www.arquivosonline.com.br
Sociedade Brasileira de Cardiologia • ISSN-0066-782X • Volume 101, Nº 6, December 2013
Figure 1 - 65-year-old male patient that came to the emergency room with atypical chest
pain, nonspecific ECG and normal myocardial necrosis markers (enzymes). Page 567
Editorial
Is Conventional Cardiac Pacing Harmful in Patients with Normal
Implementation of Multicenter Records in the Therapeutic
Ventricular Function?
Cardiovascular Assessment in Brazil
Brazilian Portuguese Validated Version of the Cardiac Anxiety
Original Articles
Questionnaire
Predictors of Hospitalization in Patients with Syncope Assisted in
Review Article
Specialized Cardiology Hospital
Coronary Computed Tomography Angiography in the Assessment of
Prevalence of Ischemia on Myocardial Perfusion Scintigraphy of Pre-
Acute Chest Pain in the Emergency Room
and Postmenopausal Women
Letter to the Editor
Chromosomal Abnormalities in Patients with Congenital Heart Disease
Clinical Significance of Histological Features of Thrombi in Patients
Coronary Trunk Dissection with Stent Displacement: Points to Remember!
The Year 2011 in Interventional Cardiology
with Myocardial Infarction
The Bleeding Risk Score as a Mortality Predictor in Patients with
Acute Coronary Syndrome
P Wave Indices to Predict Atrial Fibrillation Recurrences Post
Pulmonary Vein Isolation
Eletronic Pages
Clinicoradiological Session
Case 6/2013 – 56 years old Woman with Ebstein Anomaly in
Heart Failure
Mortality Impact of Thoracic Aortic Disease in São Paulo State from
Case Report
1998 to 2007
Pericardial Synovial Sarcoma: Case Report and Literature Review
Experimental Cardiac Arrest Treatment with Adrenaline, Vasopressin,
Point of View
or Placebo
Cardiovascular Rehabilitation, Ballroom Dancing and Sexual Dysfunction
REVISTA DA SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Publicada desde 1948
Contents
Editorial
Implementation of Multicenter Records in the Therapeutic Cardiovascular Assessment in Brazil
Luiz Felipe P. Moreira
.....................................................................................................................................................................page 478
Original Articles
Clinical Arrhythmia
Predictors of Hospitalization in Patients with Syncope Assisted in Specialized Cardiology Hospital
Leonardo Marques Fischer, João Pedro Passos Dutra, Augusto Mantovani, Gustavo Glotz de Lima, Tiago Luiz Luz Leiria
.....................................................................................................................................................................page 480
Nuclear Cardiology
Prevalence of Ischemia on Myocardial Perfusion Scintigraphy of Pre-and Postmenopausal Women
Daniel Augusto Message dos Santos, Wendy Yasdin Sierraalta Navarro, Leonardo Machado Alexandre, Priscila
Feitosa Cestari, Paola Emanuela Poggio Smanio
.....................................................................................................................................................................page 487
Pediatric Cardiology
Chromosomal Abnormalities in Patients with Congenital Heart Disease
Patrícia Trevisan, Tatiana Diehl Zen, Rafael Fabiano Machado Rosa, Juliane Nascimento da Silva, Dayane Bohn
Koshiyama, Giorgio Adriano Paskulin, Paulo Ricardo Gazzola Zen
.....................................................................................................................................................................page 495
Acute Coronary Artery Disease
Clinical Significance of Histological Features of Thrombi in Patients with Myocardial Infarction
Juliana Canedo Sebben, Eduardo Cambruzzi, Luisa Martins Avena, Cristina do Amaral Gazeta, Carlos Antonio
Mascia Gottschall, Alexandre Schaan de Quadros
.....................................................................................................................................................................page 502
The Bleeding Risk Score as a Mortality Predictor in Patients with Acute Coronary Syndrome
José Carlos Nicolau, Humberto Graner Moreira, Luciano Moreira Baracioli, Carlos Vicente Serrano Jr., Felipe
Galego Lima, Marcelo Franken, Roberto Rocha Giraldez, Fernando Ganem, Roberto Kalil Filho, José Antônio
Franchini Ramires, Roxana Mehran
.....................................................................................................................................................................page 511
Arquivos Brasileiros de Cardiologia - Volume 101, Nº 6, December 2013
Electrocardiografía
P Wave Indices to Predict Atrial Fibrillation Recurrences Post Pulmonary Vein Isolation
Ahmed Salah, Shenghua Zhou, Qiming Liu, Hui Yan
.....................................................................................................................................................................page 519
Epidemiology
Mortality Impact of Thoracic Aortic Disease in São Paulo State from 1998 to 2007
Ricardo Ribeiro Dias, Omar Asdrubal Vilca Mejia, Fábio Fernandes, Félix José Alvarez Ramires, Charles Mady,
Noedir Antonio Groppo Stolf, Fabio Biscegli Jatene
.....................................................................................................................................................................page 528
Experimental
Experimental Cardiac Arrest Treatment with Adrenaline, Vasopressin, or Placebo
Manoel Ângelo Gomes Palácio, Edison Ferreira de Paiva, Luciano Cesar Pontes de Azevedo, Ari Timerman
.....................................................................................................................................................................page 536
Pacemaker
Is Conventional Cardiac Pacing Harmful in Patients with Normal Ventricular Function?
Luiz Antonio Batista de Sá, Salvador Rassi, Márcia Andery Ludovico Batista
.....................................................................................................................................................................page 545
Cardiovascular Rehabilitation
Brazilian Portuguese Validated Version of the Cardiac Anxiety Questionnaire
Aline Sardinha, Antonio Egidio Nardi, Claudio Gil Soares de Araújo, Maria Cristina Ferreira, Georg H. Eifert
.....................................................................................................................................................................page 554
Review Article
Coronary Computed Tomography Angiography in the Assessment of Acute Chest Pain in the
Emergency Room
Carlos Eduardo Elias dos Prazeres, Roberto Caldeira Cury, Adriano Camargo de Castro Carneiro, Carlos Eduardo Rochitte
.....................................................................................................................................................................page 562
Letter to the Editor
Coronary Trunk Dissection with Stent Displacement: Points to Remember!
Marco Tulio Zanettini, Jacira Pisani Zanettini, João Otavio Zanettini
.....................................................................................................................................................................page 570
The Year 2011 in Interventional Cardiology
Pablo Avanzas, Magda Heras, Juan Sanchis
.....................................................................................................................................................................page 571
Arquivos Brasileiros de Cardiologia - Volume 101, Nº 6, December 2013
Arquivos Brasileiros de Cardiologia - Eletronic Pages
Clinicoradiological Session
Case 6/2013 – 56 years old Woman with Ebstein Anomaly in Heart Failure
Edmar Atik
................................................................................................................................................................ page e101
Case Report
Pericardial Synovial Sarcoma: Case Report and Literature Review
Sabrina Godoy Bezerra, Andrea Araújo Brandão, Denilson Campos Albuquerque, Rochelle Coppo Militão,
Marcelo Souza Hadlich, Clerio Francisco Azevedo
................................................................................................................................................................ page e103
Point of View
Cardiovascular Rehabilitation, Ballroom Dancing and Sexual Dysfunction
Tales de Carvalho, Ana Inês Gonzáles, Sabrina Weiss Sties, Gabriela Maria Dutra de Carvalho
................................................................................................................................................................ page e107
* Indicate manuscripts only in the electronic version. To view them, visit: http://www.arquivosonline.com.br/2013/english/10106/edicaoatual.asp
Arquivos Brasileiros de Cardiologia - Volume 101, Nº 6, December 2013
www.arquivosonline.com.br
A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948
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SUPPORT
Back to the Cover
Editorial
Implementation of Multicenter Records in the Therapeutic
Cardiovascular Assessment in Brazil
Luiz Felipe P. Moreira
Instituto do Coração (InCor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP - Brasil
Clinical research finds, in controlled clinical trials, its
main instrument to establish the therapeutic effectiveness
of drug or interventional therapies. On the other hand,
the evaluation of demographic, clinical and prognostic
characteristics of patients under treatment in the real world
depends on comprehensive multicenter observational
studies, whose results vary according to countries or regions
involved. In the field of cardiology, we have, in our country,
few records that represent the national reality. In this vein,
recent experiences have been conducted by the Brazilian
Society of Cardiology and by specific groups or institutions
in recording some specific conditions or therapies.
These studies include the evaluation of epidemiological
aspects, prognostic results and the factors involved in
the care of patients with acute coronary syndromes1-3,
decompensated heart failure4 or disorders at high risk of
cardiovascular events5. In parallel, the evaluation of the
characteristics and outcomes of interventional procedures
such as the use of stents in the treatment of heart failure6 and
cardiac surgeries in the treatment of valvular heart diseases or
heart failure7 have also been the subject of specific records.
The initial publications of clinical records related to acute
coronary syndromes suggest the inclusion of more than
six thousand patients treated in centers based in different
regions of Brazil. These records have become major
documents that show the demography of the disorders
involved2,3,8. The initial results of these records demonstrate
the diversity of treatments conducted at a national level,
including the regional inequality in the employment of
reperfusion therapies2. The use of these therapies relates,
on the other hand, to lower mortality and lower rates of
complications in the immediate follow-up of patients 3,8.
Keywords
Cardiovascular Diseases / therapy; Multicenter Study;
Brazil.
Mailing address: Luiz Felipe P. Moreira •
Avenida Dr. Enéas Carvalho Aguiar, 44, 2º andar, bloco 2, sala 13 Cerqueira César. CEP 05403-000, São Paulo, SP – Brazil
E-mail: [email protected]
DOI: 10.5935/abc.20130245
478
Besides this, recent data show lower rates of mortality
that are consistent with the international experience in
the treatment of unstable angina and acute myocardial
infarction with or without ST-segment elevation8.
Records focusing on the evolution of patients with heart
failure and disorders at high risk of cardiovascular events
are still at an initial stage of including patients4,5. However,
important issues on the application of confirmedly
beneficial therapies can be found in the preliminary data
of the REACT study9.
As for interventional procedures, publications of
the CENIC registry, which includes patients undergoing
percutaneous coronary intervention in several Brazilian
regions, suggest a progressive improvement of results6,10,
including the reduction of vascular complications promoted
by the technique of access through the radial artery10.
Finally, the constitution of the SP-SCORE-SUS registry to
evaluate the results of cardiac surgeries in the State of
São Paulo, based on previous publications of a national
reference center11,12, fills an important gap with respect
to the employment and results of cardiovascular surgical
therapy, expected to be expanded at a national level13.
The scenario presented shows the growing concern
of researchers and our scientific societies to better
characterize the therapeutic profile of cardiovascular
disorders in our country. The analysis of the results of a
number of multicenter records opens new perspectives for
better planning of financial, personal and technological
resources used in cardiovascular health, and contributes
with insights to deepening scientific knowledge on the
events under study.
Moreira
Multicenter cardiology records
Editorial
References
1. Mattos LA. Rationality and methods of ACCEPT registry - Brazilian registry
of clinical practice in acute coronary syndromes of the Brazilian Society of
Cardiology. Arq Bras Cardiol. 2011;97(2):94-9.
2. Nicolau JC, Franken M, Lotufo PA, Carvalho AC, Marin Neto JA, Lima FG,
et al. Use of demonstrably effective therapies in the treatment of acute
coronary syndromes: comparison between different Brazilian regions.
Analysis of the Brazilian Registry on Acute Coronary Syndromes (BRACE).
Arq Bras Cardiol. 2012;98(4):282-9.
3.
Piegas LS, Avezum A, Guimarães HP, Muniz AJ, Reis HJ, dos Santos ES, et al.
Acute coronary syndrome behavior: results of a Brazilian registry. Arq Bras
Cardiol. 2013 Jun;100(6):502-10
4.
BREATHE investigators. Rationale and design: BREATHE registry-I Brazilian
Registry of Heart Failure. Arq Bras Cardiol. 2013;100(5):390-4.
5.
Mattos LA. Rationality and methods: registry of clinical practice in high-risk
cardiovascular patients. Arq Bras Cardiol. 2011;97(1):3-7.
6. Cardoso CO, de Quadros AS, Mattos LA, Gottschall CA, Sarmento-Leite
RE, Marin-Neto JA. Use of drug-eluting stents in Brazil: the CENIC (National
Registry of Cardiovascular Interventions) registry. Arq Bras Cardiol.
2007;89(6):356-61.
7. Mejía OA, Lisboa LA, Dallan LA, Pomerantzeff PM, Trindade EM, Jatene
FB, Kalil Filho R. Heart surgery programs innovation using surgical risk
stratification at the São Paulo State Public Healthcare System: SP-SCORESUS study. Rev Bras Cir Cardiovasc. 2013;28(2):263-9.
8. Mattos LA, Berwanger O, dos Santos ES, Reis HJ, Romano ER, Petriz JL, et
al. Clinical outcomes at 30 days in the Brazilian Registry of Acute Coronary
Syndromes (ACCEPT). Arq Bras Cardiol. 2013;100(1):6-13.
9. Berwanger O, Piva e Mattos LA, Martin JF, Lopes RD, Figueiredo
EL, Magnoni D, et al. Evidence-based therapy prescription in highcardiovascular risk patients: the REACT study. Arq Bras Cardiol.
2013;100(3):212-20.
10. Andrade PB, Tebet MA, Andrade MV, Labrunie A, Mattos LA. Radial
approach in percutaneous coronary interventions: current status in Brazil.
Arq Bras Cardiol. 2011;96(4):312-6.
11. Lisboa LA, Mejia OA, Dallan LA, Moreira LF, Puig LB, Jatene FB, Stolf NA.
Previous percutaneous coronary intervention as risk factor for coronary
artery bypass grafting. Arq Bras Cardiol. 2012;99(1):586-95.
12. Mejía OA, Lisboa LA, Puig LB, Moreira LF, Dallan LA, Pomerantzeff PM, et
al. InsCor: a simple and accurate method for risk assessment in heart surgery.
Arq Bras Cardiol. 2013;100(3):246-54.
13. Mejía OA, Lisboa LA. The risk of risk scores and the dream of BraSCORE.
Rev Bras Cir Cardiovasc. 2012;27(2):xii-xiii.
Arq Bras Cardiol. 2013; [online].ahead print, PP.0-0
479
Back to the Cover
Original Article
Predictors of Hospitalization in Patients with Syncope Assisted in
Specialized Cardiology Hospital
Leonardo Marques Fischer 1, João Pedro Passos Dutra 1, Augusto Mantovani 2, Gustavo Glotz de Lima1,2,
Tiago Luiz Luz Leiria 1
Instituto de Cardiologia, Fundação Universitária de Cardiologia do Rio Grande do Sul1; UFCSPA - Universidade Federal de Ciências da Saúde
de Porto Alegre2, Porto Alegre, RS – Brazil
Abstract
Background: Risk stratification of a syncopal episode is necessary to better differentiate patients needing hospitalization
of those who can be safely sent home from the emergency department. Currently there are no strict guidelines from our
Brazilian medical societies to guide the cardiologist that evaluate patients in an emergency setting.
Objectives: To analyze the criteria adopted for defining the need for hospitalization and compare them with the
predictors of high risk for adverse outcome defined by the OESIL score that is already validated in the medical literature
for assessing syncope.
Methods: A cross-sectional study of patients diagnosed with syncope during emergency department evaluation at our
institution in the year 2011.
Results: Of the 46,476 emergency visits made in that year, 216 were due to syncope. Of the 216 patients analyzed, 39%
were hospitalized. The variables associated with the need of hospital admission were - having health care insurance,
previous known cardiovascular disease, no history of prior stroke, previous syncope and abnormal electrocardiograms
during the presentation. Patients classified in OESIL scores of 0-1 had a greater chance of emergency discharge;
2‑3 scores showed greater association with the need of hospitalization. A score ≥ 2 OESIL provided an odds ratio
7.8 times higher for hospitalization compared to score 0 (p <0.001, 95% CI:4,03-15,11). In approximately 39% no
etiological cause for syncope was found and in 18% cardiac cause was identified.
Conclusions: Factors such as cardiovascular disease, prior history of syncope, health insurance, no previous stroke
and abnormal electrocardiograms, were the criteria used by doctors to indicate hospital admission. There was a good
correlation between the clinical judgment and the OESIL criteria for high risk described in literature. (Arq Bras Cardiol.
2013; 101(6):480-486)
Keywords: Syncope / etiology; Risk Factors; Hospitalization; Emergency Medical Services.
Introduction
Syncope corresponds to approximately 1.5% of emergency
visits in the United States 1,2. In Brazil there is no real
estimation of emergency visits resulting from syncope.
Some of the causes of syncope are associated with relevant
morbidity. The identification of such causes is crucial to better
stratify patient risk of adverse events1,2. In these cases mortality
can reach 18-33%3 in one year. The differential diagnosis is
extensive, and a definitive treatment strategy is aimed at the
underlying cause, when it is detected. However, in emergency
Mailing Address: Tiago Luiz Luz Leiria •
Felix da Cunha, 1010, apt.º 601, Floresta. Postal Code 90570-000,
Porto Alegre, RS - Brazil
E-mail: [email protected], [email protected]
Manuscript received February 14, 2013; revised manuscript June
05, 2013; accepted June 28, 2013.
DOI: 10.5935/abc.20130206
480
care, the etiology of syncope is often unknown management
should be focused on risk stratification, to better differentiate
those that can be discharged from those who require urgent
intervention or hospital admission. In the United States, about
47% of patients treated in the emergency for syncope are
discharged without diagnosis4.
A good medical history associated with thorough physical
examination (including blood pressure in supine and standing
positions) and electrocardiographic study show combined
diagnostic yield of 50% for causative diagnosis of syncope5.
Electrocardiogram (ECG) can show abnormalities, such as
conduction disorders, or old myocardial infarction, suggesting
an etiology for the syncope; however, in only 5% of cases
the cause is elucidated based only in ECG5.
OESIL 6 (Osservatorio Epidemiologico sulla Sincope
nel Lazio) and EGSYS 7 scores are widely used at the
emergency level, as a tool to help decide which patient
must be hospitalized. However, they were developed for
use in general hospitals. These tools are unsuitable for
use in hospitals that are exclusive for cardiology, since the
presence of heart disease is always defined as a risk criterion
that leads hospitalization6,7.
Fisher et al
Predictors of hospitalization with syncope
Original Article
To date, there is no information about the patients’ profile
treated for syncope in cardiac emergencies in our area. Neither
do we know what are the hospitalization criteria applied by
the physicians who evaluated these patients. In our country
there is no guideline of medical society about this subject.
This study aims at the evaluation of the criteria adopted
for hospitalization and differentiate them from those used
in discharged patients. Subsequently, compare these criteria
with those described in the literature as high risk predictors
defined in risk scores already validated for syncope evaluation.
Methods
A cross-sectional study was performed in patients who
received the diagnosis of syncope, through 10th revision of
the International Statistical Classification of Diseases (ICD-10)
R55, on the patients’ charts of the emergency department
at the Cardiology Institution, from January 1st to December
31 of 2011, in order to identify factors associated with
hospitalization. For ICD-10 research, a search engine in the
emergency care system from our institution was used, which
is completely computerized, in which only one ICD-10 is
allowed in order to define the patient’s hospitalization cause.
The definition of syncope used in our study was the one
recommended by the European Society of Cardiology (8). In their
guideline, syncope is defined as an episode of transient loss of
consciousness (nontraumatic) that occurs due to transient global
cerebral hypoperfusion characterized by rapid onset, short duration
and with complete spontaneous recovery.
We excluded patients that did not had their complete
records in our computerized system, those under 18, pregnent
women and those whose diagnosis was erroneously identified
as syncope, according to anamnesis data described in the
medical record.
In this study, we aimed at identifying in our population
some of the main factors associated with a higher probability
that cardiovascular disease is the cause of syncope, also
including: age over 65, previous cardiac disease (coronary
arterial disease, heart failure, valvulopathies, congenital
cardiopathies, canulopathies, cerebrovascular disease,
peripheral arterial disease), abnormal electrocardiogram,
history of ventricular arrhythmia, history of cardiac arrest or
aborted sudden death, presence or absence of prodromes6-8.
Other variables, such as genre, diabetes, hypertension,
syncope relation with emotional stress, medications and
presence of health plan, were also investigated.
Further, it was conducted an analysis regarding which
points of OESIL score6 were present in our population, also
if they showed statistical relevance in multivariate analysis,
resulting in hospitalization. OESIL score ranges between 0
and 4, being composed of the arithmetic sum of the criteria:
1) age > 65 years; 2) history of cardiovascular disease; 3)
abnormal electrocardiogram; 4) syncope without prodromes.
Mortality increases in one year according with score: 0% for
score 0; 0.8% for 1 point; 19.6% for 2 points; 34.7% for
3 points; 57.1% for 4 points. Patients with moderate to high
risk (score higher or equal to 2), for presenting higher mortality
in one year, are eligible for hospitalization and investigation
of etiological cause.
For the definition of abnormal electrocardiogram, the
following were considered: sinus bradycardia or sinus
pause, atrioventricular block of second or third degree,
conduction disturbances, fibrillation or atrial flutter, ventricular
tachycardia, prolonged QTc interval, presence of inactive
zone or ST-T acute abnormalities, ventricular pre-excitation,
pacemaker rhythm or pacemaker dysfunction.
Statistical Analysis
Continuous variables were described in mean ± standard
deviation. Categorical variables were presented as absolute
number and percentage. Univariate comparisons were
conducted with χ², two-tailed Z test or T test, as appropriate.
Logistic regression was performed, using a model in which
variables were included with Backward method (probability),
having as entry criteria a p value of 0.05 and a removal value
of 0.20 in regression analysis. For the model, we selected
variables that compose risk scores for syncope and also those
that showed statistical difference in univariate analysis, deemed
as relevant by investigators. Database was elaborated using
the program Microsoft Office Excel 2010 for Windows® and
then transferred to program IBM SPSS Statistics version 19.0.0
(Armonk, NY: IBM Corp.).
Ethical considerations
The study was registered at the research unit of the
Cardiology Institute, University Cardiology Foundation of Rio
Grande do Sul, having been approved for implementation by
the ethics research committee of our institution, according to
the Declaration of Helsinki.
Results
In 2011 46,476 medical visits were performed on the
emergency room of our Institution. ICD-10 R55 - syncope was applied in a total of 356 patients. Of these, 63 patients
were excluded for not having syncope, 86 were excluded
for being hospitalized directly in the ward by their physician
discretion, without emergency care (there was a medical
record, but no medical consultation), and, finally, nine patients
were excluded for being under 18. A total of 216 patients
was examined.
Of the cases seen by syncope, 39% were admitted for
investigation. Table 1 describes the patient profile, already
stratified between those who were hospitalized and those
who were released from the emergency.
Table 2 shows the result of multivariate analysis between
these two groups, identifying factors most strongly related to
hospitalization for syncope.
In the comparative evaluation between hospitalized
and non-hospitalized groups, OESIL scores of 0 and 1 were
significantly associated with higher probability of patient
discharge. Similarly, scores 2 and 3 were related to higher
probability of hospitalization. Score 4 had no relevant
association, possibly due to the low number of patients
with this score (Table 3). In a multivariate analysis, controlled
for factors that are not part of OESIL score, patients with score
equal to or higher than 2 had an odds ratio 7.8 times higher
Arq Bras Cardiol. 2013; 101(6):480-486
481
Fisher et al
Predictors of hospitalization with syncope
Original Article
Table 1 - Clinical characteristics between patients discharged from the emergency visit and those hospitalized due to syncope in the year 2011
Nonhospitalized
(n = 131)
Age (years)
Hospitalized
(n = 85)
p
59.2 ± 20
67.0 ± 18
0.003
51.4 ± 18.4
59.3 ± 15.7
0.162
Male
51.6%
62.4%
0.120
SUS health plan
76.6%
61.2%
0.016
SAH
50.8%
75.3%
< 0.001
Ejection fraction (%)
Diabetes
8.4%
16.5%
0.07
Known heart pathology
23.4%
57.6%
< 0.001
CAD
14.8%
42.9%
< 0.001
CCI
4.7%
21.4%
< 0.001
Abnormal ECG
43.8%
67.1%
0.001
Previous CVA
7%
5.9%
0.110
Valvulopathy
3.9%
3.5%
0.887
Pacemaker
3.9%
7.1%
0.299
Previous syncope
21.9%
40.5%
0.004
Smoking
12.5%
10.6%
0.671
Alcoholism
0%
1.2%
0.219
Previous CRA/VT/VF
0%
2.4%
0.081
0.148
Congenital cardiopathy
0.8%
3.5%
Prodromes
60.2%
47.1%
0.060
Chest pain
4.7%
23.5%
< 0.001
Dyspnea
2.3%
3.5%
0.609
Palpitations
3.9%
5.9%
0.504
Dizziness
32.8%
32.9%
0.984
Emotional stress preceding syncope event
11%
1.2%
0.006
Headache
4.7%
5.9%
0.700
Syncope related to exertion
2.3%
7.1%
0.087
Anemia
0.8%
4.7%
0.064
CCI* physical examination
1.6%
3.5%
0.353
Physical examination, cardiac murmur identified in the emergency visit
8.6%
11.8%
0.447
Physical examination, focal neurological deficit
3.9%
2.4%
0.533
Antihypertensive
46.1%
74.1%
< 0.001
Diuretics
22.7%
38.8%
0.011
Beta-blocker
25%
47.1%
0.001
31.3%
60%
< 0.001
7%
16.5%
0.030
Alfa-blocker
3.1%
2.4%
0.739
Vasodilator
1.6%
9.4%
0.008
Digital
1.6%
4.7%
0.175
Amiodarone
0.8%
4.7%
0.064
Need transitory PM
0%
1.2%
0.219
Need final PM/ICD
0%
28.2%
< 0.001
iACE/ARB
Calcium blocker
CVA: cerebral vascular accident; ARB: angiotensin receptor blocker; ICD: implantable cardiodefibrilator; CAD: coronary artery disease; ECG: electrocardiogram; VF:
ventricular fibrillation; SAH: systemic arterial hypertension; CHF: congestive heart failure; iACE: inhibitor of angiotensinogen-conversion enzyme; PM: pacemaker.
CRA: cardiorespiratory arrest. SUS: Sistema Único de Saúde (Single Health System); VT: ventricular tachycardia.
* Presence of a third or fourth heart sound, signals of pulmonary and/or systemic venous congestion or difficult breathing, ascites and dyspnea.
482
Arq Bras Cardiol. 2013; 101(6):480-486
Fisher et al
Predictors of hospitalization with syncope
Original Article
Table 2 - Predictor factors for hospitalization - multivariate analysis
95% CI for OR
Odds ratio (OR)
p
Inferior
Superior
Previous syncope
2.4
0.015
1.18
4.92
Heart disease
5.5
<0.001
2.70
11.42
Previous CVA
0.2
0.033
0.05
0.88
Abnormal ECG
2.0
0.039
1.03
3.92
Health insurance
2.5
0.010
1.24
5.11
Variable
CVA: cerebral vascular accident; ECG: electrocardiogram; CI: confidence interval.
Logistic regression with Backward model using the following variables: abnormal ECG, previous CVA, heart disease, previous syncope, DM2, health insurance,
related to exercise, emotional stress, CRPVTVF, physical examination, hypotension TAS < 90 mmHg, prodromes.
of hospitalization compared to those with score 0 (p < 0.001,
CI 4.03-15.11).
As for syncope etiology, it was observed in this population
that approximately 39% of patients had no etiology defined.
In 18% a cardiology cause was identified (Chart 1). Among
cardiology causes, we have 13 cases of tachyarrhythmias,
bradyarrhythmias 17, three structural heart disease (myocardial
hypertrophy, right ventricular arrhythmogenic cardiomyopathy),
two of pacemaker dysfunction, two of acute coronary
syndromes and two due to valvulopathies.
Besides electrocardiogram, electrocardiographic monitoring
in the emergency and echocardiography, some other form of
examination was held in our sample during hospitalization.
With reference to these procedures, electrophysiological study
was performed in 12.5% of cases, cardiac catheterization in
12%, a 24-hour Holter monitoring in 6%, carotid ultrasound in
4%, myocardial scintigraphy in 3% and HUT (tilt-test) in 0.5%.
Discussion
Analysis of 216 patients in the emergency department at
our hospital revealed that most of them were older than 50
and there was equal distribution between sexes. The finding
that patients with previous heart disease and abnormal
electrocardiogram have greater probability of hospitalization is
in accordance with information from the literature, suggesting
a higher risk associated with these variables1-4,6,8.
An interesting observed data is the existence of health
insurance, as independent variable, was associated with a
greater chance of hospitalization. That, in the authors’ opinion,
may be due to increased pressure imposed for admission
upon emergency physicians to assist this group of patients or,
perhaps, to greater availability of private beds in public and
private institutions. However, the real reason for this rationale
was not completely clear.
European guidelines on diagnosis and treatment of
syncope 2009(8) considered high risk criteria the presence of
structural heart disease , coronary artery disease, clinical and
electrocardiographic abnormalities and the presence of major
comorbidities. Considering these criteria, we can infer that, in the
population studied, there was a agreement among the high-risk
criteria indicated in the guidelines and those that were associated
with a greater chance of hospitalization in our sample.
Low prevalence of low risk patients hospitalized (OESIL
scores 0 and 1) demonstrates that, despite of not having
an institutional protocol for assisting these patients in our
emergency department, evaluating risk criteria separately
seems to be properly carried out by cardiologists attending
the emergency unit. This finding makes us evoke the idea
that scores as OESIL appear to have greater practical utility
in emergencies at general hospitals (where they were initially
developed and validated), perhaps being unnecessary in
cardiac emergencies, where only specialists evaluate and
select patients.
Table 3 - Classification of patients stratified by OESIL score divided between patients hospitalized and those discharged from emergency visit
Nonhospitalized
OESIL
Hospitalized
N
(%)
N
(%)
0
40
31,0%*
4
4,9%
1
Z40
31,0%*
8
9,8%
2
25
19,4%
37
45,1%*
3
16
12,4%
22
26,8%*
4
8
6,2%
11
13,4%
Chi-square test <0.001.
* Z test for comparison of proportions of the columns found a relevant difference between groups using Bonferroni correction (p < 0,005). OESIL: Osservatorio
Epidemiologico sulla Sincope nel Lazio6.
Arq Bras Cardiol. 2013; 101(6):480-486
483
Fisher et al
Predictors of hospitalization with syncope
Original Article
45.00%
38.90%
40.00%
35.20%
35.00%
30.00%
25.00%
18.00%
20.00%
15.00%
10.00%
5.90%
2.80%
5.00%
0.00%
Cardiac
Postural hypotension
Vasovagal
Indefinite
Others
Chart 1 - Prevalence of syncope etiologies in emergency visits in the year 2011.
In a review of the risk assessment of patients with
syncope in emergency sectors, was stated that, although
there are many scores to stratify patients, most of them
have good sensitivity and low specificity, and the balance
between these variables, which would add safety in patients’
hospitalization or discharge, would be unattainable.
An interesting conclusion of this review was that emergency
physicians were quite sensitive and tended to hospitalize
patients who developed severe clinical outcomes, including
those who were not included in risk stratification scores9.
Other criteria used in scores - some even classified as
highest scoring criteria - such as palpitations, pre- syncope,
syncope during physical exertion, valvulopathies, dyspnea and
physical examination revealing signs of heart failure revealed
no statistical significance for hospitalization in our sample10,11.
This fact demonstrates how much scores can vary among
themselves having a low external validity. However, these
factors previously mentioned occurred with low frequency
in our population, probably leading to a beta error. Another
possibility, which must certainly explains this phenomenon, is
that a cardiologist, when attending a patient with syncope and
an ejection murmur at the base of the heart that irradiates to
the carotids, most likely would add as a cause for hospitalization
the ICD-10 for aortic stenosis instead of that for syncope.
This same phenomenon may occur with patients who arrive
at the Emergency with acute decompensated heart failure.
Our data are in accordance with the literature regarding
the causative diagnosis of the syncopal event. Vasovagal
(reflex-mediated) was the most prevalent diagnosis followed
by undetermined and cardiac cause for the syncope8,12.
The number of referrals to emergency due to syncope is
484
Arq Bras Cardiol. 2013; 101(6):480-486
of approximately 1%8,13,14, in our population this number
was slightly lower, being 0.5%. This fact may reflect those
patients in which ICD-10 of the final diagnosis of the
syncope event (e.g. aortic stenosis) has been used in the
emergency medical chart. The rate for hospitalization due
to syncope in our institution is in accordance with other
studies (approximately 40%)12-14, being 39% in our series.
Important limitations of our study are: underreporting
in medical records, the fact that other pathologies - such
as arrhythmias, heart failure - could manifest with syncopal
episodes and the ICD-10 used could have been related
to the respective pathologies while filling out the medical
record, instead of being one related to syncope, as
previously explained. However, this type of bias is inherent
to studies with historical basis. Another limitation is the fact
that we have excluded patients under 18. This decision
may underestimate the real prevalence of patients with
canulopathies, myocardial hypertrophy, Wolff-ParkinsonWhite, congenital cardiopathies and other cardiovascular
pathologies characteristic of a young population. However,
the number of patients excluded from the study was only
nine, which probably would not be significant to define
data related to syncope in young and pediatric patients.
Conclusion
Factors such as cardiovascular disease, prior history of
syncope, health insurance, no previous stroke and abnormal
electrocardiogram changes were the criteria most strongly
associated with the likelihood of hospitalization when
presenting with a syncopal episode. In a referral hospital for
cardiovascular diseases, there was good agreement beteween
Fisher et al
Predictors of hospitalization with syncope
Original Article
clinical criteria for hospitalization with those high risk criteria
already described in the medical literature.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Author contributions
Conception and design of the research: Fischer LM,
Dutra JPP, de Lima GG, Leiria TLL; Acquisition of data and
Analysis and interpretation of the data: Fischer LM, Dutra JPP,
Mantovani A, de Lima GG, Leiria TLL; Statistical analysis: de
Lima GG, Leiria TLL; Writing of the manuscript and Critical
revision of the manuscript for intellectual content: Fischer LM,
Dutra JPP, Leiria TLL.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any post-graduation
program.
References
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Huff JS, Decker WW, Quinn JV, Perron AD, Napoli AM, Peeters S, et al;
American College of Emergency Physicians. Clinical policy: critical issues in the
evaluation and management of adults patients presenting to the emergency
department with syncope. Ann Emerg Med. 2007;49(4):431-44.
2. Kapoor WN. Syncope. N Engl J Med. 2000;343(25):1856-62.
8. Moya A, Sutton R, Ammirati F, Blanc JJ, Brignole M, Dahm JB, et al; Task
Force for the Diagnosis and Management of Syncope; European Society of
Cardiology (ESC); European Heart Rhythm Association (EHRA); Heart Failure
Association (HFA); Heart Rhythm Society (HRS). Guidelines for the diagnosis and
management of syncope (version 2009). Eur Heart J. 2009;30(21):2631-71.
3. Zaidi AM, Fitzpatrick AP. Investigation of syncope: increasing the yield and
reducing the cost. Eur Heart J. 2000;21(11):877-80.
9. Kessler C, Tristano JM, De Lorenzo R. The emergency department approach
to syncope: evidence-based guidelines and prediction rules. Emerg Med Clin
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4. Alshekhlee A, Shen WK, Mackall J, Chelimsky TC. Incidence and mortality
rates of syncope in the United States. Am J Med. 2009;122(2):181-8.
10. Costantino G, Furlan R.Syncope risk stratification in the emergency
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5. Linzer M, Yang EH, Estes NA 3 rd, Wang P, Vorperian VR, Kapoor WN.
Diagnosing syncope. Part 1: Value of history, physical examination, and
electrocardiography. Clinical Efficacy Assessment Project of the American
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11. Khera S, Palaniswamy C, Aronow WS, Sule S, Doshi JV, Adapa S, et al.
Predictors of mortality, rehospitalization for syncope, and cardiac syncope
in 352 consecutive elderly patients with syncope. J Am Med Dir Assoc.
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6. Colivicci F, Ammirati F, Melina D, Guido V, Imperoli G, Santini M; OESIL
(Osservatorio Epidemiologico sulla Sincope nel Lazio) Study Investigators.
Development and prospective validation of a risk stratification system for
patients with syncope in the emergency department: the OESIL risk score.
Eur Heart J. 2003;24(9):811-9.
12. Soteriades ES, Evans JC, Larson MG, Chen MH, Chen L, Benjamin EJ, et al.
Incidence and prognosis of syncope. N Engl J Med. 2002;347(12):878-85.
7.
Brignole M, Disertoni M, Menozzi C, Raviele A, Alboni P, Pitzalis MV, et al;
Evaluation of Guidelines in Syncope Study group. Management of syncope
referred urgently to general hospitals with and without syncope units.
Europace. 2003;5(3):293-8.
13. Blanc JJ, L’Her C, Touiza A, Garo B, L’Her E, Mansourati J. Prospective evaluation
and outcome of patients admitted for syncope over a 1 year period. Eur Heart
J. 2002;23(10):815-20.
14. Blanc JJ, L’Her C, Gosselin G, Cornily JC, Fatemi M. Prospective evaluation
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Back to the Cover
Original Article
Prevalence of Ischemia on Myocardial Perfusion Scintigraphy of
Pre‑and Postmenopausal Women
Daniel Augusto Message dos Santos, Wendy Yasdin Sierraalta Navarro, Leonardo Machado Alexandre, Priscila
Feitosa Cestari, Paola Emanuela Poggio Smanio
Instituto Dante Pazzanese de Cardiologia, São Paulo, SP - Brazil
Abstract
Background: In postmenopausal women, the presence of risk factors for coronary artery disease (CAD) increases.
However, the difference in prevalence of ischemia between pre- and postmenopausal women with multiple risk factors
for CAD has not been well established.
Objectives: To compare the prevalence of ischemia on Tc99m-sestamibi myocardial perfusion scintigraphy (MPS) in
pre‑and postmenopausal women, and to evaluate whether menopause can be considered an independent risk predictor
of ischemia in women with multiple risk factors for CAD.
Methods: This study retrospectively assessed 500 MPS of pre- and postmenopausal women with multiple risk factors
for CAD. Statistical analysis was performed by using Fisher exact test and univariate and multivariate analysis, a
p value ≤ 0.05 being considered significant.
Results: Postmenopausal women represented 55.9% of the sample; 83.3% were hypertensive; 28.9%, diabetic; 32.1%,
smokers; 25%, obese; 61.2% had high cholesterol levels; and 34.3% had known CAD. Postmenopausal women were
more often hypertensive, diabetic and dyslipidemic, and had lower functional capacity on exercise testing (p = < 0.005).
The presence of ischemia on MPS did not significantly differ between the pre- and postmenopausal groups (p = 0.395).
The only variable associated with ischemia on MPS was known CAD (p = 0.004).
Conclusion: The results suggest that, in women with multiple risk factors for CAD, menopause was not an independent
predictor of ischemia on MPS. Those data support the idea that the investigation of ischemia via MPS in women with
multiple risk factors for CAD should begin prior to menopause. (Arq Bras Cardiol. 2013; 101(6):487-494)
Keywords: Myocardial Ischemia/radionuclide imaging; Women; Premenopause; Posmenopause; Risk factors.
Introduction
It was only recently that the major studies on coronary
artery disease (CAD) began to include women1-3.
Women are usually more obese and smoke more than
men; 25% of women have sedentary lifestyles, 52% of those
over the age of 45 years have arterial hypertension and 40%
of those over the age of 55 years have hypercholesterolemia1,2.
Diabetic women are at an extremely high cardiovascular risk,
comparable to that of women who already had myocardial
infarction, with more adverse outcomes4,5.
The clinical manifestations of CAD appear approximately
10 to 15 years later in women, a fact possibly related to
estrogen protection. With the increase in life expectancy, the
postmenopausal period began to represent one third of a woman’s
life, drawing more attention to that specific population1,2,6,7.
Mailing Address: Daniel Augusto Message dos Santos •
Rua do Grito, 479, apt.º 62 Life, Ipiranga. Postal Code 04217-000,
São Paulo, SP - Brazil
E-mail: [email protected], [email protected]
Manuscript received February 26, 2013; revised manuscript June 27, 2013;
accepted June 28, 2013
DOI: 10.5935/abc.20130221
487
Some of the traditional diagnostic tests for CAD investigation
do not function so properly in the female sex, and evidence
has suggested that they have a greater prognostic rather than
diagnostic value for women8,9.
Exercise testing provides important information, but its mean
sensitivity and specificity are lower than in the male sex, around
61% and 69%, respectively10. In addition, unspecific baseline
electrocardiographic alterations of the ST segment, due to
estrogenic hormone action, might generate tests whose results
“falsely” suggest ischemia10.
Myocardial perfusion scintigraphy (MPS) has become a highly
important tool for diagnostic investigation in the female sex,
particularly in women with unspecific alterations on baseline
electrocardiogram and with low functional capacity or difficulty to
achieve the proper heart rate, which is very common in the group
of diabetic women and those with peripheral vascular disease11,12.
In addition, the reduction in breast attenuation artifacts and the
acquisition of images guided by electrocardiography (gatedSPECT) increase the accuracy of the test, helping to differentiate
real defects and artifacts13.
Previous studies7,14 have reported that estrogenic protection
is associated with a reduction in cardiovascular risk; however,
there is scarce literature about the role of non-invasive diagnostic
methods, especially Tc99m-sestamibi MPS in pre/postmenopausal
women, mainly in those with multiple risk factors for CAD.
Santos et al
Schemia on Pre- and Postmenopausal Women Scintigraphy
Original Article
Objectives
The present study aimed at comparing the presence of
ischemia on Tc99m-sestamibi MPS in pre/postmenopausal
women at high risk for CAD, and at assessing whether
menopause is an independent predictive factor of ischemia
in that group of patients.
Methods
This is an observational, retrospective study carried out at
the nuclear medicine sector of the Instituto Dante Pazzanese
de Cardiologia, based on the review of medical records,
analyzing consecutive 500 MPS of women performed in
2011 and 2012. This study was approved by the committee
of ethics and research (02020312.7.0000.5462). All patients
provided written informed consent before undergoing MPS.
Exercise and pharmacological (dipyridamole and
dobutamine) stress test and acquisition and processing of
nuclear medicine images were performed by using standard
techniques, according to the guidelines of the Brazilian
Society of Cardiology/Department of Ergometry, Exercise,
Nuclear Cardiology and Cardiovascular Rehabilitation15,16.
Myocardial perfusion scintigraphy was performed by
use of the gated-SPECT technique, one-day protocol, the
baseline phase being followed by the stress phase. A GE
Ventri dedicated cardiac gamma camera was used for image
acquisition. To assess myocardial perfusion, the myocardium
was divided into 17 segments. Normal perfusion was
considered the absence of reduced uptake of the radiotracer
in both phases (baseline and stress); perfusion suggestive
of ischemia and fibrosis was considered the presence of
reversible and fixed reduced uptake of the radiotracer after
the stress phase as compared to the baseline phase, at least
in 3 of the 17 myocardial segments analyzed15.
The qualitative visual analysis of the presence or absence
of perfusion alterations was performed by two observers
specialized in cardiology and nuclear medicine, and, in
case of disagreement, a third observer also specialized in
cardiology and nuclear medicine was consulted.
This study considered the presence of myocardial
ischemia on scintigraphy. Of all patients assessed, 69 had
perfusion alterations suggestive of myocardial fibrosis, 41 of
whom were postmenopausal women and 28, premenopausal
(p = 0.069).
The patients were classified as pre/postmenopausal
according to data in medical records.
The classical cardiovascular risk factors assessed were
arterial hypertension, diabetes mellitus, dyslipidemia,
smoking and obesity, defined according to the Brazilian
Society of Cardiology guidelines17.
Patients with known CAD were those with previous
diagnosis of myocardial infarction, unstable/stable angina
and percutaneous or surgical myocardial revascularization.
In addition, patients with the following characteristics were
considered to be at equivalent high cardiovascular risk:
stroke; carotid and peripheral artery disease; abdominal
aorta aneurysm; and chronic renal failure17.
Patients with non-ischemic heart diseases and those with
no information regarding menopause in their medical records
were excluded.
Statistical analysis was performed with Fisher exact test
and univariate and multivariate analyses, and the significance
level adopted was p ≤ 0.05.
Results
Table 1 shows the clinical and epidemiological characteristics
of the patients assessed according to their menopausal status.
The physicians of the outpatient clinics where the patients
were followed up requested the MPS according to clinical
indications. Such indications were divided into symptomatic
and asymptomatic patients (Tables 2 and 3). Table 4 shows
the results of the MPS in asymptomatic patients.
Tables 5 to 7 show the number of exercise stress tests
and dipyridamole and dobutamine stress tests performed
according to the menopausal status of the patients, as well as
patients’ clinical and electrocardiographic characteristics, and
physical fitness and functional capacity.
The degree of physical fitness, known as functional capacity,
measured in metabolic equivalents (MET) on the exercise test
was significantly lower in postmenopausal women. Of all
patients, 91 reached 10 MET or less, 56 were postmenopausal
Table 1 - Clinical and epidemiological characteristics of the pre- and postmenopausal groups
Total (%)
Premenopausal N = 221
Postmenopausal N = 279
p value
Mean age ± SD
500 (100)
45.4 ± 4.16
65.7 ± 8.67
< 0.001
Hypertension
414 (83.3)
164 (74)
250 (89)
< 0.001
Diabetes
144 (28.9)
36 (16)
108 (38)
< 0.001
Dyslipidemia
305 (61.2)
100 (45)
205 (74)
< 0.001
Smoker/ex-smoker
160 (32.1)
70 (32)
90 (32)
0.92
125 (25)
49 (22)
76 (28)
0.213
171 (34.3)
69 (31)
102 (37)
0.218
Obesity
CAD
CAD: previous coronary artery disease.
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Table 2 - Indications for MPS in symptomatic patients
Functional test
Total
Premenopausal
Postmenopausal
MPS
396
179
231
Atypical chest pain
169
87
82
Typical chest pain
103
47
52
Functional class worsening
92
33
59
Palpitations
20
8
12
Vertigo
4
0
4
Syncope
8
4
4
Indications
MPS: myocardial perfusion scintigraphy.
Table 3 - Indications for MPS in asymptomatic patients
Functional test
Total
Premenopausal
Postmenopausal
MPS
104
42
62
Preoperative assessment
5
3
2
After PTCA/stent or CABG
33
9
24
To assess the etiology of dilated cardiomyopathy
10
4
6
To assess the etiology of arrhythmia
15
6
9
To assess the etiology of LBBB
2
0
2
Other altered functional test
14
10
4
Cardiovascular risk stratification or other non-specified reasons
25
10
15
Indications
MPS: myocardial perfusion scintigraphy; PTCA: percutaneous transluminal coronary angioplasty; CABG: coronary artery bypass graft surgery; LBBB: left bundle-branch block.
Table 4 - Subanalysis of asymptomatic patients
altered MPS = 60 patients
Premenopausal patients = 23
Postmenopausal patients = 37
normal MPS = 44 patients
Premenopausal patients = 19
Postmenopausal patients = 25
Asymptomatic patients = 104
MPS: myocardial perfusion scintigraphy.
and 35, premenopausal (p < 0.005). The only variable
predictive of ischemia on MPS was the presence of previous
CAD (p < 0.05).
the infusion of dipyridamole; and myocardial perfusion
showing transient reduction in radiotracer uptake in the
anterior, anteroseptal and apical walls.
Of the 500 patients assessed with MPS, ischemia was
identified in 102 (58.5%) postmenopausal patients and
in 72 (41.5%) premenopausal patients, with no statistical
significance (p = 0.395).
Discussion
Figure 1: Findings suggesting ischemia on the dipyridamole
MPS of a 46-year-old female patient with diabetes,
hypertension, obesity, dyslipidemia, sedentary lifestyle,
and known CAD (stent in the anterior descending artery for
three years): ECG showing ST-segment depression during
489
Arq Bras Cardiol. 2013; 101(6):487-494
Diagnosing CAD in the female sex is a great challenge.
Because its symptoms are less typical in women,
non‑invasive tests have an unquestionable value for its
effective investigation in women before submitting them
to invasive, sometimes unnecessary, tests. In the Coronary
Artery Surgery Study (CASS), half of the women submitted
to coronary angiography showed no significant lesions17.
Santos et al
Schemia on Pre- and Postmenopausal Women Scintigraphy
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Table 5 - Clinical and electrocardiographic characteristics and functional capacity on exercise stress testing
Total
Premenopausal
Postmenopausal
Total
200
112
88
Total of normal tests
93
55
38
Normal tests reaching > 10 MET
61
39
22
Total of altered tests
107
57
50
ECG alteration
40
23
17
Alteration due to chest pain
41
24
17
ECG alteration + chest pain
24
9
15
Complex ventricular arrhythmia during the test
2
1
1
Altered tests reaching < 10 MET
91
44
47
Other symptoms during the test
37
22
15
Unspecific chest pain
24
14
10
Dyspnea
13
8
5
Headache
0
0
0
ECG: electrocardiography.
Table 6 - Clinical and electrocardiographic characteristics on dipyridamole stress testing
Total
Premenopausal
Postmenopausal
Total
279
105
174
Total of normal tests
130
46
84
Total of altered tests
149
59
90
ECG alteration
31
9
22
Alteration due to chest pain
69
31
38
ECG alteration + chest pain
48
19
29
Complex ventricular arrhythmia during the test
1
0
1
Other symptoms during the test
50
15
35
Unspecific chest pain
23
7
16
Dyspnea
5
2
3
Headache
22
6
16
ECG: electrocardiography.
Table 7 - Clinical and electrocardiographic characteristics on dobutamine stress testing
Total
Premenopausal
Postmenopausal
Total
21
4
17
Total of normal tests
9
0
9
Total of altered tests
12
4
8
ECG alteration
5
2
3
Alteration due to chest pain
6
2
4
ECG alteration + chest pain
1
0
1
Other symptoms during the test
5
0
5
Unspecific chest pain
2
0
2
Dyspnea
0
0
0
Headache
3
0
3
ECG: electrocardiography.
Arq Bras Cardiol. 2013; 101(6):487-494
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Schemia on Pre- and Postmenopausal Women Scintigraphy
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Figure 1 - Ischemia on myocardial perfusion scintigraphy of a premenopausal woman.
491
Arq Bras Cardiol. 2013; 101(6):487-494
Santos et al
Schemia on Pre- and Postmenopausal Women Scintigraphy
Original Article
As our institution is a tertiary cardiological hospital,
women followed up there usually have multiple risk
factors for CAD, and most of them already had a previous
myocardial infarction and/or myocardial revascularization
procedure (as reported in this study, 34% with previous
known CAD). Thus, we decided to carry out a study
reflecting the reality of women referred for MPS, and those
with previous CAD were not excluded.
The objective of this study was to assess whether
menopause was an independent predictor of ischemia in
women at our institution, with and without known CAD.
It is worth emphasizing that, in our study, many women
had previous electrocardiographic alterations on baseline
ECG and low functional capacity, which motivated their
referral for MPS, aimed at diagnostic investigation and
cardiovascular risk stratification.
As already observed, the choice and interpretation
of non-invasive procedures are not easy tasks. Exercise
testing is known to have lower sensitivity and specificity
in the female sex than in the male sex18. The sensitivity
and specificity of the pharmacological or exercise stress
tests can be improved by imaging methods that increase
diagnostic accuracy 10,11,18. With the refinement of the
technique, a reduction in attenuation artifacts (breast, for
example) was observed, leading to greater specificity13.
In the present study, MPS proved to be an important
tool to investigate ischemia, which was observed in 35%
of the women assessed. Such data are in accordance with
those of the literature. Smanio et al11, studying the MPS
of 104 asymptomatic diabetic women, have reported
myocardial ischemia in 34 (32.7%).
Myocardial scintigraphy plays a role in CAD diagnosis
and cardiovascular risk stratification in both sexes,
considering that it provides information on myocardial
perfusion, left ventricular function and, if necessary,
myocardial viability. Its combination with exercise testing,
particularly in the female sex, significantly increases
diagnostic accuracy7,19.
Mieres et al 20 have assessed 46 postmenopausal
women with exercise test and MPS, and the sensitivity
and specificity values found were, respectively, 67% and
69% for the exercise test, and 88% and 87.5%, for MPS
(p < 0.0001).
The prognostic importance of scintigraphy in the female
sex is well known9,21. There is a large body of evidence
on the association of myocardial scintigraphy and stress
testing, showing that it effectively stratifies the risk in
women suspected of having CAD. Women with a normal
myocardial perfusion study have an annual event rate
much lower (0.6% per year) than those with abnormal
myocardial perfusion study (5% per year)22.
The lower cardiovascular risk in the premenopausal
phase is attributed to the protection provided by
plasma estrogen levels23,24. Such levels promote arterial
vasodilation by increasing the nitric oxide synthesis by
endothelial cells, increase HDL-cholesterol particles and
decrease LDL-cholesterol particles, and reduce the serum
levels of fibrinogen, antithrombin and protein S24.
The decreased estrogen levels of the postmenopausal
phase lead to microvascular endothelial dysfunction and
consequent progression of the atherosclerotic plaque23,24.
Differently from the endogenous estrogen effects,
exogenous hormone therapy has shown to increase the
cardiovascular disease risks23-26.
In 2002, the Women’s Health Initiative (WHI) study
showed that the benefits of hormone replacement therapy
(HRT) were restricted to a small group of women in the
so-called “window of opportunity”, at the beginning of
menopause (between 50 and 59 years), in the presence
of no cardiovascular risk factors. Recent studies have
confirmed that information 27 . However, a recent
publication of the American Heart Association (AHA)
contra-indicates the use of HRT as primary and secondary
prevention of cardiovascular diseases28.
Leuzzi et al 29 , in an interesting editorial, have
reported that, despite the higher prevalence of CAD after
menopause, further studies are required to clarify whether
menopause is a cardiovascular risk factor.
The association between menopause and presence
of CAD might be observed in low-risk women, but
for those with multiple risk factors, such as diabetes,
hypertension, dyslipidemia, obesity, sedentary lifestyle, as
seen in our study, menopause might not be a predictive
factor of ischemia. These same findings have been
observed by Sood et al14 when assessing 2,194 pre- and
postmenopausal women at an intermediate risk for CAD
according to Duke score on exercise testing and according
to MPS. In that study, menopause has not proved to predict
cardiovascular events, and MPS provided risk stratification
beyond the Duke score. A study with a larger number of
patients should be performed to confirm that statement.
Conclusion
The results obtained suggest that, in women with
multiple risk factors for CAD, menopause was not an
independent predictor of ischemia on Tc 99m-sestamibi
MPS. The only proven predictor in that group was the
presence of known CAD. Those data support the idea
that the investigation of ischemia via MPS in women
with multiple risk factors for CAD should begin prior to
menopause.
Author contributions
Conception and design of the research, Acquisition of
data, Analysis and interpretation of the data, Statistical
analysis, Writing of the manuscript, Critical revision of the
manuscript for intellectual content: Santos DAM, Sierralta
WY, Alexandre LM, Smanio PEP, Cestari PF.
Arq Bras Cardiol. 2013; 101(6):487-494
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Schemia on Pre- and Postmenopausal Women Scintigraphy
Original Article
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Study Association
This article is part of the thesis of specialization in
Cardiology submitted by Daniel Augusto Massage dos Santos
e Wendy Yasdin Sierraalta by Institute Dante Pazzanese.
Sources of Funding
There were no external funding sources for this study.
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494
Back to the Cover
Original Article
Chromosomal Abnormalities in Patients with Congenital Heart Disease
Patrícia Trevisan1, Tatiana Diehl Zen1, Rafael Fabiano Machado Rosa1,2,3, Juliane Nascimento da Silva1, Dayane
Bohn Koshiyama1, Giorgio Adriano Paskulin1,3, Paulo Ricardo Gazzola Zen1,3
Programa de Pós-Graduação em Patologia da Universidade Federal e Ciências da Saúde de Porto Alegre (UFCSPA)1, Porto Alegre, RS; Genética
Clínica, Hospital Materno-Infantil Presidente Vargas (HMIPV)2, Porto Alegre, RS; Genética Clínica, Universidade Federal de Ciências da Saúde
de Porto Alegre (UFCSPA) e Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA)3, Porto Alegre, RS - Brazil
Abstract
Background: Chromosomal abnormalities (CAs) are an important cause of congenital heart disease (CHD).
Objective: Determine the frequency, types and clinical characteristics of CAs identified in a sample of prospective and
consecutive patients with CHD.
Method: Our sample consisted of patients with CHD evaluated during their first hospitalization in a cardiac intensive
care unit of a pediatric referral hospital in Southern Brazil. All patients underwent clinical and cytogenetic assessment
through high-resolution karyotype. CHDs were classified according to Botto et al. Chi-square, Fisher exact test and odds
ratio were used in the statistical analysis (p < 0.05).
Results: Our sample consisted of 298 patients, 53.4% males, with age ranging from 1 day to 14 years. CAs were observed
in 50 patients (16.8%), and 49 of them were syndromic. As for the CAs, 44 (88%) were numeric (40 patients with +21, 2
with +18, 1 with triple X and one with 45,X) and 6 (12%) structural [2 patients with der(14,21), +21, 1 with i(21q), 1 with
dup(17p), 1 with del(6p) and 1 with add(18p)]. The group of CHDs more often associated with CAs was atrioventricular
septal defect.
Conclusions: CAs detected through karyotyping are frequent in patients with CHD. Thus, professionals, especially those
working in Pediatric Cardiology Services, must be aware of the implications that performing the karyotype can bring
to the diagnosis, treatment and prognosis and for genetic counseling of patients and families. (Arq Bras Cardiol. 2013;
101(6):495-501)
Keywords: Heart Defects, Congenital; Chromosome Aberrations; Down Syndrome; Karyotype; Metaphase.
Introduction
The incidence of congenital heart defects ranges from 4-50
per 1,000 births1,2. They are defined as a group of alterations
that affect the heart and great vessels2. Depending on the
type and severity of the alteration, patients may require
different interventions3, and the need for intensive care unit
(ICU) admission is frequently observed4. Furthermore, studies
have shown the great impact that congenital heart defects
have on mortality in children5.
The etiology of cardiac malformations is still little
understood6 and their determination is a very important
factor for adequate patient management and treatment.
Among the known causes of congenital heart disease,
chromosomal abnormalities are highlighted 7 . It was
from the second half of the twentieth century, with the
Mailing Address: Paulo Ricardo Gazzola Zen •
Rua Sarmento Leite, 245/403, Centro. Postal Code 90050 170, Porto Alegre,
RS - Brasil
E-mail: [email protected]
Manuscript received January 30, 2013, revised manuscript June 19, 2013,
accepted June 24, 2013.
DOI: 10.5935/abc.20130204
495
development of new cell culture techniques associated
with the use of colchicine and hypotonic solutions in the
treatment of metaphases, that cytogenetics, i.e., is the study
of chromosomes, disseminated.
In 1970, Caspersson et al 8 developed a staining
technique that yielded a more precise identification of each
chromosome through its unique more or less intense region
staining patterns (bands). Moreover, with the emergence of
high-resolution chromosome analysis by Yunis9, in 1981,
chromosomes could be investigated at an early stage of
mitosis (prometaphase), allowing chromosomal bands to
be more detailed10.
Several studies have been developed in recent decades,
aiming to evaluate the frequency and types of chromosomal
abnormalities identified through karyotype in patients
with congenital heart disease. The observed rates usually
range from 3-18%. However, these studies are mostly
retrospective and based on databases3,6,11-22. Moreover,
it is noteworthy the virtual lack of studies carried out in
Latin America20.
Thus, our study aimed to determine the frequency, type
and clinical characteristics of chromosomal abnormalities
identified by high-resolution karyotype in a prospective
and consecutive sample of patients with congenital heart
disease.
Trevisan et al
Chromosomal Abnormalities and Congenital Heart Diseases
Original Article
Methods
Patients
Our sample consisted of patients from to the studies by
Rosa et al23 and Zen et al24. They comprised a prospective and
consecutive cohort of patients with congenital heart disease
hospitalized in the ICU of a pediatric referral hospital in
southern Brazil. Only those patients at their first hospitalization
were included. The total evaluation period was 1.5 year.
This study was approved by the Research Ethics Committee
of the hospital and the university. We only included patients
whose families agreed to participate in the study.
Clinical protocol
An evaluation form was completed by clinical geneticists for
each subject participating in the study. This was accomplished
through direct interviews with family members, review of
hospital records and clinical evaluation of patients. In our study,
we used general data such as gender, patient age, reason for
admission, origin and syndromic appearance. As for origin,
the patients were divided into those who came from Porto
Alegre (the city where the study was carried out), Porto Alegre
suburbs, from other cities in the state of Rio Grande South and
other states.
The syndromic diagnosis was made before the results
of cytogenetic analysis and was defined solely on physical
examination, taking into account both quantitative (number of
minor and major anomalies) and qualitative (types and pattern
of dysmorphic features, presence of neurological alterations)
data25. The cardiac diagnosis was obtained from the results
of echocardiographic examinations, surgery and/or cardiac
catheterization. Congenital heart defects were then defined
and classified according to Botto et al26. Furthermore, congenital
heart defects were classified as complex and cyanotic.
Cytogenetic study through high-resolution karyotype
A blood sample was collected from each patient, and
high‑resolution karyotype (≥ 550 bands) was performed
according to the modified technique of Yunis9. This technique,
unlike conventional karyotyping, allows the chromosomes to
be analyzed at a very early stage of mitosis, in prometaphase,
when chromosomes are less condensed. Thus, it allows better
identification of minor structural chromosomal abnormalities,
such as small deletions. In summary, this technique is based
on the procedure of cell culture of lymphocytes stimulated
with phytohemagglutinin for 72 hours, synchronization
with methotrexate/thymidine and GTG-banding staining.
The analysis of the slides in each case was performed in an
Axioskop Zeiss microscope using a count of 25 metaphase
plates, which excludes a degree of mosaicism of up to 12%
for a 95% confidence level27.
Statistical Analysis
Data processing and analysis were performed using SPSS
for Windows (release 18.0), Microsoft ® Excel 2002 and PEPI
(release 4.0). The statistical analysis used the chi‑square and
Fisher’s exact two-tailed tests for comparison of frequencies,
and odds ratios to assess the association between cardiac
defects and chromosomal abnormalities. Values ​​were
considered significant when p < 0.05.
Results
General sample data
During a period of one year and six months, 333 patients
with congenital heart disease met the criteria for inclusion in the
study. However, 31 of them did not participate in the study, due
to death (n = 12) or because they had been discharged prior to
the application of informed consent (n = 4), or because their
parents did not agree to participate (n = 15). Of 302 patients
with consent, the karyotype was successfully performed in 298,
and these comprised our final sample. Of these 298 patients, 159
(53.4%) were males, ranging in age from one day to 14 years of
age, with just over half of them (58.7%) in the first year of life.
The main reason for admission was cardiac surgery (76.2%);
among the remaining patients, about half was there for cardiac
evaluation and half for cardiac catheterization.
As for the origin, 13.8% were from the city of Porto Alegre,
21.1% were from the city suburbs, 55% were from other cities
in the state of Rio Grande do Sul and 10.1% were from other
states. As for the physical examination, 29.5% of patients were
classified as syndromic. Of these, 70.5% had a classic syndrome
phenotype.
The anatomical types of cardiac malformation observed are
shown in Table 1. Ventricular (VSD) and atrial (ASD) septal defect
were the most frequent alterations, each observed in 14.8% of
cases. According to the classification of Botto et al26, the main
group of observed cardiac alterations was septal defects (29.5% Table 1). Complex heart disease was observed in 34.6% of cases,
and cyanotic disease, in 35.2%.
Chromosomal alterations
Chromosomal abnormalities were observed in 50 subjects
(16.8%) and the full trisomy of chromosome 21 was the most
frequent of them (n = 40). Of the remaining cases, four had
numerical and six structural abnormalities (Figure 1, Tables 1
and 2). Although most patients with chromosomal abnormalities
were from the countryside of the state of Rio Grande do Sul,
there was no statistically significant difference (p = 0.998) when
evaluating the presence or absence of these alterations regarding
patient origin.
Most patients with chromosomal abnormalities were admitted
at the ICU for cardiac surgery (76.2%) and cardiac evaluation
(11.7%). The main clinical characteristics of the 50 patients with
chromosomal abnormalities are shown in Tables 1 and 2. According
to the classification by Botto et al26, the group of heart defects in
our sample more often associated with chromosomal abnormalities
was atrioventricular septal defect (66.7%, OR: 16.929, 95% CI:
7.434 to 38.55, p < 0.001). Septal malformations were frequent
(19.3%); however, they did not show a statistically significant
association (OR: 1.284, 95% CI: 0.673 to 2.452, p = 0.448).
Right and left obstructive cardiac defects, on the other hand,
showed an inverse association, i.e., they were statistically not
associated with chromosomal abnormalities.
Arq Bras Cardiol. 2013; 101(6):495-501
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Trevisan et al
Chromosomal Abnormalities and Congenital Heart Diseases
Original Article
Table 1 - Congenital heart defects, classified by Botto et al26 and karyotype findings observed in patients from the sample
Chromosomal alteration
Numerical
Normal
karyotype
+21
+18
56
6
1
(26)
(6)
(1)
11
21
Ebstein’s Anomaly
3
1
Left obstructive defects
45
1
Aortic coarctation
(28)
(1)
Aortic valve
stenosis
(4)
Heart defects
Outflow tract defects
Tetralogy of Fallot
Atrioventricular septal
defect
Septal defects
Ventricular septal
defects
(30)
(9)
(1)
Atrial septal defects
(41)
(2)
248
add(18p)
i(21q)
del(6p)
Total
(%)
1
64
21.5
(1)
(34)
1
33
11.1
4
1.3
47
15.8
der(14;21),+21
(1)
1
Total
dup(17p)
(29)
11
62
45,X
1
71
Other heart defects
XXX
Structural
40
1
(5)
1
1
1
1
88
(1)
(1)
(1)
(1)
(44)
(1)
2
1
29.5
(44)
1
1
1
1
1
2
62
20.8
298
100
+18: full trisomy of chromosome 18; +21: full trisomy of chromosome 21; 45,X: monosomy X; add (18p): additional material by the end of the short arm of chromosome
18; del (6p): deletion of the short arm of chromosome 6; der(14;21),+21: trisomy of chromosome 21 secondary to translocation between chromosomes 14 and 21;
dup (17p): duplication of the short arm of chromosome 17; i(21q) Down syndrome secondary to isochromosome of the long arm of chromosome 21; XXX: trisomy X.
When evaluating anatomic types belonging to the groups
classified according to Botto et al26 separately, it was observed that
the atrioventricular septal defects (66.7%, OR = 16.929, 95% CI:
7.434 to 38.55, p < 0.001) and ventricular septal defects (31.8%;
OR: 2.826, 95% CI: 1.368 to 5.839, p = 0.005) were more often
associated with chromosomal abnormalities (Figure 2). All cases
of chromosomal alteration associated with atrioventricular septal
defect consisted of patients with Down syndrome. On the other
hand, D-transposition of the great arteries was statistically not
associated with chromosomal abnormalities (none of the cases
with this defect had the latter, p = 0.0310 - Table 1). On physical
examination, 49 of 50 patients with chromosomal abnormalities
were considered syndromic (only the patient with triple X was
nonsyndromic - Table 2).
Discussion
In our review of the literature using the PubMed and
SciELO databases, we identified 14 studies similar to ours,
which evaluated the frequency and types of chromosomal
abnormalities identified through karyotype in patients with
congenital heart disease3,6,11-22. Studies such as the one by
Schellberg et al28, which excluded patients with frequent
chromosomal alterations (such as trisomy 21) from the
sample, were not included in our analysis. The vast majority
497
Arq Bras Cardiol. 2013; 101(6):495-501
of similar studies were developed in the United States and
Europe. Only one (by Amorim et al20) was carried out in Latin
America and Brazil. However, it is noteworthy that, unlike
us, most studies (including the one by Amorim et al20) were
performed retrospectively, based mainly on databases. Due to
this fact, the karyotype was not performed in a standardized
way in many studies (the testing often appeared to be
limited primarily to the cases with suspected chromosomal
abnormality)12,18. Furthermore, our study was the only one
in which a geneticist assessed and carried out the syndromic
classification of patients based on data from the physical and
dysmorphologic assessment (Table 2).
The frequency of chromosomal abnormalities identified
through karyotyping in our study (16.8%) was similar to
that found in the studies of Ferencz et al11, Pradat13, Harris
et al19 and Amorim et al20, who found rates of 12.9-23.1%.
Significant differences were observed in relation to the work
of Stoll et al12, Hanna et al14, Goodship et al15, Grech and
Gatt3, Meberg et al16, Roodpeyma et al6, Bosi et al17, Calzolari
et al18 Dadvand et al21 and Hartman et al22, who found rates
of 3-12.1% (p < 0.05). These were characterized by having
distinct samples, both regarding the number and the clinical
characteristics of their patients. In our sample, the frequency of
chromosomal abnormalities did not differ regarding the origin
of patients, suggesting that perhaps there was no selection
Trevisan et al
Chromosomal Abnormalities and Congenital Heart Diseases
Original Article
Figure 1 - Partial GTG-banded karyotype and ideograms of chromosomal abnormalities observed in the sample.
Table 2 - Classification according to the syndrome characteristics, based only on physical examination
Chromosomal alteration
Classic syndrome
Undefined Syndrome
Heart disease + dysmorphism
Isolated heart disease
Total
+21
40
0
0
0
40
+18
1
1
0
0
2
XXX
0
0
1
0
1
45,X
1
0
0
0
1
der(14;21),+21
2
0
0
0
2
i(21q)
1
0
0
0
1
dup(17p)
0
1
0
0
1
del(6p)
0
1
0
0
1
add(18p)
0
1
0
0
1
Total
44
5
1
0
50
+18: full trisomy of chromosome 18; +21: full trisomy of chromosome 21; add (18p): additional material by the end of the short arm of chromosome 18; 45,X:
monosomy X, del (6p): deletion of the short arm of chromosome 6; der(14;21),+21: trisomy of chromosome 21 secondary to translocation between chromosomes 14
and 21; dup (17p): duplication of the short arm of chromosome 17; i(21q) Down syndrome secondary to isochromosome of the long arm of chromosome 21; XXX:
trisomy X.
Arq Bras Cardiol. 2013; 101(6):495-501
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Chromosomal Abnormalities and Congenital Heart Diseases
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Groups according to Botto et al.26
Outflow tract defects
OR=0,653; 95% CI=0,29-1,472
Atrioventricular septal defects
OR=16,929; 95% CI=7,434-38,55
Septal defects
OR=1,284; 95% CI=0,673-2,452
Anatomical types
Tetralogy of Fallot
OR=1,626; 95% CI=0,689-3,837
Atrioventricular septal defects
OR=16,929; 95% CI=7,434-38,55
Ventricular septal defect
OR=2,826; 95% CI=1,368-5,839
1
odds Ratio
10
Figure 2 - Chart showing odds ratios with confidence intervals (95%CI) of the main groups and anatomical types of heart defects observed in the sample regarding the
presence of chromosomal abnormalities.
associated with chromosomal abnormalities. That is, there
was no difference between the frequency of patients with
severe alterations that came from the city capital compared
to those that came from the countryside of the state.
Down syndrome, especially in individuals with full trisomy
of chromosome 21, was the most frequently observed
chromosomal abnormality in our series of patients (14.4%),
which is consistent with the literature. The full trisomy of
chromosome 18 was the second most frequent one and
recurrent among patients with congenital heart disease.
Another condition often described in the studies, but absent
from our sample was trisomy of chromosome 1311-13,16-22.
Regarding structural changes, only the deletion of the
short arm of chromosome 6 was also observed in another
study22. The patient with duplication of the short arm of
chromosome 17 has been described in detail by Paskulin et
al29. The frequency of structural alterations observed in our
sample (12%) was similar to the one in most other studies
(4.2 to 16.7%), differing only in relation to Ferencz et al11,
who found a lower frequency (4.4%). It is noteworthy that
this study was the oldest, developed in the early 1980s,
at a time when the high-resolution technique was being
described 10. In our series, in spite of the count of 25
metaphase slides (which excludes a degree of mosaicism
of up to 12% for a 95% confidence level)27, no cases of
mosaicism were observed. These have been reported in
low frequencies only in the studies by Goodship et al 15
and Hartman et al22. Nevertheless, the overall frequency
of chromosomal abnormalities was lower than the one in
our study.
499
Arq Bras Cardiol. 2013; 101(6):495-501
As for the association of chromosomal alterations
with types of heart defects, we observed, according
to Botto et al 26 , a very significant association with
atrioventricular septal defect, at the expense mainly of
patients with Down syndrome (our frequency was 66.7%).
This finding is consistent with the literature, which describes
rates of 40‑50% 30. Thus, when assessing a patient with
atrioventricular septal defect, there is a high probability
(of up to one in two) that the patient has Down syndrome.
It was noteworthy the lack of association of chromosomal
alterations with some defect groups, such as, left and right
obstructive defects (including defects such as pulmonary
stenosis and aortic coarctation). Alone, that was observed
only in relation to an outflow tract defect, D-transposition
of the great arteries. Although we did not observe an
association between chromosomal abnormalities and
septal defects, separately we found an association with
ventricular septal defects. In the literature, chromosomal
abnormalities have been described in approximately 4.6 to
18.2% of patients with ventricular septal defects11,18,19 and
in our sample, this frequency was 31.8%.
Although our study was the only one that had the
syndromic classification description made by a clinical
geneticist, based only on the dysmorphologic physical
examination findings of patients, our frequency of syndromic
patients (29.5%) was similar to that reported by Calzolari
et al18 and Amorim et al20. Unlike ours, in these studies the
patients were retrospectively divided into syndromic or not
after the karyotype evaluation results and the presence of
abnormalities in other organs. Chromosomal abnormalities
Trevisan et al
Chromosomal Abnormalities and Congenital Heart Diseases
Original Article
are frequent in syndromic individuals. In our sample,
only one of 50 patients with chromosomal abnormalities
was considered nonsyndromic, who was an individual
with triple X syndrome. This finding is consistent with the
literature, as individuals with triple X often go unnoticed
amid the general population, as they usually do not have
associated major findings. In our case, we cannot rule out
the possibility that the association with congenital heart
disease may have been coincidental, as both conditions
are relatively frequent (triple X occurs in one in 1,000
live female births)31.
In spite of the advances in cytogenetics that occurred
in recent decades with the development of molecular
techniques, such as fluorescent in situ hybridization
(FISH) and comparative genomic hybridization (CGH),
karyotyping remains a crucial and basic tool in genetic
evaluation10.
In our country, it is one of the few tests available for
the evaluation of patients treated by the Unified Health
System, the public health system of Brazil. Despite its
limitations in detecting small chromosomal rearrangements
such as microdeletions or microduplications, the
frequency of chromosomal abnormalities detected by
karyotyping in patients with congenital heart disease is
remarkable. Thus, professionals, especially those working
in pediatric cardiology services, should be aware of the
implications that karyotype assessment can bring, both for
the diagnosis, treatment and prognosis of these patients,
as well as for genetic counseling of their families.
Acknowledgements
We thank Coordenação de Aperfeiçoamento de Pessoal
de Nível Superior (Capes) and the Scientific Initiation
Program of Universidade Federal de Ciências da Saúde de
Porto Alegre (PIC-UFCSPA) for the grants received.
Author contributions
Conception and design of the research, Acquisition of data,
Analysis and interpretation of the data, Statistical analysis,
Obtaining funding and Writing of the manuscript: Trevisan P,
Zen TD, Rosa RFM, da Silva JN, Koshiyama DB, Paskulin GA,
Zen PRG; Critical revision of the manuscript for intellectual
content: Trevisan P, Rosa RFM, Paskulin GA, Zen PRG
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
This study was funded by CAPES and PIC-UFCSPA.
Study Association
This article is part of the thesis of master submitted by
Patrícia Trevisan, Rafael Fabiano Machado Rosa e Paulo
Ricardo Gazzola Zen from Universidade Federal de Ciências
da Saúde de Porto Alegre.
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Arq Bras Cardiol. 2013; 101(6):495-501
Back to the Cover
Original Article
Clinical Significance of Histological Features of Thrombi in Patients
with Myocardial Infarction
Juliana Canedo Sebben, Eduardo Cambruzzi, Luisa Martins Avena, Cristina do Amaral Gazeta, Carlos Antonio
Mascia Gottschall, Alexandre Schaan de Quadros
Instituto de Cardiologia / Fundação Universitária de Cardiologia – IC/FUC, Porto Alegre, RS - Brazil
Abstract
Background: Percutaneous Coronary Intervention (PCI) is the most common strategy for the treatment of Acute ST
segment elevation Myocardial Infarction (STEMI), and thromboaspiration has been increasingly utilized for removal of
occlusive thrombi.
Objectives: To analyze the influence of histopathological features of coronary thrombi in clinical outcomes of patients
with STEMI, and the association of these variables with clinical, angiographic, and laboratory features and medications
used in hospitalization.
Methods: Prospective cohort study. All patients were monitored during hospitalization and thirty days after the event.
Aspirated thrombi were preserved in formalin and subsequently stained with hematoxylin-eosin and embedded in
paraffin. Thrombi were classified as recent and old. The primary outcome was the occurrence of major cardiovascular
events within thirty days.
Results: During the study period, 1,149 patients were evaluated with STEMI, and 331 patients underwent thrombi
aspiration, leaving 199 patients available for analysis. It was identified recent thrombi in 116 patients (58%) and old
thrombi in 83 patients (42%). Recent thrombi have greater infiltration of red blood cells than old thrombi (p = 0.02), but
there were no statistically significant differences between other clinical, angiographic, laboratory, and histopathological
features and medications in both group of patients. The rates of clinical outcomes were similar in both groups.
Conclusions: Recent thrombi were identified in 58% of patients with STEMI and it was observed an association with
infiltration of red blood cells. There was no association between histopathological features of thrombi and clinical
variables and cardiovascular outcomes. (Arq Bras Cardiol. 2013; 101(6):502-510)
Keywords: Coronary thrombosis; Percutaneous coronary intervention; Thrombectomy; Myocardial infarction.
Introduction
Acute ST Segment Elevation Myocardial Infarction (STEMI)
is generally caused by sudden occlusion of a coronary
artery due to fracture or erosion of atherosclerotic plaque,
and it is one of the main causes of deaths worldwide1-3.
Primary Percutaneous Coronary Intervention (pPCI) is the
most common strategy for the treatment of this disease4,5.
A metanalysis published by Keeley et al5 in 2003 demonstrated
that treatment by PCI results in significant decrease in
mortality when compared to thrombolytic treatment.
The mortality rates of STEMI have significantly decreased
after the use of routine pPCI, representing approximately
7% in contemporary practice5-7. These results can further
Mailling Address: Alexandre Schaan de Quadros •
Av. Princesa Isabel, 395, Santana. Postal Code 90620-000,
Porto Alegre, RS - Brazil
E-mail: [email protected], [email protected]
Manuscript received April 05, 2012; revised manuscript June 19, 2013;
accepted July 10, 2013.
DOI: 10.5935/abc.20130212
502
improve with thromboaspiration, and this approach also
reduces stent thrombosis and improves myocardial blush8-10.
Thrombectomy by manual aspiration can be effectively
carried out with several devices available in the market11.
Aspirated thrombi present different histopathological
and morphometric features, and it has been suggested
that thrombi may be classified as recent, lytic and
organized8,12,13. Other studies demonstrate that there may
be a period of days or weeks between thrombus formation
and infarction symptoms12,14,15. It was also demonstrated
that old thrombi may be present in patients with chest pain
only for a couple of hours, and that the age (progression
time) of thrombus is related to worst prognosis and partial
resolution of ST segment12,16,17.
Recent studies demonstrated an association between
histological features of thrombi and major cardiovascular
outcomes8,13,15,17,18. However, these studies were performed
over ten years ago, and with different thromboaspiration
devices, and this limits its applicability in contemporary
clinical practice. This study aims at analyzing the influence
of histopathological features of coronary thrombi in clinical
outcomes of patients with acute ST segment elevation
Sebben et al.
Histopathological evaluation of coronary thrombi
Original Article
myocardial infarction undergoing manual aspiration in
contemporary clinical practice, and the association of these
variables with clinical, angiographic, and laboratory features
and medications administered during hospitalization.
Methods
Study design
Prospective cohort study of patients with STEMI treated
at the Cardiology Institute of Rio Grande do Sul, University
Cardiology Foundation, Porto Alegre, Brazil, in the period of
April, 2010 to January, 2012.
Patients
Inclusion criteria were STEMI and indication of
pPCI and thrombectomy by aspiration (at the attending
physician’s discretion). Exclusion criteria were under age,
failure at thromboaspiration and refusal to sign the consent
form. The project was approved by the Ethics Research
Committee of the Cardiology Institute of Rio Grande do
Sul. The patients signed the informed consent form.
Logistics
All patients were interviewed at hospital admission
and followed-up during the study period by one of the
investigators. Data collections were performed using paper
forms elaborated by the group of investigators involved, and
these data were stored in a specific database in Microsoft
Access. Data included in the database were verified by
another investigator. Clinical, angiographic, laboratory, and
histopathological features and medications used during
the first 24 hours of hospitalization and cardiovascular
outcomes within thirty days were analyzed.
Delta T was defined as the time between onset of chest pain
and patient’s arrival at the emergency room. Door-to-balloon
comprised time between patient’s arrival at the emergency
room and first balloon inflation inside the infarct-related artery.
Total ischemia time was the sum of these two times.
Procedures of primary percutaneous coronary intervention
PPCI procedures were carried out as described in the
literature19,20. All patients were treated with aspirin 300mg
and clopidogrel 300 to 600mg at hospital admission. Heparin
(100 U/Kg EV) was administered before PCI. Inhibitors of
glycoprotein IIb/IIIa and other technical aspects, such as
the number of stents used and pre- and post-dilation, were
used at the operators’ discretion, as well as the decision
of performing thrombectomy by aspiration. In this study,
the following manual aspiration devices were used: Export
(Medtronic Vascular Inc., Santa Rosa, United States), Pronto
(Vascular Solutions, Minneapolis, United States), Diver
(Invatec, Brescia, Italy) or Thrombuster (Kaneka Medix
Corporation, Osaka, Japan). The aspiration procedure
technique was that described in the literature9, passing the
catheter several times through the occlusion site.
Angiographic analyses were performed in two orthogonal
projections by experienced operators. The coronary flow was
analyzed before and after the procedure according with TIMI
criterion21. Myocardial perfusion was evaluated by myocardial
blush score, previously described22.
Histopathological analysis
We included in the study 199 thrombi of patients
with STEMI subjected to pPCI, 116 recent thrombi and
83 old thrombi. Immediately after thrombus aspiration
by manual device, the device filter was placed in 10%
formalin, aspirated and fixed for 24 hours. Then, the
material was embedded in paraffin, subjected to series
of 8µm-thick hemoxylin‑eosin‑stained histological cuts.
In histopathological analysis, we evaluated the quantities
of white blood cells, red blood cells and fibrin, described
according to their percentage. The number of fragments
of each aspirated thrombus was also analyzed. Thrombotic
material was classified according with its composition.
Thrombi were classified in three groups, accordingly with
previously published data: recent thrombus, composed
of patterns of layers of platelets, fibrin and white blood
cells; lytic thrombi, characterized by areas of necrosis
and apoptosis; white blood cells; and organized thrombi,
which showed proliferation of smooth muscle cells and/
or deposition of connective tissue12,13. Thrombi collected
in this study were divided in two groups: recent and old
(lytic/organized). Pathological analyses were carried out
by three pathologists blinded to clinical features.
Clinical follow-up and outcomes
Each patient was monitored during hospitalization by
one of the investigators, and telephone call was made
within 30 days after STEMI. The study primary outcome
was the combination of cardiovascular events: death, AMI
and myocardial revascularization. Myocardial infarction
was defined as recurrence of chest pain with new ST
segment elevation or elevation of biomarkers serum levels.
New revascularization was carried out by surgical
myocardial revascularization or percutaneous coronary
intervention procedure, at the attending physician’s
discretion. We also evaluated secondary outcomes, such
as Cerebrovascular Accident (CVA) and stent thrombosis.
Ischemic stroke was considered when there was a rapid loss
of neurological function. Thrombosis was defined according
to the Academic Research Consortium definitions23.
Statistical analysis
The data were analyzed using the statistical program
SPSS 19.0. Quantitative variables are described as mean
± standard deviation or median, interquartile range.
Categorical variables are described through absolute and
relative frequency. The patients were divided in recent
thrombus group and old thrombus group, and comparisons
were carried out using Chi-square test, Fischer’s Exact test,
t or Mann-Whitney test, as appropriate. Values considered
significant are those with p < 0.05.
Arq Bras Cardiol. 2013; 101(6):502-510
503
Sebben et al.
Histopathological evaluation of coronary thrombi
Original Article
Results
In the study period, we evaluated 1,149 patients with
STEMI, and 331 patients underwent thrombi aspiration.
The success rate was of 69%, and 199 samples were available
for analysis. The study flowchart is shown in Figure 1.
Recent thrombi were identified in 116 patients (58%),
and due to the small number of lytic and organized thrombi
(N = 43 and N = 40, respectively), we formed a group of
old thrombi with 83 patients (42%). Comparisons between
clinical and angiographic features of both groups of patients
are shown in Table 1. Patients with recent thrombi presented
a more frequent history of coronary artery disease (p = 0.09)
and 2/3 TIMI flow after the procedure (p = 0.09). Patients
with old thrombi present higher abdominal circumference
(p = 0.09). Delta T did not present a statistically relevant
association with histological features of thrombi.
Laboratory features of these two groups of patients are
shown in Table 2. There were no statistically relevant differences
regarding fibrogen, C-Reactive Protein (CRP), Creatinine
phosphokinase (CK), Creatinine phosphokinase-MB (CKMB),
Ultra-sensitive Troponin (USTN) and other analyses.
In Table 3 are shown the medications used during the
first 24 hours of hospitalization, and there was no statistically
relevant difference between these two groups of patients.
Histopathological analyses are shown in Table 4. Patients
with recent thrombus presented significantly higher
infiltration of red blood cells (p = 0.02), and the group of
old thrombus had a tendency for higher fibrin infiltration
(p = 0.07). As for other histopathological and morphometric
characteristics, such as the number of fragments removed,
dimension and volume of thrombus and infiltration of white
blood cells, there were no statistically relevant differences
between these two groups of patients.
In the 30-day clinical follow-up there were no statistically
relevant differences regarding death (recent thrombus = 7.8%
vs. old thrombus = 4.8%; p = 0.59), AMI (recent
thrombus = 2.6% vs. old thrombus = 2.4%; p = 1), ischemic
stroke (recent thrombus = 0.9% vs. old thrombus = 2.4%;
p = 0.77), stent thrombosis (recent thrombus = 1.7% vs.
old thrombus = 2.4%; p = 1) and combined outcomes
(recent thrombus = 9.5% vs. old thrombus = 6%; p = 0.53).
Results of the clinical follow-up are described in Figure 2.
Recent and old thrombi are illustrated in Figures 3 and 4,
respectively.
Discussion
In this study we demonstrated that there was no
correlation between the histopathological classification
of thrombus as recent or old and the progression time
of infarction, other clinical, angiographic, and laboratory
features and clinical progression of patients. The infiltration
of white blood cells was significantly higher in thrombi
classified as recent and there was a tendency for higher
infiltration of fibrin in old thrombi, which is consistent with
the criteria used to define these thrombi.
The absence of an association between histological
pathology of thrombus and progression time of infarction
had already been previously described by other authors12,15.
Kramer et al15, in 2009, reported that the time between
plaque rupture and thrombi formation is still unpredictable,
and Rittersma et al12 have also demonstrated a discrepancy
between thrombotic process and onset of infarction
symptoms. However, another study recently published by
Silvain et al24 showed that ischemic time is a determining
factor in thrombus composition, its formation during
infarction coronary occlusion is a rapid evolution process,
changing its composition rapidly during ischemic process24.
But our results corroborate the findings of Kramer et al15
and Rittersma et al12 because they showed that coronary
thrombi in our analysis have no relation with ischemic time.
On the other hand, our results are different from other
previous studies that demonstrated that recent thrombi
1,149 patients with STEMI
331 undergoing aspiration
69% of success (229)
119 available thrombi
Figure 1 - Study flowchart. STEMI: Acute ST segment elevation Myocardial Infarction.
504
Arq Bras Cardiol. 2013; 101(6):502-510
Sebben et al.
Histopathological evaluation of coronary thrombi
Original Article
Table 1 - Clinical and angiographic features according to thrombus histopathological classification
Variables
Recent (N = 116)
Old (N = 83)
p
Age, years
58.37 ± 12.35
58.67 ± 10.89
0.86
Male, %
72
68
0.64
87.4
92.6
0.35
Weight
77.09 ± 14.75
78.64 ± 13.67
0.46
Height
167.9 ± 8.35
169.11 ± 9.07
0.35
AC, %
94.01 ± 13.71
97.58 ±14.32
0.09
58.6
54.3
0.66
18
21
0.74
Dyslipidemia, %
24.3
34.6
0.16
Smoking, %
48.6
49.4
0.92
36
23.5
0.09
PCI, %
14.4
11.1
0.65
MRS, %
0
3.7
0.15
AMI, %
12.6
13.6
1
CCI, %
1.8
4.9
0.42
CRI, %
1.8
3.7
0.72
CVA, %
6.3
8.6
0.74
Previous infarction, %
49.5
42
0.37
Caucasian, %
Hypertension, %
Diabetes, %
History CAD, %
Medical history
Delta T, hours
4 (1.97;6.67)
3.97 (2.54;6.47)
0.51
1.25 (0.92;1.62)
1.25 (0.92;1.5)
0.96
5.24 (0;8)
5.35 (3.77;8.12)
0.51
25.2
19.8
0.47
One, %
50.9
59
Two, %
35.3
32.5
Three, %
13.8
8.4
Door-to-balloon, hours
Ischemic time, hours
Use ASA, %
Compromised vessels:
0.38
ADA, %
49
43
0.51
XCA, %
11.2
9.6
0.9
RCA, %
39.7
44.6
0.58
Bypass, %
0
2.4
0.34
3.36 ± 0.51
3.35 ± 0.53
0.96
19.28 ± 10.97
18.3 ± 7.11
0.5
Pre, %
7.8
10.8
0.62
Post, %
99.1
93.9
0.09
5.2
1.2
0.26
Reference diameter, mm
Extension, mm
2/3 TIMI flow:
Blush 2/3
Pre, %
Post, %
71.6
70.4
0.98
TIMI score
3 (2;5)
3 (2;5)
0.53
AC: abdominal circumference; CAD: Coronary Artery Disease; PCI: percutaneous coronary intervention; MRS: myocardial revascularization surgery; AMI: acute
myocardial infarction; CCI: congestive cardiac insufficiency; CRI: chronic renal insufficiency; CVA: cerebrovascular accident; ASA: acetylsalicylic acid; ADA: anterior
descending artery; XCA: circumflex coronary artery; RCA: right coronary artery.
Arq Bras Cardiol. 2013; 101(6):502-510
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Sebben et al.
Histopathological evaluation of coronary thrombi
Original Article
Table 2 - Laboratory features according to thrombus histopathological classification
Variables
Blood glucose, mg/dL
HbA1c, %
Cholesterol, mg/dL
Recent (N = 116)
Old (N = 83)
p
169.88 ± 64.47
156.26 ± 54.14
0.15
5.44 ± 0.22
5.75 ± 0.7
0.12
200.8 ± 50.54
209.5 ± 48.59
0.27
HDL, mg/dL
39.56 ± 12.11
41.02 ± 10.06
0.42
Triglycerides, mg/dL
105 (64.5;195)
108 (69;173.5)
0.8
CRP, mg/dL
0.45 (0.24;0.89)
0.42 (0.2;0.88)
0.39
Fibrinogen, mg/dL
218.7 ± 56.6
226.11 ± 83.23
0.51
Hematocrit, %
40.51 ± 4.55
41.22 ± 3.36
0.25
Red blood cells, g/dL
White blood cells, mm3
Platelets, mm3
13.61 ± 1.52
13.97 ± 1.37
0.11
13643.73 ± 4604.43
14402.69 ± 447.78
0.26
258542.55 ± 76548.06
254828.57 ± 64027.16
0.74
Creatinine, mg/dL
1.02 ± 0.35
0.98 ± 0.31
0.37
CK, U/L
160 (70;464)
129 (59;473.25)
0.45
12 (5;38)
12 (6;35)
0.93
384 (50;2767)
251 (44.5;1218)
0.49
CK-MB, ng/mL
Troponin US, ng/dL
HbA1c: glycated hemoglobin; HDL: high-density lipoprotein; CRP: C reactive Protein; CK: creatinine phosphokinase; CK-MB: creatinine phosphokinase MB;
TNT‑US: ultras-sensitive.
Table 3 - Medications administered in the first 24 hours of hospitalization according to thrombus histopathological classification
Variables
Recent (N = 116)
Old (N = 83)
p
Aspirin, %
95.5
100
0.14
16.4
12
0.52
Clopidogrel
300 mg, %
600 mg, %
82
88
0.33
IIb/IIIa Inhibitor
534
43.4
0.21
Heparin, %
100
97.6
0.34
Statin, %
85.6
83.8
0.88
Beta blocker, %
73
67.5
0.51
ECA inhibitor, %
72.1
68.8
0.74
Nitrate, %
24.3
20
0.5
ACE: angiotensin-converting enzymes.
Table 4 - Histopathological and morphometric features according to thrombus classification
Variables
Recent (N = 116)
Old (N = 83)
p
Number of fragments, n
2 (1;5)
3 (2;5)
0.28
Dimension (width), mm
4 (3;6)
4 (3;7)
0.93
14 (6.5;24)
12 (7;28)
0.77
40 (10;50)
25 (10;40)
0.02
10 (5;20)
10 (10;20)
0.36
50.9±22.86
56.7±20.45
0.07
Volume, µm
3
Red blood cells, %
White blood cells, %
Fibrin, %
506
Arq Bras Cardiol. 2013; 101(6):502-510
Sebben et al.
Histopathological evaluation of coronary thrombi
Original Article
Figure 2 - Cardiovascular outcomes in the 30-day follow-up (%) according to histopathological classification. AMI: acute myocardial infarction; Isc CVA: ischemic
cerebrovascular accident; MACE: major adverse cardiac events: death, AMI, MRS, and PCI.
Figure 3 - Photograph with optical microscope of recent thrombi, characterized by the composition of red blood cells, fibrin and white blood cells.
Arq Bras Cardiol. 2013; 101(6):502-510
507
Sebben et al.
Histopathological evaluation of coronary thrombi
Original Article
Figure 4 - Photograph with optical microscope of an old thrombus, characterized by the presence of loose connective tissue.
are associated with lower mortality. In spite of not
being a statistically relevant difference, our study
demonstrated a higher mortality rate in patients with
recent thrombi than with old thrombi in the 30-day
follow-up, as opposed to a study of Kramer et al 16 ,
which demonstrated an association between the age of
thrombi and mortality. The presence of old thrombi in
that study was an independent predictor of long-term
mortality, and there was a higher risk of death during
the first 14 days in patients with old thrombi compared
to patients with recent thrombi. After 14 days, both
groups had similar mortality rate, demonstrating the
difference in death occurs primarily within a few weeks
after pPCI 16 . Unlike the study abovementioned, our
series reflects a contemporary medical practice, in
which thrombi were obtained exclusively by means of
manual aspiration devices, which could contribute to
the difference in results.
To date, there are few studies on histopathological
analyses of thrombi aspirated during pPCI in patients
with STEMI, some with small samples of patients and/or
others with long duration 16,24,25. Our study analyzed 199
thrombi aspirated by thrombectomy in pPCI in almost
two years of collection, exceeding many published
studies. This is an important aspect to interpret these
data. Difficulties related to the study of thrombi
aspirated in pPCI procedures are due to the relatively
small number of these procedures in most centers, to
partial penetration of thromboaspiration procedure,
to success rates of approximately 70% and to logistic
problems resulting from collection and processing of
material.
508
Arq Bras Cardiol. 2013; 101(6):502-510
Confirming our results with the literature, 2/3 TIMI flow
post-pPCI presented a tendency for association with the
recent thrombi group, and there were studies demonstrating
that recent thrombus can be formed within one day12,13,15,
therefore, it can contribute to improve myocardial reperfusion
and myocardial blush grade after thromboaspiration and rapid
recanalization of the injured artery.
As previously mentioned, in the recent thrombi of this
study we found more red blood cells than in the old thrombi
group, with a statistically relevant difference. Red blood cells
are one of the most common components found in thrombi,
and may contribute more in the composition of thrombi
in later stages and not during acute STEMI phase24,26. Our
findings related to infiltration of red blood cells in the
recent group and tendency for infiltration of fibrin in the
old group corroborate the literature findings, claiming
that recent thrombi have higher composition of red blood
cells, and over time, fibrin fibers increase and transform in
old thrombi, rich in fibrin24,27,28. In addition to red blood
cells and other cell constituents, plasma compartment
supports the fibrin formation and, consequently, thrombus
formation29,30. Red blood cells need to be further studied,
since they seem to mediate the formation of fibrin fibers
and influence in clot viscoelasticity 24,26, reinforcing the
importance of studies with histopathological analysis of
coronary thrombi aspirated during STEMI.
Our study merits validation, for it confirms many
findings in the literature. However, for a clearer
understanding of the influence of coronary thrombi
histopathological features in STEMI in the contemporary
clinical practice, it is necessary to carry out further studies.
Sebben et al.
Histopathological evaluation of coronary thrombi
Original Article
Limitations
Author contributions
The small number of patients is one of the limitations of
this study. However, it is important to consider that our series
compares favorably to several recently published studies,
with less than 100 patients. Studies dedicated to collection
and analysis of coronary thrombi by aspiration thrombectomy
have been limited by a relatively small number of patients
undergoing primary coronary intervention even in reference
centers, through incomplete penetrance of this procedure in
clinical practice, its success rates around 70% and difficulties in
processing and analysis of material. Due to the restrict number
of patients included in this analysis, it was not possible to
carry out a multivariate analysis for the evaluation of possible
confounding variables.
Conception and design of the research and Critical
revision of the manuscript for intellectual content: Sebben
JC, Cambruzzi E, Gottschall CAM, de Quadros AS;
Acquisition of data: Sebben JC, Cambruzzi E, Avena LM,
Gazeta CA; Analysis and interpretation of the data: Sebben
JC, Cambruzzi E, Avena LM, Gazeta CA, de Quadros AS;
Statistical analysis and Writing of the manuscript: Sebben
JC, de Quadros AS.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
Conclusion
In this study, most patients with STEMI had recent thrombi,
which confirms the findings in literature. Recent thrombi showed
a significantly higher infiltration of red blood cells, and there was
no relation between thrombus histopathological classification and
clinical or angiographic features. Clinical outcomes in patients
with old or recent thrombi were similar.
There were no external funding sources for this study.
Study Association
This article is part of the thesis of master submitted by
Juliana Canedo Sebben from Instituto de Cardiologia /
Fundação Universitária de Cardiologia IC/FUC.
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Arq Bras Cardiol. 2013; 101(6):502-510
Back to the Cover
Original Article
The Bleeding Risk Score as a Mortality Predictor in Patients with
Acute Coronary Syndrome
José Carlos Nicolau1, Humberto Graner Moreira1, Luciano Moreira Baracioli1, Carlos Vicente Serrano Jr.1, Felipe
Galego Lima1, Marcelo Franken1, Roberto Rocha Giraldez1, Fernando Ganem1, Roberto Kalil Filho1, José Antônio
Franchini Ramires1, Roxana Mehran2
Instituto do Coração (InCor) – Universidade de São Paulo1, SP – Brazil; Mount Sinai School of Medicine2, New York, NY - USA
Abstract
Background: It is well known that the occurrence of bleeding increases in-hospital mortality in patients with acute
coronary syndromes (ACS), and there is a good correlation between bleeding risk scores and bleeding incidence.
However, the role of bleeding risk score as mortality predictor is poorly studied.
Objective: The main purpose of this paper was to analyze the role of bleeding risk score as in-hospital mortality predictor
in a cohort of patients with ACS treated in a single cardiology tertiary center.
Methods: Out of 1,655 patients with ACS (547 with ST-elevation ACS and 1,118 with non-ST-elevation ACS), we
calculated the ACUITY/HORIZONS bleeding score prospectively in 249 patients and retrospectively in the remaining
1,416. Mortality information and hemorrhagic complications were also obtained.
Results: Among the mean age of 64.3 ± 12.6 years, the mean bleeding score was 18 ± 7.7. The correlation between
bleeding and mortality was highly significant (p < 0.001, OR = 5.296), as well as the correlation between bleeding
score and in-hospital bleeding (p < 0.001, OR = 1.058), and between bleeding score and in-hospital mortality (adjusted
OR = 1.121, p < 0.001, area under the ROC curve 0.753, p < 0.001). The adjusted OR and area under the ROC curve
for the population with ST-elevation ACS were, respectively, 1.046 (p = 0.046) and 0.686 ± 0.040 (p < 0.001); for
non‑ST‑elevation ACS the figures were, respectively, 1.150 (p < 0.001) and 0.769 ± 0.036 (p < 0.001).
Conclusions: Bleeding risk score is a very useful and highly reliable predictor of in-hospital mortality in a wide
range of patients with acute coronary syndromes, especially in those with unstable angina or non-ST-elevation acute
myocardial infarction. (Arq Bras Cardiol. 2013; 101(6):511-518)
Keywords: Acute Coronary Syndrome/complications; Hemorrhage/mortality; Probability.
Introduction
The administration of an adequate and intensive
antithrombotic treatment while minimizing bleeding
complications presents a major challenge to the effective
management of Acute Coronary Syndromes (ACS). In the
last decade, antithrombotic regimen options have increased
substantially, resulting in numerous unique combinations of
the available drugs. Previously, bleeding complications were
considered to be a manageable "side effect" of antithrombotic
therapy. However, the development of increasingly potent
drugs along with concomitant utilization of antithrombotic
therapies, has raised concern for bleeding risk, as there is also
Mailing Address: José Carlos NIcolau •
Aureliano Coutinho 355, apt. 1401. Postal Code 01224-020. São Paulo - Brazil
e-mail: [email protected]
tel.: +55-11-26615058/+55-11-26615196
fax: +55-11-30883809
Manuscript received August 15, 2013; revised manuscript August 22, 2013;
accepted August 22, 2013.
DOI: 10.5935/abc.20130223
511
mounting evidence to suggest an independent association
between bleeding complications and other detrimental
outcomes in patients with ACS, including higher rates of
reinfarction, stroke and death1-5.
The development of effective tools for predicting
patient bleeding risk may help in therapeutic decision
making to maximize the benefits and minimize the risk of
bleeding associated with antithrombotics. Although there
are well established models for ischemic complications
risk stratification as TIMI, GRACE, and PURSUIT, among
others, tools for predicting the bleeding risk are less
common. Several studies identified bleeding risk factors
for complications but most did not use them to develop a
stratification tool for predict bleeding6-8. The demonstration
that a more intensive antithrombotic regimen increases
bleeding, which in turn increases ischemic events, has led
investigators to conclude that antithrombotic treatment in
patients with ACS should be personalized9. The recently
published American College of Cardiology/American Heart
Association 2011 focused update of the guidelines for the
management of patients with unstable angina/non–STelevation myocardial infarction (NSTEMI) reiterates the
Nicolau et al.
Bleeding risk score and mortality in ACS
Original Article
importance of balancing antithrombotic strategies with the
bleeding risk10. Actually, despite more aggressive treatment,
bleeding rates did not increase over time, suggesting that
clinicians are better tailoring antithrombotic therapy to each
patient, which support the idea that better and more reliable
bleeding scores would be welcome11. On the other hand,
is is well demonstrated the correlation between bleeding
and in-hospital mortality, and between bleeding scores and
incidence of bleeding; however, the predictive value of
bleeding risk score for in-hospital mortality is poorly studied.
We contend that valuable advancements are obtained
by continually developing simpler and improved calculation
methods. Recently, Mehran et al8 published a simple and easy
to assess tool for bleeding risk stratification. They combined the
ACUITY and HORIZONS-AMI data, both contemporary and
complimentary ACS trials, and proposed a score comprised
of 6 baseline factors (gender, age, creatinine, leukocyte,
anemia, type of ACS) and 1 modifiable parameter based
on antithrombotic regime (heparin + GP IIb/IIIa inhibitor
or bivalirudin)8. The main purpose of the present study was
to evaluate the role of this score as in-hospital mortality
predictor in a cohort of patients with ACS treated in a single
cardiology tertiary center, comparing its value in STEMI and
non-ST-elevation ACS.
which were already included in the bleeding score). Different
models were constructed to better analyze the influence of the
bleeding score on mortality. The first envisioned scenario was at
the patient’s hospital arrival where the models in this situation
included baseline variables for the global population and the
corresponding TIMI risk scores12,13 in the subgroups with or
without ST-elevation ACS. In order to analyze the influence of
in-hospital invasive therapies on the obtained results, a second
set of analyses were developed in the same subgroups, with the
inclusion of primary angioplasty, non-primary angioplasty, and
surgical revascularization in the models.
Finally, the discriminatory power of the bleeding score and
the TIMI risk scores as in-hospital mortality predictors was
analyzed by Receiver Operator Characteristic (ROC) curves,
with the DeLong method14, being applied for the statistical
comparisons between the curves.
All the above analyses were developed separately for the
whole population and also for the ST-elevation ACS and
non‑ST-elevation ACS.
Table 1 - Characteristics of the population
Baseline Characteristics
Methods
Age [median (25th, 75th) years]
We included 1,655 patients with ACS (547 with
ST‑elevation ACS and 1,118 with non-ST-elevation ACS).
The bleeding score was calculated prospectively in
249 patients and retrospectively in the remaining 1,416.
The mean age of the population was 64.3 ± 12.6 years and
67% were male. It is important to note that because bivaluridin
is not available in Brazil, the component of the score regarding
antithrombotic therapy was always zero. Despite that just
48.1% of the total population was administered with IIb/IIIa
inhibitors, there were no significant differences between the
groups with or without IIb/IIIa inhibitors with respect to the
role of the bleeding score as a mortality or bleeding predictor.
Bleeding score [median (25th, 75th)]
64 (55,74)
18 (13,23)
TIMI-NSTEACS score [median (25 , 75 )]
4 (2,5)
TIMI-STEMI score [median (25th, 75th)]
4 (3,5)
th
th
Male gender
67%
Previous angina pectoris
31.4%
Previous coronary angioplasty
23.4%
Previous surgical myocardial revascularization
19.9%
Previous heart failure
10%
Previous stroke
5.2%
Previous myocardial infarction
33.6%
Known diabetes
32.4%
Categorical variables are described as numbers and
percentages and continuous variables as median (25th, 75th
percentiles) or mean ± SD.
Known dyslipidemia
55.9%
Known hypertension
79.2%
Relatives with coronary artery disease
22.5%
For the developed univariate analyses regarding the
correlation between bleeding score and mortality or
in‑hospital bleeding, the Mann-Whitney U test was applied.
The Chi-square test was applied for the comparison between
categorical variables.
Smokers
22.7%
Primary angioplasty
16.8%
Multivariate stepwise logistic regression models with 0.05 for
entry and 0.10 for removal were applied in order to adjust the
results for confounding factors. Mortality was the dependent
variable, and the baseline and in-hospital variables listed in Table
1 were included as independent variables (except age and gender,
Non-primary angioplasty
39.3%
Surgical myocardial revascularization
17.4%
Statistical Analyses
Anterior wall myocardial infarction
28%
In-hospital invasive therapies
NSTEACS: non-ST-elevation acute coronary syndromes; STEMI: ST-elevation
acute myocardial infarction.
Arq Bras Cardiol. 2013; 101(6):511-518
512
Nicolau et al.
Bleeding risk score and mortality in ACS
Original Article
P-values < 0.05 (2-sided) were considered significant.
MedCalc version 11.4.2.0 statistical software (MedCalc
Software, Marakerke, Belgium) was used for the ROC curve
comparisons and SPSS version 19.0 (SPSS Inc., Chicago, Il)
was used for the other analyses.
Results
The characteristics of the population are depicted in
Table 1. The median bleeding score was 18; from the analyzed
population, 14.8% were classified as low risk, 20.3% as
medium risk, 24.3% as high risk, and 40.8% as very high risk.
One third of the patient population had diabetes, another
third previous myocardial infarction, 43.3% were submitted
previously to surgical or catheter revascularization, and 73% were
revascularized during the present hospitalization. Our patient
population was comprised of a typical contemporary population
commonly seen in a tertiary cardiology center.
Correlation between bleeding score and in-hospital mortality
Univariate analyses showed highly significant correlations
between bleeding score and mortality. As shown in Figure 1,
p-values <0.001 were obtained for the correlation between
both variables in the global population as well as in the
subgroups with or without ST-segment-elevation ACS. Other
variables that correlated significantly with in‑hospital mortality
included previous heart failure (p = 0.005, OR = 2.033) or
stroke (p = 0.041, OR = 1.951), current smoking (p = 0.006,
OR = 0.465), relatives with coronary artery disease (p = 0.001,
OR = 0.397), and anterior wall location (p = 0.047,
p =1.481). As expected, the correlation between bleeding
and mortality was also statistically significant (p < 0.001,
OR = 5.296) as was the correlation between bleeding
score and in-hospital bleeding (p < 0.001, OR = 1.058).
Finally, for patients with ST-elevation ACS and with
non‑ST‑elevation ACS, the correlations between the respective
TIMI risk scores with mortality were also significant (p < 0.001,
OR = 1.586 and p < 0.001, OR = 1.454, respectively).
Discussion
Different bleeding scores have been proposed in order
to better evaluate patients with ACS, allowing the attending
physician to better utilize the available antithrombotic
therapies. In common, these bleeding scores show excellent
correlation with bleeding1,6,8. However, there are important
differences between them regarding their complexity and
difficulty of utilization. The score proposed by Mehran et al8,
and tested in the present paper, is one of the most user-friendly
in the literature, and in this population derived from a tertiary
center, also showed excellent correlation with bleeding.
In our databank the definition for bleeding is broad, and
takes any bleeding requiring specific action from the staff
including that for surgery for pseudo aneurysm, transfusion,
or that requiring a third party opinion – generally a
angiologist/vascular surgeon, neurologist or hematologist
into account. Interestingly, the observed incidence of
in‑hospital bleeding in the present population was the same
as described by Mehran et al8 for 30 days (4.3%,) and close
to the percentage described in the GRACE Registry (3.9%)
for in-hospital major bleeding1.
On the other hand, it is well demonstrated that the presence
of bleeding during hospitalization in patients with ACS increases
significantly the incidence of ischemic events, including
mortality, in this population4,5,15. Consequently, we found a
significant correlation between the presence of bleeding and
mortality, with an odds-ratio > 5.
Discriminatory value of bleeding score and TIMI risk scores
for in-hospital mortality prediction
Regarding the TIMI risk scores in both, ACS with
or without ST-segment elevation, they show clear
correlations with mortality/ischemic events, which could
also be demonstrated in the present population 12,13 .
The discriminatory power of the non-ST-elevation ACS
TIMI risk score to predict ischemic events (all-cause
mortality, myocardial infarction, urgent revascularization)
was 0.6513, being 0.62 in the present publication, that took
into account only all-cause mortality. The ST-elevation
myocardial infarction TIMI risk score was studied in a broad
population of patients included in the North‑American
registry of myocardial infarction (submitted to fibrinolysis,
primary angioplasty or without reperfusion)16; overall, its
discriminatory power for all-cause mortality was 0.74,
being 0.798 in the present study. This value is near the
0.83 proposed by Diamond17 as the maximal value for
a perfectly calibrated prediction rule, while at the same
time the authors explain that higher values are possible
but come at the cost of poorer calibration.
Figure 2 shows the ROC curve for bleeding score for
the whole population. As can be seen, this score is a good
predictor of in-hospital mortality, showing an area under the
An analysis of bleeding score as a mortality risk factor, and
its relationship with TIMI risk scores and in-hospital bleeding,
have not been published previously. Our major findings were 1)
The main results of the adjusted models are shown
in Tables 2, 3 and 4. The bleeding score correlated
significantly and independently with mortality in all models,
however, the TIMI risk score showed a stronger correlation
with mortality than the bleeding score for patients with
ST‑elevation myocardial infarction. Conversely, the bleeding
score showed a better correlation relative to the TIMI risk
score for patients with non-ST-elevation ACS. Importantly,
the inclusion of in-hospital bleeding in the final models
did not change the results for the bleeding score where
p < 0.001 (OR = 1.123) for the whole population, and
p-values of 0.050 (OR = 1.045) and < 0.001 (OR = 1.146),
respectively, were obtained for patients with or without
ST-elevation ACS. These findings are further evaluated in
the following ROC curve analyses (Figure 2).
513
curve (AUC) of 0.753. Table 5 shows the comparison of the
AUC for bleeding score and TIMI risk score in the subgroups
with and without ST-elevation ACS. As suggested by the
multivariate analyses, in comparison with the respective
TIMI scores the bleeding score is a better predictor of
in‑hospital mortality for patients without ST-elevation
ACS and, vice versa, is a worse mortality predictor in the
population with ST-elevation ACS.
Arq Bras Cardiol. 2013; 101(6):511-518
Nicolau et al.
Bleeding risk score and mortality in ACS
Original Article
Figure 1 - A) Bleeding score and in-hospital mortality for the whole population; B) subgroup with ST-elevation myocardial infarction; and C) subgroup with non-ST-elevation ACS.
BS - bleeding score; ACS - acute coronary syndromes.
Arq Bras Cardiol. 2013; 101(6):511-518
514
Nicolau et al.
Bleeding risk score and mortality in ACS
Original Article
Table 2 - Variables that correlated significantly and independently with in-hospital mortality in the whole population
A. Only baseline variables included in the model
Variables
Adjusted odds-ratio
p-value
Bleeding score
1.121
< 0.001
Previous surgical myocardial revascularization
0.577
0.041
Relatives with coronary artery disease
0.516
0.032
B. Baseline variables and in-hospital invasive therapies included in the model
Variables
Adjusted odds-ratio
p-value
Bleeding score
1.126
< 0.001
In-hospital surgical myocardial revascularization
2.040
0.003
Relatives with coronary artery disease
0.500
0.025
Table 3 - Variables that correlated significantly and independently with in-hospital mortality in patients with ST-elevation acute myocardial infarction
Baseline variables (including STEMI TIMI risk score) included in the model*
Variables
Adjusted odds-ratio
p-value
Bleeding score
1.046
0.046
Previous myocardial infarction
2.329
0.022
Smoking
0.361
0.032
Known diabetes
2.066
0.032
Known dyslipidemia
0.477
0.038
STEMI TIMI risk score
1.535
< 0.001
*The inclusion of invasive in-hospital therapies in the model did not change the showed results; STEMI: ST-elevation acute myocardial infarction.
Table 4 - Variables that correlated significantly and independently with in-hospital mortality in the subgroup with non-ST-elevation acute
coronary syndromes
A. Baseline variables (including NSTEACS TIMI risk score) included in the model
Variables
Adjusted odds-ratio
p-value
Bleeding score
1.142
< 0.001
Previous surgical myocardial revascularization
0.478
0.031
NSTEACS TIMI risk score
1.402
0.004
B. Baseline variables (including NSTEACS TIMI risk score) and in-hospital invasive therapies included in the model
Variables
Adjusted odds-ratio
p-value
Bleeding score
1.150
< 0.001
In-hospital surgical myocardial revascularization
2.109
0.015
NSTEACS TIMI risk score
1.297
0.020
NSTEACS: non-ST-elevation acute coronary syndromes.
The bleeding risk score proposed by Mehran et al8 is an excellent
predictor of in-hospital mortality in patients with acute coronary
syndromes and 2) Regarding in-hospital mortality when
compared with the TIMI risk scores, the bleeding risk score
515
Arq Bras Cardiol. 2013; 101(6):511-518
was more reliable than the corresponding TIMI risk score for
patients with non-ST-elevation ACS, and performed worse as
an indicator in patients with ST-elevation myocardial infarction.
However, we found that both variables correlated significantly
Nicolau et al.
Bleeding risk score and mortality in ACS
Original Article
Figure 2 - ROC curve for the whole population (area under the curve = 0.753 ± 0.025, p < 0.001).
Table 5 - Results of the ROC curves for the whole population and subgroups with or without ST segment elevation acute coronary syndromes
AUC (± SE)
p-value
0.753 ± 0.025
< 0.001
Bleeding score
0.686 ± 0.040
< 0.001
TIMI risk score
0.798 ± 0.032
< 0.001
Bleeding score
0.769 ± 0.036
< 0.001
TIMI risk score
0.616 ± 0.037
0.002
Global population
Bleeding score
STEMI
NSTEACS
*p = 0.029 for the comparison between bleeding score and TIMI risk score; **p = 0.003 for the comparison between bleeding score and TIMI risk score; AUC: area under
the curve; STEMI: ST-elevation acute myocardial infarction; NSTEACS: non-ST-elevation acute coronary syndromes.
and independently with mortality in the broad spectrum of
patients with ACS that we analyzed for this study. Interestingly,
despite the excellent correlation between the bleeding risk
score and the observed bleeding, both variables correlated
significantly and independently with in-hospital mortality.
These findings suggest that other variables included in
the bleeding score could influence in-hospital mortality
independently of bleeding itself, as could be the case for age.
Limitations of the Study
As with any databank-derived study, it is possible that
confounders not included in the adjusted models could
have influenced the results with respect to the correlation
of the bleeding score and mortality. Certainly the ROC
curve analyses, which showed excellent discriminatory
power of the bleeding score to predict mortality, is useful
in order to give a more reliable and complete answer
Arq Bras Cardiol. 2013; 101(6):511-518
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Nicolau et al.
Bleeding risk score and mortality in ACS
Original Article
to the proposed hypothesis. Secondly, bivalirudin is
not available in Brazil and this could have affected the
results. However, the non-utilization of bivalirudin is
a common scenario even in countries where the drug
is available. In the USA alone, more than one million
angioplasties are performed each year (http://www.nhlbi.
nih.gov/health/health-topics/topics/angioplasty), whereas
the worldwide sales of bivalirudin (2010) is estimated at
about $400 million per year (http://prescriptions.blogs.
nytimes.com/2010/10/05/angiomax-may-get-patentextension) at a cost varying between $824/patient18 up to
$1675/patient19, which comes out to a number between
238,000 and 485,000 patients per year worldwide.
Author contributions
Conception and design of the research: Nicolau JC. Acquisition
of data: Nicolau JC, Moreira HG. Analysis and interpretation of
the data: Nicolau JC. Statistical analysis: Nicolau JC. Writing of
the manuscript: Nicolau JC, Mehran R. Critical revision of the
manuscript for intellectual content: Nicolau JC, Moreira HG,
Baracioli LM, Serrano Jr CV, Lima F, Franken M, Giraldez RR,
Ganem F, Kalil Filho R, Ramires JAF, Mehran R.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Conclusion
Sources of Funding
The bleeding score proposed by Mehran et al is an
excellent predictor of in-hospital mortality in the broad
spectrum of patients with acute coronary syndromes,
especially those with unstable angina or non-ST-elevation
acute myocardial infarction.
There were no external funding sources for this study.
Study Association
This study is not associated with any post-graduation program.
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Back to the Cover
Original Article
P Wave Indices to Predict Atrial Fibrillation Recurrences Post
Pulmonary Vein Isolation
Ahmed Salah, Shenghua Zhou, Qiming Liu, Hui Yan
Second Xiangya Hospital of Central South University - China
Abstract
Background: P-wave indices are appealing markers for predicting atrial fibrillation (AF) recurrences post ablation.
Objective: This study evaluates the value of P wave indices to predict recurrences post pulmonary vein isolation (PVI) in
patients with paroxysmal AF.
Methods: We selected 198 patients (57 ± 8 years, 150 males) with symptomatic drug-refractory paroxysmal AF
undergoing PVI in our hospital. A 12-lead electrocardiogram was used to measure P wave duration in lead II,
P wave terminal force (PWTF) in lead V1, P wave axis and dispersion.
Results: During a follow-up of 9 ± 3 months, recurrences occurred in 60 (30.3%) patients. The patients that had AF
recurrence had longer mean P wave duration (122.9 ± 10.3 vs 104.3 ± 14.2 ms, p < 0.001), larger P wave dispersion
(40.7 ± 1.7 ms vs 36.6 ± 3.2 ms, p < 0.001). P wave duration ≥ 125 ms has 60% sensitivity, 90% specificity, positive
predictive value (PPV) of 72% and negative predictive value (NPV) of 83.7%, whereas P wave dispersion ≥ 40 ms has
78% sensitivity, 67% specificity, PPV of 51% and NPV of 87.6% 48/66 (72.7%) patients with PWTF ≤ -0.04 mm/second
vs 12/132(9%) with PWTF > -0.04 mm/second showed recurrence of AF (p < 0.001). P wave axis was not different
between two groups. On multivariate analysis, P wave indices were not independent from left atrial size and age.
Conclusions: P wave duration ≥ 125 ms, P wave dispersion ≥ 40 ms and PWTF in V1 ≤ -0.04 mm/sec are good
clinical predictors of AF recurrences post PVI in patients with paroxysmal atrial fibrillation; however they were
not independent from left atrial size and age. (Arq Bras Cardiol. 2013; 101(6):519-527)
Keywords: Atrial Fibrillation; P Wave; Ventricular Fibrillation; Pulmonary Veins.
Introduction
Atrial fibrillation (AF) is the most common sustained cardiac
arrhythmia, of which importance derives from the fact that
it is one of the most common leading causes of circulatory
instability and stroke. The main goals in the management of AF
are heart rate or rhythm control and anticoagulation. If rhythm
control is desired and cannot be maintained by medication
or cardioversion, then catheter ablation may be attempted.
Radiofrequency catheter ablation (RFCA) of AF is effective
in 70-80% of the cases, but recurrences are frequent and at the
present time, accurate markers of recurrences are lacking1–4.
The natural history of AF is characterized by self-perpetuating
mechanisms, rate-induced electrophysiological changes and
structural remodeling that involves the atrial myocardium5.
Mailing Address: Shenghua Zhou •
Department of Cardiology, The Second Xiangya Hospital of Central South
University, middle Ren-Min road, 139, Changsha. Postal Code 410011,
Hunan, China
E-mail: [email protected]
Manuscript received February 19, 2013, revised July 29, 2013, accepted
August 05,2013.
DOI: 10.5935/abc.20130214
519
Atrial remodeling is both electrical and structural; it causes
slow electrical conduction and enlargement of the atria, which
is reflected by changes in the morphology of the P wave in
the electrocardiogram (ECG). Predictors to discriminate who
will benefit from ablation are needed to save money, time and
effort. Using ECG parameters as a predictor is very useful, as it
is low-cost, feasible and can yield a lot of information. In our
study we evaluated the use of P-wave indices to predict the
recurrence of atrial fibrillation post pulmonary vein isolation
(PVI) in patients with paroxysmal atrial fibrillation.
Methods
Population
After informed consent, 198 consecutive patients
(57 ± 8 years, 150 males, and 48 females) with symptomatic
drug-refractory paroxysmal AF, undergoing RFCA were enrolled
in our study. AF was classified as paroxysmal when episodes
were generally self-terminating and lasted no longer than 7 days,
according to the European Society of Cardiology guidelines6.
Prior to the procedure, all patients underwent a
comprehensive transthoracic echocardiographic examination
to assess left atrial (LA) size and function, left ventricular (LV)
function and to exclude structural heart disease; additionally,
Salah et al.
P wave indices to predict AF recurrences post PVI
Original Article
all patients underwent transesophageal echocardiography
immediately before the ablation procedure to exclude LA
thrombi. Clinical characteristics are summarized in Table 1.
A control group including 120 normal subjects (80 males;
40 females; mean age 44 ± 17 years) without any history of
AF, structural heart disease or hypertension was used to define
normal values for P-wave characteristics.
Standard 12 Lead Electrocardiogram (ECG)
After the ablation, all patients were systematically
evaluated at the outpatient clinic during a mean follow up
of 9 ± 3 months. ECG recordings were acquired on each
visit and 24-h Holter recordings were scheduled after 3, 6
and 9 months of follow-up. Importantly, all patients were
encouraged to immediately obtain an ECG registration when
experiencing palpitations. Antiarrhythmic medications were
interrupted after the ablation procedure and AF recurrence
was defined as any recording of AF on ECG or an episode
longer than 30 s on 24-h Holter recording.
Standard 12 lead ECG was performed in all patients
during sinus rhythm just before the ablation procedure
using commercially available equipment (MAC 1200 ST
General Electric Medical Information Technology). The ECG
recorded before ablation procedure was the one used for
statistical analysis, while another ECG recorded after ablation
was used to confirm that the patient was in sinus rhythm
post‑procedure. Before ablation ECGs were recorded for
10 seconds first at a sweep speed of 25 mm/s and calibrated
to 1 mV/cm in the standard leads and then at a sweep speed
of 50 mm/s and calibrated to 2 mV/cm in the standard
leads to obtain further precise measurements. Scanning and
digitizing of ECG signals from paper records using an optical
scanner were performed for all ECG recordings; the onset
and offset of the P wave were defined as the start of the
upward deflection of the P-wave pattern and its return to the
isoelectric baseline in lead II7. All the following parameters
were assessed; P-wave duration in lead II, P wave terminal
force (PWTF) in lead V1, P wave axis and dispersion.
P-wave dispersion was measured manually by subtracting
the minimal P wave (Pmin) duration from the maximal P
wave (Pmax) duration (Pmax - Pmin), measured by multiple
surface ECG leads, from a single beat and mean values for
three complexes were calculated.
Calculation of the PWTF was performed by measuring the P
wave duration in seconds multiplied by the P wave amplitude of
the negative terminal portion of the P wave in V1 in millimeters
as shown in Figure 1. The patients were further divided in to two
groups, the first group in which the PWTF was > -0.04 mm/sec.
(smaller than one small square) and the second group in which
the PWTF was ≤ -0.04 mm/sec. (larger than one small square).
P-wave indices in each ECG trace was evaluated by two
independent blinded investigators and Bland–Altman analyses
were performed to assess the inter- and intra-observer
reproducibility of P-wave duration, P-wave dispersion, P-wave
axis and P-wave terminal force in V1. Measurements showed
minimal biases (1.2±11 and 1.3±10 ms, respectively for P
wave duration), (1.6±10 and 1.5±10 ms, respectively for P
wave dispersion), (2±8 and 2±9 degree, respectively for P
wave axis), (1.8+10 and 1.7+10 mm/sec., respectively for P
wave terminal force in V1)8.
Radiofrequency Catheter Ablation Procedure
The ablation procedure was performed in a fasting state.
The right femoral vein was used for the insertion of catheters,
a single transseptal puncture was performed using FAST-CATH
trans-septal guiding introducer (SL1 8.5 F St. Jude medical).
Two catheters were inserted: one duodecapolar lasso catheter
for PV recording (introduced through the SL0 long sheath and
positioned at the ostium of each PV sequentially) and a 4-mm
irrigated-tip ablation catheter for pulmonary veins isolation.
The right internal jugular vein was used for the insertion of
one decapolar (2 mm spacing) steerable catheter in the distal
Table 1 - Clinical characteristics of the total population and the two groups
Clinical characteristics of the two groups
Total
Recurrence
Non-recurrence
Number
198
60
138
Mean age (years)
57 ± 7.5
64.6 ± 5.12
53.9 ± 5.98
< 0.001
Male/female
150/48
48/12
102/36
0.23
History of DM
13/198
6/60
7/138
0.16
History of SAH
86/198
30/60
56/138
0.14
History of Stroke
Duration of atrial fibrillation (months)
Body mass index (mean Kg/m2)
p value
1/198
1/60
0/138
0.3
11.4 ± 6.4
16.4 ± 8.1
9.34 ± 4
< 0.001
27.5 ± 1.1
27.7 ± 1.09
27.4 ± 1.2
0.06
109.9 ± 15.6
122.9 ± 10.3
104.3 ± 14.2ms
< 0.001
Mean P wave dispersion(ms)
37.9 ± 3.4
40.7 ± 1.7ms
36.6 ± 3.2ms
< 0.001
Mean ejection fraction (%)
59.6 ± 4.7
59.4 ± 4.3
59.7 ± 5
0.08
Mean LA diameter(mm)
42.9 ± 4.5
47.5 ± 2.8
40.9 ± 3.6
< 0.001
Mean P wave duration(ms)
DM: diabetes mellitus; SAH: systemic arterial hypertension; ms: millisecond; LA: left atrium.
Arq Bras Cardiol. 2013; 101(6):519-527
520
Salah et al.
P wave indices to predict AF recurrences post PVI
Original Article
Figure 1 - Calculation of the P wave terminal force in lead V1.
coronary sinus. After transseptal puncture, a bolus of 5000 U
of intravenous heparin was administered and activated clotting
time was maintained above 280 s throughout the procedure.
Three-dimensional electro-anatomical mapping was
performed in all cases using the CARTO3 system (Biosence
Webster, Johnson & Johnson). Radiofrequency catheter
ablation was aimed at creating circular lesions initially
applied in the whole circumference in the antral region
of the veins (ipsilateral vein-to-vein), with subsequent
electrical isolation provided it was not achieved in the
circumferential application of the lesions. Isolation of all four
PVs was performed using the ablation catheter guided by
the circumferential mapping catheter in the PV [maximum
power 30-35 W; maximal temperature 40; duration of
the radiofrequency (RF) application 60 s]. The endpoint
of RF application was complete PVI, demonstrated by the
absence of PV potentials in the PV during sinus rhythm or
coronary sinus pacing, by the absence of PV-left atrium
conduction during PV pacing, and by recording of very-low
(0.5 mV) voltage inside the PVs in the final voltage map.
Reconfirmation of PV isolation was performed 30 min after
ablation for each PV. Patients were followed with continuous
ECG monitoring for 24 h and were discharged from the
hospital two days after the procedure.
Statistical Analysis
Data are expressed as mean ± standard deviation for
continuous variables and frequencies for categorical variables.
Differences between groups were assessed using Chi-square
statistics for categorical variables and analysis of variance
for continuous variables. A p value < 0.05 was considered
significant. Pearson's correlation coefficient and multivariate
Cox regression analysis using significant variables was also
performed. Statistical analyses were performed using SPSS
version 16.0 statistical software (SPSS Inc., Chicago, IL).
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Arq Bras Cardiol. 2013; 101(6):519-527
A receiver operating characteristic (ROC) curve was generated
to evaluate P wave indices as a predictor of AF recurrences
post PVI and different cut-off values for P wave duration and
P wave dispersion were chosen to evaluate probability of AF
recurrences. The AF-free rates according to P wave duration
of < 125 ms and ≥ 125 ms along with P wave dispersion
< 40 ms and ≥ 40 ms were calculated using Kaplan-Meier
analysis with the log-rank test.
Results
Paroxysmal AF patients in comparison to control cases had
longer P wave duration (109.9 ± 15.6 ms vs 99.5 ± 11.6 ms,
p < 0.001), larger P wave dispersion(37.9 ± 3.4 ms vs
24.9 ± 9.1 ms, p < 0.001), larger left atrial diameter
(42.9 ± 4.5 mm vs 30 ± 6.3 mm, p < 0.001); 66 of 198 patients
showed PWTF ≤ -0.04 mm/second, while the entire control
group had PWTF > -0.04 mm/second (p < 0.0001).
All patients had successful pulmonary vein isolation
and all patients were in sinus rhythm at the end of the
procedure. No AF recurrence was observed during the first
24 h after the ablation procedure. During a mean follow-up
of 9 ± 3 months, recurrences occurred in 30.3% (60/198).
The clinical characteristics of the total paroxysmal AF patients
and the two groups are summarized in Table 1.
Patients with AF recurrence had longer mean P-wave
duration (122.9 ± 10.3 vs 104.3 ± 14.2 ms, p < 0.001),
larger P-wave dispersion (40.7 ± 1.7 ms vs 36.6 ± 3.2 ms,
p < 0.001) when compared with patients without recurrence
of atrial fibrillation (Figures 2 and 3). Further subgroup analysis
for patients with normal LA size showed that patients with
normal LA size and recurrence of AF post PVI had longer
P-wave duration (119.5 ± 13.5 ms vs 100.6 ±11.38 ms,
p = 0.01) and larger P-wave dispersion (38.09 ± 2.7 ms vs
35.86 ± 3.38 ms, p = 0.03) in comparison with normal LA
size patients without recurrence of AF.
Salah et al.
P wave indices to predict AF recurrences post PVI
Original Article
Forty-eight of 66 (72.7%) patients with P wave terminal
force ≤ -0.04 mm/second showed recurrence of AF when
compared with 12/132 (9%) patients with P-wave terminal
force > -0.04 mm/second (p < 0.001). P-wave axis was not
significantly different between patients with and without AF
recurrences (p > 0.09).
Receiver operating characteristic (ROC) curve analysis
was performed for different P-wave duration and P wave
dispersion cutoff points (Figures 4 and 5). The area under
the ROC curve for P wave duration was 0.858 (95%
confidence interval 0.805–0.912) (p < 0.001). The area
under the ROC curve for P wave dispersion was 0.852 (95%
confidence interval 0.8–0.904) (p < 0.001). By observing
different cutoff values, P wave duration ≥ 125/ms and
P wave dispersion ≥ 40 ms were found to discriminate
patients prone to AF recurrences over time according to
log-rank test (Figures 6 and 7). P wave duration of 125 ms
has the best combined sensitivity and specificity (60% and
90% respectively) along with positive predictive value of
72% and negative predictive value of 83.7%, whereas P
wave dispersion of 40 ms has the best combined sensitivity
and specificity (78% and 67% respectively) along with
positive predictive value of 51% and negative predictive
value of 87.6%.
Multivariate cox regression analysis showed that P wave
indices were not independent from left atrial size and age;
however, P wave duration was moderately correlated with age
(r = 0.3, p < 0.001) and a good correlation with left atrial
size (r = 0.5, p < 0.001). No significant correlation was found
between P-wave duration and P-wave axis (r = 0.03, p = 0.6).
P-wave dispersion had a moderate positive correlation with
age (r = 0.41, p < 0.001) and left atrial volume (r = 0.42,
p < 0.001). P-wave duration and P-wave dispersion had a
moderate positive correlation (r = 0.3, p < 0.001).
Discussion
AF is one of the most important arrhythmias found in
the field of cardiology, as it is the most prevalent and causes
many complications. Several strategies have been used in its
management and the importance of AF ablation has increased
as it is believed it can cure arrhythmia. The challenge of post
ablation atrial fibrillation recurrence is still high, so the present
study proposes a non-invasive and easy-to-apply predictor for
AF recurrence, which are the P wave indices obtained from
standard 12 lead ECG.
Multiple independent predictors of AF recurrences after
RF ablation have been identified, such as age, persistent
AF1, hypertension, hyperlipidemia, left atrial diameter, white
blood cell count before ablation2,3, and atrial remodeling by
delayed-enhancement MRI4, but quantitative non-invasive
markers are still lacking.
Prolonged P-wave duration denotes inter- and intraatrial abnormal conduction. Dogan et al9 reported that
maximum P wave duration and P wave dispersion were
predictors for the maintenance of sinus rhythm after AF
cardioversion and that increased P wave dispersion could
be used to identify patients at risk of such post procedural
recurrence.
Previous studies were performed to evaluate different P
wave duration and dispersion values to predict occurrence of
atrial fibrillation post cardioversion, post myocardial infarction
and also post-cardiac surgery. Rosiak et al10 demonstrated that
P-wave duration >125 ms and P-wave dispersion >25 ms,
when measured very early after an acute myocardial infarction,
were independently associated with AF. 10
The association between P-wave duration and atrial
electromechanical delay assessed by tissue Doppler
echocardiography by Dabrowska-Kugacka et al11 concluded
that P-wave duration of the surface ECG is highly correlated
with the atrial electromechanical delay and based on
this association, one can verify the importance of P-wave
duration on the surface ECG as a predictor of atrial fibrillation
recurrence post pulmonary vein isolation.
Other studies that used P-wave signal averaging to predict
atrial fibrillation recurrences after pulmonary vein isolation
concluded that Filtered P wave duration > 140 ms on the
P-wave signal averaged electrocardiogram is a useful marker
of AF recurrences over time after pulmonary vein isolation.
Although this technique is still not widely used, it confirms
that prolonged P-wave duration probably reflects inter- and/
or intra-atrial conduction delays and could be related to the
extent of atrial scarring and fibrosis, as shown by the longer
P-wave duration in patients with recurrent AF12.
P-wave morphology represents atrial electrical activation,
which depends mainly on the distance traveled by
the electric current from the first to the last point of
depolarization, along with the velocity of the electric current.
Atrial remodeling, which is the main substrate of AF, is
divided mainly into structural and electrical remodeling and
in most cases, both will occur together. Structure remodeling
is mainly represented by atrial enlargement detected by
echocardiography, while electrical remodeling is represented
by prolonged electromechanical time demonstrated by
tissue Doppler imaging or invasively by measuring total atrial
activation time between the first atrial potential detected by
an intracardiac electrode positioned in high right atrium and
the last atrial potential detected by an intracardiac electrode
positioned in distal coronary sinus. The main characteristics
of the electrical remodeling process are the shortening of
the refractory period with increased dispersion and atrial
conductivity reduction. Based on this point of view about
atrial electrical remodeling, one can clarify our findings
regarding patients with normal LA size, as we found that
even in patients with normal LA size patients with recurrence
of AF post PVI had longer P wave duration and larger P
wave dispersion in comparison with normal LA size patients
without AF recurrence.
AF recurrences post PVI are mainly due to PV
re‑conduction in ablated myocardium or sometimes to
non-PV foci13-16. To test the hypothesis that P-wave duration
could be a marker of a successful PVI, Date et al17 studied
the contribution of PV cardiac muscles to the P-wave using
standard vectorcardiography and electrocardiography
recorded before and after the procedure. They found that
the morphology of the P-wave changed after PVI and that
the myocardial sleeves of the PV played an important role
in the formation of the middle part of the P-wave.
Arq Bras Cardiol. 2013; 101(6):519-527
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Salah et al.
P wave indices to predict AF recurrences post PVI
Original Article
p < 0.001
Figure 2 - Significant difference between mean P wave duration in the recurrence and non-recurrence groups.
p < 0.001
Figure 3 - Significant difference between mean P-wave dispersion in the recurrence and non-recurrence groups.
523
Arq Bras Cardiol. 2013; 101(6):519-527
Salah et al.
P wave indices to predict AF recurrences post PVI
Original Article
Figure 4 - ROC curve for different P-wave duration cut off points.
Figure 5 - ROC curve for different P-wave dispersion cut off points.
Arq Bras Cardiol. 2013; 101(6):519-527
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Salah et al.
P wave indices to predict AF recurrences post PVI
Original Article
p < 0.001
P wave duration ≥ 125 ms
Figure 6 - Kaplan–Meier event-free analysis for patients with P-wave duration ≥ 125 ms compared with patients with P wave duration < 125 ms.
p < 0.001
Figure 7 - Kaplan–Meier event-free analysis for patients with P-wave dispersion ≥ 40 ms compared with patients with P wave dispersion < 40 ms.
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Salah et al.
P wave indices to predict AF recurrences post PVI
Original Article
P wave dispersion is still under study and it remains
unknown whether it is determined only by heterogeneity
of atrial conduction or by other factors as well18,19. In our
study, we found that P-wave duration ≥ 125 ms and P -wave
dispersion ≥ 40 ms are associated with higher rate of AF
recurrence post PVI in patients with paroxysmal AF.
Large P terminal force in lead V1 along with prolonged
P-wave duration predicts left atrial abnormality, particularly in
patients with underlying cardiovascular diseases (sensitivity,
82%; specificity, 40%; positive predictive value, 70%; and
negative predictive value, 55%) and its presence indicates
the need for further evaluation20. Moreover, P-wave terminal
force in lead V1 has been independently associated with
ischemic stroke after adjustment for other stroke risk factors
(odds ratio, 2.32; 95% confidence interval, 1.29-4.18)21.
The higher prevalence of PTFV1 ≤ -0.04 mm/second
in patients with prolonged P-wave duration and wider
P-wave dispersion, as noted in our study, probably reflects
the associated delayed impulse conduction through already
abnormal and enlarged left atria.
Clinical Implication
Our findings indicate that P-wave duration, P-wave
dispersion along with P wave terminal force in V1 may be
useful markers of AF recurrence post PVI, probably reflecting
the extent of the atrial disease and remodeling.
Study Limitation
Pre-ablation antiarrhythmic drug therapy was not
discontinued before radiofrequency catheter ablation; drugs
such as amiodarone and flecainide may have influenced
the recurrence. AF duration data were derived from the
patient’s history and ECG recordings; thus, the existence
of asymptomatic AF cannot be excluded and the duration
of AF might not be accurate. The asymptomatic episodes
of AF may also confound the results of AF recurrence
during the follow-up. The sample size is relatively small
and results of the present study should be confirmed by
larger prospective trials.
Conclusion
P wave duration ≥ 125 ms, P wave dispersion ≥ 40 ms,
as well as a P wave terminal force in V1 ≤ -0.04 mm/sec are
good clinical predictors of the already known deleterious
sequelae, mainly atrial fibrillation recurrence, post PVI in
patients with paroxysmal atrial fibrillation; however, they
were not independent from left atrial size and age.
Author contributions
Conception and design of the research: Salah A, Zhou S.
Acquisition of data: Salah A, Zhou S, Liu Q, Yang H. Analysis
and interpretation of the data: Salah A, Zhou S, Liu Q, Yang
H. Statistical analysis: Salah A, Zhou S, Yang H. Writing of the
manuscript: Salah A, Yang H. Critical revision of the manuscript for
intellectual content: Salah A, Zhou S, Liu Q, Yang H. Supervision /
as the major investigator: Salah A, Zhou S. Performing pulmonary
vein isolation in EP catheter Lab.: Salah A, Liu Q.
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 post-graduation
program.
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Back to the Cover
Original Article
Mortality Impact of Thoracic Aortic Disease in São Paulo State from
1998 to 2007
Ricardo Ribeiro Dias1, Omar Asdrubal Vilca Mejia1, Fábio Fernandes2, Félix José Alvarez Ramires2, Charles Mady2,
Noedir Antonio Groppo Stolf1, Fabio Biscegli Jatene1
Divisão de Cirurgia Cardiovascular do Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo1;
Divisão de Cardiologia do Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo2,
São Paulo, SP - Brazil
Abstract
Background: The epidemiological characteristics of thoracic aortic diseases (TAD) in the State of São Paulo and in Brazil,
as well as their impact on the survival of these patients have yet to be analyzed.
Objectives: To evaluate the mortality impact of TAD and characterize it epidemiologically.
Methods: Retrospective analysis of data from the public health system for the TAD registry codes of hospitalizations,
procedures and deaths, from the International Code of Diseases (ICD-10), registered at the Ministry of Health of
São Paulo State from January 1998 to December 2007.
Results: They were 9.465 TAD deaths, 5.500 men (58.1%) and 3.965 women (41.9%); 6.721 dissections (71%) and
2.744. aneurysms. In 86.3% of cases the diagnosis was attained during autopsy. There were 6.109 hospitalizations, of
which 67.9% were males; 21.2% of them died (69% men), with similar proportions of dissection and aneurysm between
sexes, respectively 54% and 46%, but with different mortality. Men with TAD die more often than women (OR = 1.5).
The age distribution for deaths and hospitalizations was similar with predominance in the 6th decade. They were 3.572
surgeries (58% of hospitalizations) with 20.3% mortality (patients kept in clinical treatment showed 22.6% mortality;
p = 0.047). The number of hospitalizations, surgeries, deaths of in-patients and general deaths by TAD were progressively
greater than the increase in population over time.
Conclusions: Specific actions for the early identification of these patients, as well as the viability of their care should be
implemented to reduce the apparent progressive mortality from TAD seen among our population. (Arq Bras Cardiol.
2013; 101(6):528-535)
Keywords: Aorta, Thoracic / pathology; Aortic Diseases; Health Profile.
Introduction
Cardiovascular disease is the leading cause of mortality in
the modern era in most developed and developing countries.
This behavioral change in developing countries is mainly due
to changes in lifestyle brought on by industrialization and
urbanization, coupled with the increase in life expectancy,
poor eating habits, smoking and the concomitant decrease
in infectious and nutritional diseases 1.
Despite the documented decline in cardiovascular disease
mortality in the developed world (myocardial and cerebral
infarction), this curve is still markedly ascending in developing
countries, and at least 2.8 times higher than in developed
ones. The expectation is that this difference will be further
accentuated in coming years, according to Reddy and Yusuf 1.
Mailling Address: Ricardo Ribeiro Dias •
Avenida Dr. Enéas de Carvalho Aguiar, 44, 2.º andar, sala 13.
Postal Code: 05403-000, São Paulo, SP - Brazil
E-mail: [email protected]
Manuscript received February 28, 2013; revised manuscript May 10, 2013;
accepted June 11, 2013.
DOI: 10.5935/abc.20130203
528
But Lotufo et al. 2, analyzing the trend of heart disease mortality
in São Paulo in the 1996-2010 period, demonstrated the
same kind of behavior in developed countries and even more
marked in the social classes with greater purchasing power.
Thoracic aortic diseases (TADs) represent a significant
percentage of these deaths, which predominate as
dissections and aneurysms. It is believed that, in conjunction
with abdominal aortic aneurysms, they are the 13th most
frequent cause of death in Western countries, accounting
for 15,000-30,000 deaths per year in the United States 3​​.
Others claim that these numbers can be between 43,000
to 47,000 deaths per year 4.
Much has been written about the complex pathogenesis
of TADs, their natural history, the ideal time for interventions,
different surgical techniques, outcomes and much is being
written about the endovascular approach of diseases of the
aorta and its branches 5-9. Little is known, however, about
the epidemiological characteristics of TADs in São Paulo
and Brazil, as well as their impact on patient survival and
socioeconomic cost to the national health system. Therefore,
the aim of this study is to evaluate the impact of TAD mortality
in the state of São Paulo, to epidemiologically characterize
Dias et al
Mortality impact of thoracic aortic disease
Original Article
it and analyze the results of the treatment received by this
population of patients.
Method
A retrospective analysis of data from the Hospitalization
and Procedure Registry of the Brazilian Unified Health System
(SUS) for TAD codes from the International Classification of
Diseases (ICD-10, Table 1) and deaths from TAD, collected from
the General Mortality Registry of the Department of Forensic
Medicine (DFM) of the State of São Paulo, recorded at the Health
Secretariat of the State of São Paulo, allowed the creation of the
study database comprising all patients registered during the period
of January 1998 to December 2007.
Patients with aortic disease with ICD I71.3, I71.4, I71.8,
I71.9, which are respectively related to ruptured abdominal
aortic aneurysm, abdominal aorta aneurysm with no mention
of rupture, ruptured aortic aneurysm at unspecified site and
aortic aneurysm at unspecified site with no mention of rupture,
were excluded from the study.
SUS assists approximately 75.4% of the population,
and for highly complex procedures, such as cardiovascular
surgery, assists almost all of the population 10. Based on this
information, it is possible to infer that the analyses of the study
data represent approximately 75% of hospital admissions from
TAD, almost all surgical procedures, and 100% of the deaths.
The figures related to the total population of the state
of São Paulo, with discrimination by year and gender were
provided by the Health Department of the State of São
Paulo, from the census data from the Brazilian Institute of
Geography and Statistics (Instituto Brasileiro de Geografia e
Estatística - IBGE). Data interpretation was performed ​​based
on the descriptive analysis of the data for the population of
the state of São Paulo. Nonparametric Wilcoxon test was used
for comparisons between population groups and Spearman’s
correlation coefficient for the analysis of the event/deaths/year
correlation, using SPSS 13.
This study was approved by the Research and Ethics
Committee of the institution and Free and Informed Consent
Form request does not fit the study model.
Results
Aneurysms and aortic dissections (ICD I71) occupied the
30th position as the most frequent cause of death among the
population of the state of São Paulo, according to the SEADE
(Data Analysis State System) ranking in the period January
1998 to December 2006 (Table 2) totaling 18,042 deaths
from diseases of the aorta. During this period, there were
8,448 deaths from TAD in the ICDs reported in the study,
4,922 deaths in men (58.3%), with 3,539 being secondary
to aortic dissection (71.9%) and 1,383 secondary to rupture
of thoracic aortic aneurysm (28.1%). The 3,526 women that
died from TAD (41.7%) had a similar distribution to that of
men, with 71.6% of deaths secondary to aortic dissection and
28.4% secondary to thoracic aortic aneurysm.
During the study extended period, from January 1998 to
December 2007, TADs were responsible for 9,465 deaths
(0.39% of the total of 2,396,588 deaths in the state of
Table 1 - Thoracic aortic diseases according to the International
Classification of Diseases (ICD-10)
ICD 10
Diagnostic
I71.0
Dissecting aortic aneurysm
I71.1
Ruptured thoracic aortic aneurysm
I71.2
Thoracic aortic aneurysm with no mention of rupture
I71.3
Ruptured abdominal aortic aneurysm
I71.4
Abdominal aortic aneurysm with no mention of rupture
I71.5
Ruptured thoracoabdominal aortic aneurysm
I71.6
Thoracoabdominal aortic aneurysm with no mention of rupture
I71.8
Ruptured aortic aneurysm at unspecified site
I71.9
Ruptured aortic aneurysm at unspecified site with no mention
of rupture
São Paulo in the same period). A total of 5,500 men (58.1%)
and 3,965 women (41.9%) died. In these patients, the
diagnosis of death attributed to TAD was attained at the DFM
in 8,167 patients (86.3%), being 4,601 in men (56.3%) and
3,566 in women (43.7%). There was a total of 6,721 patients
(71%) that died with a diagnosis of thoracic aortic dissection
(ICD I71.0) and 2,744 (29%) due to thoracic aortic aneurysm
(ICD I71.1, I71.2, I71.5, I71.6).
During the same period, TADs were responsible for
6,109 SUS hospitalizations (0.025% of the total 24,009,860
hospitalizations that occurred in São Paulo in the same period),
being 4,147 males (67.9%) and 1,962 females (32.1%). During
the hospitalization period, 1,298 patients died (21.2%), being
899 men (69.3%) and 399 women (30.7%).
The proportion of men and women hospitalized due to
aortic dissection and aneurysm of the thoracic aorta was
similar, respectively, 54% (2,238 patients) and 46% (1,909
patients) in the male population versus 53.5% (1,049 patients)
and 46.5% (913 patients) in the female population. However,
the proportion of mortality between the sexes in relation to
diagnosis was different, being in dissections and aneurysms,
respectively, 24.7% (554 patients) and 18.1% (345 patients)
in men versus 20.8 % (218 patients) and 19.9% (181 patients)
in women.
Table 3 shows the progressive increase in mortality from
TAD in the state of São Paulo, the high number of patients
whose diagnosis of death from TAD was attained in the autopsy
room and that the increase in mortality from the disease
(36.7%) was higher than the increase of the population (18%)
during the same time period.
The distribution of TAD in the population of the state of
São Paulo – determined by the number of SUS admissions
and the number of deaths of these patients – was different
between men and women. Hospital admissions were more
frequent in men and they were also responsible for more
deaths, respectively, at ratios of 1.65/1 and 1.44/1. There was
also a progressive increase in the number of hospitalizations
and deaths from TAD over the years (Tables 3 and 4).
When analyzing the trend of increase in the number
of hospitalizations from TAD, the number of deaths of
Arq Bras Cardiol. 2013; 101(6):528-535
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Dias et al
Mortality impact of thoracic aortic disease
Original Article
Table 2 - Ranking of mortality rate by different causes in the state of
São Paulo from January 1998 to December 2006
Cause
Ranking
N. of deaths
AMI
1st
177,484
Pneumonia
2
111,427
nd
CVA
3
rd
80,952
Firearm
5th
76,691
DM
6
th
75,428
CHF
8th
64,479
Automobile accidents
14
th
35,962
Breast cancer
18th
28,496
Prostate cancer
23
th
26,941
Aortic diseases
30th
18,042
Pulmonary embolism
36
th
14,400
Emphysema
45th
11,668
Cardiac Arrhythmia
52th
10,181
Alzheimer’s
58
9,376
th
Source: Fundação Seade, SESSP; AMI: acute myocardial infarction;
CVA: cerebral vascular accident; DM: diabetes mellitus; CHF: cardiac heart failure.
hospitalized patients and the total number of deaths, which
was above the annual increase in the population, we observed
a significant positive correlation in all three situations,
respectively, r = 0.976 – p <0.001; r = 0.891 – p <0.001
and r = 0.915 – p <0.001.
Figure 1 illustrates the progressive increase in deaths over
the years, which was than the population increase (r = 0.796,
p = 0.006), its differential increase between men and women,
and significantly higher mortality in men over the years.
The odds ratio (OR) of a man with TAD to die is 1.5 times
greater than that of a woman dying from the same cause
(OR = 1.498 [CI: 0.95:1.13-1.19, p <0.0001]).
The 6,109 hospital admissions due to TAD generated
3,572 surgeries (58.5% of patients) for the correction of the
underlying disease. Patients maintained exclusively on clinical
treatment had a mean hospital mortality of 22.5%. There was
a decrease in mortality to 20.3% in those patients in whom
drug treatment was associated with surgical treatment. This
difference was significant. Figure 2 illustrates the difference in
outcome year by year with both types of treatment.
Patients hospitalized due to TAD were predominantly at
the age range of 60-70 years, with the distribution shown in
Figure 3A, as well as the highest number of deaths (Figure 3B).
The number of surgeries to correct TAD ranged from
0.7-1.5 patient/100,000 inhabitants/year. The mortality of
these procedures had little impact when compared with the
overall mortality from TAD (7.7%).
The number of hospitalizations from TAD when compared
to the number of hospitalizations for all causes in the state of
São Paulo is very significant, but when comparing the mortality
of these patients in relation to the total SUS admissions, the
disease severity can be observed, as well as the progressive
increase in its prevalence (Table 3).
During part of the study period, from January 2004 to
December 2007, it was possible to identify SUS admissions
from TAD throughout the national territory, and São Paulo
accounted respectively for 38.5%, 38.8%, 39.2% and 48.4%
of these hospital admissions (Table 5). Regardless of regional
differences in health systems and the greatest concentration of
these patients in the state of São Paulo, the result of medical
Table 3 - Number of hospitalizations and deaths from TAD and from all causes and their association with population increase in the state of
São Paulo from 1998 to 2007
TAD/
Year
Total of
HAA
HAA from
TAD
% HAA TAD/
total
Deaths/
DFM
Deaths/
hospitalized
Total
deaths
% deaths TAD/
general
Pop. SP
Deaths TAD x 10-5
1998
2,380,248
337
0.01%
656
88
744
0.32%
35,283,992
2.1
1999
2,393,348
398
0.02%
728
94
822
0.35%
35,816,704
2.3
2000
2,398,344
385
0.02%
756
85
837
0.35%
37,032,403
2.26
2001
2,345,452
450
0.02%
763
102
865
0.37%
37,630,105
2.3
2002
2,360,704
566
0.02%
795
116
911
0.38%
38,177,734
2.4
2003
2,376,517
563
0.02%
868
145
1013
0.42%
38,709,339
2.6
2004
2,400,029
683
0.03%
947
133
1080
0.44%
39,239,362
2.75
2005
2,443,863
883
0.04%
899
154
1053
0.45%
40,442,820
2.6
2006
2,431,106
889
0.04%
922
201
1123
0.46%
41,055,761
2.74
2007
2,480,249
955
0.04%
0.39%
41,663,623
2.44
837
180
1017
Total
6109
8167
1298
9465
% of
variation
283%
28%
105%
36.70%
TAD: thoracic aortic diseases; HAA: hospital admission authorization
530
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Dias et al
Mortality impact of thoracic aortic disease
Original Article
Table 4 - Female and male population hospitalized due to or dead from TAD and number of deaths per year per 100,000 inhabitants in the state
of São Paulo from 1998 to 2007
TAD/year
1998
1999
2000
2001
2002
2003
2004
2005
F H+D-TAD
361
415
449
476
529
536
648
F D/year
286
332
346
354
391
406
456
F D DAT x 10
2006
2007
Total
701
711
702
5.528
458
497
439
3.965
1,6
1,8
1,8
1,8
2
2,1
2,3
2,2
2,4
2,1
M H+D-TAD
632
711
688
737
832
895
982
1081
1100
1090
8.748
M death/year
458
490
491
511
520
607
624
595
626
578
5.500
M death TAD x 10-5
2,6
2,8
2,7
2,8
2,8
3,2
3,2
3
3,1
2,8
Female pop.
17.899.523
18.167.033
18.893.040
19.207.646
19.508.370
19.793.470
19.805.188
20.723.102
20.989.036
21.351.076
Male pop.
17.384.469
17.649.671
18.139.363
18.422.459
18.669.364
18.915.869
19.434.174
19.719.718
20.066.725
20.312.547
-5
Source: Datasus. F H+D-TAD: number of women hospitalized for or who died from TAD a year. F death/year: number of deaths a year among women. F death
TAD x 10-5: number of deaths from TAD a year in women per 100,000 inhabitants. M H+D-TAD: number of men hospitalized for or who died from TAD a year. M death/
year: number of deaths a year among men. M death TAD x 10-5: number of deaths from TAD a year in men per 100,000 inhabitants. Female pop: female population in
the state of São Paulo year by year. Male pop: male population in the state of São Paulo year by year.
or surgical treatment did not show any difference in hospital
mortality (p = 1.0).
Discussion
The prevalence of TAD in the population of the state of
São Paulo cannot be properly measured by the current data
recording model of the Health Secretariat.
The Datasus database, which belongs the Executive
Secretariat of the Ministry of Health, allows the identification
of all deaths from TAD, inpatient or not, and informs all
admissions with their respective ICDs. It does not allow,
however, the identification of repeated hospitalizations of the
same patient (all readmission are counted as a new patient).
Furthermore, no patient with a TAD diagnosis being followed
as outpatient is likely to be identified and individualized by the
record system. If we add to this the large number of patients
with TAD, with no diagnosis and no access to preventive
health care, we become aware of the limitations of our health
system, and we can suppose that a large number of patients
with TAD remain unidentified at risk of aortic dissection and/
or rupture in our country.
For these reasons, more accurate statements on the
incidence and prevalence of TAD are difficult to be made
accurately. Differently from what occurs in Sweden, for
instance, where all patients have access to health care, they are
consistently recorded and easily tracked. It has been reported
that the disease is currently more prevalent there than before,
affecting men and women differently, respectively, 16.3 and
9.1 per 100,000 inhabitants per year. It has also been reported
that the number of surgeries is increasing and higher in men,
with 5.6 surgeries per 100,000 inhabitants per year versus 3.0
in women. However, it is noteworthy that in women, despite
the lower number of cases, this represents a 15-fold increase
compared to the last measurement versus a 7-fold increase in
men. The number of deaths from the disease is decreasing,
1.8
1.6
1.4
1.2
% of deaths
1
0.8
Gender
0.6
Male
0.4
Female
p=0.005
0.2
0
Year
Figure 1 - Percentage of deaths of men and women from TAD per year in the state of São Paulo from 1998 to 2007.
Arq Bras Cardiol. 2013; 101(6):528-535
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Dias et al
Mortality impact of thoracic aortic disease
% of deaths
Original Article
Treatment
Clinical
p=0.047
Surgical
Year
Year
Number of deaths
Number of hospitalizations
Figure 2 - Percentage of deaths in patients hospitalized due to TAD maintained in clinical treatment and those submitted to surgery in São Paulo state from 1998 to 2007.
Age range
Age range
Figure 3 - A) Histogram of the number of hospitalizations from TAD by age group in the state of São Paulo from 1998 to 2007. B) Histogram of the number of deaths
from TAD by age range in São Paulo state from 1998 to 2007.
but 22% of death diagnoses are made at the autopsy 11, while
in the state of São Paulo this number is 86.3%.
In São Paulo there were 18,042 deaths in nine years for a
population that ranged around 40 million during the period.
When analyzing the disease in its most advanced stages, i.e.,
when investigating patients requiring hospitalization, or those
undergoing or not non-surgical procedures and those who died
from this disease, the epidemiological observations are accurate
and capable of characterizing the aggressiveness of the disease.
Perhaps the biggest difference lies in the number of patients
with access to medical treatment and treatment outcome.
The figures show the lethality of TAD; not because it is the
30th most frequent cause of death by disease in the state, but
mainly for being responsible for 0.39% of total deaths and only
represents 0.025% of total hospital admissions (the number of
deaths is 1,600% greater than the number of hospitalizations).
Of the total of 14,276 patients identified as having TAD,
10,763 died during the study period (75.4%).
The mortality in the state of São Paulo from aortic disease is
close to the lowest estimate of the United States, with almost
14,000 deaths per year for a population of 308,745,538
Americans 12.
532
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Mortality impact of thoracic aortic disease
Original Article
Table 5 - Number of hospitalizations and deaths from TAD in
the state of São Paulo and in Brazil from 2004 to 2007 (Source:
DATASUS)
TAD/year
2004
2005
2006
2007
SP
683
883
889
955
Brazil
1772
2278
2267
1974
% deaths SP
19,5
17,4
22,6
18,8
% deaths Brazil
21,8
19
20,6
17,5
Ratio. n. of
deaths SP/Brazil
38,50
38,80
39,20
48,40
Source: Datasus. SP: number of hospitalizations from TAD in the state of
São Paulo a year. Brazil: number of hospitalizations from TAD in Brazil a
year. % deaths SP: percentage of deaths in hospitalized patients due to
TAD in the state of São Paulo a year. % deaths Brazil: percentage of deaths
in hospitalized patients due to TAD in Brazil a year. Ration of deaths SP/
Brazil: percentage of the ratio of deaths from TAD in São Paulo and in
Brazil a year.
TAD was responsible for a mortality rate that was similar
to two-thirds of all deaths due to the most common cancer in
women, and approximately 4/5 of the most common cancer
in men, as well as being responsible for twice more deaths
than Alzheimer’s disease.
It is also a matter of concern to observe that the increase
in the number of deaths was several times higher than the
progressive increase in the population. And, considering that
TAD onset is mainly related to the aging process, it is possible
to imagine the potential alarming number of citizens who will
develop the disease in our country. It should be emphasized,
however, that LeMaire and Russell 13, in a review study, showed
TAD distribution for the age range similar to that in our study
even though they reviewed studies performed mainly in
developed countries, with a life expectancy greater than ours.
It is noteworthy the fact that, similarly to other cardiovascular
diseases, males were preferentially affected (58% versus 42%),
but the distribution of aortic dissection and aneurysms was
similar between the two genders, respectively, 72% and 28%.
However, disease mortality differed; while more men died due
to aortic dissection (25% versus 21%), more women died due
to aneurysms (20% versus 18%).
Grubb and Kron, in turn, despite reporting the occurrence
of aortic dissection in women at a proportion similar to ours
(32%), showed that they had significantly higher mortality than
the male population (30% versus 21%) 14.
In addition to the number of deaths being several times
higher than the gradual increase in population, the number
of hospitalizations was 15.7 times higher than the population
growth in the period, which, although still modest, represents
a higher efficiency in the diagnostic and possible treatment
procedures offered to these patients.
These figures are initially encouraging, as they seem to
demonstrate a progressive medical care improvement in this
subgroup of patients; however, they also become a source of
concern, especially when we see the results obtained with
those patients maintained on medical therapy or referred for
surgical intervention.
The mortality with both therapeutic options is very high.
Obviously, one must stress that there are no information on
the preoperative conditions of these patients, or specifically on
the territory of the affected aorta (especially important in cases
of acute aortic dissections) or whether the patients maintained
on medical treatment had contraindications to surgery, due
to disease stage or refusal to undergo the procedure, but a
mortality rate > 20% for both options is still very high.
It also draws attention the low number of hospitalized
patients who were referred for surgery. Considering that
admissions for aortic disease treatment aim at some type of
intervention, why were only 58.5% of these patients submitted
to surgery? Do these numbers reflect the ignorance by the
medical professional on the ideal moment to refer a patient
for surgery? Does it reflect a number of inappropriate hospitals
or hospitals without adequate infrastructure to perform this
type of procedure? Does it reflect a high number of refusals
to undergo the procedure by the patient, due to inadequate
physician-patient relationship or suspicion of improper
performance of this type of procedure at the hospital of origin?
Does it reflect a lack of competent professionals to perform
this type of procedure?
One can only imagine that problems are multiple, mainly
by delayed access of the patient to the appropriate place of
treatment, due to the inefficiency of the health system as a whole.
The similarity of the results obtained in the state of São
Paulo when compared to the rest of Brazil is a matter of
concern, mainly because Sao Paulo has the most resources
in the Union and thus, it should have congregated over time,
more experience in dealing with this type of patient, and yet,
it is still unable to show lower mortality rates.
As TAD progresses asymptomatically in most patients
and the diagnosis is most often attained in the autopsy
room, objective measures at public health level should be
implemented to actively attain the diagnosis of this disease,
which is responsible for such a high number of deaths per year.
In conclusion, we can state that, despite numerous study
limitations related to the limited diagnostic information that
ICD imposes and the way patients are registered in SUS,
public health actions must be implemented in order to better
identify patients with TAD, so that better hospital centers can
be established for the care of patients with TAD, better and
more specific training can be provided to all the professionals
involved in the management of patients with TAD regarding the
multidisciplinary approach of this patient, aiming at reducing
mortality and offering better quality of life to our population.
Acknowledgements
To Vera Lúcia Rodrigues Lopes Osiano, technical assistant
from the informatics area of the Health Secretariat of the State
of São Paulo, for providing specific information from Datasus
Database of the state of São Paulo.
Arq Bras Cardiol. 2013; 101(6):528-535
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Dias et al
Mortality impact of thoracic aortic disease
Original Article
Author contributions
Sources of Funding
Conception and design of the research: Dias RR, Fernandes F,
Ramires FJA, Mady C, Stolf NAG; Acquisition of data e Writing of
the manuscript: Dias RR, Mejia OAV; Analysis and interpretation
of the data: Dias RR, Mejia OAV, Fernandes F, Ramires FJA;
Critical revision of the manuscript for intellectual content: Dias
RR, Fernandes F, Ramires FJA, Mady C, Stolf NAG, Jatene FB.
There were no external funding sources for this study.
Study Association
This study is not associated with any post-graduation
program.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
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Original Article
Arq Bras Cardiol. 2013; 101(6):528-535
535
Back to the Cover
Original Article
Experimental Cardiac Arrest Treatment with Adrenaline, Vasopressin,
or Placebo
Manoel Ângelo Gomes Palácio1, Edison Ferreira de Paiva2, Luciano Cesar Pontes de Azevedo2, Ari Timerman1
Instituto Dante Pazzanese de Cardiologia1; Hospital Sírio-Libanês2, São Paulo, SP - Brazil
Abstract
Background: The effect of vasoconstrictors in prolonged cardiopulmonary resuscitation (CPR) has not been fully clarified.
Objectives: To evaluate adrenaline and vasopressin pressure effect, and observe the return of spontaneous
circulation (ROSC).
Methods: A prospective, randomized, blinded, and placebo-controlled study. After seven minutes of untreated
ventricular fibrillation, pigs received two minutes cycles of CPR. Defibrillation was attempted (4 J/kg) once at 9 minutes,
and after every cycle if a shockable rhythm was present, after what CPR was immediately resumed. At 9 minutes and
every five minutes intervals, 0.02 mg/kg (n = 12 pigs) adrenaline, or 0.4 U/kg (n = 12) vasopressin, or 0.2 mL/kg (n = 8)
0.9% saline solution was administered. CPR continued for 30 minutes or until the ROSC.
Results: Coronary perfusion pressure increased to about 20 mmHg in the three groups. Following vasoconstrictors
doses, pressure level reached 35 mmHg versus 15 mmHg with placebo (p < 0.001). Vasopressin effect remained
at 15-20 mmHg after three doses versus zero with adrenaline or placebo. ROSC rate differed (p = 0.031) among
adrenaline (10/12), vasopressin (6/12), and placebo (2/8). Time-to-ROSC did not differ (16 minutes), nor the number
of doses previously received (one or two). There was no difference between vasoconstrictors, but against placebo,
only adrenaline significantly increased the ROSC rate (p = 0.019).
Conclusion: The vasoconstrictors initial pressure effect was equivalent and vasopressin maintained a late effect at
prolonged resuscitation. Nevertheless, when compared with placebo, only adrenaline significantly increased the
ROSC rate. (Arq Bras Cardiol. 2013; 101(6):536-544)
Keywords: Epinephrine; Arginine Vasopressin; Ventricular Fibrillation; Cardiopulmonary Resuscitation; Models, Animal.
Introduction
Epinephrine (adrenaline) was discovered over
100 years ago, and has been used in human cardiopulmonary
resuscitation (CPR) since 1922 1 . Vasopressin is also
centenary, but its use in resuscitation began in the 1990s2.
These drugs are vasoconstrictors that enhance vital organs
perfusion, increasing the chance for return of spontaneous
circulation (ROSC)3. It has been observed in animals and
humans an association between ROSC rate and coronary
perfusion pressure (CPP), which is the pressure gradient
between the aorta and right atrium during “diastolic phase”
of chest decompression 4,5. In turn, CPP has a positive
correlation with myocardial blood flow measured by
radioactive microspheres6-8.
Mailing Address: Manoel Palácio •
Av. Dante Pazzanese 500, Ibirapuera, Postal Code 04012-909,
São Paulo - SP - Brasil
E-mail: [email protected]
Manuscript received December 06, 2012; revised manuscript May 27, 2013;
accepted June 11, 2013
DOI: 10.5935/abc.20130213
536
Adrenaline acts on alpha-2 receptors causing
vasoconstriction, and on alpha-1 and beta-adrenergic
receptors causing unwanted effects, such as increased
oxygen consumption and increased energy depletion of
the fibrillating myocardium, among others9. Vasopressin
causes vasoconstriction when acting on their own
V1a receptors located in the vascular smooth muscle,
increasing the CPP without the adrenergic undesired
effects 9 . Vasopressin vasoconstrictor effect remained
equal under prolonged acidosis, in the same conditions
in which alpha-adrenergic effect decreased10. Knowledge
on vasopressin and its cardiac receptors has been growing
in the recent decades11,12.
During the development of a cardiac arrest animal
model and resuscitation, we planned this study aiming
to evaluate the pressure effect of adrenaline, vasopressin,
and the CPR itself or placebo, in addition to observing the
cardiac arrest short-term survival. The model was designed
in order to simulate an out‑of‑hospital cardiac arrest in
an adult patient with seven minutes downtime until the
emergency team arrival. In this pig model of cardiac arrest
due to eletrically induced ventricular fibrillation, with
exception of the treatment dose regimen, CPR followed
the current standards13.
Palácio et al.
Experimental cardiac arrest treatment
Original Article
Methods
A prospective, randomized, blinded, placebo-controlled
study, approved by the ethics committees in the use of
animals for research, according to local law and in line with
international standards. Thirty-two animals were successfully
prepared and subject consecutively to the protocol, one per
day and two per week.
Preparation
Large White Landrace pigs were fasted overnight
and had free access to water. After intramuscular
pre‑anesthesia with 5 mg/kg ketamine hydrochloride,
and 0.5 mg/kg midazolam, 12.5 mg/kg thiopental was
administered in a marginal ear vein. Keeping the animal in
supine position, an orotracheal intubation was performed,
inserting a N°. 7 cuffed tube. Anesthesia was maintained
by continuous intravenous infusion plus 2 mL fentanyl and
midazolam boluses, as required, along with pancuronium
for muscle paralysis. The animals were mechanically
ventilated: positive pressure, 10 mL/kg tidal volume,
40% fraction of inspired oxygen, 3‑5 mmHg positive
end expiratory pressure, and respiratory rate adjusted to
maintain 40‑45 mmHg of expired CO2 (ETCO2).
Following trichotomy, adhesive gel electrodes were
placed and electrocardiogram monitoring. The right jugular
vein was dissected, and by adaptation of the Seldinger
technique, a vascular 8.5 french (F) sheath introducer with
hemostatic valve was inserted, through which anesthesia
started to be administered. Likewise, the left jugular vein
and the right femoral artery received 8.5 F and 6 F sheaths,
respectively. Through the left jugular vein, a balloon‑tipped
7.5 F Swan-Ganz catheter was advanced to the pulmonary
artery. Through the femoral artery and with a guide wire, a
6 F pigtail catheter was advanced to the aortic root. Catheters
positioning was guided by the pressure curves. Catheters
were connected to pressure transducers, which were
previously calibrated with a mercury sphygmomanometer
and aligned at bed height.
We used the Swan-Ganz catheter atrial port to monitor
right atrial pressure. The pigtail catheter was used to monitor
the aortic pressure. A 5 F pacemaker bipolar cable was
introduced through the right jugular vein into the right
ventricle wall. This position was confirmed when ventricular
extra-systoles appear on the monitor. The cable was removed
immediately after the electrical induction of ventricular
fibrillation, which was obtained by contacting cable poles
with a common 9 V battery poles for two seconds.
Data collection
We used an intensive care unit general monitor and
an ETCO 2 common monitor during the experiment.
Electrocardiogram, ETCO 2 , aortic pressure and right
atrial pressure were recorded, along with on-line
calculated CPP. These parameters were recorded at
250 samples per second, using a computerized system for
biological data collection (MP100 System, Biopac, Inc.).
Pressures and electrocardiogram were collected directly
to the system through proper transducers and surface
electrodes. ETCO2 was collected through the specific monitor
analog output. The system software enabled to perform the
measurements later. Heart rate and mechanical ventilation,
as well as chest compression rate and manual ventilation with
AMBU, were measured over the aortic pressure curve cycles
and ETCO2, respectively.
Experimental protocol
The protocol can be seen schematically in Figure 1.
About one hour after preparation, anesthesia was
stopped, ventricular fibrillation was induced and the
mechanical ventilation was interrupted simultaneously.
In order to simulate an out-of-hospital cardiac arrest case
with downtime until the emergency team arrival, there was
no intervention in the first seven minutes. At 7 minutes,
the manual chest compression begun (100 compressions
per minute with approximately 5 cm depth), and the
1
32 PIGS
7 min → UNTREATED CARDIAC ARREST
(ELECTRICALLY INDUCED VENTRICULAR FIBRILLATION)
2
≤ 30 min → 2010 STANDARD CPR
CPR – 2 MINUTES CYCLES
(Starting at 7 min)
3
4
DEFIBRILLATOR – 4 J/kg
(At 9 min and after every cycle, if required)
5
VASOCONSTRICTOR – repeated regular doses
(An intravenous bolus at 9 min and at every 5 min)
12 PIGS
ADRENALINE
12 PIGS
VASOPRESSIN
8 PIGS
SALINE
0.02 mg/kg
0.4 U/kg
0.2 mL/kg
TREATMENT
RANDOMIZED, BLINDED, PLACEBO-CONTROLLED
Figure 1 - Protocol design of experimental cardiac arrest and cardiopulmonary
resuscitation (CPR).
Arq Bras Cardiol. 2013; 101(6):536-544
537
Palácio et al.
Experimental cardiac arrest treatment
Original Article
manual ventilation with AMBU (10 ventilations per minute
with 100% O 2 at 10L/min flowing into the reservoir).
The cardiac massage rate was mantained at about 100 based
on listening to appropriate music. After two minutes CPR
cycle, a defibrillator (4 J/kg, monophasic) was used once at
9 minutes, immediately followed by another CPR cycle.
From the first attempt on, the rhythm was always checked
at the end of each cycle, and the defibrillator was used in
the same way, if required. Cardiac massage was resumed
immediately after each attempt or after each asystole rhythm
checking or pulseless electrical activity. At 9 minutes and every
five minutes of CPR, an intravenous dose was applied in bolus:
0.02 mg/kg (n = 12 pigs) adrenaline (Epinephrine 1 mg/mL,
Cristália); or 0.4 U/kg (n = 12) arginine‑vasopressin (Encrise
20 U/mL, Biolab); or 0.2 mL/kg (n = 8) placebo, composed
of 0.9% saline solution. The vasoconstrictors dilution in 0.9%
saline solution made it possible for each dose to have equal
volume of 0.2 mL/kg. Treatment was previously randomized
and the protocol participants were blinded regarding
which treatment was applied to each animal. The same
participant always carried out the cardiac massage in order
to avoid interpersonal differences in the massages, although
current guidelines recommend switching people in this role.
The animals received 5 mg/kg of amiodarone at 11 minutes
and 2.5 mg/kg at 16 minutes, if persistent ventricular fibrillation
was observed. CPR continued to a maximum of 30 minutes or
to the ROSC, which was defined as a suitable heart rhythm
and systolic blood pressure higher than 50 mmHg for over
20 minutes. In this case, anesthetic infusion was restarted
and mechanical ventilation proceeded according to previous
settings, and animals were monitored for 120 minutes.
In these two hours, if necessary, 500 mL of 0.9% saline solution
was administered rapidly to raise mean arterial pressure
above 70 mmHg. No other drug was administered during
the entire protocol, with the heparin small doses exception
to maintain the catheters patency. At 2 hours following
ROSC, the euthanasia was induced by administering 10 mL
intravenous bolus of 19.1% potassium chloride.
Systematization of measurements
Measurements were performed after the last experience.
The measurement was systematized to occur at 20 seconds
before the timepoints marked on the parameters
curves, as on the pauses for rhythm checking. To avoid
measurement tendencies, the randomization secret was
revealed only at the end, after hundreds of measurements
performed, and after making the data spreadsheet.
Each measurement corresponds to seven seconds or about
10 chest compressions. Measurements were exported with
seven digits precision to the statistical program.
Statistical analysis
We used the Number Cruncher Statistical System (NCSS
2007) software package for the statistical analysis. ROSC
rate was compared using the chi-square and Fisher’s
exact test. Adapting a survival curve (Kaplan-Meyer) of
120 minutes with all animals potentially alive during CPR
and deaths occurring at 37 minutes, the hazard ratio (HR)
of death (Cox-Mantel) was calculated at specific time.
The mean ± standard error values of the parameters
were compared with repeated measures ANOVA and
Bonferroni (with control). Tests were considered significant
at p < 0.05 (two-tailed). The p-value is presented with
three digits and no approximation. The measurements
are presented with the appropriate precision and
approximation for each parameter.
Research supports
This research was partialy supported by Capes and
Post‑Graduation Medical Program of the Instituto Dante
Pazzanese de Cardiologia (IDPC); Fundação Adib Jatene
(IDPC); and Hospital Sírio-Libanês, Instituto de Ensino
e Pesquisa (Medical Intensive Care Laboratory and
Anesthesiology in which the experiments took place).
Results
The animals received similar volumes of anesthetic
drugs, about 50 mL of fentanyl and midazolam, and 30 mL
of pancuronium, in addition to 2,000 mL of 0.9% saline
solution. Baseline pre-cardiac arrest parameters were
similar, as can be seen in Table 1.
Table 1 - Pre-cardiac arrest baseline parameters similarity among 32 pigs, according to randomized and blinded treatment applied during
cardiopulmonary resuscitation
PARAMETER
Weight (kg)
ADRENALINE (12 PIGS)
PLACEBO (8)
p
36 ± 0.5
35 ± 0.6
36 ± 0.9
NS
37,6 ± 0.3
38,0 ± 0.4
37,7 ± 0.3
NS
ETCO2 (mmHg)
41 ± 0.5
42 ± 0.6
42 ± 0.7
NS
Respiratory rate (rpm)
24 ± 1.1
23 ± 1.2
21 ± 0.5
NS
Heart rate (bpm)
139 ± 7
127 ± 8
141 ± 9
NS
Aortic pressure (mmHg)
141 ± 4
141 ± 4
134 ± 9
NS
R-Atrial pressure (mmHg)
5 ± 0,4
5 ± 0.6
5 ± 0.7
NS
Temperature (°C)
ETCO2: expired carbon dioxide; NS: not significant; mean ± standard error.
538
VASOPRESSIN (12)
Arq Bras Cardiol. 2013; 101(6):536-544
Palácio et al.
Experimental cardiac arrest treatment
Original Article
Coronary perfusion pressure
After CPR starting, pressure increased equally in all groups
up to 9 minutes when vasoconstrictors were administered, and
the pressure level raised even more, as can be seen in Figure 3.
The first dose of vasoconstrictors significantly increased
CPP compared with placebo, and with no significant
difference between adrenaline and vasopressin. Pressure
level remained above 30 mmHg up to 13 minutes, or until
four minutes since first dose. After 19 minutes, successive
vasoconstrictors doses did not increase CPP. The vasopressin
effect remained close to 20 mmHg, but adrenaline effect
ended at the third dose, when the pressure level dropped
to near zero. The CPR plus placebo effect reached
approximately 20 mmHg and lasted only few minutes.
Time, doses and return of circulation
The time (and standard error) from cardiac arrest to ROSC
was similar among the three groups: adrenaline, 15 minutes
and 45 seconds (50 seconds); vasopressin, 18 minutes
and 12 seconds (152 seconds); placebo 14 minutes and
18 seconds (72 seconds). The 18 animals mean was 16 minutes
and 24 seconds (59 seconds), and median was 15 minutes
and 28 seconds; minimum of 13 minutes and 6 seconds,
maximum of 29 minutes and 4 seconds. Only one animal had
time‑to‑ROSC extended to over 19 minutes.
Most animals received one or two doses of treatment untill
achieving ROSC, and with no difference among count of doses per
group: adrenaline, 1.6 (0.2); vasopressin, 1.8 (0.5); and placebo,
1.5 (0.5). Fourteen animals received six doses and had no ROSC.
1.00
ROSC rate and 2h survival
ROSC rate
ROSC was observed in 18 animals that survived without
cardiac events up to 120 minutes, such as spontaneous
ventricular fibrillation, for example. The ROSC rate differed
(p = 0.031) among groups: adrenaline (10/12), vasopressin
(6/12), and placebo (2/8). ROSC rate increased following
adrenaline compared with placebo (p = 0.019), and it did
not differ following vasopressin compared with placebo or
adrenaline, as can be seen in Figure 2.
*p = 0.019 versus placebo
0.60
0.40
Vasopressin
50%
Placebo
25%
0.20
0.00
83%
Adrenaline*
0.80
p = 0.031 among three groups
0
20
40
60
80
100
120
Time (min)
Figure 2 - Return of spontaneous circulation (ROSC) rate and survival curve
adaptation of pigs in ventricular fibrillation, potentially alive during resuscitation
efforts and with all deaths occurring at 37 minutes, according to randomized
and blinded treatment.
CPP (mmHg)
Treatment
Adrenaline
Placebo
Vasopressin
* *
p < 0.001 versus placebo
14 animals
VF CPR
Cardiac arrest time (min)
Figure 3 - Coronary perfusion pressure (CPP) mean ± standard error, pre-cardiac arrest at time zero, and during cardiopulmonary resuscitation (CPR) initiated at
7 minutes of ventricular fibrillation (VF), according to randomized and blinded treatment applied (T) repeatedly. Asterisks indicate timepoints of pressure increase with
vasoconstrictors, wich remained significant with vasopressin. The pigs count decreases until 14 animals that not resuscitated: adrenaline 2/12, vasopressin 6/12, and
placebo 6/8.
Arq Bras Cardiol. 2013; 101(6):536-544
539
Palácio et al.
Experimental cardiac arrest treatment
Original Article
The ROSC occurred up to eight minutes of CPR in 2/3
cases, corresponding to four cycles of cardiac massage, or up
to three defibrillation attempts. The animals that achieved
ROSC received successive shocks and no previous rhythm was
observed other than ventricular fibrillation. The cumulative
ROSC rate can be observed in Figure 4.
Other parameters monitored during CPR
As it can be seen in Figure 5, other parameters did
not differ among treatment groups, except for the aortic
pressure, which defined the CPP, since atrial pressure
remained close to 20 mmHg for all time.
The mean cardiac massage rate (and standard error) was
99.5 (0.1) compressions per minute, and manual ventilation
rate was 10.5 (0.1) ventilations per minute. As these rates,
ETCO2 did not differ among groups, increasing during the
first massage cycle and then progressively decreasing.
Cardiac arrest nonsurvival hazard ratio
Compared with placebo, the cardiac arrest nonsurvival risk
decreased with adrenaline (HR = 0.22, 95% CI 0.05 - 0.91,
p = 0.043), and it did not differ with vasopressin (HR = 0.67,
95% CI 0.21 - 2.12). Adrenaline significantly reduced the
risk by 78%, and vasopressin reduced by 33%, but with no
statistical significance. Between these vasoconstrictors there
was no difference about short-term survival.
Post-cardiac arrest parameters
Up to two hours after achieving ROSC, the animals showed
no statistical significant difference in physiological parameters
among treatment groups, as can be seen in Table 2.
Discussion
The results of this study were interesting about CPR itself
consistent pressure effect, and about initial equivalence
of both vasoconstrictors. It was observed that CPR raised
pressure level to the threshold that favors ROSC chance,
and two placebo-treated animals survived for two hours.
Vasoconstrictors increased pressure level even more, and
the risk of cardiac arrest nonsurvival decreased with both
treatments, significantly with adrenaline. It was observed
also that adrenaline has lost its pressure effect after the
third dose; vasopressin maintained a significant pressure
effect during 30 minutes of CPR; and placebo, i.e., CPR
100
83%
10/12
ROSC rate (%)
80
58%
60
7/12
50%
41,7%
40
6/12
5/12
33%
4/12
20
25%
25%
3/12
3/12
25%
12.5%
2/8
1/8
0
13 min 15 min 19 min
13 min 15 min 19 min 29 min
13 min 15 min
Adrenaline
Vasopressin
Placebo
Figure 4 - Return of spontaneous circulation (ROSC) rate accumulated until the last resuscitated pig in each treatment group.
540
Arq Bras Cardiol. 2013; 101(6):536-544
Palácio et al.
Experimental cardiac arrest treatment
* * p < 0.001 versus placebo
Treatment
R-Atrial pressure (mmHg)
Aortic pressure (mmHg)
Original Article
Time (min)
ETCO2 (mmHg)
Respiratory rate (rpm)
Time (min)
Adrenaline
Placebo
Vasopressin
Time (min)
Time (min)
Figure 5 - Parameters: mean ± stardard error of pressures, expired carbon dioxide (ETCO2), and respiratory rate, pre-cardiac arrest at time zero, and during cardiopulmonary
resuscitation started at 7 minutes, according to randomized and blinded treatment applied in pigs electrically induced to ventricular fibrillation. Manual chest compression
rate was similar (99.5 ± 0.1). Following vasoconstrictors treatment at 9 minutes, there was significant effect (compared with placebo) on the aortic pressure only.
itself maintained a pressure effect during few minutes.
In other studies, pressure effects similar to these have
been observed14-18. It is important to highlight that blood
concentration of endogenous epinephrine and vasopressin
increases during CPR19,20.
In the current study, even with initial equivalent
vasoconstrictors pressure effect, and even with all similar
parameters, only adrenaline significantly increased ROSC
rate, and so, it deserves some considerations.
About this resuscitation study model
Swine species was chosen due to it human similarities, like
anatomical, physiological, cardiovascular, and mechanical of the
chest wall during massage, in spite of the natural species antidiuretic
hormone be lysine instead of arginine-vasopressin21,22. During the
conception of this local study model of resuscitation, it seemed
appropriate to evaluate each vasoconstrictor separately because
there were several vasopressin half-life related uncertainties, mainly
during CPR. Reference literature quotes half-lifes as from four to
24.1 minutes23, 24. During CPR, lack of in human knowledge on
repeated-doses-vasopressin pharmacokinetics led to stablished
one-dose only use25.
Dose regimen
It was observed equivalent pressure effect between the two
initial doses of epinephrine and vasopressin (Figures 3 and 5),
but only vasopressin kept effect of about 20 mmHg up to
the end of CPR. Repeated doses, considering the prolonged
vasopressin half-life, did not cause a cumulative effect of CPP
increasing, but maintained stable pressure level for 30 minutes.
However, with the same adrenaline dose regimen, CPP level
dropped to placebo similar level, despite repeated doses.
In other CPR studies, it was also observed a brief adrenaline
effect and a sustained vasopressin effect15,26,27.
Cardiac arrest time is critical
The ROSC rate can be influenced by several factors,
especially by the circulatory arrest time (no flow) and CPR time
(low flow)28,29. In this study, attention was given to every protocol
timepoint, so that there would not be any groups difference, but
is not possible to control time‑to‑ROSC. To check whether there
was influence of treatment on time‑to‑ROSC, this time was
precisely measured, and no groups difference was observed.
Therefore, the adrenaline ROSC rate advantage was not due
to differences in duration of ischemia.
Arq Bras Cardiol. 2013; 101(6):536-544
541
Palácio et al.
Experimental cardiac arrest treatment
Original Article
Table 2 - Pre (baseline) and post-cardiac arrest parameters similarity among 18 pigs treated with adrenaline (10 animals), vasopressin (6), or
placebo (2)
PARAMETER
POST-CARDIAC ARREST TIME
Treatment
Baseline
10 min
20 min
30 min
60 min
90 min
120 min
Adrenaline
37.5 ± 0.4
37.9 ± 0.4
38.1 ± 0.4
38.3 ± 0.4
38.6 ± 0.4
38.8 ± 0,4
38.9 ± 0.4
Vasopressin
38.7 ± 0.3
39.1 ± 0.3
39.2 ± 0.3
39.4 ± 0.3
39.6 ± 0.2
39.8 ± 0,2
39.9 ± 0.3
Placebo
38.4 ± 0.5
38.1 ± 1.2
38.5 ± 0.9
38.9 ± 1.0
39.1 ± 1.2
39.3 ± 1,1
39.4 ± 1.2
Adrenaline
42 ± 1
41 ± 1
42 ± 1
42 ± 1
43 ± 1
43 ± 1
43 ± 1
Vasopressin
43 ± 1
35 ± 3
37 ± 3
41 ± 2
44 ± 1
45 ± 1
42 ± 1
Placebo
41 ± 2
39 ± 1
41 ± 4
37 ± 5
44 ± 2
41 ± 3
40 ± 1
Adrenaline
24 ± 1
23 ± 1
23 ± 1
23 ± 1
23 ± 1
24 ± 1
24 ± 1
Vasopressin
25 ± 2
25 ± 2
25 ± 2
25 ± 2
24 ± 2
24 ± 2
26 ± 2
Placebo
21 ± 1
21 ± 1
21 ± 1
21 ± 1
19 ± 3
21 ± 3
21 ± 3
Adrenaline
138 ± 8
127 ± 10
135 ± 6
130 ± 5
134 ± 8
135 ± 6
143 ± 6
Vasopressin
141 ± 10
129 ± 15
130 ± 13
139 ± 12
151 ± 8
170 ± 13
159 ± 11
Placebo
145 ± 31
128 ± 6
140 ± 18
133 ± 30
128 ± 25
118 ± 35
130 ± 35
139 ± 5
99 ± 8
101 ± 8
99 ± 7
97 ± 6
106 ± 6
112 ± 6
Vasopressin
140 ± 8
82 ± 11
83 ± 8
95 ± 5
100 ± 6
99 ± 6
97 ± 7
Placebo
163 ± 15
117 ± 2
111 ± 1
116 ± 9
122 ± 15
126 ± 14
132 ± 25
Adrenaline
4±1
9±1
9±1
8±1
7±1
6±1
6±1
Vasopressin
4±1
10 ± 1
9±1
9±1
8±1
7±1
7±1
Placebo
3±1
9±1
9±1
7±1
6±1
5±1
4±1
Temperature ( C)
o
ETCO2 (mmHg)
Respiratory rate (rpm)
Heart rate (bpm)
Aortic pressure (mmHg)
Adrenaline
R-Atrial pressure (mmHg)
ETCO2: expired carbon dioxide; mean ± standard error.
Perfusion pressure and return of circulation
The duration of ischemia was similar, but the intensity
may have been different. In the microcirculation, local
differences in specific receptor density and stimulation
intensity may explain the difference in the ROSC rate, since
similar values of perfusion pressure can coexist with different
myocardial blood flows, depending on the vasoconstrictor
and on the dose6,8,11,12. Despite initial equivalent pressure
effect and overall parameters similarity, it was observed
an improve in short-term survival with adrenaline versus
placebo, and it did not differ with vasopressin versus placebo.
Between vasopressin and adrenaline, there was no significant
difference in ROSC rate and short-term survival.
This animal model and two clinical studies
R e c e n t l y, J a c o b s e t a l . c o m p a r e d a d r e n a l i n e
(n = 272 patients) with placebo (n = 262) in a randomized
542
Arq Bras Cardiol. 2013; 101(6):536-544
and double-blind clinical trial30. Survival to hospital discharge
did not differ, but ROSC chance (23.5% versus 8.4%) was
higher with adrenaline (odds ratio = 3.4, 95% CI 2.0 - 5.6).
ROSC rates were smaller than it were in this laboratory
study. This can be due to initial rhythms and downtime until
CPR, which were unfavorable in clinical setting. These are
important differences, so that the vasoconstrictor observed
result in clinical setting (23.5% of ROSC) did not even exceed
the placebo result in this laboratory study (25% of ROSC).
In both studies, it was observed that adrenaline significantly
improved ROSC rate.
In another randomized study, adrenaline (n = 158)
was compared with vasopressin (n = 178) in four doses
of 0.045 mg/kg and 0.8 U/kg at every 5‑10 minutes,
respectively 31. The study did not compare vasoconstrictor
with placebo. As occurred in the laboratory, vasoconstrictors
ROSC rates did not differ (26.6% versus 28.7%).
Palácio et al.
Experimental cardiac arrest treatment
Original Article
Final considerations
This experimental study model has some limitations: animals
are previously healthy, but in clinical setting, there are usually other
associated diseases; and duration of ischemia is usually longer;
this study was not designed to measure vital organs perfusion or
monitor cerebral perfusion pressure, much less the late survival or
neurologic function; a group with alternate or combined adrenaline
and vasopressin was not defined. Even so, the current study suggests
that vasoconstrictors can be more effectively used, and that further
studies are required to better understand this question.
Conclusion
In a pig model of cardiac arrest and 2010 standard
cardiopulmonary resuscitation, repeated doses of adrenaline
or vasopressin were equivalent for initial blood pressure
increase. Adrenaline lost its effect at the third dose, unlike
vasopressin that maintain its pressure effect following each
one of six doses. Without vasoconstrictors, manual chest
compression generated pressure for a few minutes. In spite
of that, compared with placebo treatment, the ROSC rate
and cardiac arrest short-term survival were improved with
adrenaline, and it did not differ with vasopressin.
Acknowledgements
To Andreza Conti Patara, for randomization safekeeping
and confidential preparation of treatment, and to Ernande
Xavier dos Santos, Flávio Silva de Novais and Renato
Serapião, for the general assistance in animals preparation.
Author contributions
Conception and design of the research, analysis and
interpretation of the data: Palácio MAG, Paiva EF, Timerman
A; acquisition of data: Palácio MAG, Paiva EF, Azevedo LCP;
statistical analysis and writing of the manuscript: Palácio MAG;
obtaining funding: Palácio MAG, Timerman A; critical revision
of the manuscript for intellectual content: Palácio MAG, Paiva
EF, Azevedo LCP, Timerman A.
Potential conflict of interest
No potential conflict of interest was reported.
Sources of funding
The study was partially funded by CAPES, Instituto Dante
Pazzanese de Cardiologia, Fundação Adib Jatene, and Hospital
Sírio-Libanês.
Study association
The study is part of doctoral thesis of Manoel Palácio, by
Instituto Dante Pazzanese de Cardiologia and University of
São Paulo.
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Back to the Cover
Original Article
Is Conventional Cardiac Pacing Harmful in Patients with Normal
Ventricular Function?
Luiz Antonio Batista de Sá, Salvador Rassi, Márcia Andery Ludovico Batista
Hospital das Clínicas – UFG, Goiânia, GO - Brazil
Abstract
Background: Right ventricular pacing may be deleterious in patients with left ventricular dysfunction, but in patients
with normal function the impact of this stimulation triggering clinically relevant ventricular dysfunction is not fully
established.
Objectives: To evaluate the clinical, echocardiographic findings of patients with previously normal left ventricular
function underwent implantation of a pacemaker.
Methods: Observational, cross-sectional study with 20 patients, who underwent implantation of pacemaker, prospectively
followed-up, with the following inclusion criteria: normal left ventricular function defined by echocardiography and
ventricular pacing higher than 90%. Were evaluated functional class (FC) (New York Heart Association), 6-minute
walk test (6MWT), B-type natriuretic peptide (BNP), echocardiographic assessment (conventional and dyssynchrony
parameters), and quality of life questionnaire (QLQ) (SF-36). The assessment was performed at ​​ten days (t1), four
months (t2), eight months (t3), 12 months (t4) and 24 months (t5).
Results: Conventional echocardiographic parameters and dyssynchrony parameters showed statistically significant
variation over time. The 6MWT, FC, and BNP showed worsening at the end of two years. QLQ showed initial improvement
and worsening at the end of two years.
Conclusion: The implantation of conventional pacemaker was associated with worsening in functional class, worsening
in walk test, increased BNP levels, increased duration of QRS, and worsening in some domains of the QLQ at the end
of two years. There were no changes in echocardiography measurements (conventional and asynchrony measures).
(Arq Bras Cardiol. 2013; 101(6):545-553)
Keywords: Pacemaker; Heart failure; Chagas Disease; Septal pacing; Asynchrony.
Introduction
Cardiac pacing is a treatment option for bradyarrhythmias1,
tachyarrhythmias2,3 and heart failure4. However, conventional
cardiac pacing in the right ventricle (RV), traditional for
decades, has been questioned for its possible deleterious
effects, especially in patients with previous left ventricular
dysfunction5.
In normal heart, the left ventricle (LV) contracts in a fast
and synchronized manner. Stimulation anywhere in the RV
alters the natural pattern of activation and, as a consequence,
the ventricular contraction6. This may lead to induction
of asynchrony with potential risk for the development of
ventricular dysfunction7.
In patients with normal ventricular function, the effects are
not clearly defined. In a retrospective study, Silva et al8 showed
Mailing Address: Luiz Antonio Batista de Sá •
Rua B8 Quadra 1B Lote 9, Jardim Paris. Postal Code 74885-616, Goiânia,
GO - Brazil
E-mail: [email protected], [email protected]
Manuscript received February 02, 2013; revised manuscript July 16, 2013;
accepted July 22, 2013.
DOI: 10.5935/abc.20130205
545
that in patients with pacemaker and normal ventricular
function, no significant remodeling in the left ventricle occurs.
In short-term study, Sá et al9 showed no significant deleterious
effects in patients with normal function. The mechanisms by
which not all patients develop left ventricular dysfunction are
not completely understood and may be related to stimulation
site, duration of stimulation, age or underlying disease10.
The aim of this study is to evaluate the clinical, laboratory,
and echocardiographic effects of conventional cardiac pacing
in patients with indication for pacemaker implantation and
normal ventricular function, during two years of follow-up.
Methods
This study was approved by the Research Ethics Committee
of the Hospital das Clinicas, Federal University of Goiás. This is
a prospective, observational study. All patients participating in
this study signed an informed consent form.
From March 2006 to July 2009, 178 patients were referred
for pacemaker implantation. Of these, 23 patients were
selected consecutively, with mean age of 11 ± 58 years and
60% male.
Inclusion criteria: 1) age over 18 years; 2) the indications
for conventional pacemakers followed the guidelines of
Batista de Sá et al
Cardiac pacing and asynchrony
Original Article
the Brazilian Society of Cardiology11, being accepted those
with high probability for right ventricular pacing: a) complete
atrioventricular block; b) type II second-degree AV block;
c) sinus node disease with first-degree AV block and PR
interval > 200 ms; 3) normal ventricular function defined by
echocardiography, performed immediately after implantation
of the artificial cardiac pacemaker (normal ventricular diameters
and normal ejection fraction).
Exclusion criteria: 1) severe disease with reduced survival
probability; 2) inability to perform the tests proposed in the
study; 3) patients who had right ventricular pacing of less than
90% during follow-up, whose analysis was performed by using
the generator data.
After implantation, patients were followed for a period of
two years, divided into five stages: ten days (t1), four months
(t2), eight months (t3), 12 months (t4), and 24 months (t5).
We analyzed the following parameters: 1) functional class of
the New York Heart Association; 2) Quality of Life questionnaire
(SF-36); 3) 6-minutes walk test; 4) evaluation of the data
stored in the generator; 5) ECG: duration of stimulated QRS;
6) levels of B-type natriuretic peptide (BNP); 7) echocardiogram
(chamber diameters and volumes, and ejection fraction)
and dyssynchrony.
The echocardiography was performed in the equipment
Toshiba Xario, under two-dimensional harmonic mode, and
2.5 MHz sector transducer. All examinations were performed by
a single physician. Patients remained in the left lateral position
and were monitored with electrocardiogram. All measurements
were performed with the patient in expiratory apnea.
The measurements of the LV, RV, the diameters of the left
atrium, and aorta were performed by one-dimensional mode,
according to the recommendations of the American Society of
Echocardiography12.
In the assessment of intraventricular dyssynchrony the
following criteria were employed: M mode: difference between
the onset of QRS complex and the peak contraction of the septal
wall, and then obtained from the time between the onset of the
QRS complex and the peak contraction of the posterior wall,
being considered dyssynchrony values greater than 130 ms;
Pulsed Doppler: measurement of the onset of QRS complex
up to the onset of aortic flow, being considered dyssynchrony
values greater than 140 ms; tissue Doppler: difference between
the onset of QRS complex and the S wave peak of the basal
region of the lateral, anterior, septal and inferior walls, being
considered dyssynchrony values greater than 65 ms13,14.
To assess the mean quantitative variables of normal
distribution which changed over time, we used the method
of analysis of variance (ANOVA) with repeated measures
followed by multiple comparisons via Tukey-Kramer method,
if applicable. The assumption of sphericity was assessed via
Mauchly test. When the assumption was not met, the HuynFeldt correction was applied. The normality assumption was
evaluated by visual inspection of histograms and D’AgostinoPearson omnibus normality test.
The change profile of quantitative variables with
asymmetric distribution over time was analyzed with Friedman
nonparametric test, followed by multiple comparisons according
to the Conover method.
The calculation of sample size was determined from
the ejection fraction variable which best represented the
primary endpoint.
The ANOVA for repeated measures with an intraindividual
factor (t1, t2, t3, t4 and t5) was planned in the statistical
analysis. For an average absolute difference of at least 5%, the
sample size of 20 patients would be appropriate to obtain a
90% statistical power in order to detect an average absolute
difference of at least 5% of EF between two arbitrary means
over time (t1, t2, t3, t4 and t5). The analysis of repeated
measures for variable of ordinal response was conducted with
Cochran-Mantel-Haenszel test.
Missing data of a patient at t5 were imputed according
to the last observation carried forward method (LOCF).
Quantitative variables with normal and asymmetric
distributions were described as mean ± standard deviation
and median (interquartile range), respectively.
All significance probabilities (p values) are of bilateral type,
and values lower than 0.05 were considered as statistically
significant. The software SAS 9.2 (Statistical Analysis System,
Cary, NC, USA) was applied for statistical analysis of data.
Results
In the initial sample of 23 patients, three were excluded
due to ventricular pacing lower than 90%. The most frequent
etiology was Chagas Disease (80%). Complete AV block or type
2 second-degree AV block accounted for 70% of the sample.
The electrode was implanted in the septal region in 70% of the
cases. The clinical features are shown in Table 1. The follow-up
period of two years was performed in 19 patients. One patient
died of heart failure at 14 months of follow-up.
The percentage of ventricular pacing was obtained from each
patient by analyzing the data stored in the generator. The average
percentage of stimulation was 99%. There was no statistically
significant difference between the medians over the times t1,
t2, t3, t4 and t5 (p = 0.4405).
All patients started the protocol in functional class I, and during
the course seven patients showed worsening of functional class
(p <0.001) (Figure 1). The walk test showed worsening over
time, being observed between t2 and t3, and between t2 and
t5 (p = 0.02) (Figure 2).
The duration of stimulated QRS complex increased by 12 ms
over time (p = 0.0001), this difference was observed between
t1 and t5.
Table 2 shows the data regarding conventional
echocardiographic parameters: systolic and diastolic diameters
of LV, systolic and diastolic volumes of the LV, and left atrial
dimension. No statistical differences were observed over time.
The average ejection fraction at baseline was 64.50% and at the
end was 60.65%, but there was no statistical difference (p =
0.1602) (Figure 3).
In Table 3, we observe the data regarding the echocardiographic
assessment of the ventricular dyssynchrony. By M mode, there
was no significant difference in average time between septal
activation and posterior wall activation over time. Average
value observed at the onset (t1) was 35.50 ms and at the end
of two years (t5) was 41.00 ms. By pulsed Doppler method, the
Arq Bras Cardiol. 2013; 101(6):545-553
546
Batista de Sá et al
Cardiac pacing and asynchrony
Original Article
Table 1 - Baseline Clinical Characteristics of the patients studied
1.
45
M
CD
SND + AVB 1º
septal
DDC
2.
64
M
CD
CAVB
septal
DDC
3.
68
M
CD
AVB 2º Mobitz 2
septal
DDC
4.
45
M
CD
SND + AVB 1º
apical
DDC
5.
70
F
FCS
CAVB
septal
DDC
6.
43
M
CD
SND + AVB 1º
septal
DDC
7.
67
M
CD
AVB 2º Mobitz 2
septal
DDC
8.
45
F
CD
SND + AVB 1º
apical
DDC
9.
69
F
FCS
CAVB
septal
DDC
10.
59
F
CD
SND + AVB 1º
apical
DDC
11.
55
M
CD
SND + AVB 1º
septal
DDC
12.
64
M
CD
CAVB
apical
DDC
13.
78
F
FCS
CAVB
septal
DDC
14.
76
M
CD
CAVB
septal
DDC
15.
59
F
CD
CAVB
septal
DDC
16.
67
F
FCS
CAVB
apical
DDC
17.
45
M
CD
CAVB
septal
DDC
18.
38
M
CD
CAVB
septal
DDC
19.
54
M
CD
AVB 2º Mobitz 2
septal
DDC
20.
64
F
CD
CAVB
apical
DDC
CD: Chagas disease; FCS: fibrosis of the conduction system; CAVB complete AV block; SND: sinus node disease; AVB 1: first-degree AV block; DDC:
dual chamber.
Figure 1 - Changes in functional class at t1 (10 days), t2 (four months), t3 (eight months), t4 (12 months), and t5 (24 months). Worsening between t1 and t4 and t1
and t5 (p < 0.0001).
547
Arq Bras Cardiol. 2013; 101(6):545-553
Batista de Sá et al
Cardiac pacing and asynchrony
Walk test
Original Article
Time
Figure 2 - 6-minute walk test in meters (difference between t2 and t3, and between t2 and t5), p = 0.0212.
Table 2 - Echocardiography parameters
EF
Delta D
LVDD
LVSD
LVEDV
LVESV
LA
t1
64.50 ± 5.56
35.05 ± 4.03
50.25 ± 3.44
32.20 ± 3.44
124.85 ± 29.91
43.70 ± 12.50
32.60 ± 3.23
t2
62.65 ± 7.23
34.10 ± 5.27
50.70 ± 5.50
33.45 ± 5.09
125.90 ± 27.81
47.35 ± 16.53
32.70 ± 3.16
t3
61.55 ± 7.65
33.40 ± 5.90
51.25 ± 5.24
34.10 ± 5.51
129.85 ± 32.57
50.35 ± 19.27
32.95 ± 3.86
t4
61.80 ± 6.57
32.95 ± 4.59
50.55 ± 4.88
34.15 ± 5.22
127.95 ± 29.02
49.90 ± 17.93
32.70 ± 4.03
t5
60.65 ± 8.68
32.60 ± 6.10
50.55 ± 7.18
34.45 ± 7.39
131.10 ± 33.10
51.60 ± 18.32
33.10 ± 4.05
p = 0.1602
p = 0.2654
p = 0.7559
p = 0.0270
p = 0.1592
p = 0.1400
p = 0.09141
p
EF: ejection fraction; LVDD: LV end-diastolic diameter; LVSD: LV end-systolic diameter; LVEDV: LV end-diastolic volume; LVESV: LV end-systolic volume; LA: left atrium.
average value observed was 105.40 ms at t1, and 122.00 ms at
t5. By tissue Doppler the average value observed was 38.55 ms
at t1, and 44.45 ms at t3. There was no significant difference
in the mean between the septal activation and posterior wall
activation over time.
In BNP tests, there was a significant difference between the
average levels over time. The average level was 19.75 pg / ml at
t1, and 167 pg/ml at t5, this difference being found between t1
and t5 (p = 0.0002) (Figure 4).
Table 4 shows the data regarding the answers to the Quality
of Life Questionnaire (SF-36). In the domains of functional
capacity, pain, vitality, emotional aspects, limitations due to
physical aspects, general health status, and limitation due to
social aspects, the patients had improvement between t1 and
t4. There was worsening between t2 and t5, but no difference
between t1 and t5. In the mental health domain there was no
difference over time.
Discussion
For 50 years, since its introduction15, the right ventricular
pacing, especially in the apical region, has been the preferred
site due to the ease of implantation and its stability. However,
such stimulation has been extensively revised to be related
to induction of ventricular dysfunction16.
The main etiology in our study was Chagas Disease,
whose pathophysiology is complex17. The installation of a
bradyarrhythmia may simply be a marker of inflammatory
Arq Bras Cardiol. 2013; 101(6):545-553
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Batista de Sá et al
Cardiac pacing and asynchrony
Original Article
Time
Figure 3 - Ejection fraction did not change significantly over time (p = 0.1602).
Table 3 - Echocardiography parameters related to intraventricular dyssynchrony
549
M mode
Pulsed Doppler
Tissue Doppler
t1
35.50
105.40 ± 20.89
38.55 ± 14.14
t2
42.00
118.40 ± 24.53
40.62 ± 19.02
t3
41.00
117.20 ± 15.86
42.45 ± 16.21
t4
39.00
118.05 ± 29.78
42.35 ± 16.20
t5
41.00
122.10 ± 28.48
44.45 ± 17.20
p
p = 0.6619
p = 0.0988
p = 0.6921
changes and the evolution to ventricular dysfunction can occur
independently of the presence of a pacemaker.
duration greater than or equal to 120 ms was associated with
a death risk of 34%19.
Functional class and walk test showed significant worsening
at the end of the two years, indicating clinical deterioration
over time. The stimulation time is an important factor in the
induction of ventricular dysfunction and risk for heart failure.
Sweeney et al18, in the MOST study, demonstrated that RV
pacing > 80% for more than two years increased the risk
for heart failure. In addition, they assessed the duration of
the QRS complexes and their relationship with mortality in
patients undergoing implantation of a pacemaker for sinus
node disease. The presence of paced QRS complex with
Zhang et al20, in a retrospective study with an eight-year
follow-up showed that in patients with complete AV block, the
predictive factors for developing heart failure were age, apical
pacing, duration of QRS complex pacing, and the presence of
coronary artery disease. In our sample, no increase was observed
in QRS duration over time. In studies on resynchronization, patients
with higher QRS duration have greater benefit from this therapy21.
In addition, patients with wider QRS complexes have worse
prognosis22. Therefore, we can assume that an increased QRS
duration over time may be associated with a higher dyssynchrony.
Arq Bras Cardiol. 2013; 101(6):545-553
Batista de Sá et al
Cardiac pacing and asynchrony
BNP levels pg/ml
Original Article
Time
Figure 4 - Box-plot of BNP levels; significant increase between t1 and t5 (p = 0.0004).
Table 4 - Test of quality of life SF-36
FC
LPA
Pain
GHS
Vitality
t1
90
50
73 ± 21
75 ± 19
t2
97
87
78 ± 21
77 ± 16
t3
95
100
86 ± 12
t4
97
100
90 ± 10
t5
85
50
82 ± 19
p < 0.0001
p < 0.0001
p = 0.0110
p
SA
EA
Mental Health
73 ± 21
75
100
76± 20
84 ± 12
100
100
87± 9
87 ± 11
84 ± 13
100
100
86± 8
90 ± 10
83 ± 11
97
100
87± 10
77 ± 19
68 ± 23
94
67
75± 19
p < 0.0001
p < 0.0021
p = 0.0021
p < 0.0001
p = 0.0108
FC: Functional capacity; LPA: Limitations due to physical aspects; GHS: General health status; SA: Social aspects; EA: Emotional aspects.
In the SF-36 questionnaire, initial improvement was
observed in the following domains: functional capacity, social
aspects, and general health status. The improvement arises
from the correction of bradycardia by cardiac pacing in this
group of patients previously limited. The MOST23 and PASE24
studies, comparing dual-chamber pacing versus single-chamber
pacing, used the SF-36 questionnaire. The authors observed
a significant improvement in quality of life after pacemaker
implantation in both groups, but less effective in patients
over 75 years old. In our study, after 24 months there was a
worsening in these parameters, corroborating the functional
class and walk test data.
In our study there was a prevalence of septal pacing. The
apical pacing has been more clearly associated to the deleterious
effects25. However, the cardiac pacing anywhere in the RV alters
the cardiac activation, since the stimulus conduction is slower
through the ventricular myocardium compared to His-Purkinje
system. The stimulation on outflow tract26, septal region27,
hissian region or para-hissian region28 has been investigated, but
without consistent results regarding major outcomes, such as total
mortality and cardiovascular mortality.
The use of cardiac resynchronization therapy prophylactically,
i.e. prevention of asynchrony and its deleterious effects as a
consequence, have been tested. Albertsen et al29 selected 50
Arq Bras Cardiol. 2013; 101(6):545-553
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Batista de Sá et al
Cardiac pacing and asynchrony
Original Article
patients with complete AV block, which were randomized
to biventricular pacing or conventional pacing. After one
year of follow-up, they found that biventricular pacing
minimizes asynchrony (assessed by echocardiography with
tissue Doppler), preserves the left ventricular function, and
presents lower BNP levels. There was a reduction in ejection
fraction by 2% in the DDD group, with no repercussions on
functional class or walk test. This study included patients
with and without left ventricular dysfunction.
Another strategy has been to minimize ventricular
pacing through new pacing algorithms30, because a higher
percentage of stimulation is associated with risk for heart
failure31. The SAVE PACe study32 performed in patients
with sinus node disease randomized 1065 patients to
receive conventional dual-chamber pacing or dual-chamber
minimal ventricular pacing. There was a 40% reduction
in atrial fibrillation, with no difference in mortality.
The INTRINSIC RV study33 in patients with indication for
ICD, compared DDDR modes (70 bpm) x VVI (40 bpm)
with respect to mortality and hospitalization for HF, and
no significant difference has been observed. However,
patients with complete AV block or high-grade block do not
benefit from this strategy because they require ventricular
stimulation.
In our group, we observed a significant increase in
BNP levels at the end of the two years of follow-up.
The average level at the end of the two years was
167 pg/ml. This value correlates to mild ventricular
dysfunction34. Abreu et al35 showed that in patients with
conventional pacing, intraventricular dyssynchrony was
an independent predictor of increased BNP levels, after
adjustment for age and ejection fraction. On the other hand,
Nikoo et al36 found no correlation between BNP levels and
pacing site (apical versus non-apical).
In our population, there was no worsening of conventional
echocardiography parameters and dyssynchrony
measurements, but downward trend in ejection fraction,
a value that did not reach statistical difference. The sample
size may have been insufficient to detect subtle changes
in ejection fraction. Silva et al 37 evaluated ventricular
remodeling in patients with ventricular apical pacing. The
remodeling was defined as echocardiographic changes
documented for at least six months after implantation:
> 10% increase in left ventricular diastolic diameter and
> 20% decrease in ejection fraction. The variables analyzed
were: underlying heart disease, functional class, duration
of ventricular pacing and QRS duration. Researchers have
observed that patients without ventricular dysfunction
and undergoing RV apical pacing showed low ventricular
remodeling.
A model to evaluate ventricular dysfunction related to
the use of pacemaker is the congenital complete AV block
without associated heart disease, as it excludes other
potentially confounding variables. Thambo et al38 evaluated
23 patients with congenital complete AV block and
previously normal left ventricular function, under at least
five years of cardiac pacing. The following parameters were
analyzed: ventricular filling time, cardiac output, severity
of mitral regurgitation, interventricular dyssynchrony,
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Arq Bras Cardiol. 2013; 101(6):545-553
intraventricular dyssynchrony, and exercise stress test.
The results indicate that prolonged ventricular pacing was
associated with left ventricular dilation, LV asymmetric
hypertrophy, and low physical capacity. However, from
the clinical point of view, the impact of these changes
has not been evaluated. Kim JJ et al39 evaluated patients
with congenital complete AV block and showed after 20
years of follow-up that 92% of patients had no ventricular
dysfunction assessed by echocardiography and clinical
parameters. This suggests that ventricular pacing should
not be considered as the only factor inducing ventricular
dysfunction. In our study, clinical worsening was not clearly
associated with asynchrony, suggesting evolution of the
underlying heart disease.
The limitation of this study was the sample size, which is small
and powerless to detect small changes in echocardiographic
measurements and major clinical outcomes. The prevalence
of patients with Chagas Disease, whose clinical course is
variable, may also be a confounding factor. In addition, in the
evaluation of the generator data by telemetry it is not possible
to exclude patients with pseudofusion.
The paradigm change in the current implant mode
requires solid data, especially in relation to clinically
relevant outcomes. It will be important to clearly define risk
subgroups because the reason why some patients develop
ventricular dysfunction or not requires further investigation
and probably is not related exclusively to ventricular pacing.
Conclusion
In patients with normal left ventricular function, implantation
of conventional pacemaker was associated with change in
functional class, worsening in walk test, increased BNP levels,
increased duration of QRS, and worsening in some domains
of the QLQ (SF-36) at the end of two years. There were no
changes in echocardiography measurements (conventional
and asynchrony measurements).
Author contributions
Conception and design of the research, Analysis and
interpretation of the data and Critical revision of the
manuscript for intellectual content: de Sá LAB, Rassi S;
Acquisition of data and Writing of the manuscript: de Sá LAB,
Batista MAL; Statistical analysis: de Sá LAB,
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 doctoral submitted by
Luiz Antonio Batista de Sá, from Universidade Federal de
Goiás - UFG.
Batista de Sá et al
Cardiac pacing and asynchrony
Original Article
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Back to the Cover
Original Article
Brazilian Portuguese Validated Version of the Cardiac Anxiety
Questionnaire
Aline Sardinha1,2, Antonio Egidio Nardi1,2, Claudio Gil Soares de Araújo5,6, Maria Cristina Ferreira3, Georg H. Eifert4
Laboratório de Pânico e Respiração do Programa de Pós-Graduação em Psiquiatria e Saúde Mental do Instituto de Psiquiatria da Universidade
Federal do Rio de Janeiro (UFRJ)1; Instituto Nacional de Ciência e Tecnologia - Translational Medicine (INCT-TM, CNPq)2; Programa de
Pós‑Graduação em Psicologia da Universidade Salgado de Oliveira3; Schmid College of Science and Technology Psychology, Crean School of
Health and Life Sciences - Chapman University4; Programa de Pós-Graduação em Ciências do Exercício e do Esporte da Universidade Gama
Filho5; CLINIMEX - Clínica de Medicina do Exercício6, Rio de Janeiro – Brazil
Abstract
Background: Cardiac Anxiety (CA) is the fear of cardiac sensations, characterized by recurrent anxiety symptoms, in
patients with or without cardiovascular disease. The Cardiac Anxiety Questionnaire (CAQ) is a tool to assess CA, already
adapted but not validated to Portuguese.
Objective: This paper presents the three phases of the validation studies of the Brazilian CAQ.
Methods: To extract the factor structure and assess the reliability of the CAQ (phase 1), 98 patients with coronary
artery disease were recruited. The aim of phase 2 was to explore the convergent and divergent validity. Fifty-six
patients completed the CAQ, along with the Body Sensations Questionnaire (BSQ) and the Social Phobia Inventory
(SPIN). To determine the discriminative validity (phase 3), we compared the CAQ scores of two subgroups formed
with patients from phase 1 (n = 98), according to the diagnoses of panic disorder and agoraphobia, obtained with the
MINI – Mini International Neuropsychiatric Interview.
Results: A 2-factor solution was the most interpretable (46.4% of the variance). Subscales were named “Fear and
Hypervigilance” (n = 9; alpha = 0.88), and “Avoidance”, (n = 5; alpha = 0.82). Significant correlation was found between
factor 1 and the BSQ total score (p < 0.01), but not with factor 2. SPIN factors showed significant correlations with CAQ
subscales (p < 0.01). In phase 3, “Cardiac with panic” patients scored significantly higher in CAQ factor 1 (t = -3.42;
p < 0.01, CI = -1.02 to -0.27), and higher, but not significantly different, in factor 2 (t = -1.98; p = 0.51, CI = -0.87 to 0.00).
Conclusions: These results provide a definite Brazilian validated version of the CAQ, adequate to clinical and research
settings. (Arq Bras Cardiol. 2013; 101(6):554-561)
Keywords: Cardiovascular Diseases; Anxiety; Psychometrics; Psychological Tests; Questionnaires.
Introduction
Psychiatric disorders seem to play a role as risk factors
to cardiovascular morbidity and mortality1. They also seem
to have a negative impact on disease stability2, adherence
to treatment 3 and quality of life 4 in cardiac patients.
Despite that, anxiety disorders are often unrecognized
and mistreated in this population, evidencing a gap in the
knowledge in the field5.
Distinguishing between clinically relevant cardiac-related
symptoms and manifestations of anxiety can be challenging,
Mailing Address: Aline Sardinha •
Rua Visconde de Pirajá, 156/404, Ipanema. Postal Code 22410-000,
Rio de Janeiro, RJ - Brazil
E-mail: [email protected], [email protected]
Manuscript received April 21, 2013; revised manuscript June 19, 2013;
accepted July 10, 2013.
DOI: 10.5935/abc.20130207
554
especially in patients with cardiovascular diseases and anxiety
comorbidity6. The boundaries are usually unclear, negatively
affecting clinical decision-making and treatment7.
Cardiac anxiety (CA) is the fear of cardiac-related stimuli
and sensations, perceived as negative or dangerous8. It is
a syndrome characterized by recurrent aversive sensations
or chest pain, in the absence of physical abnormalities.
Often, individuals with high CA engage in a variety
of hypochondriacal behaviors that raise the risk for
unnecessary diagnostic procedures and cause considerable
expenditure of financial and medical resources9.
CA has been demonstrated in a variety of anxiety-related
conditions, but is also significantly prevalent among cardiac
patients10-12. The cognitive-behavioral model highlights the
role of heart-focused attention and interoceptive conditioning
in the origin of cardiorespiratory manifestations and acute
thoracic pain9. To address these concerns, a psychometric
instrument – the Cardiac Anxiety Questionnaire (CAQ) - was
designed to clinical use in cardiology settings, demonstrating
Sardinha et al.
Validation of cardiac anxiety questionnaire
Original Article
good psychometric properties8. The CAQ has been translated
and tested in different cultures and samples with consistent
results11,13-15. Although the Brazilian translated version of the
instrument has been transculturally adapted, it has not yet
been validated16.
evaluated using (a) Kaiser's eigenvalue > 1 factor extraction
rule, (b) scree plot analysis20, and (c) the interpretability of
the resulting factor structures21.
Validations studies of translated instruments allow
comparisons between data from different cultures and
have been demonstrated to be a valuable contribution
to clinical and research practice17. This paper presents a
validation study comprising three distinct phases that aimed
to evaluate the psychometric properties of the Brazilian
adapted version of the CAQ. The objective was to provide
clinicians with an adapted, valid and simple tool to assess
CA in Brazilian cardiac patients.
Once the Brazilian CAQ basic factor structure and
internal consistency were established, the aim of phase 2
was to explore the convergent and divergent validity of the
scale. For this phase, a different sample of cardiac patients
was recruited in an exercise-based rehabilitation program.
Fifty-six patients with a formal diagnosis of coronary artery
disease were assessed. In this sample, 35 participants were
men and ages ranged from 58 to 94 years (mean = 71.1;
SD = 7.90). All patients read and signed an informed
consent prior to participation. All participants had at least
eight years of education and 67% (n = 37) had university
degree. Patients completed the Brazilian version of the
CAQ, followed by two other questionnaires: the Brazilian
adapted version22 of the Body Sensations Questionnaire
(BSQ)23 and the Brazilian validated version of the Social
Phobia Inventory (SPIN)24.
Methods
Phase 1 - Factor structure and reliability
The initial Brazilian adapted version of the CAQ
consisted of an 18-item 5-point Likert scale as to how
frequently the behavior typically occurs with response
anchors ranging from 0 (never) to 4 (always). Higher
scores indicate greater CA. To extract the factor structure
and assess the reliability of the instrument, this initial
version was administered to 98 patients (61 men) known
to have coronary artery disease (CAD), with ages between
34 and 89 years (mean = 64.2; SD = 10.64). Patients were
recruited in two outpatient cardiac clinics in Rio de Janeiro:
a public outpatient hospital-based service and a private
exercise‑based cardiac rehabilitation program. Thirty eight
percent of the participants had a university degree, whereas
36% had more than eight years of formal education but no
university studies and 14% (n = 14) had up to eight years of
education. All participants signed an informed consent prior
to participation. This study was approved by the institutional
Research Ethics Committee and was funded by research
grants from CNPq, INCT-TM and FAPERJ.
Besides filling in the CAQ, patients were screened for
the presence of psychiatric comorbidities by the same
trained researcher using the MINI – Mini International
Neuropsychiatric Interview, version 5.018. Data from the
MINI was used to assess discriminative validity in the third
phase of this study. The MINI is a short structured interview
designed to explore each of the necessary criteria for the
main diagnoses of DSM-IV, Axis I. Data obtained were
analyzed using the Statistic Package for Social Sciences SPSS (version 13).
The first step of the assessment of the factor structure
was to test the sample adequacy, by calculation of the
Kaiser-Meyer-Olkin measure of sampling adequacy, yielding
the significant value of .83. Bartlett's test of sphericity also
resulted in significant sample adequacy (χ = 842,55;
p < 0,001). Factor extraction was assessed by calculating
the exploratory factor analysis using Principal Axis Factor,
with Oblimin rotation. Item-total correlations were also
calculated. To be included in one subscale, item´s factor
loading should be higher than 0.3 in that factor and lower that
0.2 in any other factor19. The number of factors to retain was
Phase 2 - Convergent and divergent validity
Briefly, the BSQ is a unifactorial 17-item self-report
questionnaire that assesses the individual's level of fear of
bodily sensations associated with autonomic arousal. Patients
rated the degree to which they experience anxiety as a result
of bodily sensations on a 5-point scale with anchors ranging
from 1 (not frightened/worried by sensation) to 5 (extremely
frightened/worried by sensation)22.
The SPIN is an instrument for the evaluation of fear,
avoidance and physiological symptoms associated with
social anxiety disorder. This is a 17-item scale where each
item can be rated by respondent in a 5-point Likert-type
scale ranging from 0 (nothing) to 4 (extremely), indicating
the level of discomfort experimented in the social situation
presented. The validation process of the Brazilian version
of the SPIN indicated a three-factor structure, composed by
the following subscales: “fear and avoidance of situations of
social evaluation and of figures of authority and physiological
symptoms”, “fear and avoidance of interaction with strangers,
of public speaking, and of being the center of attention” and
“fear and avoidance of social events”24.
We assessed convergent and divergent validity of the CAQ
by computing correlations between CAQ subscales obtained
in factor analysis (phase 1) and the other measurements
subscales. To establish convergent validity, the scores of
the CAQ subscales were correlated to the BSQ total score,
once it presents a unifactorial structure. This instrument was
also used to assess convergent validity in the original scale
validation process and was selected due to the existence
of a Brazilian adapted version and psychometric properties
previously assessed for our population.
Divergent validity was calculated by the correlation
between the scores obtained by the cardiac patients in the
two subscales of the CAQ and the three subscales of the
SPIN. This instrument was selected because social anxiety
should not be conceptually related to the construct of CA.
In the original study, a social anxiety measure was also used
to assess divergent validity.
Arq Bras Cardiol. 2013; 101(6):554-561
555
Sardinha et al.
Validation of cardiac anxiety questionnaire
Original Article
Phase 3 - Discriminative validity
To determine the discriminative validity of the Brazilian
version of the CAQ we sought to test whether different
groups of cardiac patients presented significant differences
in the CAQ score. We used the same sample of phase
1 (98 coronary artery disease outpatients) and compared
the scores obtained in the CAQ using two different groups
formed according the diagnoses obtained with the MINI –
Mini International Neuropsychiatric Interview version 5.018.
For the purposes of the present study, we screened patients
for present and past prevalence of panic disorder, panic
attacks and agoraphobia, in terms of frequency, and included
those in the so-called “cardiac with panic” patient subgroup.
Patients who met the criteria for mild other psychiatric
disorders but no anxiety disorders were included in the
“cardiac without panic” subgroup. The rationale for this
design was the prediction based in some previous findings
that CA could be associated with a higher prevalence of
current and past panic disorder and agoraphobia diagnosis
or prodromal symptoms10. T-test was used to compare mean
scores obtained in the two subgroups.
Results
In the factor structure study, five factors were identified
with eigenvalues greater than one (eigenvalues: 6.53, 1.81,
1.31, 1.12 and 1.02). Cattell's scree plot analysis indicated
that the factor structure was best described as having either
two, three, or four factors. Thus, solutions with two, three,
and four factors were attempted and subjected to oblique
(Oblimin) rotation. The results clearly indicated that a
2-factor solution was the most interpretable. This solution
accounted for 46.4% of the cumulative variance, with factor
one accounting for 36.39% and factor two, 10.16%.
Theoretical analysis of the items indicated that factor
one combined items that pertained to factors I and III in
the original scale (“Fear” and “Heart-focused attention”)
and were designated in the Brazilian version as “Fear and
Hypervigilance”, comprising nine items. Factor two related
to “Avoidance” and was formed by five items, maintaining
the same structure of the “Avoidance” subscale of the original
instrument. In this solution, items 6, 8, 11 and 18 were deleted
for improving internal consistency. After deleting these items,
the scale was renumbered accordingly. Cronbach's alpha
coefficients for the subscales were, respectively, 0.88 and
0.82. Item-total correlations were assessed for all items
of the CAQ, with all correlations coefficients being higher
than 0.3019. Correlations and rotated factor loadings for the
2-factor solution are presented in Table 1.
In the convergent validity study, a higher direct
significant correlation was found between the “Fear
and Hypervigilance” subscale and the BSQ total score
(p < 0.01), as expected, but a weak non-significant
correlation was achieved with the “Avoidance” subscale.
As normality tests indicated a non-parametric distribution,
Spearman correlations were calculated. Divergent validity
assessment results showed moderate or higher direct
significant correlations between factor 1 and all SPIN
subscales (p < 0.01) and moderate direct and significant
556
Arq Bras Cardiol. 2013; 101(6):554-561
correlations between factor 2 and SPIN subscales
(p < 0.01), except for SPIN factor 2, “fear and avoidance of
interaction with strangers, of public speaking, and of being
the center of attention”. Mean scores, standard deviations
and Spearman correlations between CAQ subscales and the
other measurements are presented in Table 2.
In the discriminative validity phase, the “cardiac with panic”
subgroup consisted of thirty-seven patients (20 men = 54%;
Mean age = 69.5; SD = 11.5 years) that referred panic
disorder or past history of panic attacks, with and without
agoraphobia. From these patients, 6 (16%) met criteria
for current panic disorder, 13 (35%) presented with a past
history of panic attacks and 24 (65%) reported present
agoraphobia, according to the DSM-IV criteria. In this group,
54% (n = 20) patients reported a previous history of acute
myocardial infarction (AMI). In comparison, the “cardiac
without panic” subgroup comprised sixty-one patients
(41 men; 67%), with a mean age of 65.4 years (SD = 9.79).
In this group, 27 patients (43%) reported a history of previous
AMI. Minor differences between these subgroups were not
significant for sex distribution (p = 0.68), history of AMI
(p = 0.74) and mean age (p = 0.18).
As expected, cardiac anxiety was higher in the “cardiac
with panic” subgroup. “Cardiac with panic” patients scored
significantly higher in CAQ factor 1 (t = -3.42; p < 0.01,
CI = -1.02 to -0.27), and higher, but not significantly
different, in factor 2 (t = -1.98; p = 0.51, CI = -0.87 to
0.00). In factor 1, Fear and Hypervigilance, “cardiac with
panic” patients obtained a mean score of 2.98 (SD = 0.91)
whereas those in “cardiac without panic” subgroup
yielded a mean score of 2.34 (SD = 0.91). In factor 2,
Avoidance, patients presented, respectively, mean scores
of 2.81 (SD =1.08) and 2.37 (SD =1.05).
Discussion
The present paper comprised three complementary phases
of psychometric studies that composed the validation process
of the Brazilian version of the CAQ, formerly published in its
translated and transculturally adapted version16. The major
contribution of the current study is to provide a definite Brazilian
validated version of the instrument, composed by 14 items,
to be used in clinical and research settings (see attachment
1), herein called Questionário de Ansiedade Cardíaca (QAC).
Based on the results of these studies, it appears that
the QAC adequately measures cardiac anxiety using two
subscales: fear and hypervigilance of cardiac-related stimuli
and avoidance of activities that could bring on symptoms.
Differently from the original version of the Cardiac Anxiety
Questionnaire 8 , the Brazilian version of CAQ (QAC)
presented a two factor structure in this sample of cardiac
patients in Brazil. Reliability analyses showed that the internal
consistency of both QAC subscale scores was high. Although
these findings provide preliminary evidence that this version
of the instrument can assess CA in Brazilian cardiac patients,
it would be important for future research to confirm the factor
structure and further examine the psychometric properties of
the QAC in more diverse, independent samples to determine
the generalizability of the observed results.
Sardinha et al.
Validation of cardiac anxiety questionnaire
Original Article
Table 1 - Means (M), standard deviations (SD), corrected item-total correlations (r), and factor loadings of final CAQ items
Items
M
SD
r
Factor 1
Factor 2
1. Presto atenção nas batidas do meu coração
2.92
1.37
0.64
0.78*
-0.55
3. Meu coração acelerado me acorda à noite
1.78
1.15
0.60
0.83*
-0.27
4. Dor ou desconforto no peito me acordam à noite
1.82
1.18
0.59
0.71*
-0.06
10. Mesmo que os exames estejam normais, eu continuo me preocupando com o meu coração
3.01
1.59
0.70
0.73*
0.12
13. Preocupa-me que os médicos não acreditem que meus sintomas sejam verdadeiros
2.12
1.53
0.50
0.52*
0.12
14. Quando tenho desconforto no peito ou meu coração está acelerado, preocupa-me que posso
ter um ataque cardíaco
3.17
1.59
0.75
0.79*
0.03
15. Quando tenho desconforto no peito ou meu coração está acelerado, tenho dificuldade de me
concentrar em qualquer outra coisa
2.16
1.21
0.65
0.68*
0.05
16. Quando tenho desconforto no peito ou meu coração está acelerado, fico com medo
2.68
1.50
0.68
0.69*
0.10
17. Quando tenho desconforto no peito ou meu coração está acelerado, gosto de ser examinado
por um médico
3.45
1.53
0.56
0.63*
0.06
2. Evito esforço físico
2.68
1.31
0.62
0.15
0.76*
5. Pego leve o máximo possível
2.87
1.43
0.56
-0.06
0.73*
7. Evito fazer exercícios ou outras atividades físicas
2.16
1.39
0.58
-0.02
0.73*
9. Evito atividades que acelerem o meu coração
2.84
1.47
0.70
0.29
0.67*
12. Evito atividades que me façam suar
2.15
1.44
0.64
0.04
0.74*
6. Verifico minha pulsação
2.50
1.43
-
0.38
0.25
8. Posso sentir meu coração no meu peito
2.81
1.50
-
-0.01
0.13
11. Sinto-me seguro estando próximo a hospitais, médicos e outros serviços de saúde
2.96
1.55
-
0.39
0.25
18. Quando tenho desconforto no peito ou meu coração está acelerado, conto para minha família
ou amigos
3.04
1.55
-
0.09
0.30
Factor 1: Fear and Hypervigilance (n = 9)
Factor 2: Avoidance (n = 5)
Deleted items (n = 4)
N = 98. Salient factor loadings (>0.30) are flagged (*).
Table 2 - Means and standard deviations (SD) of convergent and divergent validity measures, and Spearman correlations between QAC,
BSQ and SPIN
Subscales
Mean
SD
QAC Factor 1: Fear and Hypervigilance
2.17
QAC Factor 2: Avoidance
Cardiac Anxiety Questionnaire (QAC)
Factor 1: Fear and Hypervigilance
Factor 2: Avoidance
0.85
-
-
1.82
0.81
-
-
BSQ (total score)
1.84
0.85
0,58*
0,28*
SPIN Factor 1: Fear and avoidance of situations
of social evaluation and of figures of authority and
physiological symptoms
0.66
0.71
0,52*
0,24
SPIN Factor 2: Fear and avoidance of interaction
with strangers, of public speaking, and of being the
center of attention
0.96
0.84
0,45*
SPIN Factor 3: Fear and avoidance of social events
0.39
0.78
0,35*
0,12
0,20
N = 56. *Correlation is significant at the 0.05 level (2-tailed).
Arq Bras Cardiol. 2013; 101(6):554-561
557
Sardinha et al.
Validation of cardiac anxiety questionnaire
Original Article
Results from the three phases of the validation process
were presented in terms of the mean scores, considering the
Likert type scale of the instrument1-5 to facilitate comparisons
with other psychometric studies conducted with this
instrument in other populations and languages. For clinical
practice, however, we have observed that some practitioners
find it more convenient to sum up all individual item scores
thereby composing a total score for each subscale. It is
important to notice that all the results presented above would
not be any different if this scoring method had been used.
Although CA was originally conceptualized as a psychological
problem of individuals without physical disease14,25 our present
findings indicate it also may be an issue to be addressed in the
treatment of patients with heart diseases2,3,13,26,27. A greater
focus on these patients is also merited by indications that after
diagnosis is made, they frequently begin to focus intensely on
their heart functioning, are overwhelmed with fear and worry
about their heart2-4,27,28.
It is noteworthy, however, that CA is frequently not
directly associated with behaviors that actually contribute
to reducing cardiovascular risk29,30. Research data indicate
that anxiety symptoms can negatively impact adherence
to exercise programs and medical treatment and,
consequently, negatively affected clinical prognosis3,31,32.
In addition, recent studies have shown that cardiac patients
who experience emotional distress have higher rates of
mortality and morbidity than those who are less anxious
and depressed2,33,34.
The value of using the CAQ for patients with heart disease
has been demonstrated in a previous German study with
90 patients before and after undergoing coronary bypass,
valve replacement or combined surgery27. Not surprisingly,
this study found that all dimensions of CA were elevated
in patients before surgery. However, a different pattern of
findings emerged after surgery. CAQ-Fear was significantly
reduced six weeks after surgery and at six-month follow-up,
whereas CAQ‑Avoidance was stable after surgery but declined
at follow‑up. Approximately 20% of patients continued
to experience clinically elevated levels of CA at six-month
follow‑up. Thus, in contrast to global psychosocial indicators,
which were not very useful in that study, the more specific
assessment of CA may help identify individuals with elevated
levels of CA who might benefit from interventions to help them
adjust to the effects of surgery and lingering cardiac problems.
The level of internal consistency for the subscales found
indicates that simply computing the score of the factors is an
appropriate and useful tool for research and/or clinical screening
activities. Identifying persons who have particularly high levels
of CA and, therefore, may be at an increased risk for elevated
anxious responding to cardiac-related stimuli and sensations
can be a simple screening strategy for the potential need of
psychological interventions, in addition to regular treatment
of cardiological conditions35. Such quick screening could
be particularly useful in busy emergency and/or outpatient
cardiology settings, to avoid unnecessary invasive procedures
and enhance adherence to the treatment prescription5,36.
By using the subscale scores, it also may be possible to identify
which specific aspects of CA are dysfunctionally high and in
need of psychological intervention35.
558
Arq Bras Cardiol. 2013; 101(6):554-561
Data from our discriminative validity study show that
anxious cardiac patients present a significantly higher
average score when compared to cardiac patients without
anxiety. A Norwegian study using QAC in patients
with general genetic risk for arrhythmias referred to a
specialized cardio-genetics outpatient clinics found lower
mean scores of CA than the present investigation (0.6,
0.8 and 1.0, in the three subscales of the original QAC)13.
These relatively low CA scores are consistent with the
hypothesis previously formulated by Sardinha et al that
CA is more strongly associated with presence of psychiatric
comorbidity rather than severity of cardiovascular illness12.
This is also supported by White et al37, who reported a full
mediation of CA in patients with pain non-cardiac chest and
found that those with a DSM-IV Axis I anxiety or mood
disorder were more body vigilant compared to patients
who did not have a disorder. We could expect, however,
that even patients without psychiatric comorbidities, who
already have a cardiac diagnosis, particularly those who
had experienced an acute cardiovascular event, might
present higher scores of CA compared to those with a
general genetic risk, as was demonstrated by Marker et al11.
These authors investigated CA in 658 individuals referred
for electron beam tomographic screening and found that
the group without coronary atherosclerosis had significantly
higher mean CA scores suggesting that people without a
diagnosed cardiac condition pay more attention to and
worry more about their cardiac related symptoms than those
people who have coronary atherosclerosis11.
In this sense, it is likely that a person with high scores
in the QAC could benefit from a more deep psychiatric
investigation to prevent and treat behaviors that could
negatively impair functioning, treatment and prognosis31.
Psychological interventions based on the cognitive behavioral
model of CA used in the QAC should be designed to help
these patients with or without cardiovascular disease to break
the cycle of cardiac-focused anxiety, increased attention
and worry, reassurance-seeking, symptom presentation and
renewed anxiety9,25,31. Following referral, the QAC also may
be useful for identifying the most pertinent treatment targets
and to measure the effectiveness of interventions targeting
specific aspects of cardiac anxiety.
Data from our convergent validity studies show a strong direct
significant correlation between the “Fear and Hypervigilance”
subscale and the BSQ, but a weak and non-significant
correlation with the “Avoidance” subscale. This finding is
actually to be expected because the BSQ assess fear of bodily
events, including cardiorespiratory distress, but it does not
assess avoidance and attention to such stimuli and sensations38.
In this sense, as proposed by the authors of the original scale,
the QAC can be considered a distinct and perhaps more
comprehensive index of CA8. The QAC thus, represent an
important contribution to the assessment of health-focused
anxiety in conditions in which CA is particularly relevant, such
as cardiology settings.
Our data did not provide support to the divergent validity
of the QAC in this population. We can hypothesize that
the shared variation found can be due the fact that patients
who seek much help and reassurance because of their CA
Sardinha et al.
Validation of cardiac anxiety questionnaire
Original Article
also may fear and worry about public display of autonomic
anxiety manifestations, like tachycardia or trembling ,
as occurs in socially anxious patients. Despite that, the
correlations found between QAC subscale scores and the
results obtained by participants in SPIN subscales indicate
that QAC was unable to adequately distinguish between CA
and social anxiety in this sample. To address that limitation,
we propose the use of other validated psychometric
instruments and, if it is the case, a structured interview such
as the MINI18, to inform differential diagnosis.
Along with that, it would be important to replicate this
validation process using samples from other populations,
such as physically healthy participants and patients with
anxiety disorders, particularly panic disorder, agoraphobia
and generalized anxiety disorder. Our study focused in
validating the QAC in cardiac patients because the main aim
of this effort was to provide a simple tool to help cardiologists
and the general practitioners screen cardiac patients for
cardiac anxiety in order to adequately address psychological
aspects that could impact treatment adherence and prognosis
and inform further psychotherapy referral. In this sense, it
was mandatory to evaluate the psychometric properties
of the instrument in the target population. A greater focus
on patients with CAD also is merited by indications that
after patients have been diagnosed with heart disease, they
frequently begin to focus intensely on their heart functioning,
are overwhelmed with fear and worry about their heart,
become overly dependent on medical and familial resources,
and erroneously avoid activities that may actually strengthen
their myocardium8. It is important, thus, to test whether the
factor structure described herein is confirmed in studies
with different populations before using data obtained with
the proposed version of the QAC with non-cardiac patients.
Fischer et al14 tested and validated a German version of
the Cardiac Anxiety Questionnaire in the general population,
providing normative data for that version14 and confirming
the original three-factor structure subscales: fear (α = 0.86),
attention (α = 0.83), and avoidance (α = 0.81). The same
structure was yield with the Greek version validations
studies, but only after deleting eight items, resulting in a
10-item instrument (fear α = 0.83, heart‑focused anxiety
α = 0.64, and avoidance α = 0.74)15. The Brazilian Version
of the QAC best fit a two-factor solution, merging the fear
and attention subscales, and maintaining the avoidance
subscale, ending up with 14 items. Despite that, the items
that composed the original subscales were confirmed in
the Brazilian version. The present version of the QAC
also reached high Crombach´s Alpha values (fear and
hypervigilance α = 0.88 and avoidance α = 0.82), similar
to the original scale and the other psychometric studies
with this instrument available in the literature.
Another relevant contribution for further studies would
be to generate Brazilian valid normative data and establish
cut‑off points that could better subside clinical decision
making, including referral of the patients with high QAC
scores for additional psychosocial assessment and support.
Future research could also add to the psychometric
evaluation of the QAC by studying its test-retest properties,
which is needed to establish the reliability of the scale over
time. Last, the stability of the instrument's factor structure
should be examined in a larger sample using confirmatory
factor analysis.
Conclusion
Our data provide a validated Brazilian version of
the QAC to evaluate CA in patients with cardiovascular
diseases in both clinical and research settings. We hope
this can be a valuable contribution to help cardiologists
and general practitioners adequately identify dysfunctional
manifestations of anxiety that can negatively impact
treatment and inform decision‑making on how to address
this issue in clinical practice. As any other psychometric
instrument, the QAC warrants further studies to verify the
stability of its properties in other contexts.
Acknowledgements
Authors would like to thank Clinimex – Clínica de
Medicina do Exercício and Instituto de Cardiologia Aloysio
de Castro for allowing data collection. This research
received financial support from CNPq, Instituto Nacional
de Ciência e Tecnologia – Translational Medicine (INCT-TM,
CNPq), CAPES and FAPERJ.
Author contributions
Conception and design of the research: Sardinha A, Nardi
AE, Ferreira MC, Eifert GH; Acquisition of data and Writing
of the manuscript: Sardinha A, Araujo CGS; Analysis and
interpretation of the data: Sardinha A, Araujo CGS, Ferreira MC;
Statistical analysis: Sardinha A, Ferreira MC; Obtaining funding:
Nardi AE; Critical revision of the manuscript for intellectual
content: Nardi AE, Araujo CGS, Ferreira MC, Eifert GH.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
This study was funded by CNPq, CAPES, FAPERJ and
Instituto Nacional de Ciência e Tecnologia.
Study Association
This article is part of PhD dissertation submitted by Aline
Sardinha to the Psychiatry Institute of the Federal University
of Rio de Janeiro.
Arq Bras Cardiol. 2013; 101(6):554-561
559
Sardinha et al.
Validation of cardiac anxiety questionnaire
Original Article
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Arq Bras Cardiol. 2013; 101(6):554-561
Sardinha et al.
Validation of cardiac anxiety questionnaire
Original Article
Appendix 1:
Questionário de Ansiedade Cardíaca (Versão Validada - Sardinha et al., 2013)
Por favor, avalie cada item marcando a resposta que melhor corresponde ao que acontece com você:
Nunca
Raramente
Às vezes
Frequentemente
Sempre
1. Presto atenção nas batidas do meu coração
2. Evito esforço físico
3. Meu coração acelerado me acorda à noite
4. Dor ou desconforto no peito me acordam à noite
5. Pego leve o máximo possível
6. Evito fazer exercícios ou outras atividades físicas
7. Evito atividades que acelerem o meu coração
8. Mesmo que os exames estejam normais, eu continuo me preocupando com
o meu coração
9. Evito atividades que me façam suar
10. Preocupa-me que os médicos não acreditem que meus sintomas sejam
verdadeiros
11. Quando tenho desconforto no peito ou meu coração está acelerado,
preocupa-me que posso ter um ataque cardíaco
12. Quando tenho desconforto no peito ou meu coração está acelerado, tenho
dificuldade de me concentrar em qualquer outra coisa
13. Quando tenho desconforto no peito ou meu coração está acelerado, fico
com medo
14. Quando tenho desconforto no peito ou meu coração está acelerado, gosto
de ser examinado por um médico
Arq Bras Cardiol. 2013; 101(6):554-561
561
Back to the Cover
Review Article
Coronary Computed Tomography Angiography in the Assessment of
Acute Chest Pain in the Emergency Room
Carlos Eduardo Elias dos Prazeres1, Roberto Caldeira Cury1, Adriano Camargo de Castro Carneiro1, Carlos Eduardo Rochitte1,2
Hospital do Coração - HCor, Associação do Sanatório Sírio1; Instituto do Coração - InCor - HCFMUSP2, São Paulo, SP – Brazil
Abstract
The coronary computed tomography angiography has
recently emerged as an accurate diagnostic tool in the
evaluation of coronary artery disease, providing diagnostic
and prognostic data that correlate directly with the data
provided by invasive coronary angiography. The association
of recent technological developments has allowed improved
temporal resolution and better spatial coverage of the
cardiac volume with significant reduction in radiation dose,
and with the crucial need for more effective protocols of risk
stratification of patients with chest pain in the emergency
room, recent evaluation of the computed tomography
coronary angiography has been performed in the setting of
acute chest pain, as about two thirds of invasive coronary
angiographies show no significantly obstructive coronary
artery disease. In daily practice, without the use of more
efficient technologies, such as coronary angiography by
computed tomography, safe and efficient stratification of
patients with acute chest pain remains a challenge to the
medical team in the emergency room.
Recently, several studies, including three randomized
trials, showed favorable results with the use of this technology
in the emergency department for patients with low to
intermediate likelihood of coronary artery disease. In this
review, we show data resulting from coronary angiography
by computed tomography in risk stratification of patients
with chest pain in the emergency room, its diagnostic value,
prognosis and cost-effectiveness and a critical analysis of
recently published multicenter studies.
Introduction
This systematic review addresses the current evidence
of computed tomography angiography of coronary arteries
and the recent impact of almost simultaneous publication of
three large controlled, multicenter, randomized studies on
the use of this new technology in clinical practice. Clinical
and epidemiological importance of coronary artery disease,
The clinical and epidemiological importance of coronary
artery disease and acute coronary syndrome
In 2008, the overall rate of deaths attributed to cardiovascular
disease (CVD) was 244.8 per 100,000 inhabitants, accounting
for 811,940 deaths out of a total of 2,471,984, or one out
of every three deaths in the United States. Based on these
data, approximately 2,200 Americans die each day in the
United States of cardiac causes, or there is one death every
39 seconds. Coronary Artery Disease (CAD) is responsible for
almost 50% of these deaths (405,309), with 195,000 cases of
acute myocardial infarction, resulting in a coronary event every
25 seconds and approximately one death per minute, despite
costs with CVD of $ 297.7 billion, which represents 16% of
total health costs, higher than any other group of diseases1.
As in the United States, cardiovascular disease in
Brazil remains the leading cause of death from chronic
noncommunicable diseases, although the financial costs
are the highest among the disease groups. In spite of a
26% decrease observed in rates of death attributed to
cardiovascular causes between 1996 and 2004, Brazil has
one of the highest death rates from CVD in South America
(286 per 100,000 inhabitants), only exceeded by the rates
presented by Guyana and Suriname. Similarly, this group
of disease has the highest rates of hospital admissions.
In 2007, 12.7% of hospital admissions unrelated to pregnancy
and 27.4% of admissions of patients aged > 60 years were
due to cardiovascular diseases2.
Coronary Artery Disease; Tomography / utilization; Chest
Pain; Emergency Service, Hospital.
Given these alarming numbers, the diagnostic evaluation
of patients with acute chest pain is a major challenge in the
emergency rooms, both from the standpoint of diagnosis
and optimization and adequate targeting of resources. As the
Acute Coronary Syndrome (ACS) represents almost one fifth
of the causes of chest pain in the emergency rooms and has
a high mortality rate, the initial approach of these patients
is always done in order to confirm or exclude the diagnosis,
seeking to optimize the time to the beginning of treatment
or safely discharge them.
Mailing Address: Prof. Dr. Carlos Eduardo Rochitte •
Rua Desembargardor Eliseu Guilherme, 123, 3o. Subsolo - Ressonância e
Tomografia Cardiovascular, Paraíso, São Paulo - SP - Brazil, Postal Code 04004-030
E-mail: [email protected], [email protected]
Manuscript received June 26; 2013, revised manuscript July 01, 2013;
accepted July 10, 2013.
Current protocols, however, are not effective in
screening this group of patients with acute chest pain of low
and intermediate risk, where myocardial necrosis markers
are normal and electrocardiographic alterations are absent
or nonspecific.
Keywords
DOI: 10.5935/abc.20130208
562
coronary artery CT angiography technology and its recent
evolution, the initial single-center studies, meta-analyses,
and finally, randomized trials, a critical analysis of the latter
data and recent data on cost effectiveness and clinical
impact are reviewed.
These protocols, until recently, did not include
diagnostic tools that provided information on the presence
Prazeres et al.
Coronary CT angiography and acute chest pain
Review Article
and severity of CAD. As a result, the confirmation or
exclusion of ACS, particularly in patients with unstable
angina, required the excessive use of diagnostic tests,
resulting in an excess of hospital admissions or possibly in
delayed treatment initiation. Thus, the recent introduction
of CT coronary artery angiography started a new scenario
in the emergency department for evaluation of patients
with acute chest pain.
The technology of computed tomography coronary artery
angiography: the coronary angiotomography
With the advances in technology over the past decades,
since the introduction of electron-beam CT scanner capable
of measuring coronary artery calcification to the current
tomography equipment with Multi-Detector Computed
Tomography (MDCT), the ability to perform cardiac imaging
has added significant gain in terms of diagnostic accuracy.
Multiple studies have shown that coronary stenoses can be
noninvasively identified by computed tomography if high
quality images are reproduced.
The quality for cardiac image on CT is directly related to
the evolution of CT scanners. The increase in the rotation
velocity of the x-ray tubes to less than 500 ms, and increase in
the number of detectors from 4 to 64 or more, as well as the
decrease in the thickness of the acquired slice to submillimeter
levels have brought a significant increase in diagnostic accuracy
of coronary artery disease by CT coronary angiography3,
allowing the diagnostic visualization of cardiac structures,
and more specifically, the anatomical evaluation of the wall
and lumen of the coronary arteries with high sensitivity and
specificity, as well as disease extent.
Nevertheless, concerns about patient safety considering
radiation exposure has always guided this technology evolution
and thus, the latest generation of CT scanners provide optimal
image quality with significantly lower radiation doses than the
previous ones, reducing exposure by more than 50%.
Thus, the computed tomography of the coronary arteries
(CTCor) has become a useful diagnostic tool in the setting of
acute chest pain in the emergency room, especially in cases
of suspected acute coronary syndrome without ST-elevation,
providing high-quality and reproducibility medical information
and a new perspective on the diagnosis, prognosis and
therapeutic decision.
Controlled studies on coronary CT angiography
Accuracy of coronary CT angiography in CAD - Metaanalyses and Controlled Clinical Trials
Since the introduction of CT scanners with 64 columns
of detectors in 2003, more than 50 studies have been
published comparing the diagnostic performance of
CTCor with the reference standard, the invasive coronary
angiography (CA). These studies have shown excellent
diagnostic performance per patient, with high sensitivity (S)
and specificity (Sp), ranging from 91% to 99% and 74%
to 96%, respectively4-8. However, the method validation
occurred with the publication of three multicenter
studies 9-11 designed to assess and detail the diagnostic
performance of CTCor in different populations (Table 1).
One of these studies was the ACCURACY (Assessment by
Coronary Computed Tomographic Angiography of Individuals
Undergoing Invasive Coronary Angiography) study9, which
involved patients without known CAD with stable angina
or those alterations in functional tests. The diagnostic
performance of CTCor to detect stenosis ≥ 70% when
compared to the CA showed S = 94%, Sp = 83%, Positive
Predictive Value (PPV) = 48% and Negative Predictive Value
(NPV) = 99%, with the area under the ROC curve = 0.95,
showing a high diagnostic accuracy to confirm as well as to
exclude significant coronary stenosis.
Another multicenter study, the CORE64 (Coronary
Evaluation on 64)10, included 291 patients with and without
known CAD with Agatston calcium score < 600, resulting
in a higher prevalence of CAD, of 56% threshold of luminal
narrowing > 50%. In this study, which was the first and
only one to quantitatively measure coronary stenosis by CT
angiography, S, Sp, PPV and NPV per patient were 85%,
90%, 91% and 83%, respectively. The findings of lower
NPV and PPV were due to a higher prevalence of CAD in
this study. The method accuracy, defined as the area under
the ROC curve, was 0.91 for CAD confirmed by coronary
angiography. Additionally, CTCor was similar to CA when
predicting the need for coronary revascularization at the
30-day follow-up.
The European prospective multicenter study evaluated
360 patients without known CAD with acute chest pain
and unstable angina11. As expected, the prevalence of CAD
was high (68%), and the diagnostic performance of CTCor
showed S, Sp, PPV and NPV of 99%, 64%, 86% and 97%,
respectively. Together, the three multicenter studies showed
high sensitivity and NPV in individuals without known
CAD, identifying the CTCor capacity to detect and exclude
significant coronary stenosis.
Initial studies of coronary CT angiography in ACS single-center studies and meta-analyses
With the validation of the method, showing its high
diagnostic performance, especially its high negative
predictive value, plus the absence of a safe and effective
protocol for risk stratification in ACS without ST-elevation
in groups with low to intermediate risk, studies investigated
the inclusion of CTCor into diagnostic research in situations
of acute chest pain in emergency rooms.
Meijboom et al12 evaluated 104 patients presenting with
ACS without ST-elevation, classified as high (n = 71) and low
risk (n = 33) according to clinical and electrocardiographic
criteria and myocardial necrosis markers. Using CA as the
reference standard, the diagnostic performance of CTCor in
detecting significant coronary lesions (stenosis ≥ 50%) showed
S = 100% (88/88, 95% CI: 95 – 100), Sp = 75% (12/16,
95% CI: 47 – 92), PPV = 96% (88/92, 95% CI: 89 – 99) and
NPV = 100% (12/12, 95% CI: 70 – 100), showing the high
sensitivity of CTCor in detecting significant coronary stenosis,
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Table 1 - Diagnostic performance of 64-detector MDCT TCCor through prospective multicenter studies
CORONARY ARTERY DISEASE
n
Prevalence CAD
Stable
ACCURACY9
230
25%
x
10
CORE 64
291
56%
x
Meijboom11
360
68%
x
Unstable
Unknown CAD Known CAD
x
x
x
x
x
Sens
Specif
PPV
NPV
95%
83%
64%
99%
85%
90%
91%
83%
99%
64%
86%
97%
CAD: coronary artery disease; Sens: sensitivity; Specif: specificity; PPV: positive predictive value; NPV: negative predictive value.
as well as excluding the presence of significant CAD in this
group of patients with high pretest probability of coronary
artery disease.
no patients in the group submitted to CTCor had any
major cardiac event, whereas one patient submitted to
conventional strategy had an acute myocardial infarction.
Similarly, Hoffmann et al13, in a cohort of 103 patients
with acute chest pain in the emergency room, with normal
ECG and cardiac enzymes, also found similar results to
those above. Of the 103 patients, 14 were diagnosed with
ACS (acute myocardial infarction without ST-segment
elevation = 5 and unstable angina = 9), and CTCor
reached the diagnosis of significant stenosis in five patients
diagnosed with AMI without ST-segment elevation. Three
other patients underwent coronary angiography due to
positive provocative test for ischemia, and, similarly to
CA, CTCor showed to be accurate in excluding coronary
atherosclerosis. In the remaining patients, CTCor was able
to exclude the disease and no significant cardiac events
were observed in this subgroup during the follow-up
period. Moreover, the presence of CAD on coronary CT
angiography added information on ACS prediction using
the traditional risk factors.
Goldstein et al 17 reached the same conclusions in
another randomized study. In addition to evaluating the
diagnostic efficacy, this study evaluated the method safety
and efficiency. CTCor was able to promptly identify and
exclude coronary disease as the cause of chest pain in 75%
of cases, including 67 patients with normal coronary arteries
and 8 patients with significant coronary disease. Regarding
safety, when compared to the standard protocol (Myocardial
Perfusion Scintigraphy [MPS]), the CTCor was as safe as the
scintigraphy. Moreover, the time to diagnosis (3.4 h x 15 h)
and costs (U.S.$ 1,586 vs. U.S.$ 1,872) were significantly
lower in the group that used the CTCor (p < 0.001), also
demonstrating that the coronary CT angiography can safely,
effectively and efficiently confirm or exclude CAD as the
cause of acute chest pain in the emergency room.
In the study by Rubinshtein et al , of a total of 58 patients,
the diagnosis of ACS was confirmed in 20 patients, with
CTCor disclosing significant coronary lesions (stenosis ≥ 50%)
in 23 subjects, resulting in S = 100%, Sp = 92%, PPV = 87%
and NPV = 100%. Of the other 35 patients, 15 showed no
CAD and the remaining 20 showed nonobstructive coronary
disease. During 15-month follow-up, there was no death or
myocardial infarction among the 35 patients in whom CTCor
showed no significant stenosis. Thus, the sensitivity of CTCor
to predict major cardiovascular outcomes (death, myocardial
infarction or revascularization) during hospitalization and
15-month follow-up was 92%, Sp = 76%, PPV = 52% and
NPV = 97%.
14
In another study involving 586 patients with suspected
ACS classified as low risk by TIMI (Thrombolysis In
Myocardial Infarction) score, a CTCor was promptly
performed in 285 patients and after 9 hours, in other
283 patients. In this scenario, the CTCor was able to exclude
significant coronary disease in 476 (84%) subjects, who
were safely and quickly discharged from the emergency
room. None of these patients died or had nonfatal
myocardial infarction within 30 days of the examination15.
Researchers from Seoul National University randomized
268 patients with acute chest pain to undergo CTCor with
64-detector MDCT and reduced the need for hospitalization
in the group classified as intermediate risk for CAD, as well
as reduced hospital length of stay. At the 30-day follow‑up,
16
564
Arq Bras Cardiol. 2013; 101(6):562-569
Because many institutional protocols use the Exercise
Testing (ET) to stratify risk in patients with acute chest
pain, the prognostic value of CTCor when compared to
ET was evaluated. Of a total of 471 patients, 424 (90%)
completed the follow-up of 2.6 years. A total of 44 major
cardiac events occurred in 30 patients (4 cardiac deaths,
6 nonfatal myocardial infarctions, 23 revascularizations
and 11 episodes of unstable angina). The presence of
obstructive CAD was associated with a significantly
higher rate of events when compared to the absence of
obstructive CAD (6.8% vs. 1.2%, p < 0.001).
The results of the ET showed an annual rate of 1.6%
events when normal, 1.9% when positive (ET with ischemic
response), and 4.6% when inconclusive. A statistically
significant increase in the overall risk analysis was detected
after adding the findings of CTCor (Chi-square 13.7
versus 37.7, p < 0.001, respectively). The increase in the
resulting net reclassification index (NRI) of the patient was
also evaluated, with NRI of 54% with ET (160 patients
reclassified as more severe and 249 as less severe) and
NRI of 80% with the results of CTCor (132 reclassified as
more severe and 277 as less severe).
Thus, the findings of CTCor show to be a strong predictor
of future cardiac events, demonstrating incremental value
over the clinical and exercise test findings18.
The ROMICAT19 study showed that in a population with
low to intermediate risk for ACS with acute chest pain, 50%
had no coronary lesions at the CTCor. In this study, CTCor
Prazeres et al.
Coronary CT angiography and acute chest pain
Review Article
showed a diagnostic performance of S = 100%, Sp = 54%,
PPV = 17%, NPV = 100% for the evaluation of presence of
any coronary atherosclerotic plaque. When analyzing the
presence of obstructive CAD (≥ 50% luminal narrowing),
S was 77%, Sp = 87%, PPV = 35% and NPV = 98%. Both
the presence of CAD and of significant stenosis were able
to predict ACS at the CTCor regardless of risk factors or
TIMI score. Through these findings, given the large number
of patients with acute chest pain, the early performance of
CTCor substantially improved the therapeutic management
in this group of patients by enabling an earlier clinical
decision, more effectively targeting the treatment or safely
allowing hospital discharge and reducing unnecessary
hospitalizations.
These same investigators, after a two-year follow‑up,
published the prognostic results of the ROMICAT
study. Of the 368 patients, 333 (90.5%) completed
the follow‑up. Thirty-five events were observed in
25 (6.8%) patients (12 AMI and 23 revascularizations).
The cumulative probability of major cardiac outcomes
(MACE) increased with the degree of coronary artery
disease (no CAD = 0%, nonobstructive CAD = 4.6% and
obstructive CAD = 30.3%, p < 0.0001), as well as when
associating the degree of CAD to left ventricular segmental
dysfunction (LVSD), evidenced by MDCT (without
stenosis or LVSD = 0.9%; one finding: LVSD = 15% or
stenosis = 10.1%, both present = 62.4%, p < 0.0001).
The C statistical test to predict MACE was 0.61 according
to the TIMI score and increased to 0.84 by adding the degree
of the CAD at the CTCor and to 0.91 by adding the degree
of CAD and LVSD. From this study it can be concluded that
among patients who come to the emergency room with acute
chest pain and low to intermediate risk of ACS, the absence
of CAD at the CTCor predicts a period free of cardiac events
of two years, while the presence of coronary stenosis with
LVSD is associated with high probability of MACE in the same
period20. Similar results were found by Chow et al21, who
showed prognostic and incremental value of CAD severity,
left ventricular ejection fraction and total CAD burden as
detected by CTCor over classical clinical predictors.
A recent meta-analysis published in 2010 that included
16 studies, some of which are listed here, with a total
of 1,119 patients, showed S = 96% (95% CI, 93-98%),
Sp = 92% (95% CI, 89-93%) and ROC curve of 0.98, also
demonstrating the high value of coronary CT angiography
for the diagnosis of significant coronary stenosis in the
presence of acute chest pain. However, S and Sp are
associated only to the test and not to the practical use
to estimate disease likelihood in the individual scenario.
The likelihood ratio (LR), in turn, is the chance that a
positive test is a true positive and a negative test is a false
negative. These last tests, therefore, provide a better
understanding of the suspected disease.
A good diagnostic test, consequently, has a high LR
for a positive test and a low LR for the negative test.
The CTCor in this analysis showed a positive LR of 10.12
and negative LR of 0.09. A value greater than 10 for positive
LR provides strong evidence to confirm the diagnosis,
virtually conclusive. Similarly, a very low value for negative
LR, of 0.09, virtually ruled out the possibility that the cause
of the chest pain is due to significant coronary disease22.
Recent randomized clinical trials in ACS
Considering the results obtained by the single-center studies,
randomized multicenter trials were designed to confirm the
previous results at a better level of evidence. With the publication
of three multicenter trials: CT-STAT23, ACRIN PA24 and ROMICAT
II25, which showed results consistent with each other, the use of
coronary CT angiography in the presence of acute chest pain,
applied to the appropriate population, reached the criterion for
Class I indication with level of evidence A (Table 2).
The “Coronary Computed Tomographic Angiography for
Systematic Triage of Acute Chest Pain Patients to Treatment
(CT-STAT)” study involved 16 centers and a total of
699 patients, of which 361 underwent CTCor and 338 MPS.
With the primary goal of diagnostic efficiency (time to
diagnosis), patients in the CTCor group had a reduction of
54% in that time (2.9 h x 6.3 h, p < 0.0001) compared to
standard protocol with MPS. The costs involved and safety
were the secondary endpoints. With respect to costs, these
also were lower among patients using CT angiography,
with a reduction of 38% ($ 2,137 x $ 3,458, p < 0.0001).
The diagnostic strategies did not differ in the rate of major
cardiac events (0, 8% vs. 0.4%, p = 0.29) during the mean
follow-up of six months. Therefore, this study showed that
among patients with acute chest pain of low risk the use
CTCor resulted in earlier diagnosis, at a lower cost than the
MPS and with the same degree of safety23.
The ACRIN PA24 study involved 1,370 patients at low
to intermediate risk in five centers in the United States,
having as the primary objective the safety profile (events
after discharge). This study showed that among patients
submitted to CTCor, 640 (83%) did not have CAD, which
allowed them to be discharged directly from the emergency
room, compared to the standard protocol (49.6% vs. 22.7%,
95% CI: 21.4 to 32.2), resulting in a significant reduction
in hospital length of stay (12.3 h vs. 24.7 h, p < 0.001).
The primary safety endpoint was also demonstrated, as
no patient with negative coronary CT angiography had
myocardial infarction or cardiac death within 30 days of the
examination. Thus, the diagnostic strategy using CTCor as
the first imaging examination in the emergency department
for patients with low to intermediate risk allowed them to be
safely discharged after negative testing, increasing medical
discharge rates and decreasing hospital length of stay24.
The most recent study, ROMICAT II25, had as primary
objective to assess the length of hospital stay (from arrival
at the emergency room until discharge), as it reflects clinical
information (diagnosis and treatment) and issues of costs
and logistics of the involved centers. Among the thousand
patients enrolled, 501 were randomized to the CTCor, and
499 patients were randomized to the standard treatment
group, which consisted in following the chest pain protocols
that were specific for the routine of the involved institutions
(serial evaluation of myocardial necrosis markers,
electrocardiogram and other diagnostic tests other than
CTCor or intervention, according to medical indication).
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Table 2 - The three multicenter, randomized controlled trials that evaluated the performance of TCCor in the setting of acute chest pain in the
emergency room
CT-STAT23
ACRIN-PA
24
ROMICAT II25
Number of Centers
n (randomization)
TIMI score
Time (h)*
30-day events‡
Cost ($)§
16
699 (1:1)
0-4
2.9 vs. 6.3*. †
0.8 vs. 0.4‡
2137 vs. 3458§
5
1370 (2:1)
0-2
18 vs. 24.8*
zero
NA
985 (1:1)
Low risk/
intermediate risk
23 vs. 30.8*
0.4 vs. 1.2‡
2101 vs. 2566§
9
n: number of patients involved in the study; TIMI: thrombolysis in myocardial infarction. * p < 0.0001. †CT-STAT time refers to the time until the diagnosis; The 30-day
event rate was not statistically significant between groups; § The difference in costs was statistically significant between groups.
When compared with the patients randomized to
the group submitted to the standard protocol, patients
undergoing CTCor had a significant reduction of 7.6 h
(p < 0.001) in the length of hospital stay. Within 8.6 h
of arrival at the emergency, 50% of patients in the CTCor
group had been discharged, compared to only 10% of
the group submitted to the standard protocol. The time
to reach a diagnosis, even in the subgroup with a final
diagnosis of ACS was significantly lower in the CTCor group
than in the standard protocol group (10.4 h x 18.7 h and
10.6 h x 18.8 h, respectively). Similarly, during the 28-day
follow-up, the rate of events (secondary objective) was
infrequent. Six events occurred in the standard protocol
group, whereas in the CTCor group there were two events.
In these two events that occurred in the CTCor group, the
tomography assessment showed significant coronary lesion
(stenosis > 50%), but with a functional negative test, and
thus, clinical treatment was initially chosen.
Critical analysis of multicenter studies
The aforementioned scientific evidence provides
subsidies for the indication of CTCor use to assess patients
with acute chest pain. Figures 1 and 2 show two cases of
chest pain in the emergency room; Figure 1 shows a case
with bulky plaque and critical proximal stenosis of the
ADA, and figure 2 shows a case with myocardial bridge
and a mild mixed plaque proximal to the myocardial
bridge, which does not cause significant stenosis of the
ADA lumen. It should be observed that although clinical
symptoms, age and presentation at the emergency room are
similar, only the first patient benefited from catheterization
procedure. However, patient selection is the key to good
diagnostic performance and therapeutic success of chest
pain evaluation protocols. In the three multicenter studies,
of the patients included, about 50% were females with
a mean age of 50 years, which significantly reduces the
pre‑test probability in this studied population.
Another important question to be asked is whether in
fact there is a need to perform additional diagnostic tests
before hospital discharge in low-risk patients. The rationale
for performing any examination is whether, when compared
to a control group, this examination will result in outcome
improvement. In the multicenter studies shown here there
was no evidence that the performance of the CTCor reduced
the incidence of infarctions or deaths. In fact, the rate of
566
Arq Bras Cardiol. 2013; 101(6):562-569
major cardiac events among all patients involved in the
studies was very low, making it impossible to know whether
the CTCor brought any benefit.
Regarding costs, in the CT-STAT study, the investigation
protocol in which the CT angiography showed stenosis
between 25% and 70%, the patients were also submitted
to the MPS. Therefore, further tests were generated and the
costs increased in the CTCor group, as lesions between 25%
and 49% are not considered significant, as shown by the
results of the 37 patients from the CTCor group submitted
to MPS, of which 30 (81%) had normal functional test.
In the ROMICAT II study, it is emphasized that even
before a more efficient screening, this gain was not achieved
under the risk of misdiagnosis. In that study, there were no
cases reported in either group, indicating that the higher
number of early discharges from the emergency department
with the use of coronary CT angiography did not result in
misdiagnosis, demonstrating the method safety. In the same
study, however, the results showed that patients undergoing
CTCor generated the use of more diagnostic resources,
findings also described by Shreibati et al26, but not observed
in the CT-STAT study23. However, when considering the final
costs, the mean costs of the index visit and at the end of
the 28-day follow-up were similar in the CTCor group and
standard protocol group (p = 0.65).
Therefore, protocols that use of coronary CT angiography
as the initial imaging test in the management of patients with
acute chest pain and possible ACS, reduce the length of
hospital stay, attain an earlier diagnosis, increase efficiency
in medical decision-making in the emergency room, without
generating an increase in the total costs and without the risk
of discharging patients with ACS (probability less than 1% in
the three multicenter trials).
Coronary CT angiography and cost effectiveness
Despite all the advantages demonstrated, for a method
to be incorporated into the diagnostic routine, it must be
cost-effective, in addition to showing accurate diagnostic
performance.
In a recent multicenter study aimed to total health
care costs and the related CAD in 8,235 low-risk patients
undergoing CTCor and MPS, the costs at the end of one year
were 25.9% lower in subjects undergoing CTCor compared
with those who underwent MPS, with an average of $ 1,075
per patient27. This difference was mainly due to a lesser
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Coronary CT angiography and acute chest pain
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Figure 1 - 65-year-old male patient that came to the emergency room with atypical chest pain, nonspecific ECG and normal myocardial necrosis markers (enzymes).
Figure 2 - 61-year-old male patient presenting to the emergency department with atypical chest pain, nonspecific ECG and normal myocardial necrosis
markers (enzymes).
need for invasive examination and revascularization among
patients undergoing coronary CT angiography.
These findings can be extended to a similar study with
9,690 intermediate-risk individuals also submitted to CTCor
or MPS28. In a nine-month follow-up, the costs related to
CAD were one-third lower for patients undergoing CTCor,
with an average of $ 467 per patient. The cost related to
medication and the need for revascularization was similar
between the groups and the difference was due to the need
for additional diagnostic tests among patients undergoing
MPS, especially CA.
In 2011, Miller et al. added CTCor to the standard
protocol in the risk stratification of patients with acute chest
pain in the emergency room and randomized resource
utilization with the standard protocol. A total of 60 patients
were enrolled in this study. The total amount of resources
used in CTCor group in up to 90 days of follow-up was
$ 10,134 vs. $ 16,579 in the standard group. By using
this additional resource, in addition to reduction in total
costs, there were fewer hospital readmissions (6/30 vs.
16/30, p = 0.007) and greater diagnostic power of CAD
(19 patients were diagnosed with CAD, of which 18 (95%)
belonged to the CTCor group)29.
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Clinical impact of new evidence
As almost about 10% of stress tests are inconclusive
leading to coronary angiography, and these are negative
in the majority of cases, the ACIC study evaluated the
correlation between stress testing (MPS, ET and stress
echocardiography) with CTCor, and compared the
diagnostic performance with CA in 47 centers. Of a total
of 6,198 patients, 1,548 (24.9%) had normal tests, 1,027
(16.6%) were inconclusive and 3,623 (58.5%) were positive.
In the multivariate analysis, the result of the stress test did
not bring incremental value over the Framingham risk score.
Overall S, Sp, PPV and NPV of the stress testing was 60.4%,
34.2%, 59.3% and 35.2%, respectively.
The diagnostic performance for stenosis ≥ 50% of the
CTCor was S = 93.7%, Sp = 37.9%, PPV = 70.6% and
NPV = 79.1%. The association between the CTCor and CA
findings was statistically significant (OR: 9.1, 95% CI: 5.57
to 14.81, p < 0.001), while results from stress testing and
coronary angiography showed no association (OR: 0.79, 95%
CI: 0.56 to 1.11, p = 0.17). Thus, the degree of stenosis in
CTCor was the strongest additional predictor of significant
coronary lesion in CA, with the results of the stress test having
no incremental value over the clinical variables30.
In a recent publication of the CONFIRM registry, the
use of CTCor showed to be a cost-effective diagnostic tool
in CAD investigation. With approximately 15,000 patients
included, of which 56.4% of patients had typical and atypical
chest pain, CA rates were very low in patients without CAD
or with mild CAD detected by CTCor, showing that in real
life doctors are accepting the results obtained by CTCor, in
this case, its high negative predictive value. Nevertheless,
these same patients showed no increase in the rates of major
cardiac events, confirming the examination safety.
Similarly, of the patients submitted to invasive angiography
after undergoing CTCor, the rate of percutaneous
revascularization was directly related to the degree of
coronary artery disease detected by CT, increasing from
2% to 28.5% for those with mild disease and obstructive
disease respectively, as well as for surgical revascularization.
Thus, this registry, which translates real-life medical practice,
clarifies that the inclusion of CTCor into routine practice
does not translate into increased resource utilization and
therefore, costs. Rather, there was a reduction in the
procedures, particularly high-cost ones, showing to be a
highly effective and safe examination in the screening of
patients for atherosclerosis investigation31.
Conclusion
In the setting of acute chest pain, the use of CT coronary
angiography in groups of low to intermediate risk has shown
to be an efficient, effective and safe method, with significant
prognostic value, reducing costs and hospitalization time and
optimizing treatment in emergency rooms.
Author contributions
Conception and design of the research and Writing of
the manuscript: dos Prazeres CEE, Cury RC, Carneiro ACC,
Rochitte CE; Acquisition of data and Statistical analysis: dos
Prazeres CEE, Rochitte CE; Analysis and interpretation of the
data: dos Prazeres CEE, Carneiro ACC, Rochitte CE; Critical
revision of the manuscript for intellectual content: Cury RC,
Carneiro ACC, Rochitte CE.
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 post-graduation
program.
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Hamon M, Morello R, Riddell JW. Coronary arteries: diagnostic performance
of 16- versus 64-section spiral CT compared with invasive coronary
angiography-meta-analysis. Radiology. 2007;245(3):720-31.
Prazeres et al.
Coronary CT angiography and acute chest pain
Review Article
9. Budoff MJ, Dowe D, Jollis JG, Gitter M, Sutherland J, Halamert E,
et al. Diagnostic performance of 64-multidetector row coronary
computed tomographic angiography for evaluation of coronary
artery stenosis in individuals without known coronary artery disease:
results from the prospective multicenter ACCURACY (Assessment
by Coronary Computed Tomographic Angiography of Individuals
Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol.
2008;52(21):1724-32.
21. Chow BJ, Wells GA, Chen L, Yam Y, Galiwango P, Abraham A, et al. Prognostic
value of 64-slice cardiac computed tomography severity of coronary artery
disease, coronary atherosclerosis, and left ventricular ejection fraction. J Am
Coll Cardiol. 2010;55(10):1017-28.
10. Miller JM, Rochitte CE, Dewey M, Arbab-Zadeh A, Niinuma H, Gottlieb I, et
al. Diagnostic performance of coronary angiography by 64-row CT. N Engl
J Med. 2008;359(22):2324-36.
22. Athappan G, Habib M, Ponniah T, Jeyaseelan L. Multi-detector computerized
tomography angiography for evaluation of acute chest pain--a meta analysis
and systematic review of literature. Int J Cardiol. 2010;141(2):132-40.
11. Meijboom WB, Meijs MF, Schuijf JD, Cramer MJ, Mollet NR, van Mieghem
CA, et al. Diagnostic accuracy of 64-slice computed tomography coronary
angiography: a prospective, multicenter, multivendor study. J Am Coll
Cardiol. 2008;52(25):2135-44.
23. Goldstein JA, Chinnaiyan KM, Abidov A, Achenbach S, Berman DS, Hayes
SW, et al. The CT-STAT (Coronary Computed Tomographic Angiography for
Systematic Triage of Acute Chest Pain Patients to Treatment) trial. J Am Coll
Cardiol. 2011;58(14):1414-22.
12. Meijboom WB, Mollet NR, Van Mieghem CA, Weustink AC, Pugliese F,
van Pelt N, et al. 64-Slice CT coronary angiography in patients with non-ST
elevation acute coronary syndrome. Heart. 2007;93(11):1386-92.
24. Litt HI, Gatsonis C, Snyder B, Singh H, Miller CD, Entrikin DW, et al. CT
angiography for safe discharge of patients with possible acute coronary
syndromes. N Engl J Med. 2012;366(15):1393-403.
13. Hoffmann U, Nagurney JT, Moselewski F, Pena A, Ferencik M, Chae CU,
et al. Coronary multidetector computed tomography in the assessment of
patients with acute chest pain. Circulation. 2006;114(21):2251-60. Erratum
in: Circulation. 2006;114(25):e651.
25. Hoffmann U, Truong QA, Schoenfeld DA, Chou ET, Woodard PK, Nagurney
JT, et al; ROMICAT-II Investigators. Coronary CT angiography versus standard
evaluation in acute chest pain. N Engl J Med. 2012;367(4):299-308.
14. Rubinshtein R, Halon DA, Gaspar T, Jaffe R, Karkabi B, Flugelman MY, et
al. Usefulness of 64-slice cardiac computed tomographic angiography for
diagnosing acute coronary syndromes and predicting clinical outcome
in emergency department patients with chest pain of uncertain origin.
Circulation. 2007;115(13):1762-8.
15. Hollander JE, Chang AM, Shofer FS, McCusker CM, Baxt WG, Litt HI.
Coronary computed tomographic angiography for rapid discharge of lowrisk patients with potential acute coronary syndromes. Ann Emerg Med.
2009;53(3):295-304.
16. Chang SA, Choi SI, Choi EK, Kim HK, Jung JW, Chun EJ, et al. Usefulness of
64-slice multidetector computed tomography as an initial diagnostic approach
in patients with acute chest pain. Am Heart J. 2008;156(2):375-83.
17. Goldstein JA, Gallagher MJ, O’Neill WW, Ross MA, O’Neil BJ, Raff GL. A
randomized controlled trial of multi-slice coronary computed tomography
for evaluation of acute chest pain. J Am Coll Cardiol. 2007;49(8):863-71.
18. Dedic A, Genders TS, Ferket BS, Galema TW, Mollet NR, Moelker A, et al.
Stable angina pectoris: head-to-head comparison of prognostic value of
cardiac CT and exercise testing. Radiology. 2011;261(2):428-36.
19. Hoffmann U, Bamberg F, Chae CU, Nichols JH, Rogers IS, Seneviratne SK, et
al. Coronary computed tomography angiography for early triage of patients
with acute chest pain: the ROMICAT (Rule Out Myocardial Infarction using
Computer Assisted Tomography) trial. J Am Coll Cardiol. 2009;53(18):1642-50.
20. Schlett CL, Banerji D, Siegel E, Bamberg F, Lehman SJ, Ferencik M, et
al. Prognostic value of CT angiography for major adverse cardiac events
in patients with acute chest pain from the emergency department:
2-year outcomes of the ROMICAT trial. JACC Cardiovasc Imaging .
2011;4(5):481-91.
26. Shreibati JB, Baker LC, Hlatky MA. Association of coronary CT angiography
or stress testing with subsequent utilization and spending among Medicare
beneficiaries. JAMA. 2011;306(19):2128-36.
27. Min JK, Kang N, Shaw LJ, Devereux RB, Robinson M, Lin F, et al. Costs and
clinical outcomes after coronary multidetector CT angiography in patients
without known coronary artery disease: comparison to myocardial perfusion
SPECT. Radiology. 2008;249(1):62-70.
28. Min JK, Shaw LJ, Berman DS, Gilmore A, Kang N. Costs and clinical outcomes
in individuals without known coronary artery disease undergoing coronary
computed tomographic angiography from an analysis of Medicare category
III transaction codes. Am J Cardiol. 2008;102(6):672-8.
29. Miller AH, Pepe PE, Peshock R, Bhore R, Yancy CC, Xuan L, et al. Is coronary
computed tomography angiography a resource sparing strategy in the risk
stratification and evaluation of acute chest pain? Results of a randomized
controlled trial. Acad Emerg Med. 2011;18(5):458-67.
30. Chinnaiyan KM, Raff GL, Goraya T, Ananthasubramaniam K, Gallagher MJ,
Abidov A, et al. Coronary computed tomography angiography after stress
testing: results from a multicenter, statewide registry, ACIC (Advanced
Cardiovascular Imaging Consortium). J Am Coll Cardiol. 2012;59(7):688-95.
31. Shaw LJ, Hausleiter J, Achenbach S, Al-Mallah M, Berman DS, Budoff MJ,
et al; CONFIRM Registry Investigators. Coronary computed tomographic
angiography as a gatekeeper to invasive diagnostic and surgical procedures:
results from the multicenter CONFIRM (Coronary CT Angiography
Evaluation for Clinical Outcomes: An International Multicenter) registry. J
Am Coll Cardiol. 2012;60(20):2103-14.
Arq Bras Cardiol. 2013; 101(6):562-569
569
Back to the Cover
Letter to the Editor
Coronary Trunk Dissection with Stent Displacement: Points to
Remember!
Marco Tulio Zanettini, Jacira Pisani Zanettini, João Otavio Zanettini
Eletrocor Laboratório de Diagnóstico Ltda, Caxias do Sul, RS – Brazil
Dear Editor,
We would like to congratulate Marchiori et al1 for the
successful conduction of a rare and serious complication
which happened during hemodynamic procedure.
Nevertheless, we consider that some considerations about
this case should be made.
The stent migration, precipitated by know predictors2, tends
to follow the antegrade coronary flow. In this case, the opposite
situation has occurred, with stent embolization to the aorta and
brachial arteries. Therefore, there are some questions to be
presented. Is there any possibility that the balloon catheter was
inadvertently pulled during post-dilation? Was there spontaneous
migration of the stent or recovery of the device through the snare
loop or inflated balloon? Why was a conventional stent used for
treating the left coronary trunk, as there is evidence advocating
the use of pharmacological devices?3
Keywords
Coronary Vessels; Dissection; Angioplasty, Balloon,
Coronary.
Mailing address: Marco Tulio Zanettini •
Rua Bento Gonçalves, Centro. Postal Code 95020-412, Caxias do Sul, Rio
Grande do Sul – Brazil
Email: [email protected], [email protected]
Manuscript received June 15, 2013, revised June 20, 2013, accepted
August 1, 2013.
DOI: 10.5935/abc.20130237
References
1. Marchiori GGA, Ximenes Meireles GC, Kreimer S, Galon MZ. Stent
dislodgement in the treatment of left main coronary artery dissection. Arq
Bras Cardiol.2013;100(6):e71-e74.
2.
570
Ahmar W, Malaiapan Y, Meredith IA. Transradial retrieval of a dislodged stent
from the left main coronary artery. J Invas Cardiol. 2008;20(10):545-7.
3. Mattos LA, Lemos Neto PA, Rassi A Jr, Marin-Neto JA, Sousa AGMR,
Devito FS, et al. Diretrizes da Sociedade Brasileira de Cardiologia sobre
intervenção coronária percutânea e métodos adjuntos diagnósticos em
cardiologia intervencionista. Arq Bras Cardiol.2008;91(6 supl.1):1-58.
Back to the Cover
Letter to the Editor
The Year 2011 in Interventional Cardiology
Pablo Avanzas1, Magda Heras2, Juan Sanchis3
Associate Editor - Revista Española de Cardiología1; Editor-in-Chief - Revista Española de Cardiología2; Associate Editor - Revista Española de
Cardiología3, Madrid, Spain
Dear Editor,
We are delighted to show Arquivos Brasileiros de
Cardiologia readers a review of the most relevant studies
on Interventional Cardiology published in Revista Española
de Cardiología in the last two years.
In relation to national protocols of emergency transfer for
primary percutaneous coronary intervention in ST elevation
myocardial infarction patients, we have published two papers
from northern Galicia and the Southern Metropolitan area
of Barcelona. Of importance, the implementation of both
programs resulted in an increase in the number of patients
receiving primary angioplasty1,2.
We have also published important studies regarding
transcatheter aortic valve implantation, a hot topic in
interventional cardiology. Lopez-Otero et al3 reported the
experience of three Spanish hospitals with the use of the
axillary approach in patients who have contraindication
to the femoral approach. They showed that the axillary
approach using the CoreValve® was safe and efficient
for selected patients, with excellent results in terms of
success implantation and in-hospital and 30-day mortality.
Lopez‑Otero et al4 also published the joint experience of four
hospitals regarding safety and effectiveness of the treatment of
degenerated aortic homograft in patients refused for surgery.
They showed that transcatheter treatment of degenerated
Keywords
Percutaneous Coronary Intervention; Angioplasty; Aortic
Valve Stenosis.
Mailing Address: Revista Española de Cardiología - P. Avanzas •
Nuestra Sra. de Guadalupe 5, 28028 Madrid, Spain
E-mail: [email protected]
Manuscript received June 17, 2013, revised manuscript June 18, 2013,
accepted June 20, 2013.
DOI: 10.5935/abc.20130238
571
aortic homografts and aortic insufficiency was safe and
effective. Hernandez‑Antolin et al5 compared the results
obtained in transfemoral implantation of an Edwards-SAPIEN
or CoreValve® aortic valve prosthesis in patients with severe
aortic stenosis and a high surgical risk. They showed that
in‑hospital mortality, the complication rate and medium‑term
outcomes were similar with the two devices. The only
difference observed was a higher implantation success rate
with the CoreValve®, although at the expense of a greater
frequency of atrioventricular block.
In the intracoronary imaging field, Jiménez-Quevedo et al6
investigated the clinical consequences and predictive factors
of the change in the type of plaque as assessed by serial
intracoronary ultrasound in type II diabetic patients with
known coronary artery disease. They showed that qualitative
changes in mild stenosis documented by intracoronary
ultrasound in type II diabetics were associated with
suboptimal secondary prevention. Also with intracoronary
ultrasound, Medina et al7 studied plaque distribution in
the coronary bifurcation and the prevalence of carina
involvement. They showed plaque at the carina in one-third
of the bifurcations. The incidence of plaque was higher in
those bifurcations, with the minimal lumen area point distal
to the carina, and was associated with a lower incidence of
damage to the side branch ostium.
Avanzas et al.
Interventional Cardiology in Rev Esp Cardiol 2011
Letter to the Editor
References
1.
2.
Gómez-Hospital JA, Dallaglio PD, Sánchez-Salado JC, Ariza A, Homs S,
Lorente V, et al. Impact on Delay Times and Characteristics of Patients
Undergoing Primary Percutaneous Coronary Intervention in the Southern
Metropolitan Area of Barcelona After Implementation of the Infarction Code
Program. Rev Esp Cardiol. 2012;65(10):911-8.
Barge-Caballero E, Vázquez-Rodríguez JM, Estévez-Loureiro R, CalviñoSantos R, Salgado Fernández-J, Aldama-López G, et al. Primary Angioplasty
in Northern Galicia: Care Changes and Results Following Implementation of
the PROGALIAM Protocol. Rev Esp Cardiol. 2012;65(4):341-9.
3. López-Otero D, Muñoz García-AJ, Avanzas P, Lozano I, Alonso-Briales
JH, Souto Castro-P, et al. Axillary Approach for Transcatheter Aortic Valve
Implantation: Optimization of the Endovascular Treatment for the Aortic
Valve Stenosis. Rev Esp Cardiol. 2011;64(2):121-6.
4. López-Otero D, Teles R, Gómez-Hospital JA, Balestrini CS, Romaguera R,
Saaibi-Solano JF, et al. Transcatheter aortic valve implantation: safety and
effectiveness of the treatment of degenerated aortic homograft. Rev Esp
Cardiol (Engl Ed). 2012;65(4):350-5.
5. Hernández-Antolín RA, García E, Sandoval S, Almería C, Cuadrado A,
Serrano J, et al. Findings of a Mixed Transfemoral Aortic Valve Implantation
Program Using Edwards and CoreValve Devices. Rev Esp Cardiol.
2011;64(1):35-42.
6. Jiménez-Quevedo P, Suzuki N, Corros C, Ferrer MC, Angiolillo DJ, Alfonso
F, et al. Assessment of Dynamic Coronary Plaque Changes and the Clinical
Consequences in Type-II Diabetic Patients: a Serial Intracoronary Ultrasound
Study. Rev Esp Cardiol. 2011;64(7):557-63.
7.
Medina A, Martín P, Suárez de Lezo J, Nóvoa J, Melián F, Hernández E, et al.
Ultrasound Study of the Prevalence of Plaque at the Carina in Lesions That
Affect the Coronary Bifurcation: Implications for Treatment With Provisional
Stent. Rev Esp Cardiol. 2011;64(1):43-50.
Arq Bras Cardiol. 2013; 101(6):571-572
572
Back to the Cover
Clinicoradiological Session
Case 6/2013 – 56 years old Woman with Ebstein Anomaly in Heart
Failure
Edmar Atik
Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, SP – Brazil
Clinical Data: Progressive fatigue on exertion has been
noted for two decades, despite operative intervention 10 years
ago for the closing of interatrial communication, valvar and
tricuspid annulus plastia, and plication of the right atrium.
Currently, it is presented with fatigue for small efforts, lower
limbs edema and in use of furosemide, hydrochlorothiazide,
amiodarone and spironolactone.
Physical exam: Slightly dyspneic, cyanotic, diminished
pulses. Clear jugular turgence at 30º. Weight: 61 kg. Height:
154 cm. Blood Pressure (BP): 100/65 mmHg. Heart Rate
(HR): 80 bpm. Oxygen Saturation = 95%. The aorta was not
palpable at suprasternal notch.
In precordium, ictus cordis was palpable diffusely and
it had discrete systolic impulses in the left sternal border.
The heart sounds were markedly hypophonetic and no cardiac
murmur was auscultated. The liver was palpable 3 cm from
the right costal margin, with discrete ascites. Lower limbs
edema was moderate.
Supplementary tests
Electrocardiogram it showed junctional rhythm and signs
of right bundle branch block with QRS complex duration
(QRS) of 0.16' and low voltage in all leads. Electrical axis of
the QRS complex (QRS): +120º, electrical axis of the T wave
(AT): +180o.
Chest Radiography showed an enlarged cardiac area in
very marked degree (cardiothoracic ratio of 0.78), with long
and globular atrial and ventricular arches. Pulmonary vascular
markings were markedly decreased.
Echocardiogram (Figure 1) showed marked increase in
right heart chambers, absent septal, anterior and posterior
valves mobility and important degree of insufficiency.
The right ventricle was so dilated that occupied the apex of the
heart. The left cavities were very depressed and compressed
by the accentuated increase in the right cavities. Inferior vena
cava with 31 mm and suprahepatic veins very dilated and
with spontaneous contrast. Left superior vena cava drained
in dilated coronary sinus. The tricuspid annulus measured
58 mm in relation to the mitral annulus of 26 mm. The area
of the right atrium was 90.1 cm² (normal value < 18 cm²)
Keywords
Heart failure; Ebstein anomaly / surgery; Cardiomegaly.
Mailing Address: Edmar Atik •
Rua Dona Adma Jafet 74, cj 73 01308-050 São Paulo, SP - Brazil
E-mail: [email protected]
DOI: 10.5935/abc.20130234
e101
and with spontaneous contrast. The right ventricle dilated so
occupied the apex of the heart, showing pronounced systolic
and diastolic dysfunction with Myocardial Performance Index
(MPI) = 0.92.
Chest computed tomography (Figure 1) stress out the same
aspect showed by the echocardiography, calculating that the
final diastolic volume of the right ventricle was of 508 mL/m2
and left ventricle was 48 mL/m2. Corresponding function of both
ventricles, right and left, was of 15 and of 68%, respectively.
Blood biochemical analysis: Hemoglobin: 11 g/dL, urea:
61 mg/dL, creatinine: 2.07 mg/dL; Brain Natriuretic Peptide
(BNP): 684 pg/mL.
Clinical Diagnosis: Ebstein Anomaly in severe heart failure,
even after operative correction, 10 years ago.
Clinical Rationale: Clinical findings were consistent with
the diagnosis of right heart failure due to Ebstein anomaly
with severe dysfunction of the right ventricle and tricuspid
valve. The absence of heart murmur expressed that the right
cavities formed a single cavity with firm adherence of the
tricuspid valve into the right ventricular muscle. The great
cardiomegaly seen on chest radiograph with decreased
pulmonary vascular markings guided to the diagnosis of this
anomaly. Other imaging tests, such as echocardiography and
cardiac CT, consolidated the severity of the anomaly by severe
dilation and right ventricular dysfunction.
Differential Diagnosis: The clinical profile of right heart
failure allied with the severe increase in the cardiac area seen
on chest radiography, could also be present in pericardial
processes, which are accompanied by severe pericardial
effusion or pericardial cysts and yet in cardiac tumors.
Conduct: Due to the strong repercussion of the Ebstein anomaly
with heart failure with functional class IV, extreme dilatation of the
right cavities with clear compression of the left cavities and with
cardiac arrhythmia, that heart transplantation was considered as
the only viable therapeutic solution. The surgical repair of Ebstein
anomaly with necessary replacement of the tricuspid valve would
not be enough to reverse the long-standing ventricular dysfunction
and under extreme operative risk.
Comments: Despite the Ebstein Anomaly being
constituted in the greater longevity among all congenital heart
diseases, rarely, however, it reaches the sixth decade of life.
The unfavorable evolutionary problems, frequently in adulthood
are related to right heart failure, to supraventricular and
ventricular arrhythmias and thromboembolic phenomena.
Therefore, most of these defects must be operated in the first
decade of life, even without strong hemodynamic disturbances,
particularly because it is today considered that cardiac surgery
is corrective and even curative, as it happens with the cone
technique introduced in our means by Da Silva1.
Atik
Anomalia de Ebstein em insuficiência cardíaca
Clinicoradiological Session
Figure 1 - Echocardiography in the apical 4-chamber view stands out the diagnostic elements of Ebstein anomaly with tricuspid septal valve coupling with strong increase
of the right cavities responsible for the extreme rebound of the left cavities (A), strong enlargement of right atrium and coronary sinus with tricuspid posterior valve still
in subcostal view (B), and the contrast of the right cavities very enlarged and compressed left cavities in cross section view of the chest CT (C). RA: right atrium; LA: left
atrium; CS: coronary sinus; RV: right ventricle; LV: left ventricle.
References
1.
da Silva JP, da Silva Lda F. Ebstein’s anomaly of the tricuspid valve: the cone repair.
Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2012;15(1):38-45.
Arq Bras Cardiol. 2013; 101(6):e101-e102
e102
Back to the Cover
Case Report
Pericardial Synovial Sarcoma: Case Report and Literature Review
Sabrina Godoy Bezerra1-3, Andrea Araújo Brandão2, Denilson Campos Albuquerque1,2, Rochelle Coppo Militão1,3,
Marcelo Souza Hadlich1,3, Clerio Francisco Azevedo1-3
Instituto D’Or de Pesquisa e Ensino (IDOR)1, Rio de Janeiro, RJ; Universidade do Estado do Rio de Janeiro2, Rio de Janeiro, RJ; Rede Labs D’Or
- Grupo Fleury3, Rio de Janeiro, RJ – Brazil
Introduction
Pericardial synovial sarcoma is an extremely rare primary
malignant tumor of the heart and has an unclear prognosis.
The purpose of this report is to describe the case of a patient
with pericardial synovial sarcoma whose initial presentation
was severe pericardial effusion and dramatic weight loss.
Despite treatment, the patient died in one year. Then, we
reviewed the medical literature for the epidemiology, clinical
picture, relevance of complementary imaging tests, therapeutic
conduct and prognosis of this neoplasm.
Case Report
Female patient, 29 years old, developed dyspnea on
mild exertion that evolved into orthopnea in four days;
associated with mild chest pain that improved with
knee‑chest position. The patient lost 11 kg in two months.
She denied smoking or alcohol consumption. The patient’s
mother had presented breast neoplasm.
On examination, she was mildly tachypneic with a respiratory
rate of 24 rpm and decreased breath sounds in the lung bases,
no adventitious sounds. The patient had tachycardia, heart rate
of 110 bpm, hypophonetic heart sounds, paradoxical pulse
characterized by a drop in blood pressure of 105 x 63 mmHg
to 80 x 58 mmHg during deep inspiration and pathological
jugular venous distention at 450.
Electrocardiogram showed signs of low ventricular voltage.
Echocardiography revealed significant pericardial effusion with
signs of diastolic restriction and oval, hyperechoic image with
a diameter of 2 cm in the pericardial sac adjacent to the Left
Atrium (LA) wall, suggesting clot.
On this occasion, the echocardiogram revealed a large
hyperechoic mass in posterior topography, extending from
the LA to the middle portion of the left ventricle (LV). Within
the mass, there were oval hypoechoic images, some of which
presented septa suggestive of central necrosis.
Magnetic Resonance imaging (MRI) of the heart was
requested, which revealed a large heterogeneous mass
within the pericardial sac, adjacent to the free wall of the LA
and the mid-basal portion of the LV lateral wall, measuring
9.3 x 8.0 x 4.3 cm in diameter and multiple septa inside
(Figure 1). The central portion of the mass was hypointense
on T1-weighted spin-echo sequence, hyperintense on
T2‑weighted spin‑echo sequence and showed no decrease in
signal intensity in the fat saturation pre-pulse sequence. The
first-pass perfusion imaging revealed good vascularization
of the mass periphery and septa, and no significant central
vasculature. On late enhancement sequence, there was
intense gadolinium uptake by the mass periphery and
septa and absence of gadolinium uptake by the central
region. The appearance suggested a large malignant tumor
of the pericardium with multiple areas of central necrosis,
apparently without invasion of adjacent structures by the
tumor.
It was decided to refer the patient to cardiac surgery in
order to achieve complete excision of the mass for diagnosis
and therapeutic purposes.
The patient underwent urgent pericardial drainage
with removal of 1000 mL of serohemorrhagic fluid, which
laboratory analysis showed the presence of exudate with
large amount of red blood cells. Gram-positive bacteria,
Acid‑Alcohol Resistant Bacilli (AARB), neither neoplastic cells
were found. Adenosine deaminase levels were normal.
During the surgery, a capsule covering the mass was
found. The capsule was opened and inside it, there was
a large friable tumor with the appearance of “fish meat”.
It had multiple septa and a large amount of necrotic material
inside. The tumor had ill-defined borders and was extremely
attached to the heart, without cleavage plane, which
prevented its complete excision (Figure 2). Therefore, only
one partial resection of the tumor was performed.
Keywords
Pathological examination showed spindle cells consistent
with the diagnosis of pericardial synovial sarcoma.
Sarcoma, Synovial / surgery; Heart Neoplasms / surgery;
Pericardial Effusion; Magnetic Resonance Imaging.
Mailing address: Clerio Francisco Azevedo •
Instituto D’Or de Pesquisa e Ensino - Rua Diniz Cordeiro 30, Botafogo.
Postal Code 22281-100, Rio de Janeiro, RJ, Brazil
E-mail: [email protected] , [email protected]
Manuscript received December 06, 2012; manuscript revised March 25,
2013; accepted March 25, 2013.
DOI: 10.5935/abc.20130235
e103
After ten days in hospital, during which the patient
was clinically stable, she was discharged for outpatient
investigation. With a medical appointment scheduled for the
following week, the patient returned only after five months,
complaining of fatigue on mild exertion.
Chemotherapy and radiotherapy were indicated, but the
patient failed to follow treatment from the start. She only
started chemotherapy nine months later. After the second
cycle, the patient developed progressive dyspnea, fever, dry
cough and significant decline in overall condition. Admitted
on an emergency, she was diagnosed with severe communityacquired pneumonia associated with severe neutropenia.
Despite the prescription of appropriate antibiotic therapy,
Bezerra et al.
Pericardial synovial sarcoma
Case Report
Figure 1 - Cardiac magnetic resonance imaging. A. Cine imaging sequence showing a large heterogeneous tumor with multiple septa inside, located within the pericardial
sac, adjacent to the LA free wall and the mid-basal portion of the LV lateral wall. B. First-pass perfusion sequence. Note the tumor periphery and septa perfusion. There is
no perfusion of the central region of the tumor (necrosis). C. Delayed enhancement sequence. Note the intense gadolinium uptake by the tumor periphery and the septa.
There is no gadolinium uptake by the central region (necrosis). RA: right atrium; RV: right ventricle; LA: left atrium; LV: left ventricle.
Arq Bras Cardiol. 2013; 101(6):e103-e106
e104
Bezerra et al.
Pericardial synovial sarcoma
Case Report
Figure 2 - Photos of the surgery. A: Capsule covering the tumor. B: The capsule (white arrow) was open and inside there is a large friable pericardial tumor (black arrow) with
the appearance of “fish meat”, imprecise borders and extremely attached to the heart. C: Tumor fragments with multiple septa and a large amount of necrotic material inside.
recombinant human granulocyte colony‑stimulating factor
and the support of intensive care, the patient developed
respiratory failure and septic shock in two days and died.
e105
Discussion
of the heart and pericardium by extracardiac tumors is
twenty times more common than primary cardiac tumors.
The neoplams that most often secondarily affect the cardiac
structures are the tumors of lung and breast, melanoma and
lymphoma, either by distant metastasis or by direct invasion1.
Primary cardiac tumors are rare, with a reported incidence of
0.05% in a study of 12,485 autopsies. Secondary involvement
Around 80% of primary cardiac tumors are benign. The
atrial myxoma is the most common one. About 20% of
Arq Bras Cardiol. 2013; 101(6):e103-e106
Bezerra et al.
Pericardial synovial sarcoma
Case Report
primary cardiac tumors are malignant. The sarcoma is the
one most frequently found, followed by mesothelioma and
linphoma2. Among the cardiac sarcomas, the pericardial
synovial sarcoma is extremely rare. It originates from
mesenchymal pluripotent cells and gets its name from the
histologic similarity to synovial tissue in formation3.
The signs and symptoms caused by the primary cardiac
sarcoma are extremely variable and nonspecific. Clinical
manifestations can be divided into four categories: systemic;
embolic; cardiac; and secondary to metastasis.
The most common systemic manifestations are fever,
chills, fatigue and weight loss, and this patient showed
significant weight loss of 11 kg in two months. Embolic
manifestations occur mainly in sarcomas invading the
cardiac cavities, causing pulmonary or systemic embolism.
Cardiac manifestations depend on the location of the tumor:
predominantly pericardial, intramural or intracavitary.
In the case of pericardial sarcoma, the most common initial
clinical picture results from massive hemorrhagic pericardial
effusion and cardiac tamponade3,4. The organs most often
affected by primary cardiac sarcoma metastases are the
lungs, brain and bones.
Imaging methods are extremely important for the diagnosis
of cardiac tumors, which are often an incidental finding in tests
performed for other reasons. In the case of pericardial tumors,
echocardiography can identify the mass and it is important for
quantifying pericardial effusion and evaluating the presence
of signs of diastolic restriction, as in the case of this patient.
MRI and computer-aided tomography help determining the
location and extent of the tumor and assessing local invasion of
adjacent organs. They are also essential for surgical planning.
MRI, by using multiple techniques, is important to characterize
the tumor tissue in a detailed manner, enabling the evaluation
of characteristics suggestive of malignancy5. Due to the rapid
growth of malignant tumors, they may present central necrotic
areas characterized for being hypointense on T1‑weighted
spin-echo sequence, hyperintense on T2-weighted spin‑echo
sequence and for not presenting gadolinium uptake in
the sequences of perfusion and delayed enhancement, as
demonstrated in the present pericardial sarcoma. Other
characteristics suggestive of malignancy, well demonstrated by
MRI, include: involvement of more than one heart chamber,
if the tumor is attached to the heart through a large base,
extracardiac extension and presence of pericardial effusion5.
The pericardial sarcoma is a highly aggressive neoplasm.
Therefore, in most cases it is not possible to perform a
complete surgical resection. In a study with 24 patients, only
22.7% of resected cardiac sarcomas had free lesion edges6.
Complete surgical resection is the main impact factor in
patient survival. Adjuvant chemotherapy and radiotherapy
are recommended when the surgery is incomplete or for
recurrent tumors7. However, despite treatment, the prognosis
of patients with cardiac sarcoma is reserved, with median
survival of only 25 months6.
This report described the case of a pericardial synovial
sarcoma, an extremely rare primary cardiac tumor which,
despite proper treatment, has an unclear prognosis.
References
1. Lam KY, Dickens P, Chan AC. Tumors of the heart:a 20-year experience
with a review of 12,485 consecutive autopsies. Arch Pathol Lab
Med.1993;117(10):1027-31.
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2. Burke AP, VirmaniR. Tumors of the heart and the great vessels. In:
Atlas of tumor pathology. Washington, DC:Armed Forces Institute of
Pathology;1996.p. 127-70.
6. Kim CH, Dancer JY, Coffey D, Zhai QJ, Reardon M, Ayala AG, et al.
3. Moorjani N, Peebles C, Gallagher P, Tsang G. Pericardial synovial sarcoma.
J Card Surg.2009;24(3):349-51.
4.
de Zwaan C, Bekkers SC, van Garsse LA, Jansen RL, van Suylen RJ. Primary
monophasic mediastinal, cardiac and pericardial synovial sarcoma: a young
man in distress. Neth Heart J. 2007;15(6):226-8.
Luna A, Ribes R, Caro P, Vida J, Erasmus JJ. Evaluation of cardiac tumors with
magnetic resonance imaging. Eur Radiol.2005;15(7):1446-55.
Clinicopathologic study of 24 patients with primary cardiac sarcomas: a
10-year single institution experience. Hum Pathol.2008;39(6):933-8.
7. Zhang PJ, Brooks JS, Goldblum JR, Yoder B, Seethala R, Pawel B, et al.
Primary cardiac sarcomas: a clinicopathologic analysis of a series with
follow-up information in 17 patients and emphasis on long-term survival.
Hum Pathol.2008;39(9):1385-95.
Arq Bras Cardiol. 2013; 101(6):e103-e106
e106
Back to the Cover
Viewpoint
Cardiovascular Rehabilitation, Ballroom Dancing and Sexual Dysfunction
Tales de Carvalho, Ana Inês Gonzáles, Sabrina Weiss Sties, Gabriela Maria Dutra de Carvalho
Universidade do Estado de Santa Catarina (UDESC), Florianópolis, SC - Brazil
Sexual dysfunction is an important public health
concern, highly prevalent among men and women1,2. It is
related to the major cardiovascular and metabolic diseases
eligible for cardiopulmonary and metabolic rehabilitation
(CPMR), such as systemic arterial hypertension, coronary
arterial disease, heart failure, and diabetes mellitus 3,4.
Of the vascular, structural and functional abnormalities
related to sexual dysfunction, the following stand out:
endothelial changes; systolic pressure elevation; and
atherosclerosis5.
Sexual function is a good parameter to assess the
treatment of cardiovascular diseases, known to improve
the quality of life of patients6, most of whom show interest
in maintaining an active sexual life. Nevertheless, the
manifestations of sexuality are usually underestimated by
physicians and other health care professionals, in part due to
cultural aspects, taboos and prejudice7. That should change,
because, after a cardiovascular event or intervention, the
instructions about sexual activity are as relevant as those
concerning return to work and engagement into exercise
programs8. The complexity of that relationship and the need
for instructions have become evident in studies, such as
the COPE-ICD, which reported, contrary to the expected,
expressive sexual function worsening in patients of both
sexes who underwent defibrillator implantation8.
H i s t o r i c a l l y, t h e m e d i c a m e n t o u s t r e a t m e n t o f
cardiovascular diseases has been associated with worse
sexual performance 5,9,10. However, the new generation
medications, such as modern beta-blockers (nebivolol and
bisoprolol), diuretics (indapamide) and angiotensin‑receptor
blockers, seem to contribute to improve erectile dysfunction,
especially by improving endothelial function and increasing
cardiac fitness10,11, enabling the simultaneous treatment of
sexual dysfunction.
Sexual function is mediated by a complex interaction of
psychological and physiological factors (hormonal, vascular,
muscular and neurological), which might all be influenced
Keywords
Cardiovascular diseases; Rehabilitation; Exercise; Dance
therapy; Sexual dysfunction physiological.
Mailing Address: Tales de Carvalho •
Avenida Jornalista Rubens de Arruda Ramos, 2.354, apto. 201, Centro.
Postal Code 88015-702, Florianópolis, SC – Brazil
E-mail: [email protected]
Manuscript received February 25, 2013; revised manuscript May 27, 2013;
accepted June 24, 2013.
DOI: 10.5935/abc.20130236
e107
by exercise3, emphasis given to the greater production and
lower degradation of nitric oxide, considered the major
mediator of male and female sexual function12. It is worth
noting that research related to exercise and sexual function
has shown that high doses of physical activity reduce the
risk of acute myocardial infarction and sudden death during
sexual intercourse13. In addition, among young men, those
with better cardiorespiratory fitness are less susceptible
to erectile dysfunction14. Thus, it is evident that physical
exercise should be included among the interventions that
benefit cardiovascular and sexual health11.
The effects of exercise on physical fitness, endothelial
function, autonomic modulation and emotional aspects
(anxiety, depression, self-esteem) evidence the broad
spectrum of action of exercise, resulting beneficial for the
treatment of cardiovascular and metabolic diseases, as well
as for the management of sexual dysfunction.
However, the conventional forms of physical exercise
offered in CPMR programs seem little attractive to provide the
necessary adherence to treatment, justifying the search for new
strategies3,15-19. In that context, ballroom dancing, a popular,
ludic, pleasurable and socializing activity, should be considered,
because it might contribute to increase adherence to exercise
practice and optimize its benefits. The manifestation of sexuality
can be potentiated by the combination of music and physical
activity, in a situation that naturally propitiates high levels of
well-being hormones, such as endorphins6,15.
Since 2007, in our CPMR programs in the city of
Florianópolis, Santa Catarina state, ballroom dancing has
been a mean of physical conditioning, with the adoption
of various rhythms (forró, bolero, samba, merengue,
waltz, rock and roll, and salsa). Rather than teaching the
technique, which would require frequent interruptions,
we have been aiming at maintaining patients active as long
as possible to sustain their target heart rate zone during
exercise training. By doing so, we have achieved higher
adherence, with a better chronotropic response and arterial
blood pressure control, factors widely associated with sexual
dysfunction and even cardiovascular outcomes20,21.
The advantage of dancing as compared to conventional
exercise methods incorporated to CPMR is mainly due
to its characteristic of bringing people closer together,
both physically and emotionally. In that context, ballroom
dancing can be seen as a strategy to concomitantly treat
cardiovascular diseases and sexual dysfunction.
Author contributions
Conception and design of the research and Critical
revision of the manuscript for intellectual content: Gonzáles
Carvalho et al.
Dancing and cardiovascular rehabilitation
Viewpoint
AI, Carvalho GMD, Sties SW, Carvalho T; Writing of the
manuscript: Sties SW, Carvalho T.
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
Ana Inês Gonzáles from Universidade do Estado de Santa
Catarina (UDESC).
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erectile dysfunction between 1995 and 2025 and some possible policy
consequences. BJU Int. 1999;84(1):50-6.
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program on the chronotropic response of participants in a cardiopulmonary
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Arq Bras Cardiol. 2013; 101(6):e107-e108
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