mean period of 4.9 years.
Three random measurements were made for every patient by
each observer and the average of measurements was used for
further analysis. For a comprehensive diastolic evaluation, the
following mitral flow parameters were evaluated by pulsed wave
Doppler echocardiography: E and A waves, E/A wave ratio and
E-wave deceleration time. Likewise, pulse wave TDI velocities
were obtained in the apical four-chamber view, at septal and
lateral mitral annulus. In each segment, peak systolic (S´), early
(E´) and late (A´) peak diastolic velocities were measured.
The E/E´ ratio and TDI Tei index were also calculated. All data
were prospectively collected.
Statistical analysis
According to the Kolmogorov-Smirnov test, the variables
that showed a normal distribution were summarized as
mean ± standard deviation. The differences between two
groups were compared by unpaired t-test. Independent
variables showing significant univariate differences related
to the development of LV dysfunction were entered into a
backward stepwise logistic regression analysis, where the
Odds ratio (OR) and Wald statistics for each variable were
identified. Significance level was set at 5%. The statistical
software Medcalc Version 12 was used for the analyses.
Cabrera Ortega et al.
LV diastolic function in paced children
Brief Communication
Results
Discussion
A total of 29 patients (surgical atrioventricular block in 26),
with mean age at first implantation of 9.82 ± 2.75 years were
evaluated. Tetralogy of Fallot (8 cases, 27%) and ventricular
septal defect (7 patients, 24.13%) were the main CHD
corrected before pacemaker implantation. Anatomic surgical
correction was performed in all patients and mild residual
atrioventricular regurgitation was present in 10 (34.48%) children.
Thirteen (44.82%) cases underwent treatment with
angiotensin‑converting enzyme inhibitors at the time of
implantation. Twelve children (41.37%) received a single‑chamber
pacemaker, while 11 (24.13%) patients underwent DDD/DDDR
pacing. Mean pacing duration was 4.9 years.
Our study confirms that chronic stimulation from RV
apex results in diastolic function impairment in pediatric
patients with CHD and further demonstrates the superiority
of septal stimulation in this context.
Compared to RV septum, transmitral E-wave was
significantly affected in RV apical pacing (95.38 ± 9.19 vs
83 ± 18.75, p = 0.038) (Table 1). Likewise, the following
parameters of the lateral annular TDI were significantly
affected in children paced at the RV apex compared with
RV septum group: E´ wave (12.5 ± 4.42 vs 15.3 ± 2.1;
p = 0.046), A´ wave (8.12 ± 2.63 vs 6.22 ± 2.11; p = 0.045),
E/E´ ratio (8.2 ± 1.29 vs 6.3 ± 0.72; p = 0.0001) and Tei
index (0.39 ± 0.04 vs 0.34 ± 0.04; p = 0.002). The E´ wave
correlated inversely with TDI lateral Tei index (R2 = 0.9849,
p ≤ 0.001) (Figure 1). At the logistic regression, pacing from
the RV apex (OR, 0.648; confidence interval, 0.067-0.652;
Wald, -0.915; p = 0.003) and TDI lateral Tei index (OR, 31.21;
confidence interval, 54.6-177.4; Wald, 3.046; p = 0.025)
predicted significantly decreased LV diastolic function.
The deterioration of diastolic function after RV pacing
has been previously reported in animals5 and in the adult
population 6,7. Aoyagi et al 5 showed that wall motion
asynchrony prolongs LV isovolumic relaxation time (IVRT)
in dogs; this impairment correlated with the degree of wall
motion asynchrony. In the research performed by Kolettis et
al6, compared to RV outflow tract pacing, RV apical pacing
decreased maximum negative dp/dt and increased the
IVRT. These findings were confirmed in an analysis of nine
studies7, reporting a significant benefit of RV outflow tract
over apical pacing. On the other hand, few investigations3,8,9
have focused on LV diastolic function in the pediatric
population. Forwalt et al8 evaluated the effects of acute
ventricular pacing in children who underwent ablation
therapy; the authors observed that RV apical pacing resulted
in acute systolic dyssynchrony with preserved diastolic
synchrony. Nevertheless, Koh et al9 provided evidence of
LV diastolic dysfunction after chronic RV apical stimulation,
associated with the presence of LV dyssynchrony. In our
study, the impaired diastolic indices in the lateral mitral
annulus could be associated with the pattern induced by
RV apical pacing, characterized by early activation of the
RV and delayed activation of the LV lateral wall.
Table 1 - Comparison of LV function between RV septal and apical pacing
RV Septum (n = 13)
RV Apex (n = 16)
p*
Before PM
implantation
At last follow-up
p
Before PM
implantation
At last
follow-up
p
64.16 ± 1.75
61.43 ± 2.26
0.004
65.21 ± 2.08
64.22 ± 3.14
0.352
0.009
E(cm/s)
90.72 ± 13.81
95.38 ± 9.19
0.321
90.53 ± 11.45
83 ± 18.75
0.181
0.038
A(cm/s)
61.46 ± 15.19
56.69 ± 7.2
0.316
65.87 ± 18.31
67.06 ± 19.66
0.860
0.100
LVEF
Mitral Inflow Doppler indices
E/A
1.59 ± 0.51
1.71 ± 0.33
0.483
1.51 ± 0.54
1.41 ± 0.65
0.639
0.142
170.38 ± 23.54
172.07 ± 17.45
0.837
170.68 ± 24.06
172.8 ± 25.84
0.811
0.931
E´(cm/s)
15 ± 3.41
15.3 ± 2.1
0.789
15.6 ± 3.31
12.5 ± 4.42
0.032
0.046
A´(cm/s)
6.41 ± 2.13
6.22 ± 2.1
0.820
7.1 ± 2.11
8.12 ± 2.63
0.235
0.045
EDT(ms)
Lateral Mitral Valve Annular TDI
E/E´
6.1 ± 0.81
6.3 ± 0.72
0.512
5.8 ± 0.62
8.2 ± 1.29
< 0.0001
0.0001
Tei index
0.33 ± 0.04
0.34 ± 0.04
0.529
0.35 ± 0.05
0.39 ± 0.04
0.018
0.002
E´(cm/s)
15.30 ± 4.23
14.84 ± 3.51
0.765
15.12 ± 3.28
13.81 ± 3.97
0.317
0.470
A´(cm/s)
7.23 ± 2.35
7.24 ± 2.33
0.991
7 ± 2.55
6.56 ± 2.65
0.616
0.474
E/E´
6.19 ± 1.11
6.68 ± 1.22
0.294
6.11 ± 0.74
6.13 ± 0.56
0.931
0.118
Tei index
0.34 ± 0.06
0.35 ± 0.04
0.621
0.33 ± 0.01
0.36 ± 0.08
0.147
0.685
Septal Mitral Valve Annular TDI
Data expressed by mean ± standard error. p*: septum vs. apex at last follow-up.
EDT: E-wave deceleration time; LVEF: Left ventricular ejection fraction; PM: Pacemaker; RV: Right ventricular; TDI: Tissue doppler imaging.
Arq Bras Cardiol. 2015; 105(2):184-187
185
Cabrera Ortega et al.
LV diastolic function in paced children
Brief Communication
20
R2 = 0.9849
p ≤ 0.001
y = 31.1684 + -0,4868x
95% CI = -0.9965 - 0.9835
18
E (cm/s)
16
14
12
10
8
6
4
0.2
0.3
0.4
0.5
0.6
Tei index
Figure 1 – Association between E´-wave and TDI Tei index at lateral mitral valve annulus.
The Tei index has been used to assess LV function in a
wide variety of diagnoses in children10; it is the most accurate
for the detection of diastolic and combined dysfunction10.
Considering that the results of our research reflect the high
predictive value of this parameter, it could be used as an
echocardiographic tool to predict the deterioration of both
systolic and diastolic functions in patients with chronic
ventricular pacing.
Conclusions
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Of the two assessed sites, RV septum showed to prevent
pacing-induced reduction of LV diastolic function.
Sources of Funding
Author contributions
Study Association
Conception and design of the research: Ortega MC,
Morejon AEG; Acquisition of data, Analysis and interpretation
186
of the data and Critical revision of the manuscript for
intellectual content: Ortega MC, Morejon AEG, Serrano GR,
Ramos DBB; Statistical analysis: Ortega MC, Serrano GR,
Ramos DBB; Writing of the manuscript: Ortega MC.
Arq Bras Cardiol. 2015; 105(2):184-187
There were no external funding sources for this study.
This article is part of the thesis of Doctoral submitted by Michel
Cabrera Ortega, from Cardiocentro Pediátrico William Soller.
Cabrera Ortega et al.
LV diastolic function in paced children
Brief Communication
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pediatric patients. J Am Soc Echocardiogr. 2009;22(2):152-8.
Arq Bras Cardiol. 2015; 105(2):184-187
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Back to the Cover
Review Article
Nobel Prizes: Contributions to Cardiology
Evandro Tinoco Mesquita, Luana de Decco Marchese, Danielle Warol Dias, Andressa Brasil Barbeito, Jonathan
Costa Gomes, Maria Clara Soares Muradas, Pedro Gemal Lanzieri, Ronaldo Altenburg Gismondi
Universidade Federal Fluminense, Niterói, RJ – Brazil
Abstract
The Nobel Prize was created by Alfred Nobel. The first
prize was awarded in 1901 and Emil Adolf von Behring was
the first laureate in medicine due to his research in diphtheria
serum. Regarding cardiology, Nobel Prize’s history permits a
global comprehension of progress in pathophysiology, diagnosis
and therapeutics of various cardiac diseases in last 120 years.
The objective of this study was to review the major scientific
discoveries contemplated by Nobel Prizes that contributed
to cardiology. In addition, we also hypothesized why Carlos
Chagas, one of our most important scientists, did not win the
prize in two occasions. We carried out a non-systematic review
of Nobel Prize winners, selecting the main studies relevant to
heart diseaseamong the laureates. In the period between 1901
and 2013, 204 researches and 104 prizes were awarded in
Nobel Prize, of which 16 (15%) studies were important for
cardiovascular area. There were 33 (16%) laureates, and two
(6%) were women. Fourteen (42%) were American, 15 (45%)
Europeans and four (13%) were from other countries. There was
only one winner born in Brazil, Peter Medawar, whose career
was all in England. Reviewing the history of the Nobel Prize in
physiology or medicine area made possible to identify which
researchers and studies had contributed to advances in the
diagnosis, prevention and treatment of cardiovascular diseases.
Most winners were North Americans and Europeans, and male.
Introduction
The Nobel Prize was created by Alfred Nobel (1833-1896)
(Figure 1)1,2. In his will, the Swedish researcher determined the
creation of a foundation that would carry his name, of which
main objective would be to reward every year, individuals
that provided outstanding contributions to mankind in the
areas of Peace/Diplomacy, Literature, Chemistry, Physics and
Physiology/Medicine. The first prizes were awarded in 1901
and the first winner in Medicine was Emil Adolf von Behring,
for his work with diphtheria serum1. Since that date, there
have been 876 Nobel Prize winners, of which 104 awards
and 204 researchers in the area of Medicine or Physiology1.
Keywords
Cardiology; Nobel Prize; History; Cardiovascular Diseases
/ trends.
Mailing Address: Ronaldo Altenburg Odebrecht Curi Gismondi •
Universidade Federal Fluminense. Rua Ministro Otávio Kelly, 185/701, Icaraí.
Postal Code 24220-300, Niterói, RJ – Brazil
E-mail: [email protected], [email protected]
Manuscript received November 22, 2014; revised manuscript February 9,
2015; accepted February 11, 2015.
DOI: 10.5935/abc.20150041
188
The objective of the present study was to review the major
scientific discoveries that received the Nobel Prize and directly
or indirectly contributed to advances in physiopathology,
diagnosis and treatment of cardiovascular diseases.
Methods
We performed a systematic search of the main non
Nobel Prize winners from 1901 to 2013. The winners list
was obtained from the Nobel Prize site3 and, subsequently,
information about the authors and their research were
obtained from the Medline/PubMed database. Moreover, due
to the specific nature of the research involving historical and
bibliographical data, the Google search engine was utilized,
using as descriptors the names of the researchers awarded
the Nobel Prize. The results are displayed in ascending
chronological order.
Results
A brief history of the Nobel Prize
For many historians, the interest of Alfred Nobel in
medicine derived from a poor health2. There are reports of
dyspepsia, headaches and bouts of depression. In adulthood,
he would have suffered from coronary artery disease, with
frequent episodes of angina. His doctors recommended
the use of nitroglycerin, a substance Nobel manipulated in
the explosives industry, but he would have refused. In later
life he had a stroke and had to live with motor sequelae.
Skeptical and suspicious, Nobel expressed in his will the wish
that after his death, his veins were "open" and the signs of
death confirmed by "competent doctors," before the body
was sent to be cremated1.
Nobel’s choice of the Karolinska Institute in his will
surprised many scientists. This institute was created in
1810 from the merging of a Medical School and a small
surgical center where barbers were trained to perform
amputations. For years it did not have the status of School
of Medicine and depended on a contract with the University
of Uppsala, in Sweden, for the training of its professionals1.
Currently, the institute is one of the leading Assistance
Medicine and Research centers in Europe. Five Nobel Prize
winners over the last 120 years, came from this institute1.
The Nobel Prize and Cardiology
In the area of cardiology, specifically regarding heart
failure (HF), knowledge of the history of the Nobel Prize helps
to understand important diagnostic and therapeutic advances
made in the last 120 years (Chart 1). The first laureate in this
area was Alexis Carrel, for his discoveries related to blood
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Figure 1 – Nobel Prize Logo. Source: http://en.wikipedia.org/wiki/Nobel_Prize
vessel suture, an important step in the further development of
cardiac surgery1,3. Only one Brazilian, who lived in England,
was awarded. His name is Peter Medawar and he has carried
out researches in the immunosuppression area, with future
applicability in renal and cardiac transplant4,5.
Although Carlos Chagas researched and discovered the
etiological agent, the vector, the mode of transmission and
clinical forms of trypanosomiasis, a unique feat in the history
of world’s science, he was a candidate for the Nobel a few
times, but was unsuccessful. There are hypotheses that
attempt to explain why a genuinely Brazilian contribution
in the field of cardiology has not been contemplated with
the Nobel prize6,7.
Major studies important for Cardiology that were awarded
the Nobel Prize
Alexis Carrel – 1912: blood vessel suture
Alexis Carrel, was born in Sainte-Foy-lès-Lyon, France,
graduated in Medicine from the School of Medicine of
Lyon in 1893 and completed his doctorate in 1900, with
a research on blood vessel sutures. He taught Anatomy
and Surgery at the University of Lyons and moved to the
United States in 1904, where he worked at the University
of Chicago. Later, he joined the Rockefeller Institute for
Medical Research in New York, where he performed most
of the experiments that led to the Nobel Prize in Physiology
or Medicine in 1912. He served the medical corps of the
French Army during World War I (1914 -1918), where he
successfully used the Carrel-Dakin method of constant
irrigation of wounds with antiseptic solution, which
decreased cases of death and amputations1-3,8.
His early work was on surgical techniques in blood vessels and
arteriovenous anastomoses. After 1908, he developed methods
for organ cryopreservation and transplantation1-3,8. In 1935, he
created a system for sterile oxygen supply and preservation of
organs removed from the body. He also cooperated with other
researchers for the development of cardiac valvotomy surgery
and sarcoma cell culture. He published the books “The culture
of organs” and “Treatment of infected wounds”1-3,8. The suture
of blood vessels was essential for the development of vascular
surgery in later years.
Willem Einthoven – 1924: The Electrocardiogram
Willem Einthoven was born on May 21, 1860 on the
island of Java, now Indonesia, and moved to the Netherlands
in 1870, where he graduated from Medical School at the
University of Utrecht, one of the oldest and most traditional
medical schools in Europe. He was a physiologist and in
the early 20th century, he published several papers on the
use of the galvanometer in the recording of the human
electrocardiogram (ECG), which served as the basis for the
current devices. The original equipment weighed more than
270 kg and was operated by several people in his laboratory.
He described the P, QRS and T waves, as well as and their
alterations in several diseases, especially in valvular heart
disease. Showing great wisdom, he wrote after his initial
research, “the electrocardiogram should not be used, at
least exclusively, to diagnose valvular alterations, because
the ECG is the expression of the heart muscle contraction
and changes only to the extent that a valvular function failure
has influence on such contraction”1,2,9.
In addition to the ECG, Einthoven played an important
role in the development of the phonocardiogram 1,2,9.
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Chart 1 – Main scientific discoveries that received the Nobel Prize in Physiology or Medicine related to the Cardiology area
Year
Author
Prize
1912
Alexis Carrel
Work on vascular suture and transplant of blood vessels and organs
1924
Willem Einthoven
Electrocardiogram
1953
Hans Adolf Krebs
Citric acid cycle (Krebs cycle)
1956
Werner Forssmann, Andre Cournard and Dickinson W. Richards
Cardiac catheterization
1960
Frank Burnet and Peter Medawar
Discovery of the immunological tolerance mechanism
1964
Konrad Bloch and Feodor Lynen
Understanding of cholesterol metabolism
1979
Allan Cormack and Godfrey Hounsfield
Computed tomography techniques
1982
Bengt Samuelsson, Sune Bergström and John Vane
"Discovery" of the angiotensin-converting enzyme inhibitors
1985
Michael Brown and Joseph Goldstein
Discovery of LDL-cholesterol receptors
1988
James Black, Gertrude Elion and George Hitchings
Development of beta-blockers
1990
Joseph Edward Murray and Edward Thomas
Development of organ and tissue transplant
1998
Robert Furchgott, Ferid Murad and Louis Ignarro
Discoveries about nitric oxide
2003
Paul Lauterbur and Peter Mansfield
Magnetic Resonance
LDL: low-density lipoprotein.
This device, now a museum piece in many medical schools, was
crucial in the supplementary examination to medical workup.
Before the invention of echocardiography, many valvular
heart disease diagnoses were attained by auscultation and the
phonocardiogram. The valvular diseases were, until the early
20th century, one of the most important causes of heart failure,
particularly those of rheumatic origin.
Hans Adolf Krebs – 1953: Krebs cycle
Hans Adolf Krebs was born on August 25, 1900, in
Hildeshiem, northern Germany10. He served as a military in
the German army in World War I. Although he graduated
in Medicine, he had to go into exile and left Germany in
the 1930s, because of his Jewish descent. He chose to live
in England, where he developed his research related to cell
physiology. He described, together with other researchers,
the urea cycle, the citric acid cycle, and especially, cellular
respiration, which produces adenosine triphosphate (ATP)
from glucose and oxygen10,11. In his honor, this sequence of
biochemical reactions is known as "Krebs cycle".
It has long been known that mitochondrial diseases are a
group of diseases related to neuromuscular dysfunction and
cardiomyopathy12,13. Moreover, in cardiology, the study of the
mitochondrial function in the myocyte is a new research frontier,
which some have called "mitochondrial bioenergetics"12,13.
One of the key areas is HF, due to the role of aerobic metabolism
in myocardial performance. Drugs are being developed that act
on mitochondrial pathways, correcting occasional dysfunctions,
and it is expected that they can improve myocardial function14,15.
Werner Otto Theodor Forssmann, André Cournard and
Dickinson Richards – 1956: cardiac catheterization
The history of cardiac catheterization started in 1711,
based on the works of Stephen Hales, who inserted tubes
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Arq Bras Cardiol. 2015; 105(2):188-196
in both ventricles of a horse 1,16-19. In the 19 th century,
cardiac catheterization continued with the work of Claude
Bernard, the father of modern physiology; it became more
sophisticated with the skills of Chauveau and Marey;
and started to be applied in the human heart thanks to
the self‑confidence of Forssmann in 1929, becoming
therapeutic in 196620. According to Cournnand17, cardiac
catheterization can be considered the "key that opened
the lock to reveal the secrets of the heart." Due to the
advancement of the technique proposed by the laureates,
currently the hemodynamic study has applicability in the
diagnosis, treatment and monitoring of cardiovascular disease
- including Coronary Artery Disease (CAD) and HF.
The Nobel Prize in Physiology or Medicine in 1956
was awarded to three researchers, due to their researches
on catheterization that revolutionized the studies on
heart disease1. They would not accept with the scarcity
of semiotic methods, of which provided diagnoses were
rebuffed by autopsies, which served as motivation to initiate
their studies1.
Werner Forssmann was a German physician, born in
Berlin, who developed the hypothesis that a catheter could be
inserted through blood vessels to the heart, aiming to injecting
medications, perform contrast studies and measure chamber
pressures. In order to test his hypothesis, he performed the
first human catheterization in himself, guiding a catheter into
his left atrium with the aid of a fluoroscopy device1,16-19.
Andre Cournard, born in Paris, France and Dickinson
Richards, from Orange, United States, were physicians who
worked in the development of the cardiac catheterization
technique, with emphasis on pulmonary diseases and patterns
of circulatory shock. They described the shock patterns,
particularly cardiogenic and hemorrhagic (trauma) and
analyzed the hemodynamic changes with treatment, either
by fluid replacement or drug infusion1,16-19.
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Frank Macfarlane Burnet and Peter Brian Medawar –
1960: immunological tolerance
Sir Frank Macfarlane Burnet was born in Australia and
was the son of Scottish parents. He obtained a degree
in Medicine in his native country and post-graduated in
England. He specialized in the virology area, with important
research related to influenza virus and herpes simplex.
He played a key role in virus isolation from human tissue,
and the first attempts to develop a vaccine for influenza.
After World War II, he also developed researches related
to the immune system, especially autoimmune mechanisms
and immunological tolerance1,2,21-23.
Peter Brian Medawar (Figure 2) was born in Petropolis
(RJ), and had an English mother and Lebanese father.
The family moved to England when he was only 14, where
he developed his studies and career. Differences with the
Brazilian government, which required his mandatory military
service, made him give up his Brazilian nationality. He majored
in zoology at Oxford and began transplantation research
during World War II. The main objectives were skin grafts in
burned skin areas. His studies led to the theory of acquired
immunological tolerance, the basis for the development of
solid organ transplants in the future1,2,4,5. The connection made
between his research and Cardiology was the applicability
of his results on immunological tolerance for the future
development of heart transplantation.
Konrad Bloch and Feodor Lynen – 1964: cholesterol
metabolism
The Nobel Prize in Physiology or Medicine of 1964 was
awarded jointly to two German chemists, Konrad Bloch and
Feodor Lynen. Bloch was born on January 21, 1912, in Neisse
(now Nysa), formerly part of Germany and currently in Poland.
He graduated in chemical engineering in 1934 in Munich.
In 1936, due to the persecution of Jews by the Nazis, Bloch
immigrated to the United States and joined the Department of
Biochemistry at Columbia University, where he developed the
research that led him to be awarded the Nobel Prize.
Feodor Lynen was born on April 6, 1911, in Munich,
Germany, where he graduated in chemistry. He developed
his entire career in Germany, living there even during the
world wars1,24.
Even without performing a real joint work, both
researchers carried out important discoveries in their
universities on the cholesterol regulation mechanism and
the fatty acid metabolism1,24. Starting from the idea that the
acetic acid, with slow reaction in the chemical essays, had to
show a more rapid and spontaneous reaction in the body, the
concept of activated acetic acid was formulated, in which,
in addition to adenyl-phosphoric acid as an energy source,
also included coenzyme A. They were able to determine not
only the structure of cholesterol, as well as the participation
of coenzyme A in the oxidation of the fatty acids 1,24.
Years later, these discoveries were crucial to demonstrate
the importance of cholesterol in atherosclerosis and, more
importantly, helped the development of statins, the major
class of drugs for treatment of hypercholesterolemia and
atherosclerotic disease.
Allan M. Cormack and Godfrey Hounsfield - 1979:
computed tomography
Allan Cormack was a South African biochemist and
nuclear physicist born in Johannesburg (South Africa), who
became a naturalized American in 1966. He is considered
one of the inventors of computed tomography and shared
the Nobel Prize in Physiology or Medicine with British
professor Godfrey Hounsfield. Cormack performed his
research in radiology initially at the University of Cape
Town until he immigrated to the United States, where he
worked at Harvard and Tufts University. There, he tested a
mathematical model based on the X radiation, essential to
the development of computed axial tomography1,25.
Sir Godfrey Hounsfield was an electrical engineer who
had the position of "inventor" at the Central Research
Laboratories in London. He started his career working on a
radar project as a weapon of war and designed the first British
transistorized computer in 1958, "EMIDEC 1100". Based on
the mathematical calculations of radiation developed by
Cormack, he developed Computed Tomography (CT) – so
that the first machine to "scan" the brain was marketed by
EMI. Three years later, he developed the first CT for the
entire body. He continued to make improvements in CT and
received numerous awards and honors, in addition to the
Nobel prize, with his latest award being the title of Knight of
the Queen of England - Sir, in 19811,25. CT developed further
in the following years and now has several applications
in cardiology, for instance, determination of the coronary
anatomy and the calcium score, and in the assessment of
pulmonary thromboembolism.
Bengt Samuelsso, Sune Bergström and John Vane – 1982:
prostaglandin function and development of angiotensinconverting enzyme inhibitors
Bengt Ingemar Samuelsso was a Swedish biochemist born
in 1934 in Halmstad, a researcher at the Karolinska Institute in
Sweden, and Nobel Prize laureate in Physiology or Medicine
with his institute colleague and also Swedish biochemist Sune
K. Bergström, and with the English chemist and pharmacologist
John Robert Vane 1. His research involved prostaglandin function,
purification, determination of their chemical structure and
identification of their mechanism of formation from unsaturated
fatty acids1,26,27. This information allowed the proposition of
acetylsalicylic acid mechanism of action, practically indispensable
treatment in coronary heart disease.
In addition to the research on prostaglandins, John Vane
is also considered one of the "discoverers" of AngiotensinConverting Enzyme inhibitors (ACE inhibitors) 1,26,27 .
During the 1960s and 1970s, and with the participation of
Brazilian Sergio Ferreira, Vane and his colleagues demonstrated
key steps in the synthesis of angiotensin and bradykinin,
which, in 1982, culminated in the launching of the first ACEI,
captopril1,26,27. This class of drugs has a vital role in the treatment
of hypertension, heart failure and coronary artery disease.
Michael Brown e Joseph Goldstein – 1985: LDLcholesterol receptors
Joseph L. Goldstein was born on April 18, 1940 in Sumter,
South Carolina, in the United States. He initially graduated
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Figure 2 – Peter Medawar’s picture. Source: http://www.nobelprize.org/nobel_prizes/medicine/laureates/1960/medawar-facts.html
in chemistry from Washington and Lee University and
subsequently, obtained his medical degree at UT Southwestern
Medical Center Dallas. He was a resident at Massachusetts
General Hospital, where he met Michael S. Brown, who later
would become his collaborator and together, they won the
Nobel Prize3. During the two following years, he worked at
the National Heart, Lung, and Blood Institute of the United
States, which contributed to increase his skills and taste for
scientific experimentation from the perspective of molecular
biology in human disease1,28-30.
Michael Stuart Brown was born on April 13, 1941, in
Brooklyn, New York. Similarly to Goldstein, he first obtained
a degree in chemistry and only then in Medicine. He also
worked at the National Heart, Lung, and Blood Institute of
the US, but in the area of gastroenterology and hereditary
diseases. In biochemistry laboratory, he learned enzymatic
manipulation techniques, among which, an enzyme that could
be related to familial hypercholesterolemia1,28-30.
Goldstein and Brown were awarded the Nobel Prize
for scientific research in which they identified receptors on
the surface of cells that mediate the uptake of Low-Density
Lipoprotein (LDL) circulating in the bloodstream. Furthermore,
they found that severe familial hypercholesterolemia is closely
related to these receptors, as with the decrease in the number
of membrane receptors, there is a lower uptake of circulating
cholesterol in the form of LDL, thus increasing levels of the
substance in the bloodstream from1,28-30. In this example, once
again, one can observe the close association between high
cholesterol levels, atherosclerosis, and ischemic heart disease.
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James Black, Gertrude Elion and George Hitchings –
1988: beta-blockers
James W. Black, from Uddington, Scotland, studied
medicine at the University of St. Andrews. In 1948, he
started an investigation on cardiac adrenergic alpha and
beta receptors, resulting in the synthesis of propranolol,
the prototype of beta-blockers, essential medications for
the treatment of heart failure and coronary artery disease.
Later, in 1976, he concluded the synthesis of cimetidine,
histamine H2-receptor antagonist, used in peptic disease
treatments. Together with James W. Black, researchers
Gertrude B. Elion (New York, United States) and George H.
Hitchings (Hoquiam, United States) were also awarded the
Nobel Prize of Medicine, for the development of drugs used
in chemotherapy, antibiotics and antivirals1,31.
Joseph Edward Murray and Edward Thomas – 1990:
organ transplantation
Joseph Murray was born on April 1st, 1919 in the city of
Milford, State of Massachusetts (United States) and died in
2012 due to a stroke. He graduated from Harvard medical
school and specialized in plastic surgery. He served in the US
military and had a very important role in the care of wounded
soldiers in World War II. When caring for burned patients, he
observed that many patients responded well to donor skin
grafts and decided to develop a research related to organ
transplantation. On December 23, 1954, he was part of the
team that made the first renal transplantation and, some years
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later, the first transplantation using a cadaveric source. Over the
years, he participated in studies on immunosuppressive drugs
such as azathioprine, aimed at reducing graft rejection1,32.
Edward Donall Thomas was born on March 20, 1920, in
the city of Mart, State of Texas (United States), and also died
in 2012. He graduated from medical school at Harvard and,
early in his career, he devoted himself to laboratory studies
related to bone marrow transplantation. Together with Joseph
Edward Murray, he received the Nobel Prize in Physiology or
Medicine as his studies helped to develop the transplantation of
organs and tissues. In the field of HF, heart transplantation was
indicated for patients that remained very symptomatic despite
optimal medical treatment, which was performed for the first
time in history in South Africa by Dr. Christiaan Barnard1,32.
Robert F. Furchgott, Ferid Murad and Louis J. Ignarro –
1998: nitric oxide
The Nobel Prize in Physiology or Medicine in 1998
was awarded jointly to Robert F. Furchgott (Charleston,
United States), Louis J. Ignarro (New York, United States)
and Ferid Murad (Whiting, United States) due to their
findings on Nitric Oxide (NO) as a signaling molecule in
the cardiovascular system1. NO is a soluble gas naturally
found in the human body, which acts on the signaling of
several biological processes.
The synthesis of NO occurs through the action of an
enzyme called NO synthase (NOS) from L-arginine and
L-citrulline amino acids, requiring for this enzymatic reaction,
the presence of two cofactors, oxygen and Nicotinamide
Adenine Dinucleotide Phosphate (NADPH). There are three
types of NOS, two of them called constitutive and calciumdependent NOS (cNOS), which are the endothelial and
neuronal forms that synthesize NO in normal conditions and
the calcium-independent form (iNOS), which is not expressed
or is in a much lesser amount under physiological conditions.
NO plays an important role in endothelial homeostasis,
contributing with its vasodilating and anticoagulant properties.
There is evidence that a decreased NO production is an
important factor in ischemic events in patients with coronary
artery disease and other suggesting that NO can exert
antiatherosclerotic actions. Furthermore, the nitrates, the most
widely used drugs in coronary artery disease and heart failure,
act by indirectly increasing NO bioavailability33-36.
Paul C. Lauterbur and Peter Mansfield – 2003: magnetic
resonance
Paul Lauterbur was born on May 6, 1929 in the United
States, having obtained his PhD in Chemistry at the University
of Pittsburgh in Pennsylvania (United States). Throughout his
career has received numerous awards for his work related to
magnetic resonance, including the gold medal of the Society
of Magnetic Resonance in Medicine in 1982, the European
Prize of Magnetic Resonance in 1986, the International Society
for Magnetic Resonance in Medicine Award in 1992, the gold
medal of the European Congress of Radiology in 1999, the
NAS Award for Chemistry in Service to Society in 2001 and
the Nobel Prize in Physiology or Medicine in 2003 together
with Englishman Sir Peter Mansfield1,37-39.
Peter Mansfield was born on October 9, 1933 in London
and a received his Ph.D. in physics in his hometown in 1962.
In the course of his career as an investigator he received
several awards, including the Gold Medal of the Society for
Magnetic Resonance in Medicine in 1983, the European
Prize of Magnetic Resonance in 1988, the title of Sir of the
British Crown in 1993, the Gold Medal of the European
Congress of Radiology and the European Association of
Radiology in 1995 and the Nobel Prize for Physiology and
Medicine, for his discoveries related to nuclear magnetic
resonance imaging in 20031,37-39.
Based on the initial findings of Lauterbur and Mansfield,
MRI has developed and now has wide application in
cardiology. It is considered, for instance, the gold standard
in non-invasive myocardial and heart function assessment.
Special Considerations
Carlos Chagas – 1911: an unjustly overlooked scientist
in relation to the Nobel Prize
Carlos Chagas (Figure 3) was the first researcher in the
world's scientific history to describe the complete cycle of a
disease, currently known as Chagas disease40. His research
with Trypanosoma cruzi started between the years 1907 and
1909, when he was sent to the countryside of the state of
Minas Gerais to help fight malaria among workers building
the Brazilian Central Railway7. In 1909, he identified the
parasite in the blood of a child with "fever, anemia, edema
and generalized lymphadenopathy" and later described the life
cycle of T. cruzi 7. Aided by a small team, he changed history
as a scientist that inspired a new era of knowledge, as he was
able to draw a clinical profile from his own observations.
Throughout his career, he received honors of national
importance, such as public health management positions,
as well as international prizes, such as the Schauddinn
award in Germany, for the most important discovery
of protozoology. For these reasons, he was nominated
four times for the Nobel Prize, but none fructified.
Researchers and historians have assessed, among other
sources, files from Oswaldo Cruz Foundation and the
Karolinska Institute to identify the reasons why Carlos Chagas
was not awarded the Nobel prize6,7,41-43.
Bestetti et al.6,7,41,42, in their set of historical publications,
solidly based the reasons why Chagas was not a Nobel
Prize laureate. These researchers even went to the Swedish
institute in person to review the original documents of the
time; their research, published in prestigious international
journals, are less disseminated than they should be in
Brazilian cardiology.
Gunnar Hedrèn was the board member of the
Karolinska Institute who analyzed and issued an opinion
on Chagas’ first nomination for the Nobel Prize in 19216,7.
Although there is no formal written opinion, the analysis of
documents from that time suggests that the counselor did
not value Chagas’ discovery6,7. Although now recognized
as renowned researcher, Chagas had opponents in South
America and Brazil. A group linked to the Bacteriology
Institute in Buenos Aires, including a Brazilian member,
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Figure 3 – Carlos Chagas picture. Source: Lagoeiro B, Gemal P. Carlos Chagas. Um homem, uma doença, uma história. Niterói: Ed. UFF; 2012.
insisted in the early years of Chagas' discovery, that there
was no association between the symptoms reported by
Chagas and the presence of T. cruzi6,44. Another group,
from the very Oswaldo Cruz Foundation and the School
of Medicine of Rio de Janeiro, disagreed with Chagas for
political reasons and, on several occasions, questioned
the importance of trypanosomiasis6. Among his opponents
were Figueiredo de Vasconcellos, Cardoso Fontes and
Plinio Marques6.
Chagas also lost prestige among the local population for
unpopular measures at the time when he was appointed
Director of Public Health, an equivalent post at the time of
the "Minister of Health". The mandatory vaccine for smallpox
was one of those most criticized measures, being even the
reason of a popular revolt6,42. Finally, the methods used by
the then President of the Karolinska Institute, JE Johansson,
are criticized. It is suggested that he excessively valued
researches related to physiology, rather than those related
to clinical medicine42.
A new indication and a Nobel award after Chagas’ death
are no longer expected. It persists, though, in the light of the
centenary of the discovery by Chagas, our pride in a great
Brazilian who, with all the honors and merits, made such a
contribution to humankind.
Bernard Lown – a brilliant clinical cardiologist that
received the Peace Nobel Prize of 1985
Bernard Lown was born on June 7, 1921, in the city
of Utena, Lithuania, and moved at age 13 with his family
to the USA and settled in the state of Maine, where he
became a medical doctor and completed his specialization
194
Arq Bras Cardiol. 2015; 105(2):188-196
in cardiology at the current Brigham and Women's hospital
in Boston 1,45. Together with engineer Baruch Berkowitz,
in 1961, he created the direct current used in the
defibrillator, allowing greater safety and efficacy in relation
to the then AC defibrillator created by Paul Zoll. Lown also
discovered the correct moment of the cardiac cycle in ECG
for the electrical discharge in ventricular tachyarrhythmias.
This therapy received the name of "cardioversion".
The defibrillator designed by Lown and Berkowitz was
used as standard therapy in cardiac arrhythmias until
the 1980s, when the models with biphasic current were
created. He also has researched the use of lidocaine as
an antiarrhythmic drug and the importance of serum
potassium in digitalis intoxication. Lidocaine, until then,
was basically used as a local anesthetic by dentists.
In the presence of HF, electrical therapies are essential in
preventing sudden death (of which ventricular dysfunction
is one of the most important risk factors) and in the
treatment of symptomatic arrhythmias, highly prevalent
in this group; digoxin is one of the drugs indicated for
patients with reduced ejection fraction and symptomatic
ones with functional class III or IV1,45.
Despite all these contributions to Medicine, his Nobel
Prize was won by other merits: a peacekeeper, he created the
International Physicians for the Prevention of Nuclear War,
in association with the then Soviet citizen Yevgeniy Chazov.
His association has also had the participation of Brazilian
physicians. He also published two famous books: “The lost art
of healing” and “Prescription for survival: a doctor's journey
to end nuclear madness”. He is currently a Professor Emeritus
at Harvard University and founder of the Lown Institute, of
which mission is described on their website as: “to help set
up a sustainable and compassionate health system, where
Mesquita et al.
Nobel Prize and Cardiology
Review Article
doctors can serve as healers and lawyers, where patients
receive the services they need and are protected from
unnecessary treatment and damage, and where financial
incentives are removed from clinical decision-making”1,45.
Conclusion
The Nobel Prize aims to reward researchers whose actions
and discoveries have contributed exceptionally to the progress
and the good of society. Regarding heart failure, the final pathway
of several forms of heart disease, 33 researchers in 16 awards
performed studies that yielded great contributions to its diagnosis
and treatment. Brazil, despite its growing scientific contributions
in recent decades, in the fields of Physiology and Medicine, has
no "genuinely" Brazilian laureates, despite the contributions of
Dr. Peter Medawar and Dr. Carlos Chagas - the latter unjustly
not a recipient of this honor.
Author contributions
Conception and design of the research:Mesquita ET,
Marchese LD, Gismondi RA. Acquisition of data: Marchese
LD, Dias DW, Barbeito AB, Gomes JC, Muradas MCS,
Gismondi RA. Analysis and interpretation of the data:
Mesquita ET, Marchese LD, Gismondi RA. Writing of the
manuscript:Mesquita ET, Marchese LD, Dias DW, Barbeito AB,
Gomes JC, Muradas MCS, Lanzieri PG, Gismondi RA. Critical
revision of the manuscript for intellectual content: Mesquita
ET, Marchese LD, Gismondi RA.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
The study is associated with the Post-Graduate Program in
Cardiovascular Sciences of Universidade Federal Fluminense.
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hundred years ago. Card Electrophysiol Rev. 2003;7(1):99-104.
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al. Anti-remodeling and anti-fibrotic effects of the neuregulin-1β glial
growth factor 2 in a large animal model of heart failure. J Am Heart Assoc.
2014;3(5):e000773.
15. Yang Y, Zhang H, Li X, Yang T, Jiang Q. Effects of PPARα/PGC-1α
on the myocardial energy metabolism during heart failure in the
doxorubicin induced dilated cardiomyopathy in mice. Int J Clin Exp Med.
2014;7(9):2435-42.
16. Ventura HO. Dickinson Woodruff Richards and cardiac catheterization. Clin
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Arq Bras Cardiol. 2015; 105(2):188-196
Back to the Cover
Viewpoint
Sudden Death in Brazil: Epilepsy Should be in Horizon
Fulvio Scorza and Paulo José Ferreira Tucci
Escola Paulista de Medicina – Unifesp, São Paulo, SP - Brazil
To date, a considerable amount of valuable information
about the problem of sudden cardiac death (SCD) has
been described. The incidence of SCD in the United
States ranges between 180000-400000 cases per year 1.
Martinelli et al demonstrated an incidence of 21270 cases
of SCD per year in the Metropolitan Area of São Paulo2.
Recently, Braggion-Santos et al.3 described the characteristics
of SCD in Ribeirão Preto, Brazil, according to autopsy
reports3. Revising 4501 autopsies, they identified 899 cases
of SCD (20%); the rate was 30/100000 residents/year3.
The vast majority of SCD cases involved coronary artery
disease (64%). Based on available scientific knowledge
related to SCD, it is extremely important to identify new
areas of research that might improve understanding of this
problem and to establish effective preventive measures to
minimize or even control the occurrence of SCD.
Although studies have shown that the increase in the
number of SCD caused by a combination of factors2,3, an
equally important risk factor for SCD which is not reported
and not explored in cardiologic research is epilepsy. Indeed,
a series of data could be put forward to explain it.
Epilepsy affects approximately 65 million individuals
worldwide and is one of the most common, chronic and
severe neurological diseases4-7. In developing and poor
countries, the incidence of epilepsy is higher when compared
with that of developed countries4-7. The prognostic evolution
has clearly shown that seizures are successfully controlled
with currently available antiepileptic drugs in approximately
two-thirds of individuals with epilepsy, which results in
one-third with refractory epilepsy4,8. For these patients
with uncontrolled seizures, epilepsy should be considered
a malignant condition, as it carries a mortality rate that
is 2‑3 times higher than that in the general population9.
Therefore, sudden unexpected death in epilepsy (SUDEP)
is the most frequent cause of epilepsy-related death9-12.
By definition, SUDEP is a sudden, unexpected, witnessed
or unwitnessed, non‑traumatic and non-drowning death
in individuals with epilepsy, with or without evidence of
seizures, in which post-mortem examination does not
reveal a toxicological or anatomical cause of death 13.
Keywords
Death, Sudden / prevention & control; Death, Sudden,
Cardiac; Coronary Artery Disease / mortality; Epilepsy / mortality.
Mailing Address: Paulo José Ferreira Tucci •
Escola Paulista de Medicina – UNIFESP. Rua Estado de Israel, 181/94, Vila
Clementino. Postal Code 04022-000, São Paulo, SP – Brazil
E-mail: [email protected], [email protected]
Manuscript received February 05, 2015; revised March 18, 2015; accepted
March 30, 2015.
DOI: 10.5935/abc.20150072
197
Epidemiological studies indicate that SUDEP is responsible
for 7.5% to 17% of all deaths in epilepsy and has an incidence
among adults between 1:500 and 1:1000 patient/year14.
The main risk factors for SUDEP include the number of
generalized tonic–clonic seizures, nocturnal seizures, young
age at epilepsy onset, longer duration of epilepsy, dementia,
absence of cerebrovascular disease, asthma, male gender,
symptomatic etiology of epilepsy and alcohol abuse12,15.
The cause or causes of SUDEP are still unknown, but one
of the main proposed mechanisms is related to autonomic
dysregulation, promoting cardiac abnormalities during and
between seizures16-18.
In this line of reasoning, our experimental data clarified
some possibilities. Using the pilocarpine model of temporal
lobe epilepsy, we evaluated heart rate in rats with epilepsy
in vivo and in an isolated ex vivo preparation (Langendorff
preparation)17. Baseline heart rate in vivo in animals with
chronic epilepsy (346 ± 7 bpm) was higher than in control
rats (307 ± 9 bpm) 17. Incidentally, no difference was
observed in the isolated ex vivo situation (control animals:
175 ± 7 bpm; chronic epilepsy: 176 ± 6 bpm), suggesting
that autonomic modulation of the heart is altered in epileptic
animals, explaining the maintenance of an increased basal
heart rate in these animals17. In addition, we also evaluated
heart rate responses during stage 5 of amygdala kindling
model, the phase when animals develop generalized
seizures18,19. Animals did not show significant differences in
basal heart rate; however, basal heart rate was higher during
stage 5 of kindling, possibly resulting from sympathetic
activation caused by the chronic epileptic condition 18,19.
As demonstrated in previous studies20, intense bradycardia at the
beginning of seizure was followed by rebound tachycardia18,19.
Moreover, the intensity of tachycardia was directly related
to the number of generalized seizures, suggesting that
repeated generalized tonic-clonic seizures affect sympathetic
outflow18,19. For that reason, a plausible explanation is that
continuous and intermittent sympathetic activation due to
uncontrolled seizures is capable of maintaining cardiac rhythm,
modulating the heart in accelerated-state permanently.
Considering all these translational information, it is clear
that epilepsy-related mortality, particularly SCD, is a significant
public health concern. Thus, it is crucial that a concerted
and collaborative approach be implemented to solve this
problem. In order to do so, it is extremely necessary to attain
a real convergence between cardiologists and neurologists to
carefully evaluate and discuss the electroencephalographic
and electrocardiographic recordings, the cardiac and cerebral
imaging findings and refined histopathological studies in order
to detect or prevent the occurrence of a tragic fatal event
among individuals with epilepsy.
Scorza & Tucci
Epilepsy and sudden cardiac death
Viewpoint
Acknowledgements
This study has been supported by: UNIFESP, FAPESP
(Fundação de Amparo à Pesquisa do Estado de São
Paulo); CNPq (Conselho Nacional de Desenvolvimento
Científico e Tecnológico); CEPID/FAPESP; FAPESP/
PRONEX and FAPESP/CNPq/MCT (Instituto Nacional de
Neurociência Translacional).
Author contributions
Conception and design of the research:Scorza F,
Tucci PJF. Acquisition of data:Scorza F. Analysis and
interpretation of the data: Scorza F, Tucci PJF. Statistical
analysis: Scorza F. Writing of the manuscript:Scorza F,
Tucci PJF. Critical revision of the manuscript for intellectual
content: Tucci PJF.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
This study was funded by FAPESP, CNPq, Capes e Unifesp.
Study Association
This study is not associated with any thesis or dissertation work.
References
1. Chugh SS, Reinier K, Teodorescu C, Evanado A, Kehr E, Al Samara M, et al.
Epidemiology of sudden cardiac death: clinical and research implications.
Prog Cardiovasc Dis. 2008;51(3):213-28.
12. Hesdorffer DC, Tomson T, Benn E, Sander JW, Nilsson L, Langan Y, et al.
Commission on Epidemiology; Subcommission on Mortality. Combined
analysis of risk factors for SUDEP. Epilepsia. 2011;52(6):1150-9.
2.
13.Nashef L. Sudden unexpected death in epilepsy: terminology and
definitions. Epilepsia. 1997;38(11 Suppl):S6-8.
Martinelli M, Siqueira SF, Zimerman LI, Neto VA, Moraes AV Jr, Fenelon G.
Sudden cardiac death in Brazil: study based on physicians’ perceptions of the
public health care system. Pacing Clin Electrophysiol. 2012;35(11):1326-31.
3. Braggion-Santos MF, Volpe GJ, Pazin-Filho A, Maciel BC, Marin-Neto JA,
Schmidt A. Sudden cardiac death in Brazil: a community-based autopsy
series (2006-2010). Arq Bras Cardiol. 2015;104(2):120-7.
4. Laxer KD, Trinka E, Hirsch LJ, Cendes F, Langfitt J, Delanty N, et al. The
consequences of refractory epilepsy and its treatment. Epilepsy Behav.
2014;37:59-70.
5. Banerjee PN, Filippi D, Allen Hauser W. The descriptive epidemiology of
epilepsy -- a review. Epilepsy Res. 2009;85(1):31-45.
6. Forsgren L, Beghi E, Oun A, Sillanpää M. The epidemiology of epilepsy in
Europe -- a systematic review. Eur J Neurol. 2005;12(4):245-53.
7. Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol.
2003;16(2):165-70.
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Kwan P, Sander JW. The natural history of epilepsy: an epidemiological view.
J Neurol Neurosurg Psychiatry. 2004;75(10):1376-81.
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Gaitatzis A, Sander JW. The mortality of epilepsy revisited. Epileptic Disord.
2004;6(1):3-13.
14. Schuele SU, Widdess -Walsh P, Bermeo A, Lüders HO. Sudden
unexplained death in epilepsy: the role of the heart. Cleve Clin J Med.
2007;74(Suppl 1):S121-7.
15. Hesdorffer DC, Tomson T. Sudden unexpected death in epilepsy: potential
role of antiepileptic drugs. CNS Drugs. 2013;27(2):113-9.
16. Surges R, Taggart P, Sander JW, Walker MC. Too long or too short? New
insights into abnormal cardiac repolarization in people with chronic
epilepsy and its potential role in sudden unexpected death. Epilepsia.
2010;51(5):738-44.
17. Colugnati DB, Gomes PA, Arida RM, de Albuquerque M, Cysneiros
RM, Cavalheiro EA, et al. Analysis of cardiac parameters in animals
with epilepsy: possible cause of sudden death? Arq Neuropsiquiatr.
2005;63(4):1035-41.
18. Pansani AP, Colugnati DB, Sonoda EY, Arida RM, Cravo SL, Schoorlemmer
GH, et al. Tachycardias and sudden unexpected death in epilepsy: a gold
rush by an experimental route. Epilepsy Behav. 2010;19(3):546-7.
19. Pansani AP, Colugnati DB, Schoorlemmer GH, Sonoda EY, Cavalheiro EA,
10. Nashef L, Ryvlin P. Sudden unexpected death in epilepsy (SUDEP): update
and reflections. Neurol Clin. 2009;27(4):1063-74.
Arida RM, et al. Repeated amygdala-kindled seizures induce ictal rebound
11. Nei M, Hays R. Sudden unexpected death in epilepsy. Curr Neurol Neurosci
Rep. 2010;10(4):319-26.
20. Devinsky O. Effects of seizures on autonomic and cardiovascular function.
Epilepsy Curr. 2004;4(2):43–6.
tachycardia in rats. Epilepsy Behav. 2011;22(3):442-9.
Arq Bras Cardiol. 2015; 105(2):197-198
198
Back to the Cover
Clinicoradiological Session
Case 6 / 2015 – A 27-Year-Old Male Patient with Double Aortic and
Pulmonary Valve Lesion after Double Valvotomy in Childhood
Edmar Atik
Clínica Privada Dr. Edmar Atik, São Paulo, SP – Brazil
Clinical data: The patient underwent correction of congenital
pulmonary and aortic valve stenosis, both with manifestations,
at 7 years of age. Afterwards, there was progressive residual
lesion of both valves, with predominance of regurgitation,
and development of acute arrhythmias such as paroxysmal
atrial fibrillation, in addition to ventricular extrasystoles.
The obstructions were significant, with pressure gradients of
90 and 60 mmHg in the pulmonary and aortic valves, respectively.
The patient was asymptomatic, and the loud systolic murmur was
accompanied by thrill all over the precordium and neck vessels.
There was right ventricular overload on the electrocardiogram
(ECG). Double valvoplasty in the three-leaflet valves resulted
in a good anatomical solution initially. To date, the patient
reports shortness of breath on moderate exertion and precordial
palpitations. He is on antiarrhythmic drug (amiodarone), after
atrial fibrillation was controlled.
Physical examination: Good general state of health,
normal breathing, acyanotic, normal pulses. Weight: 77 kg;
height: 181 cm; blood pressure (BP): 110/70 mmHg; and heart
rate (HR): 51 bpm. The aorta (Ao) was moderately palpable
on the suprasternal notch.
The apical impulse was not palpable on the precordium,
and there were mild systolic impulses on the left sternal
border. Heart sounds were normal, and there was a grade
1-2/4 coarse systolic murmur in the pulmonic and aortic
areas, and a grade 1-2/4 coarse diastolic murmur along the
left sternal border. The liver was not palpable and the lungs
were clear to auscultation.
Laboratory tests:
Electrocardiogram showed normal sinus rhythm and signs
of left anterior hemiblock, with no chamber overload, and
normal ventricular repolarization. PA: +20o, QRSA: -60o,
TA: +40o. QRS complex duration was 0.11”, PR = 0.16”
and QTc = 0.45” (Figure 1).
Chest radiograph showed moderately enlarged cardiac
silhouette due to enlarged atrial and ventricular arches; the
Keywords
Pulmonary Valve Stenosis; Aortic Valve Stenosis; Balloon
Valvoplasty; Heart Defects, Congenital.
Mailing address: Edmar Atik •
Rua Dona Adma Jafet, 74, conj. 73, Bela Vista. Postal Code 01308-050.
São Paulo, SP – Brazil
E-mail: [email protected]; [email protected]
Manuscript received July 23, 2014; revised manuscript October 06, 2014;
accepted October 06, 2014.
DOI: 10.5935/abc.20140214
199
pulmonary vascular network was normal. Cardiomegaly
progressed since the surgical correction, and the current
cardiothoracic ratio was 0.58 (Figure 1).
Echocardiogram showed dilated right and left cardiac
chambers (right ventricle − RV = 35, left atrium − LA = 46;
left ventricle − LV = 64; Ao = 31 mm); RV ejection fraction
(RVEF) of 53% (Simpson’s method); LV ejection fraction
(LVEF) of 58%; RV- pulmonary trunk (PT) pressure gradient
of 14 mmHg; LV - Ao pressure gradient of 15 mmHg; and
severe pulmonary and aortic regurgitation. The pulmonary
systolic pressure was 40 mmHg. Ascending aorta and PT
dilatation (40-mm diameter).
Magnetic resonance imaging (Figure 2) also showed
enlargement of right and left cardiac chambers with preserved
ventricular function. RV end-diastolic volume of 200 mL/m2,
LV end-diastolic volume of 211 mL/m2, RVEF of 54% and
LVEF of 58%. Ascending aorta of 45 mm, and PT of 36 mm.
24-hour dynamic ECG (Holter monitoring) showed
627 ventricular extrasystoles and 121 supraventricular
extrasystoles. Two episodes of non-sustained ventricular
tachycardia with 6 complexes and two of atrial tachycardia
with 16 complexes.
Clinical diagnosis: Double pulmonary and aortic valve
lesion with manifestations, showing signs of progressive
dilatation of both ventricles, in late course after surgical
correction in childhood.
Clinical reasoning: during the course of the disease, the
clinical elements were consistent with the diagnosis of double
pulmonary and aortic valve lesion, with predominance of
the first. Shortness of breath and development of ventricular
arrhythmias and paroxysmal atrial fibrillation are related to
the residual lesions, which progressively increased since
childhood. Noteworthy, despite the evident biventricular
dilatation, no electrical overload of these chambers was
observed. Perhaps both ventricular dilatations had electrically
counterbalanced one another.
Differential diagnosis: Concomitant lesion of both
semilunar valves as congenital defects is usually associated
with some genetic syndrome, which was not the case.
Residual lesions of both valves commonly occur after
correction of obstructive defects alone or in association, as
occurs in the tetralogy of Fallot.
Management: in view of the progression of the residual
defects with excessive dilatation of both ventricles, although
with biventricular function still preserved, a surgical approach
was chosen with valve replacement for a mechanical prosthetic
valve in the aortic position and for a biological prosthetic
valve in the pulmonary position. Because of the ascending
aorta dilatation, a dacron tube was inserted inside the vessel.
Edmar Atik
Double aortic and pulmonary valve lesion
Clinicoradiological Session
Figure 1 – Chest radiograph shows moderate enlargement of the cardiac silhouette. Electrocardiogram shows left anterior hemiblock, with no signs of cardiac overload.
Commentaries: residual valve regurgitation after
surgical or percutaneous valvotomy, whether pulmonary or
aortic, has become a common outcome that requires the
performance of other operative techniques, such as Ross’
technique. It is estimated that approximately 30% of these
patients undergoing heart valve correction require surgical
reintervention to prevent further progression of the heart
valve defects, which ultimately result in ventricular dilatation
and dysfunction.
The reintervention usually implies the need for valve
replacement. The values currently recommended to prevent
further deterioration of the ventricular function are 120 mL/m2
for the end-diastolic volume and of 90 mL/m2 for the end-systolic
volume. In practice, however, we have observed much higher
values until surgical reintervention is indicated, as incidentally
occurred in the present case. Ideally, these patients should be
duly monitored, in order to follow the parameters recommended
for a more favorable outcome in the long term.
Arq Bras Cardiol. 2015; 105(2):199-201
200
Edmar Atik
Double aortic and pulmonary valve lesion
Clinicoradiological Session
Figure 2 – Magnetic resonance imaging shows clear enlargement of the right and left ventricles, with preserved function of both, in four-chamber and cross-sectional views.
201
Arq Bras Cardiol. 2015; 105(2):199-201
Back to the Cover
Case Report
Profound Sustained Hypotension Following Renal Denervation: A
Dramatic Success?
Ganiga Srinivasaiah Sridhar1, Timothy Watson1,2, Chee Kok Han1, Wan Azman Wan Ahmad1
Departamento de Cardiologia - Universidade Malaya Medical Center - Kuala Lumpur Malaysia1; Departamento de Medicina - Universidade de
Auckland - Auckland, New Zealand2
Introduction
A 67-year-old woman with drug-refractory essential
hypertension was admitted for renal sympathetic denervation
(RDN). The secondary causes of hypertension were fully
investigated in this patient. A 24-h ambulatory blood pressure (BP)
monitor documented a mean daytime BP of 172/101 mmHg, a
mean nighttime BP of 151/84 mmHg, and an overall mean BP
of 167/97 mmHg despite compliance with metoprolol (50 mg
twice daily), amlodipine (10 mg once daily), lisinopril (20 mg
once daily), prazosin (2 mg thrice daily), and hydrochlorothiazide
(50 mg once daily).
The patient was fasted for 4 h. Her usual antihypertensive
drug therapy was continued. After the administration
of 5,000 international units of heparin and 100 μg of
fentanyl, a 7-F Renal Double Curve guide catheter (Cordis
Corporation, Fremont, CA ,USA) was inserted into the right
renal artery (no accessory vessel). A 0.014-in Runthrough
floppy guide wire (Terumo Medical Corporation, Somerset,
NJ, USA) was advanced into place. A 6-mm ONESHOTTM
(Covidien, Mansfield, MA, USA) irrigated RDN balloon
was advanced into place (Figure 1), and a single ablation
was performed. The procedure was then repeated on the
other side. The patient remained hemodynamically stable
throughout and at the completion of the procedure with
a BP of 150/80 mmHg. Hemostasis was achieved with the
Perclose ProGlide Suture-Mediated Closure System (Abbott
Vascular, Santa Clara, CA, USA), and the patient was then
returned to our ward for monitoring.
One hour later, the patient complained of dizziness
and blurring of vision. Her Glasgow Coma Scale score
remained 15 with preserved mentation. She was not in pain.
Her pulse rate was 87 bpm, and her BP was 77/38 mmHg.
However, she appeared well perfused and was clinically
euvolemic. There was no evidence of a groin hematoma,
and her abdomen was soft. A 12-lead electrocardiogram
showed no change, and a transthoracic echocardiogram
Keywords
Hypertension; Sympatectomy; Medication Therapy;
Management; Hypotension.
Mailing Address: Timothy Watson •
Department of Cardiology, University Malaya, Lembah Pantai,
Postal Code 59100, Kuala Lumpur, Malaysia
Email: [email protected]
Manuscript received July 26, 2014; revised manuscript August 21, 2014;
accepted October 06, 2014.
DOI: 10.5935/abc.20150100
202
showed normal left ventricular function. Her hemoglobin
level was similar to baseline, and her arterial blood gas
levels, including lactate, were unremarkable.
She was given intravenous dopamine that was titrated to
response. At 10 μg/kg/min, her BP rose to 120/70 mmHg, and
her symptoms resolved entirely. Over the subsequent 48 h, she
was extremely sensitive to reductions in the dose of dopamine
and exhibited a markedly fluctuating BP. However, by 72 h, the
dopamine had been carefully weaned and discontinued. She was
discharged home after she remained stable for a further 24 h.
At a 3-month review, she remains well with a mean daytime office
BP of 124/72 mmHg while on amlodipine (5 mg once daily).
Discussion
Around 12% of patients with essential hypertension who are
considered resistant to conventional therapy have persistently
elevated BP despite the use of three or more pharmacological
agents1,2. In such instances, abnormal renal excretory function,
which is largely influenced by renal sympathetic nerve activity,
may have a central role3. Catheter-based RDN, which is a
modern incarnation of a historically effective treatment, has
recently emerged as a novel therapeutic strategy. Proof of
concept and subsequent randomized (unblinded) data that were
collected while using the Symplicity® catheter (Medtronic, Inc.,
Minneapolis, MN, USA) have demonstrated reductions in office
BP of 20/10, 24/11, 25/11, and 23/11 mmHg at 1, 3, 6, and
12 months, respectively, in a group of patients taking an average
of five antihypertensive drugs4,5. Such early exciting reports have
stimulated the development of numerous other similar devices,
including the ONESHOTTM catheter that was used in this case6.
In some cases, early BP reductions have been reported
following RDN. However, in other cases, the response is
not always immediate, or it can take several months to
appear. Additionally, RDN is associated with a failure rate of
10%–30%, and the only predictor of response in early studies
is the magnitude of the systolic BP elevation at baseline7.
Explanations for this broad variability in outcome are
uncertain, except that raw BP measurements may lack the
sensitivity required for them to be considered a true measure
of successful RDN8. This may in part explain the lackluster
performance of RDN in the Symplicity-3 trial, in which
RDN failed to demonstrate superiority over conventional
treatments when compared to a sham-control procedure9.
However, despite this, the use of RDN does seem to significantly
reduce renal norepinephrine spillover10. Therefore, it is possible
that those patients who exhibit more sympathetic over-activity
may experience a greater degree of BP reduction with RDN.
Because sympathetic over-activity is not routinely measured in
clinical practice, this remains speculative.
Sridhar et al.
Dramatic success of RDN
Back to the Cover
Case Report
Right Kidney
Left Kidney
Figure 1 – Renal Denervation Procedure. Selective angiography performed with a 7-F Renal Double Curve guide catheter in the left anterior oblique 10° projection.
Note that a single renal artery supplies each kidney and that the caliber and length of the main renal artery prior to bifurcation is ideally suited to denervation.
Nonetheless, the role of RDN in the treatment of resistant
hypertension remains uncertain, but the sustained and
impressive BP reductions that were observed in this and
other cases should encourage further research to improve the
understanding of the mechanisms through which hypertension
is mediated and to identify those patients who are likely to
achieve the most dramatic responses with RDN.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Author contributions
Study Association
Acquisition of data: Sridhar GS, Han CK, Ahmad WAW;
Writing of the manuscript: Sridhar GS, Watson T, Han
CK, Ahmad WAW; Critical revision of the manuscript for
intellectual content: Watson T.
This study is not associated with any thesis or dissertation work.
Arq Bras Cardiol. 2015; 105(2):202-204
203
Sridhar et al.
Dramatic success of RDN
Case Report
References
1.
Persell SD. Prevalence of resistant hypertension in the United States, 20032008. Hypertension. 2011;57(6):1076-80.
2. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al.
2013 ESH/ESC guidelines for the management of arterial hypertension: the
Task Force for the Management of Arterial Hypertension of the European
Society of Hypertension (ESH) and of the European Society of Cardiology
(ESC). Eur Heart J. 2013;34(28):2159-219.
3. DiBona GF. The sympathetic nervous system and hypertension: recent
developments. Hypertension. 2004;43(2):147-50.
4. Krum H, Barman N, Schlaich M, Sobotka P, Esler M, Mahfoud F, et al;
Symplicity HTN-1 Investigators. Catheter-based renal sympathetic
denervation for resistant hypertension: durability of blood pressure
reduction out to 24 months. Hypertension. 2011;57(5):911-7.
5.
204
Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal
sympathetic denervation in patients with treatment-resistant hypertension
(The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet.
2010;376(9756):1903-9.
Arq Bras Cardiol. 2015; 105(2):202-204
6. Ormiston JA, Watson T, van Pelt N, Stewart R, Stewart JT, White JM,
et al. Renal denervation for resistant hypertension using an irrigated
radiofrequency balloon: 12-month results from the Renal Hypertension
Ablation System (RHAS) trial. Eurointervention. 2013;9(1):70-4.
7. Thomas G, Shishehbor MH, Bravo EL, Nally JV. Renal denervation
to treat resistant hypertension: guarded optimism. Cleve Clin J Med.
2012;79(7):501-10.
8.
Sathananthan J, Watson T, Whitbourn RJ, Stewart JT, Doughty RN, Ormiston
JA, et al. Renal sympathetic denervation: indications, contemporary devices
and future directions. Interv Cardiol. 2014;6(1):57-69.
9.
Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, et
al; SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation
for resistant hypertension. N Engl J Med. 2014;370(15):1393-401.
10. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus
K, et al. Catheter-based renal sympathetic denervation for resistant
hypertension: a multicentre safety and proof-of-principle cohort study.
Lancet. 2009;373(9671):1275-81.
Back to the Cover
Imagem
Giant Right Atrial Mass Following Surgical Aortic Valve Replacement
Teresa Bastante and Fernando Alfonso
Hospital Universitario de La Princesa, Madrid – Spain
A 75-year-old man underwent elective biological aortic
valve replacement. Two weeks after surgery, transthoracic
echocardiography (TTE) showed a small pericardial effusion.
On the following day, the patient suffered from syncope.
A repeated TTE revealed a “giant” echo-dense mass
(90x80 mm) occupying the entire right atrium and severely
limiting tricuspid valve inflow. Although the initial differential
diagnosis included the development of an intracavitary
process, the rapidly-growing mass with a characteristic
echo‑lucent layer at its atrial aspect (consistent with the
atrial wall and visceral pericardium) (arrows) led to the final
diagnosis of a pericardial hematoma mimicking a huge atrial
mass. Emergency surgical exploration confirmed the diagnosis.
Author contributions
Acquisition of data: Bastante T. Analysis and interpretation
of the data: Bastante T. Writing of the manuscript: Bastante
T, Alfonso F. Critical revision of the manuscript for intellectual
content: Bastante T, Alfonso F. Supervision / as the major
investigador: Alfonso F.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
There were no external funding sources for this study.
Keywords
Aortic Valve/surgery; Pericardial Effusion; Heart Atria/
abnormalities.
Study Association
This study is not associated with any thesis or dissertation work.
Mailing Address: Fernando Alfonso •
Hospital Universitario de La Princesa. C. Diego de Leon, 62, Madrid.
Postal Code 28006. Madrid – Spain
E-mail: [email protected]
Manuscript received March 09, 2015; revised manuscript March 13, 2015;
accepted March 24, 2015.
DOI: 10.5935/abc.20150066
Figure 1 – Transthoracic echocardiography: giant eco-dense mass occupying the entire right atrium (Panel A) and severely limiting tricuspid valve inflow (Panel B).
Atrial wall and visceral pericardium (arrows)
205
Back to the Cover
Letter to the Editor
Subclinical Ventricular Dysfunction Detected by Speckle-Tracking
Two Years after Use of Anthracycline
Aguinaldo Figueiredo Freitas Jr., Raquel Oliveira Santos, Salvador Rassi
Serviço de Cardiologia da Faculdade de Medicina da Universidade Federal de Goiás, Goiânia, Goiás - Brazil
Dear Editor
We would like to congratulate the authors for the publication
of their article “Subclinical Ventricular Dysfunction Detected
by Speckle-Tracking Two Years after Use of Anthracycline”,
considering the great practical applicability of the theme.
Cardiotoxicity secondary to chemotherapy drugs is a reality
that imposes, on cardiologists and oncologists, the challenge of
prevention and/or early detection of this complication, which
has high morbidity and mortality1.
In this regard, we read with interest the abovementioned
article, which highlights the usefulness of speckle-tracking to
attain an early diagnosis of subclinical ventricular dysfunction,
Keywords
Heart Failure; Ventricular Dysfunction Left/chemically
induced; Echocardiography; Anthracyclines/adverse effects.
Mailing Address: Aguinaldo Figueiredo de Freitas Junior •
Rua T-51, n 964 – apto. 1902, Bueno. Postal Code 74215-210, Goiânia,
GO – Brazil
E-mail: [email protected], [email protected]
Manuscript received May 11, 2015; revised manuscript June 29, 2015;
accepted June 29, 2015.
although this finding does not directly imply in implementing
treatment due to the lack of current scientific evidence,
which makes studies in this area even more important.
However, we would like to point out some aspects to
add to the scientific information brought on by this article.
In the Results section, the authors demonstrate that almost
80% of patients had also received cyclophosphamide as a
chemotherapy drug, an alkylating agent that may be associated
with ventricular dysfunction rates of up to 25% of the cases2,3,
which cannot be minimized in the Discussion and Conclusion
sections of this study. This same rationale can be applied to
the more than 50% of patients receiving radiotherapy in the
mediastinal region, regardless of the treated hemithorax, since
the incidence of coronary heart disease in these patients is a
side effect of significant incidence4.
We also observed a high rate of hypertension in both groups
of patients and controls and that the systolic and diastolic
BP levels were higher in the latter than in the first group.
We would like to know if there was any difference between
the groups regarding the class of antihypertensive drug used,
as data in the literature suggest some protective effect of ACE
inhibitors and beta-blockers on the incidence of ventricular
dysfunction and major clinical outcomes5.
DOI: 10.5935/abc.20150102
References
1. Vejpongsa P, Yeh ET. Topoisomerase 2: a promising molecular target for
primary prevention of anthracycline-induced cardiotoxicity. Nature.
2014;95(1):45-52.
206
2.
Kalil Filho R, Hajjar LA, Bacal F, Hoff PM, Diz Mdel P, Galas FR, et al; Sociedade
Brasileira de Cardiologia. I Brazilian guideline for cardio‑oncology from
Sociedade Brasileira de Cardiologia. Arq Bras Cardiol. 2011;96(2 Suppl1):1-52.
3.
Gardner SF, Lazarus HM, Bednarczyk EM, Creger RJ, Miraldi FD, Leisure G,
et al. High-dose cyclophosphamide-induced myocar- dial damage
during BMT: assessment by positron emission tomography. Bone Marrow
Transplant. 1933;12(2):139-44.
4. Kirova YM. Recent advances in breast cancer radiotherapy: evolution
or revolution, or how to decrease cardiac toxicity? World J Radiol.
2010;2(3):103-8.
5. Kalam K, Marwick TH. Role of cardioprotective therapy for prevention
of cardiotoxicity with chemotherapy: A systematic review and
meta‑analysis. Eur J Cancer. 2013;49(13):2900-9.
Freitas Jr. et al.
Subclinical ventricular dysfunction and anthracyclines
Letter to the Editor
Reply
Dear authors
We appreciate your interest and comments about our article.
Cyclophosphamide-associated cardiotoxicity presents
as a syndrome of heart failure, myocarditis, pericarditis,
or their association and can lead to death. It has an acute
onset, with signs and symptoms occurring within one to ten
days after the first dose, lasting for approximately one week1.
Delayed cardiotoxicity development (> 3 weeks) is very rare
in patients that survive the initial event2-4. In our sample,
patients were assessed after a median of two years after the
end of chemotherapy, making it unlikely that the obtained
results can be attributed to the use of cyclophosphamide.
The observation about the increased incidence of coronary
artery disease (CAD), as a side effect of radiotherapy in patients
with breast cancer is absolutely pertinent. This increase is
proportional to the number of cardiovascular risk factors the
patients have and the mean dose of radiation to the heart.
Previous data demonstrated that CAD development after
radiation therapy occurred after a longer period of follow-up:
82 months, on average5.
Recently, Darby et al6 showed an increase of 16.3%
(per Gray of radiation) in the rate of major coronary events
in the first four years after radiation therapy in women
with breast cancer6. This increase begins in the first five
years after radiotherapy and persists for at least 20 years6.
The development of new technologies in the field of radiation
therapy has shown to be favorable to reduce this side effect7.
In our study, however, none of the patients had coronary
event during the study period.
Although there was no difference in the percentage of
participants considered hypertensive in both groups (p = 0.71),
the controls had higher levels of systolic and diastolic BP at
the time of evaluation. As stated in the Discussion section,
we attribute this fact to greater adherence to antihypertensive
therapy among patients who were undergoing more stringent
medical follow-up in the post-chemotherapy period.
The increase in blood pressure levels tends to compromise strain
values8. However, despite these higher blood pressure levels in
the control group, the strain values were more compromised
in the group using doxorubicin (DOX), which reinforces the
importance of this drug as an independent predictor of reduced
εLL and εCC in our patients.
There was no significant difference between the
groups regarding the class of antihypertensive drug used:
fourteen patients (34%) from the control group used
angiotensin‑converting enzyme inhibitors or Angiotensin
II‑receptor blockers vs. ten patients (25%) in the group
treated with DOX (p = 0.367). One (2.4%) participant from
the control group used a beta-blocker vs. five (12.5%) in the
DOX group (p = 0.109).
Sincerely,
André L C Almeida
Edval Gomes dos Santos Júnior
References
1. Ayash LJ, Wright JE, Tretyakov O, Gonin R, Elias A, Wheeler C, et al.
Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and
tumor response. J Clin Oncol 1992;10(6):995-1000.
5.
Kalil Filho R, Hajjar LA, Bacal F, Hoff PM, Diz M del P, Galas FR, et al; Sociedade
Brasileira de Cardiologia. I Brazilian guideline for cardio‑oncology from
Sociedade Brasileira de Cardiologia. Arq Bras Cardiol. 2011;96(2 Supll.1):1-52.
2. Gottdiener JS, Appelbaum FR, Ferrans VJ, Deisseroth A, Ziegler
J.Cardiotoxicity associated with high dose cyclophosphamide therapy.
Arch Intern Med. 1981;141(6):758-63
6.
Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman, Bronnum D,
et al. Risk of ischemic heart disease in women after radiotherapy for breast
cancer. N Engl J Med. 2013;368(11):987-98.
3.
Braverman AC, Antin JH, Plappert MT, Cook EF, Lee RT. Cyclophosphamide
cardiotoxicity in bone marrow transplantation: a prospective evaluation of
new dosing regimens. J Clin Oncol. 1991;9(7):1215-23.
4.
Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents - incidence,
treatment and prevention. Drug Saf. 2000;22(4):263-302.
7. Travis LB, Ng AK, Allan JM, Pui CH, Kennedy AR, Xu XG, et al. Second
malignant neoplasms and cardiovascular disease following radiotherapy.
J Natl Cancer Inst. 2012;104(5):357-70.
8.
Marwick TH, Leano RL, Brown J, Sun JP, Hoffmann R, Lysyansky P, et al. Myocardial
strain measurement with 2-dimensional speckle-tracking echocardiography:
definition of normal range. JACC Cardiovasc Imaging. 2009;2(1):80-4.
Arq Bras Cardiol. 2015; 105(2):206-207
207
Back to the Cover
Erratum
December issue of 2014, vol. 103 (6), pages. e73-e80
In the Original Article “Case 6/2014 – A Case of a 61-Year-old Woman with Diastolic Heart Failure”, pages e73-e80, by authors
Fabio Grunspun Pitta, Natalia Quintella Sangiorgi Olivetti, Diego Simões Peniche, Andrea Maria Dercht, Paulo Sampaio
Gutierrez, Luiz Alberto Benvenuti, please be aware that the correct spelling for to Andrea Maria Bercht is Andrea Maria Dercht.
June 2015 Issue, vol. 104 (6), pages 433-442
In the original article “I Brazilian Registry of Heart Failure - Clinical Aspects, Care Quality and Hospitalization Outcomes”,
published in the June 2015 of the Arquivos Brasileiros de Cardiologia [Arq Bras Cardiol. 2015; 104(6): 433-442], suffered
the following correction:
Correcting the text:
In the analysis of the etiologies by region, patients from the South, Southeast and Northeast showed a predominance of the
ischemic etiology (33.6%, 32.6%, and 31.9%, respectively). In patients in the Northern region the hypertensive etiology (37.2%)
predominated, while among patients in the Northern region the Chagasic etiology predominated (42.4%) (Table 2).
And considering the following text:
In the analysis of the etiologies by region, patients from the South, Southeast and Northeast showed a predominance of the
ischemic etiology (33.6%, 32.6%, and 31.9%, respectively). In patients in the Northern region the hypertensive etiology (37.2%)
predominated, while among patients in the west-central region the Chagasic etiology predominated (42.4%) (Table 2).
DOI: 10.5935/abc.20150103
208

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