Original Research
Received: April 22, 2013
Accepted after revision: July 25, 2013
Published online: November 1, 2013
Cardiology 2014;127:38–44
DOI: 10.1159/000355157
Exercise-Induced Muscle Vasodilatation
and Treadmill Exercise Test Responses in
Individuals without Overt Heart Disease
Rafael Amorim Belo Nunes a Viviana Giampaoli b
Humberto Felício Gonçalves de Freitas a Alexandre da Costa Pereira a
Fernando Araújo a Gustavo Ferreira Correia a Maria Urbana Pinto Brandão Rondon a
Carlos Eduardo Negrão a Alfredo José Mansur a Heart Institute (InCor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, and b Centro de
Estatística Aplicada, Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, Brazil
Key Words
Muscle vasodilation · Exercise capacity · Exercise blood
pressure · Exercise heart rate
Abstract
Background: The beneficial effects of exercise on cardiovascular health may be related to the improvement in several
physiologic pathways, including peripheral vascular function. The aim of this study was to evaluate the relationship
between cardiovascular responses during the treadmill exercise test and exercise-induced muscle vasodilatation in individuals without overt heart disease. Methods: The study
included 796 asymptomatic subjects (431 females and 365
males) without overt heart disease. We evaluated the heart
rate (chronotropic reserve and heart rate recovery), blood
pressure (maximum systolic and diastolic blood pressure as
well as systolic blood pressure recovery) and exercise capacity during symptom-limited treadmill exercise testing. Exercise-induced muscle vasodilatation was studied with venous
occlusion plethysmography and estimated by forearm blood
flow and vascular conductance responses during a 3-min
handgrip maneuver. Results: Forearm blood flow increase
during the handgrip exercise was positively associated with
heart rate recovery during treadmill exercise testing (p <
© 2013 S. Karger AG, Basel
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0.001). Forearm vascular conductance increase during the
handgrip exercise was inversely associated with exercise diastolic blood pressure during exercise treadmill testing (p =
0.038). No significant association was found between exercise capacity and exercise-induced muscle vasodilation.
Conclusion: In a sample of individuals without overt heart
disease, exercise-induced muscle vasodilatation was associated with heart rate and blood pressure responses during
treadmill exercise testing, but was not associated with exercise capacity. These findings suggest that favorable hemodynamic and chronotropic responses are associated with
better vasodilator capacity, but exercise capacity does not
predict muscle vasodilatation.
© 2013 S. Karger AG, Basel
Introduction
Cardiovascular performance during aerobic exercise
and peripheral vasodilator capacity has been demonstrated to be influenced by age [1–4], gender [5–7], body mass
index, and physical fitness [8, 9]. Good performance durThis article is part of the doctoral thesis submitted by Rafael Amorim
Belo Nunes, of Pós-Graduação de Cardiologia da Faculdade de Medicina da Universidade de São Paulo.
Rafael Amorim Belo Nunes
Unidade Clínica de Ambulatório Geral, Instituto do Coração do Hospital das Clínicas da
Faculdade de Medicina da Universidade de São Paulo
Av. Dr. Enéas de Carvalho Aguiar 44, São Paulo 05403-900 (Brazil)
E-Mail rafael.nunes @ incor.usp.br
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a
laboratory work-up (blood cell count, fasting plasma glucose, cholesterol and lipoproteins, triglycerides, creatinine, thyroid test and
high-sensitivity C-reactive protein). Demographic data included
gender, age, ethnicity, body mass index, and smoking status.
Exclusion Criteria
Participants with evidence of heart disease, including a past
medical history of any heart disease, coronary heart disease, valvular heart disease, and congenital heart disease were excluded. Patients with diabetes mellitus, cerebrovascular disease, cancer,
chronic obstructive pulmonary disease, thyroid disease, or other
significant systemic diseases were also excluded. Participants who
met electrocardiographic criteria for myocardial ischemia or with
significant arrhythmias during treadmill exercise testing [48] and/
or with echocardiographic evidence of structural heart disease
were excluded.
Treadmill Exercise Test
The participants underwent a symptom-limited treadmill exercise test according to the Ellestad protocol [28]. The criteria for
interruption of the exercise were physical exhaustion or exceeding
maximum heart rate predicted for the patient’s age. Individuals
were encouraged to exercise until they experienced limiting symptoms, even if 85% of the maximum predicted heart rate was
achieved. Peak exercise capacity was estimated from exercise time
and reported as metabolic equivalents [29].
During each exercise and recovery stage, symptoms, blood
pressure and heart rate were recorded. The predicted peak heart
rate was calculated as 220 – age. The peak heart rate achieved and
the maximum systolic and diastolic blood pressure achieved were
recorded at the end of the exercise stage.
Chronotropic reserve was estimated by (peak heart rate
achieved – baseline heart rate)/(predicted peak heart rate – baseline heart rate). Peak exercise was followed by the recovery stage,
in which individuals walked for a 3-min cool-down period at
1.5 mph without an incline. Heart rate recovery was defined as
peak heart rate – heart rate at 1, 2 and 3 min of the recovery stage.
The exercise test responses included in the analysis were
chronotropic reserve, heart rate recovery, maximum systolic
blood pressure, maximum diastolic blood pressure, and exercise
capacity.
Study Sample
We studied 796 asymptomatic subjects (431 women and 365
men) from a cardiovascular prevention program at a tertiary care
university hospital. The participants were enrolled if they were 18
years or older and had not past medical history of heart disorders.
Participants underwent anamnesis, physical examination, 12lead electrocardiography, chest X-ray, echocardiography, and a
Forearm Blood Flow Measurements
Forearm blood flow was measured by venous occlusion plethysmography, as previously described [26]. The non-dominant arm
was elevated above heart level to ensure adequate venous drainage.
A mercury-filled silastic tube attached to a low pressure transducer was placed around the forearm and connected to a plethysmograph (model EC6, Hokanson®, Bellevue, Wash., USA). Sphygmomanometer cuffs were placed around the wrist and upper arm.
At 15-second intervals, the upper cuff was inflated above venous
pressure for 7–8 s. Forearm blood flow (ml · min–1 · 100 ml–1 of tissue) was determined on the basis of a minimum of 4 separate readings. Forearm vascular conductance was computed as the ratio of
forearm blood flow and mean arterial pressure. Forearm blood
flow was measured at rest and during handgrip isometric exercise.
Mean blood pressure was monitored noninvasively and intermittently from an automatic and oscillometric cuff (DX 2710, Dixtal) placed on the left ankle with the cuff width adjusted to the
ankle circumference. The heart rate was monitored continuously
Muscle Vasodilatation and Exercise
Performance
Cardiology 2014;127:38–44
DOI: 10.1159/000355157
Methods
39
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ing exercise, including favorable responses for heart rate,
blood pressure and functional capacity, has been associated with cardiovascular health [10–12]. These beneficial
effects of exercise may be associated with improved vascular function of coronary arteries and peripheral circulation. Additionally, physiologic pathways such as the autonomous nervous system and endothelium regulate cardiovascular control during exercise [10, 13, 14] and may
also contribute to muscle vasodilatation [15, 16].
Studies of heterogeneous samples ranging from 16 to
105 subjects investigated the relationship between peripheral vasodilatation, estimated by different methods
such as flow-mediated vasodilation induced by limb ischemia or nitroglycerin infusion and exercise test responses
[17–21]. These findings suggest that cardiovascular performance during aerobic exercise may be associated with
peripheral vasodilatation as an expression of endothelial
function. However, the association between exercise performance and peripheral vasodilation, induced by physiological maneuvers such as the handgrip exercise, has not
yet been addressed in a large sample.
Handgrip isometric exercise has been shown to cause
significant non-exercise muscle vasodilatation in humans
[7, 22]. This strategy was successfully used to assess muscle vasodilator dysfunction in patients with obesity [23],
hypertension [24], heart failure [25, 26], and Chagas disease [27]. Moreover, reactive hyperemia of the forearm
induced by the handgrip exercise may reflect a vasodilator stimulus with a closer relation with hemodynamic
changes during treadmill exercise testing than other commonly used vasodilator stimuli.
We hypothesized that exercise-induced forearm vasodilation may be associated with cardiovascular responses
to exercise testing. To test this hypothesis, we studied the
influence of treadmill exercise testing variables (exercise
capacity, chronotropic reserve, heart rate recovery, systolic blood pressure recovery, and maximum systolic and
diastolic blood pressure) on forearm blood flow and vascular conductance responses to handgrip exercise in men
and women without overt heart disease.
Table 1. Baseline characteristics (mean ± SD) of the study subjects
Variable
Total (n = 796)
Women (n = 431)
Men (n = 365)
Age, years
Body mass index, kg/m2
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
Hemoglobin, g/dl
Leukocyte count/mm3
Serum creatinine, mg/dl
Serum glucose, mg/dl
Total cholesterol, mg/dl
HDL cholesterol, mg/dl
LDL cholesterol, mg/dl
Triglycerides, mg/dl
C-reactive protein, mg/l
43±13.2
26.3±4.4
124.1±13.5
80.9±9.3
14.4±1.3
6,785±1,857
0.85±0.18
92.4±8.6
193.5±38
49.1±13.5
121.43±32.6
117.60±77.4
2.54±3.03
43.5±13.5
26.3±4.6
105.6±43.8
68.6±28.5
13.4±7.4
6,362±2,543
0.72±0.17
89.5±14.8
191±45.5
51±16.1
119.5±37.1
100.1±57.2
1.88±2.32
42.9±12.9
26.1±4.8
106±42.9
72.3±28.5
14.8±3.1
6,401±2,168
0.94±0.22
94.2±10
191.2±45.2
42.0±12.1
120.6±32.7
139.4±97.3
1.42±1.9
HDL = High-density lipoprotein; LDL = low-density lipoprotein.
Statistical Analysis
Continuous data were expressed as the mean ± standard deviation. Categorical and ordinal data were expressed as absolute
values and percentages. Descriptive and exploratory analyses of
forearm blood flow and forearm vascular conductance were performed in the different study conditions. Pearson correlation coefficients were computed to access the correlation among the
studied variables. Linear mixed models were developed to identify exercise testing variables (independent variables) significantly associated with forearm blood flow and vascular conductance
responses (dependent variables). Forearm blood flow and vascular conductance values underwent logarithmic transformation.
Demographic (age, gender, smoking, body mass index, baseline
diastolic and systolic blood pressure) and laboratory variables
(cholesterol and lipoproteins, serum triglycerides, fasting plasma
glucose, serum creatinine, hemoglobin, leukocyte count, and
high-sensitivity C-reactive protein) were used as covariates. p values <0.05 were considered significant. Analysis of residuals was
performed to test whether the hypotheses of the models were
properly met.
40
Cardiology 2014;127:38–44
DOI: 10.1159/000355157
Protocol
FBF
MBP
HR
Instrumentation
Rest period
Baseline
Handgrip exercise
15 min
3 min
3 min
Fig. 1. Protocol for the estimation of forearm blood flow increase
during the handgrip maneuver. FBF = Forearm blood flow; MBP =
mean blood pressure; HR = heart rate.
Ethics
The study protocol was approved by the Hospital Ethics Committee on Human Research and all participants were instructed
about the study and signed an informed consent.
Results
The characteristics of the study participants are shown
in table 1. The mean age was 43 years (age range 18–73).
Most were middle-age subjects, with normal levels of arterial blood pressure, serum lipids and glucose, despite
the tendency to be overweight (50% of the participants
had a body mass index >25), and 122 (16%) participants
were current smokers.
Variables of the treadmill exercise test and the forearm
vasodilator responses during the handgrip exercise of the
study participants are shown in tables 2 and 3. Rest and
exercise blood pressures, exercise capacity and chronoNunes et al.
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using lead II of electrocardiography. The electrocardiography signal was recorded at a frequency of 500 Hz and then analyzed in an
AT/CODAS program.
After the maximal voluntary contraction rate (mean of 3 trials)
was obtained, handgrip isometric exercise at 30% of maximal voluntary contraction was performed with the dominant arm by using a handgrip dynamometer. This maneuver has been shown to
cause substantial muscle vasodilatation in previous studies [23,
30]. Participants were instructed to breathe normally during exercise and to avoid inadvertent performance of a Valsalva maneuver.
Forearm blood flow, blood pressure, and heart rate were recorded every minute during the handgrip exercise (fig. 1).
The exercise-induced forearm vasodilation was estimated by
the absolute changes between forearm blood flow and forearm vascular conductance during the handgrip exercise (1st, 2nd and 3rd
min) and baseline values [30], respectively, designated as forearm
blood flow response and forearm vascular conductance response.
Table 2. Treadmill exercise testing responses
Variable
Total (n = 796)
Women (n = 431)
Men (n = 365)
Chronotropic reserve1, unit
Heart rate recovery2 1st min, beats/min
Heart rate recovery2 2nd min, beats/min
Heart rate recovery2 3rd min, beats/min
Baseline systolic blood pressure, mm Hg
Peak exercise systolic blood pressure, mm Hg
Baseline diastolic blood pressure, mm Hg
Peak exercise diastolic blood pressure, mm Hg
Exercise time, s
Exercise capacity (metabolic equivalents)
0.87±0.14
41.3±15.4
56.5±14.5
62.4±14.36
126.0±14.5
170.7±22.47
82.4±9.4
85.5±10.5
444.7±110.7
9.6±2
0.85±0.15
42.1±14.0
57.6±13.9
63.2±14.4
123.6±14.4
161±23.8
80.7±8.6
83.1±12.0
403±98
8.8±1.8
0.9±0.13
40.9±16.6
55.4±15.1
61.6±14.1
129.2±13.9
179.9±25.1
84.6±9.9
87.2±12.9
491±103
10.5±1.9
1
Choronotropic reserve was calculated with the following equation: (peak heart rate – baseline heart rate)/(predicted peak heart
rate – baseline heart rate).
2 Heart rate recovery = peak heart rate – heart rate at recovery phase.
Women
Forearm blood flow, ml∙min–1∙100 ml–1 of tissue
Baseline
1.77±0.51
Handgrip (1st min)
2.09±0.65
Handgrip (2nd min)
2.28±0.74
Handgrip (3rd min)
2.51±0.85
Forearm vascular conductance1, units
Baseline
1.95±0.62
Handgrip (1st min)
2.2±0.81
Handgrip (2nd min)
2.29±0.82
Handgrip (3rd min)
2.47±0.98
Men
2.02±0.62
2.52±0.92
2.79±1.13
3.01±1.19
2.07±0.67
2.07±0.67
2.49±0.99
2.59±1.09
1
Forearm vascular conductance was computed as the ratio of
forearm blood flow and mean blood pressure.
associated with forearm blood flow (p = 0.001) and forearm vascular conductance responses to exercise (p <
0.001). The baseline diastolic blood pressure was inversely associated with the forearm blood flow response to exercise (p = 0.011). Triglyceride levels were inversely associated with the forearm vascular conductance response
to exercise.
Forearm blood flow response to exercise was positively associated with heart rate recovery (p < 0.001), i.e., a
higher heart rate recovery after the treadmill exercise test
predicted a higher increase in forearm blood flow during
the handgrip exercise (table 4). Forearm vascular conductance response was inversely associated with exercise diastolic blood pressure (p = 0.038), i.e., a lower exercise diastolic blood pressure during the treadmill exercise testing predicted a higher increase in forearm vascular
conductance during the handgrip exercise (table 4). We
did not demonstrate a relationship between exercise capacity and forearm vasodilator responses to the handgrip
exercise.
tropic reserve were higher in men than in women. Heart
rate recovery was slightly higher in women than in men.
The forearm blood flow and forearm vascular conductance increased significantly during the handgrip exercise
in relation to the baseline values in men and women (p <
0.05). Baseline forearm blood flow absolute values (2.02
vs. 1.77 ml/min/100 ml of tissue) and those at the end of
the handgrip exercise (3.01 vs. 2.59 ml/min/100 ml of tissue) were higher in men than in women; however, gender
did not influence the forearm blood flow and forearm
vascular conductance responses to exercise.
The covariates significantly associated with the forearm blood flow and vascular conductance responses are
presented in table 4. The body mass index was inversely
The main finding of this study was that exercise-induced forearm vasodilation was associated with chronotropic (heart rate recovery) and hemodynamic (exercise
diastolic blood pressure) responses during treadmill exercise testing, but not with exercise capacity. To our
knowledge, this is the first study to investigate the association between exercise-induced muscle vasodilation
and exercise test responses in a large sample size. In other
Muscle Vasodilatation and Exercise
Performance
Cardiology 2014;127:38–44
DOI: 10.1159/000355157
Discussion
41
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Table 3. Forearm blood flow and forearm vascular conductance
values at baseline and during handgrip exercise according to gender
Table 4. Variables associated with logarithm of the forearm blood flow and vascular conductance responses in the multivariate analysis
Forearm blood flow response1
Heart rate recovery
Body mass index
Baseline diastolic blood pressure
Forearm vascular conductance response2
Exercise diastolic blood pressure
Body mass index
Triglycerides
Estimate
Standard error
Degrees of freedom
t value
p value
0.004
–0.013
–0.007
0.001
0.004
0.003
980
267
267
3.55
–3.36
–2.55
<0.001
0.001
0.011
–0.006
–0.017
–0.001
0.003
0.004
0.001
319
261
261
–2.08
–4.29
–2.25
0.038
<0.001
0.025
1
Forearm blood flow response was estimated by the absolute changes between forearm blood flow during handgrip exercise (1st,
2nd and 3rd min) and baseline values.
2
Forearm vascular conductance response was estimated by the absolute changes between forearm vascular conductance during
handgrip exercise (1st, 2nd and 3rd min) and baseline values.
42
Cardiology 2014;127:38–44
DOI: 10.1159/000355157
sure during exercise testing may be associated with an
attenuated vasodilation of resistance vessels. Diastolic
blood pressure is influenced by cardiac output and peripheral vascular resistance [33]. Exaggerated diastolic
blood pressure during exercise is associated with greater
risk of cardiovascular events [34]. This increase in risk has
been attributed to exacerbated vascular resistance for and
reduction in vascular compliance [35]. Higher mean
blood pressure during handgrip exercise was demonstrated to be associated with decreased flow-mediated vasodilatation after exercise, indicating that impaired local
vascular function may play a role in blood pressure stimuli in healthy individuals [36]. Inhibition of nitric oxide
synthase and adenosine blunted exercise-induced forearm vasodilation [37]. Impaired release of nitric oxide
and adenosine during exercise may be possible pathways
linked to decreased vasodilation and higher blood pressure during exercise.
Unlike previous studies, with selected populations,
that have suggested a relationship between flow-mediated vasodilation and functional capacity [4, 17, 19, 21, 38],
an association between muscle vasodilation during the
handgrip exercise and exercise capacity was not found.
Exercise capacity is influenced by complex mechanisms,
including the interaction between cardiovascular, respiratory, muscle and neurohumoral systems [39]. It is possible that in our study sample of subjects without overt
heart disease, vasodilator capacity may not be a major determinant of exercise capacity, even considering the differences in the evaluation of muscle flow between our
study sample in relation to other studies. In fact, because
maximal oxygen consumption during aerobic exercise
involves less than half of the total body musculature, the
Nunes et al.
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studies, the exercise testing was compared with flow-mediated dilation or nitroglycerin-mediated vasodilation,
which causes different stimulation of the vascular bed in
relation to exercise-induced vasodilation [19–21].
Heart rate recovery was positively associated with an
increase in forearm blood flow during the handgrip exercise. Such a relationship may be ascribed to the balance
between sympathetic and parasympathetic tonus during
exercise. Sympathetic withdrawal and parasympathetic reactivation are important determinants of the heart rate recovery after exercise testing [10, 31]. In addition, parasympathetic cholinergic mechanisms participate in muscle vasodilatation control [15], including the exercise-induced
forearm vasodilatation [32]. Data about the association
between heart rate recovery after exercise testing and muscle vasodilatation have shown divergent results. A study of
66 patients with suspected coronary artery disease found
that lower heart rate recovery values were associated with
an attenuated flow-mediated vasodilation and hypothesized that endothelial dysfunction would be related to
worse outcomes in patients with lower heart rate recovery
after exercise [18]. In contrast, a study of 25 healthy young
men showed that nitroglycerin-mediated vasodilation was
inversely correlated with heart rate recovery and no correlation was demonstrated between flow-mediated vasodilation and heart rate recovery [20]. Our findings suggest
that increased heart rate recovery after exercise testing is
associated with higher forearm blood flow during the
handgrip exercise, which may be partially mediated by the
response of autonomic function during exercise.
Exercise diastolic blood pressure and forearm vascular
conductance response were inversely related. Our observation suggests that the increase in diastolic blood pres-
maximal oxygen consumption may be more limited by
maximal cardiac output than by peripheral variables [40].
Our study has several limitations. We used upper limbs
to study the peripheral vasodilator response, while exercise treadmill testing was dependent on the performance
of lower limbs. The handgrip isometric exercise used to
induce vasodilation in the non-exercising forearm may
have some differences in relation to the vasodilation during aerobic exercise. However, evidences suggest that
handgrip exercise-induced forearm vasodilation can be
improved with aerobic exercise training [23, 41]. In a
study with 12 young subjects, the brachial artery blood
flow of the inactive upper limb increased significantly during physical activities, like cycling and walking [42]. Furthermore, evaluation of the vascular reactivity of the upper
limbs has been extensively used to evaluate vascular health
and endothelial function in previous studies [43–47]. The
cross-sectional study design limited inferences about the
causality between vasodilation measurements and exercise testing variables. However, considering that blood
pressure and heart rate responses are associated with vascular function, these findings can raise hypotheses, which
need to be tested in future studies, that individuals with
unfavorable responses to exercise testing may have clinical
benefits with interventions on vascular function such as
exercise training, treatment of dyslipidemia and others.
Variables of exercise beyond segment ST such as exercise capacity, chronotropic reserve, heart rate recovery,
and exercise blood pressure have been associated with
cardiovascular prognosis as well as with peripheral vasodilatation. However, the pathways involved with these
physiologic responses are not well defined. Our findings
suggest that hemodynamic and heart rate responses during exercise appear to be associated with muscle vasodilatation. Associations between favorable responses of
blood pressure and heart rate during exercise and muscle
vasodilatation may be a possible link between cardiovascular outcome and exercise performance. Intriguing, we
did not observe a relation between exercise capacity and
muscle vasodilatation, suggesting that in this population
apparently without established heart disease, the impact
of functional capacity on cardiovascular health may not
be strongly associated with peripheral vascular function.
Conclusion
In a sample of individuals without overt heart disease,
exercise-induced forearm vasodilation was associated
with heart rate and blood pressure responses during
treadmill exercise testing, but was not associated with exercise capacity. These findings suggest that favorable hemodynamic and chronotropic responses are associated
with better vasodilator capacity, but exercise capacity
does not predict muscle vasodilation.
Acknowledgments
We thank Davi Augusto C. de Jesus, Marcos Roberto T. Komatsu and Renata M.P. Delgado for conducting the statistical analysis.
This study was supported in part by Fundação de Amparo à
Pesquisa do Estado de São Paulo 2009/52992-1.
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