To confirm the improvement in arterial endothelial function by aerobic exercise training, flow-mediated dilation (FMD) was tested by ultrasonography.
Patients who received percutaneous coronary intervention due to acute coronary syndrome were included. The patients who participated in cardiac rehabilitation (CR) program were categorized as the CR group, and others who did not participate as the control. Both groups underwent initial graded exercise test (GXT) and FMD testing. Subsequently, the CR group performed aerobic exercise training sessions. Patients in control only received advice regarding the exercise methods. After six weeks, both groups received follow-up GXT and FMD testing.
There were 16 patients in each group. There were no significant differences in the general characteristics between the groups. The VO2peak was 28.6±4.7 mL/kg/min in the CR group and 31.5±7.4 mL/kg/min in the control at first GXT, and was 31.1±5.1 ml/kg/min in the CR group and 31.4±6.0 ml/kg/min in the control at the follow-up GXT in six weeks. There was a statistically significant improvement in VO2peak only for CR group patients. FMD value was 7.59%±1.26% in the CR group, 7.36%±1.48% in the control at first and 9.46%±1.82% in the CR group, and 8.31%±2.04% in the control after six weeks. There was a statistically significant improvement in FMD value in the CR group.
According to the results of GXT and FMD testing, six-week exercise-based CR program improved VO2peak and endothelial functions significantly. Thus, exercise-based CR program is necessary in patients with coronary artery disease.
Endothelium maintains the homeostasis of blood vessel by secreting various bioactive factors, and nitric oxide (NO) is one of the most important endothelium-derived factors [
As endothelial dysfunction of peripheral blood vessel is closely related to endothelial dysfunction of coronary artery and reflects general aspects of atherosclerosis, the evaluation of cardiovascular endothelial function and therapeutic effect is possible by non-invasive FMD in peripheral arteries [
The purpose of this study is to see if aerobic exercise can improve endothelial function as measured by FMD test, observe changes in exercise capacity through exercise test, and examine the relationship between exercise capacity improvement and endothelial function improvement.
The subjects for this study were patients younger than 70 years of age who were hospitalized at Cardiovascular Center of Inje University Sanggye Paik Hospital from April 2011 to July 2012 due to acute coronary syndrome and underwent successful percutaneous coronary intervention (PCI), and were then referred to cardiac rehabilitation (CR) clinic. Patients with previous history of cardiac diseases-such as heart failure or valvular disease, cardiovascular disease, ejection fraction of left ventricle lower than 40% on echocardiography, deterioration or paralysis due to cerebrovascular disease or musculoskeletal disease, limb defect-and suffering from pain due to musculoskeletal disease were excluded from this study. Those who were educated on the requirements of CR and the contents of the program and participated in the hospital's CR program for aerobic exercise were classified as the CR group, while those who continuously visited the hospital and whose progress was observed without participating in the hospital's CR program were classified as the control. According to the questionnaire survey, control group did not exercise more than just taking a walk, and patients who regularly exercised were excluded from the study. We retrospectively reviewed the medical records of 32 patients. The study was further reviewed and approved by the Institutional Review Board.
Prior to the exercise program, patients in the CR group visited the CR clinic to be evaluated with graded exercise test (GXT) and other preliminary tests including the FMD test. After a six-week exercise program, GXT and FMD tests were repeated. Those in the control group also visited the CR clinic for baseline GXT and other preliminary tests including the FMD test. These patients were educated on risk factor management and self-exercise, and were encouraged to reduce these risk factors and exercise on their own. GXT and FMD test were also repeated after six weeks for this group.
Numerous factors affect flow-mediated vascular reactivity, including food, drug, and sympathetic stimuli. Therefore, patients stopped taking medication, such as antihypertensive drugs and vasodilator, etc., for three days prior to the FMD test and stopped taking foods and drinks containing caffeine for 48 hours prior to the test. After a 5-minute resting period in supine posture, the right upper extremity was examined with iE33 ultrasound scanner (Philips Healthcare, Andover, MA, USA) with an 11 MHz linear transducer (
GXT was performed according to the symptom limited method of modified Bruce protocol by the recommendation of the American Association of Cardiovascular and Pulmonary Rehabilitation. During exercise, patients were observed in terms of electrocardiogram (ECG) change, heart rate, and blood pressure as objective monitoring indicators and Borg rating of perceived exertion as subjective indicators.
After obtaining the maximum heart rate and resting heart rate from GXT, heart rate reserve was calculated, and 40%-85% of the heart rate reserve was determined as the target heart rate. During exercise training, patients were observed in terms of ECG change, heart rate, and blood pressure as objective monitoring indicators while Borg rating of perceived exertion as subjective indicators. Each exercise consisted of 10-minute warm-up, 30-minute main exercise, and 10-minute cool-down exercise. The main exercise consisted of 8 minutes of treadmill, 3 minutes of rest, 8 minutes of bicycle ergometer, 3 minutes of rest, and 8 minutes of treadmill, respectively. Patients participated in such 50-minute exercise programs three times a week for six weeks (18 exercises in total). To control risk factors of coronary artery disease, all the patients were educated on diet, nutrition, and smoking cessation, and were prescribed cardiovascular medications for hypertension, diabetes, and dyslipidemia. Afterwards, risk factors of coronary artery disease were evaluated, educated, and continuously strictly controlled through the six weeks.
All statistical analyses were performed using SPSS ver. 18 (SPSS Inc., Chicago, IL, USA). Mann-Whitney U test was used for continuous variables, and Pearson chi-square test for comparing nominal variables between the CR group and the control, such as sex, age, name of diseases, smoking status, the location of stent insertion, time from PCI to FMD, medications taken, cardiovascular risk factor information, initial VO2peak, and FMD value. Changes in VO2peak and FMD between each group after the six-week exercise program were compared using Wilcoxon signed rank-sum test. To see the correlation between initial FMD and FMD change rate, bivariate correlation test was made using Spearman correlation coefficient. The p-values less than 0.05 were considered to be statistically significant.
A total of 32 patients were included in the study with 16 patients divided into each group. In the CR group, there were 15 men and 1 woman, while there were 14 men and 2 women in the control (p>0.05). The average age of the CR group was 52.9 years, while the average age of the control was 54.8 years (p>0.05). Both groups took FMD tests and GXT after an average of 25 days from PCI. The patterns of acute coronary syndrome were classified as unstable angina, ST elevation myocardial infarction, and non-ST elevation myocardial infarction. There existed no significant intergroup differences in the number and location of blood vessels where the stents were placed. There were also no baseline differences in terms of left ventricle ejection fraction, risk factors (hypertension, diabetes, dyslipidemia, smoking history, and body mass index), and medications taken between the groups (
The baseline VO2peak from the initial GXT was 28.6±4.7 mL/kg/min in the CR group and 31.5±7.4 mL/kg/min in the control. After six weeks, VO2peak was 31.1±5.1 mL/kg/min in the CR group and 31.4±6.0 mL/kg/min in the control. The baseline VO2peak values did not show statistically significant difference between the groups (p=0.19). Comparisons between baseline and after exercise VO2peak values showed statistically significant improvement in the CR group (p<0.001), while there was no such improvement in the control (p=0.71) (
The baseline FMD values were 7.59%±1.26% in the CR group and 7.36%±1.48% in the control. After six weeks, these were 9.46%±1.82% in the CR group and 8.31%±2.04% in the control. There was no statistically significant difference between the two groups (p>0.05). Comparisons between baseline and after exercise FMD value showed statistically significant improvements in the CR group (p<0.001), while there no significant improvement in the control (p=0.09) (
In this study, CR program with six-week aerobic exercise training have shown to improve exercise capacity and endothelial function in patients with coronary artery disease, compared to the control group. It is well known that regular aerobic exercise is effective for primary and secondary prevention of cardiovascular diseases [
Cornelissen et al. [
As these results show, endothelial function is improved with aerobic exercise, and its main cause is known to be the stimulation of NO secretion. Physiologically, exercise temporarily produces hyperemia in the extremities and coronary artery circulation. In this way, aerobic exercise repeatedly increases the blood flow in coronary artery and peripheral blood vessels so that the shear stress in endothelial cell increases with increased NO bioavailability. According to a recently report, after an aerobic exercise, there is a correlation between the increase in FMD and the increase in endothelial nitric oxide synthase protein expression that is necessary for NO synthesis [
According to the study reported by Luk et al. [
Even though there were no statistically meaningful changes in control group of this study, we were able to find the improving tendency of FMD after six weeks of exercise. This result has probably been influenced by the effect of statins [
This study has several limitations. First, it was not a random comparative research, as patients themselves decided whether they would participate in the CR program. Second, the sample size was small with 16 subjects in each of the groups. Third, we have seen an improvement of endothelial function and exercise capacity by performing aerobic exercise in relatively short period of six weeks. But in longer period of exercise and in larger patient group study, the correlation between VO2peak and FMD change has to be proved. Fourth, even though an experienced sonographer performed the FMD tests by manually measuring the diameter of brachial artery, there is variability in a patient and across patients due to the nature of the FMD test, which may have created bias coming from the variability of brachial diameter. Other researches have used computerized correction and wall tracking software to minimize such bias [
This study verifies that exercise-based CR program can improve exercise capacity and arterial endothelial function in patients with coronary artery disease.
In conclusion, CR program with six-week aerobic exercise training can improve exercise capacity and endothelial function in patients with coronary artery disease, compared to the control group. It can be verified by non-invasive FMD test and GXT. Thus, it is recommended that coronary heart disease patients participate in exercise-based CR program.
No potential conflict of interest relevant to this article was reported.
Flow-mediated dilation testing in the right brachial artery longitudinally 2-3 cm above the antecubital fossa, by means of iE33 ultrasound scanner (Philips) with the linear transducer 11 MHz.
Flow-mediated dilation was calculated as an increase of vascular diameter from the difference between maximum and baseline brachial artery diameter. The diameter of brachial artery was measured 45, 60, and 120 seconds after cuff release, and the maximum value of the three was used for analysis. (A) Baseline, (B) reactive hyperemia.
Demographic data of study subjects
Values are presented as means and occasionally mean±standard deviation.
CR, cardiac rehabilitation; UA, unstable angina; NSTEMI, non-ST elevation myocardial infarction; STEMI, ST elevation myocardial infarction; PCI, percutaneous coronary intervention; FMD, flow-mediated dilation; LAD, left anterior descending coronary artery; RCA, right coronary artery; LCX, left circumflex coronary artery; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker.
Baseline clinical parameters between groups
Values are presented as mean±standard deviation.
CR, cardiac rehabilitation; BMI, body mass index; HRrest, resting heart rate; SBPrest, resting systolic blood pressure; DBPrest, resting diastolic blood pressure; HRpeak, peak heart rate; SBPpeak, peak systolic blood pressure; DBPpeak, peak diastolic blood pressure; RER, respiratory exchange ratio; Exercise duration, maximal time to endure exercise test by modified Bruce protocol; LDL, low density lipid; HDL, high density lipid; TG, triglyceride; hs-CRP, high sensitivity C-reactive protein; HbA1c, hemoglobin A1c; LVEF, left ventricle ejection fraction; VO2peak, peak oxygen consumption; FMD, flow-mediated dilation.
Endothelial parameters before and after six weeks of exercise
Values are presented as means ± standard deviation.
CR, cardiac rehabilitation; VO2peak, peak oxygen consumption; FMD, flow-mediated dilation.
*Statistically significant at p<0.05 within groups.