Is it possible that a cardiac rehabilitation program can reduce the cardiovascular risk in individuals with metabolic syndrome?

Background: Metabolic syndrome is a complex disorder represented by a set of cardiovascular risk factors usually related to central fat deposition, insulin resistance, hypertension, and dyslipidemia. It is associated with accelerated atherosclerosis in response to chronic inflammation and vascular endothelial dysfunction, increasing overall mortality. Objective: We aimed to evaluate the effect of a cardiac rehabilitation program on cardiovascular risk factors in patients with metabolic syndrome. Methods: This is prospective interventional study. All patients underwent a 20-session cardiac rehabilitation program with aerobic and resisted exercises as well as an educational program for lifestyle changes. Results: Forty-seven patients participated in the present study. After the cardiac rehabilitation program (CRP), a significant reduction (p = 0,0092) for cardiovascular risk and fatigue (p > 0.001) was observed; 78% of the patients had positive effects on physical capacity, 72% of the patients presented HbA1c reduction, 51% increased HDL-cholesterol, 70% reduced total cholesterol, 63% reduced triglycerides, 61% reduced systolic blood pressure and 53% reduced diastolic blood pressure. Conclusion: Cardiac rehabilitation program with aerobic and resisted exercises associated with educational program for lifestyle changes is an effective approach in the treatment of patients with metabolic syndrome mainly seen by a reduced cardiovascular risk factors and reducing fatigue, improved physical capacity and reduced components of metabolic syndrome.


Introduction
Metabolic Syndrome (MS) is a complex disorder represented by a set of cardiovascular risk factors usually related to central fat deposition, insulin resistance, hypertension, and dyslipidemia. It is associated with cardiovascular disease increasing overall and cardiovascular mortality up to two and threefold, respectively. Studies have shown that the prevalence of MS is high and varies with age [1]. Its prevalence accounts for up to 21.8% and 23.7% of subjects with unadjusted and adjusted age matched peers, respectively [2]. Prevalence increases from 6.7% among subjects aged 20-29 years to 43.5% and 42.0% for subjects aged 60-69 and at over 70 years, respectively [3].
Health-related lifestyle can be a very effective strategy that is being used mainly in the prevention of chronic degenerative diseases [4]. Some studies have already shown positive associations between health-related lifestyle and components of MS improvement: systemic arterial blood, hypertriglyceridemia, high blood glucose and HDL-c reductions. In addition, cardiac rehabilitation programs are considered adequate strategies for overall survival; it includes physical training, eating habits reeducation, smoke cessation and stress management [5].
Adopting a healthy lifestyle associated to a cardiopulmonary rehabilitation program may be an effective low-cost alternative treatment to reduce cardiovascular diseases risks, fatigue and loss of functional capacity associated to MS [6][7][8][9][10]. The aim of this study was to evaluate the effectiveness of a cardiac rehabilitation program and a therapeutic healthy lifestyle approach on the cardiovascular risk factors, fatigue and functional capacity of MS in adult volunteers.

Methods
This is a prospective study. The Research Ethics Committee of UNASP approved this research under the number 2.170.175, in agreement with Resolution No. 466/2012 of the National Health Council and Declaration of Helsinki (WMA, 2013) [11].
The sample of this study consisted of 47 patients with MS invited to participate in our facility Cardiac Rehabilitation Program (CRP). Both genders participated in the study who presented minimally 3 of the 5 criteria for MS; also subject aged between 40 and 60 years old. Patients with MS receiving chemotherapy, with hemodynamic instability and uncontrolled arrhythmias were excluded.
To evaluate cardiovascular risk, the Framingham Questionnaire was used; to assess individual's lifestyle we used the Individual Lifestyle Profile (PEVI) [12] questionnaire, and to evaluate global fatigue, the Chalder's Fatigue Scale [13]. Every questionnaire was performed pre and post rehabilitation.
For cardiovascular risk assessment, all patients underwent measurements of total and fractioned cholesterol, triglycerides, fasting blood glucose, blood pressure, weight, body mass index (BMI) and abdominal circumference. Also, patients performed an incremental lower limb test (BRUCE treadmill protocol) [14] and a six-minute walk test. All patients accomplished a comprehensive cardiac rehabilitation program.
Framingham cardiovascular risk has a score of 0 to 25 points, and the higher the score, the higher the cardiovascular risk.
The global fatigue was assessed using the Chalder scale, which has six questions. All individuals should have answered the first two questions, and only individuals who responded positively to the first two questions should have answered the last four questions. The last four questions were ought to quantify the individual's overall fatigue, and the higher the score, the greater the fatigue.
To assess total, fractionated cholesterol (HDL-C, LDL-C) triglycerides, fasting glucose and Hb1Ac all participants underwent venous blood collection. Total cholesterol below 200 mg/dl was considered normal. Reference values for LDL cholesterol were < 130 mg/dl, for HDL in men was > 40 mg/dl and in women was > 50 mg/dl. Triglycerides were normal when the value found was below 150 mg / dl on an empty stomach. For glycosylated hemoglobin (Hb1Ac) a normal value was considered between 4.0 and 5.6% Body composition BMI was classified according to criteria proposed by the World Health Organization (BMI < 18.5 kg/m² was considered as low weight, BMI between 18.5 and 24.9 kg/m² as eutrophic; BMI betwwen 25 and 29.9kg/m² as overweight; BMI between 30 and 34.9 kg/m² as grade I obesity; BMI between 35 and 39.9kg/m² as grade II obesity and BMI > 40 kg/m² as grade III obesity. For the elderly population aged 60 or over in this study, the classification recommended by the WHO was adopted in which BMI up to 18.49 kg/m2 is classified as low weight, between 18.5 to 24.99 k /m 2 as eutrophic, between 25 and 29.9 kg/m 2 as overweight and > 30kg/m 2 as obesity. MS was defined using the International Diabetes Federation (IDF) diagnosis criteria. It include five components: waist circumference, blood pressure, high-density lipoprotein (HDL) cholesterol, triglycerides and fasting glucose. 3 abnormal results assume the MS diagnosis.

Cardiac rehabilitation program
Patients with metabolic syndrome performed a comprehensive rehabilitation program with 20 sessions, each lasting 60 minutes, 4 times per week. All patients were assessed by our team doctors and then referred to rehabilitation. Each session had 30 minutes of aerobic training for lower limbs on a treadmill. This training started with 3 minutes of warm-up, with 2.6 km/h of speed, twenty-two minutes at a fixed speed and treadmill inclination ranging from 60 to 80% intensity of the maximum value reached during the Bruce protocol; finally, the last five minutes had 2.7km/h speed decreased for cool down purposes.
Upper limbs and lower limbs strengthening exercises comprised of 15 minutes each; 2 sets of 10 reps for each exercise (with dumbbells and ankle weights ranging from 1 to 3 kg, theraband and Swiss ball). Specific loads were given for each individual and an interval of 60 seconds between each exercise was provided.
The participants were encouraged to practice health-promoting practices, through classes three times per week by our physiotherapists, athletic trainers, and nutritionists. Adoption of a diet rich in fruits and vegetables was oriented to meet metabolic targets [15] (mostly 3 to 5 times a day of fruit intake -the diet provided was comprehensive and, generally, oriented to all). No individual diet consult was provided; we oriented physical activity practice for at least 30 minutes three times a week, breathing fresh air and frequent water intake, smoking cessation and avoidance of alcoholic beverages and soft drinks, 7-8 h/day of sleeping period, adequate exposure to sunlight [16].

Statistical analysis
The Shapiro-Wilk normality test was used to evaluate the distribution of data in relation to normality. The data are presented in mean and standard deviation, the paired test was used to compare the differences between the anthropometric variables and the functional capacity before and after intervention within groups. Proportions were analyzed using the chi square test. Univariate logistic regression analysis was used to identify which baseline variables were significantly associated with being a non-responder treatment patient. Due to the small number of non-responder patients, a multivariate logistic regression model was performed including the four baseline variables that showed the strongest association for being a non-responder in the univariate analyses. p < 0.05 was considered as statistically significant.

Results
The sample consisted of 47 patients with metabolic syndrome; out of these, 70.2% were female (n = 33). Sample's age ranged from 53 to 69 years. BMI was classified according to criteria proposed by the World Health Organization [17]. 29.5% patients with grade I obesity, 27.7% with grade II obesity and 23.4% with grade III obesity. Initially, only 8% of patients had their blood arterial hypertension controlled, 55% of patients had total cholesterol over 200 mg/dl, 64.2% had low HDL, 31.9% had high LDL and 76.5% had high triglycerides.
None of the women presented belly obesity; on the other hand, 28% of men presented abdominal circumference < 102 cm. After the cardiac rehabilitation program there was an increase in patients' proportion who had controlled blood pressure and total cholesterol lower than 200 mg/dl (table I).   Figure 1 compares the Framingham scores before and after the cardiac rehabilitation program. At the end of the program, the cardiovascular risk reduction was statistically significant in our patients with metabolic syndrome (p = 0.0092, Figure  1). Among the entire cohort of 47 subjects, we identified 29 individuals considered as "non-responders" (Non-responders were defined as subjects that continued to have diagnostic criteria for metabolic syndrome after cardiac rehabilitation). Table  III describes the baseline univariate predictors for being a non-responder. BMI, waist circumference, fasting glucose, total cholesterol, hypertriglyceridemia, were all significant predictors of being a non-responder to treatment; also lower HDL-cholesterol levels and exercise tolerance (Bruce protocol and six-minute walking distance) were significant variables either (table III). We created a multivariate logistic regression model containing the four baseline variables most closely associated with being a non-responder patient considering the univariate analyses (Table IV). High waist circumference, BMI and fasting glucose, low physical capacity in the six-minute walk test were variables that remained significant predictors of maintaining the diagnosis of MS (table IV).

Discussion
The objective of this study was to evaluate the effect of a cardiac rehabilitation program on cardiovascular risk factors of patients with metabolic syndrome. Among the main results of this study, we can highlight that, after the cardiac rehabilitation program, there was reduction for cardiovascular risk (Framingham score). 78% of our patients had a positive effect on physical ability, 72% had hemoglobin glycosylated reduction, 51% increased HDL cholesterol, 70% reduced total cholesterol, 63% reduced triglycerides, 61% reduced SBP, 53% reduced DBP and 5% reduced overall fatigue.
Pontes et al. [18], while evaluating the effects of physical exercises in metabolic syndrome patients, also noticed significant reductions in cardiovascular risk assessed by the Framingham Score. Other authors showed that physical inactivity is one of the leading modifiable risk factors for global mortality in these patients -an estimated 20% to 30% increased risk of death compared with those who are physically active [19]. Physically active people of all age groups have higher levels of cardiorespiratory fitness, health, wellness and a lower risk for developing several chronic medical illnesses, including cardiovascular disease -compared with those who are physically inactive [20,21]. Another study [22], also obtained significant values for reduction of cardiovascular risk with exercise and life style changes in a sample of obese, hypertensive and dyslipidemic women.
The positive effects to reduced cardiovascular risk caused by the aerobic training are associated with the speed and load imposed on the treadmill. Pontes et al. [18] confirm that disease burden imposes a positive impact on the cardiorespiratory performance. In this study, training speed was based on maximal heart rate and a load of 60 to 80% of maximum HR was applied. When performing exercise in this modality, some effects are known such as the increase of the shear stress mediated by the flow in the arteries walls that improves endothelial function. This mechanism increases the synthesis and release of nitric oxide that leads to endothelium vasodilation and inhibits multiple processes involving atherogenesis and thrombosis [23].
One of the ways to reduce cardiovascular risk is to reduce blood pressure. The mechanism for blood pressure reduction is already well described both at short and long term; the short term it is due to the release of pro-vasodilation factors by the vascular endothelium after moderate to high intensity load exercise. In the long term, it occurs by vascular neo-formation in the muscles during anaerobiosis [24]. Reductions of only 2 mmHg in diastolic blood pressure can substantially reduce the risk of diseases and deaths associated with hypertension [25].
Aerobic training may reduce the risk of death from cardiac events due to reduced ventricular tachyarrhythmias by reducing sympathetic activity and increasing parasympathetic (vagal) activity, as evidenced by increased heart rate variability and increased baroreceptor sensitivity [23].
When assessing fatigue by Chalder's scale, patients in our study reported a significant decrease in fatigue after CRP. Fatigue symptoms may be due in part to the inability of the muscle to use oxygen reducing heart overload [26][27][28]. Physical exercise is able to reverse this situation through adaptations of skeletal muscle, such as improvement of mitochondrial capacity, decrease of insulin resistance [3] and reduction of systemic oxidative stress and improvement in well-being [29].
A systematic review with a meta-analysis [30] that evaluated cardiovascular risk factors during exercise testing in metabolic syndrome patients observed significant mean reductions in waist circumference, blood pressure, HDL cholesterol, glucose and triglycerides.
Aerobic and resistive physical exercises have positive effects on insulin sensitivity [27]. One study showed that exercises have effects on insulin sensitivity between 12 and 48 hours after exercise, but these changes returned to pre-activity levels 3 to 5 days after the last exercise session. Exercise improves the dyslipidemic profile by increasing the ability of muscle tissue to consume fatty acids and increases the activity of the lipoprotein lipase enzyme in the muscle, causing an improvement in dyslipidemia in individuals with MS [31].
As previously shown [32,33], therapeutic lifestyle changes and cardiac rehabilitation programs can be extremely beneficial for MS patients. Other studies have seen clinical improvement in MS patients such as ours [34,35]. For instance, Met Fit program showed significant reductions in waist circumference, body fat, systolic and diastolic blood pressures in those patients accomplishing a comprehensive 12 week sessions of 45 minutes of exercise and 45 minutes of education. The target 150 to 200 minutes weekly exercise and 5% loss in body weight were achieved by all patients [34]. Another study showed a significant improvement at 6 weeks and at 6 months period in waist circumference, body weight, diastolic blood pressure, and total cholesterol occurred in 240 patients with MS after a cardiometabolic program [35].
This study brings important clinical applications mainly related to the fact that cardiac rehabilitation program and small lifestyle changes may improve cardiovascular risk in patients with MS. The limitations of this study are related to the fact that we only measured the behavior of these variables after the cardiac rehabilitation program, not being able to measure the effects over a long period, as well as to follow other end points such as hospitalization and mortality. However, this cannot invalidate our results.

Conclusion
After evaluating the effect of the cardiac rehabilitation program on the cardiovascular risk factors, physical capacity, and metabolic changes in patients with metabolic syndrome, our study can conclude that this is an effective result in the treatment of these patients by reducing cardiovascular risk factors, fatigue, blood pressure, triglycerides, total cholesterol and LDL cholesterol and fasting glucose and improving physical ability and HDL cholesterol.