Abstract
Background:
Hypertension is common in patients with metabolic syndrome (MS), and it is an important risk factor for cardiovascular-related morbidity and mortality. Compared to moderate-intensity continuous training (MICT), high-intensity interval training (HIIT) is considered a time-efficient exercise strategy for cardiometabolic health. We compared the effects of HIIT and MICT on epicardial fat thickness (EFT) and endothelial function in patients with hypertensive MS.
Methods:
In total, 34 participants with hypertensive MS (mean age: 50.9 ± 7.9 years) were randomized to either the HIIT (n = 17) or MICT (n = 17) group. In the HIIT group, participants performed for 3 min at 40% heart-rate reserve (HRR), which was alternated with 3 min at 80% HRR, whereas participants in the MICT group performed at 60% of HRR thrice a week for 8 weeks. EFT was measured with echocardiography, and endothelial function was determined by quantifying endothelial progenitor cells (EPCs), nitric oxide (NO), and flow-mediated dilation (FMD).
Results:
After exercise training, patients in both the groups showed significantly decreased EFT (P < 0.001 and P < 0.01) and improved FMD (P < 0.001 and P < 0.01). NO (P < 0.05) and EPCs (CD34/KDR, P < 0.01; CD34/CD117, P < 0.05; CD34/CD133, P < 0.05) were significantly improved in the HIIT group, but not in the MICT group. In addition, HIIT had a greater effect than MICT on FMD (group difference, P < 0.05) and EFT (group difference, P < 0.05).
Conclusions:
Compared to MICT, HIIT seems to better improve FMD and EFT. This finding suggests that HIIT could be more effective than MICT in improving endothelial function in patients with hypertensive MS.
Introduction
Hypertension is common in patients with metabolic syndrome (MS) and is an important risk factor for cardiovascular (CV)-related morbidity and mortality. 1 Both insulin resistance and obesity elevate blood pressure (BP) through increased oxidative stress, inflammation, salt retention, and impaired nitric oxide (NO) production, 2 which promote endothelial dysfunction and atherosclerosis. 3
Endothelial dysfunction is an early key element in the development of atherosclerosis, 4 and it is one of the best known predictors of CV disease risk. 5 Endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial function and organ perfusion via endothelial repair and neovasculogenesis. 6 With regard to cardiometabolic parameters, epicardial adipose tissue has recently emerged as a new cardiometabolic risk factor. Epicardial fat thickness (EFT) is significantly higher in patients with MS, 7 and reduction of EFT was independently associated with improvements in cardiac parameters in obese individuals. 8
Aerobic exercise training is a well-established nonpharmacological intervention for the prevention and treatment of several chronic and CV diseases. 9,10 Recent studies have shown that compared with moderate-intensity continuous training (MICT), high-intensity interval training (HIIT) may result in a superior or equal improvement in fitness and CV health. 11 –14 However, no studies have compared the effects of HIIT versus MICT on epicardial fat and endothelial dysfunction in patients with hypertensive MS. Therefore, this study aimed to determine and compare the therapeutic efficacy of continuous and interval training programs on, flow-mediated dilation (FMD), EPCs, NO, EFT, and other CV risk factors, including resting heart rate (HR), BP, and lipid profiles among patients with hypertensive MS.
Materials and Methods
Participants and study design
This single-center study included 37 patients with hypertension and MS (male = 19, female = 18, average age: 50.9 ± 7.9 years) who were taking antihypertensive medication or had systolic BP (SBP)/diastolic BP (DBP) ≥140/90 mmHg from May 2015 to April 2016. MS in South Korean adults was defined using the International Diabetes Federation criteria (Table 1). 15,16 They were sedentary and had not participated in any type of regular exercise training for at least 3 months before this study. Participants who were pregnant; current smokers; alcohol abusers; and those with uncontrolled hypertension, renal failure, established CV disease, chronic obstructive pulmonary disease, or musculoskeletal disease were excluded. The participants were then randomly assigned to the HIIT (n = 18) or MICT (n = 19) group. The characteristics of the participants at inclusion are summarized in Table 2.
Metabolic Syndrome Definition Criteria
HDL, high-density lipoprotein.
Baseline Characteristics of Participants
Data are presented as mean ± SD.
HIIT, high-intensity interval training; MICT, moderate-intensity continuous training; SD, standard deviation.
After an 8-hr overnight fast, venous blood was collected to measure NO metabolites (NOx), EPCs, glucose, and lipids; BP, resting HR, height, and weight were assessed. In premenopausal women, blood sampling was done at the follicular phase of the menstrual cycle. At 2 days after the first visit, FMD, EFT, and graded exercise treadmill test were performed. Participants were asked to refrain from intense physical activity and coffee or alcohol intake, which could affect HR for 24 hr, before all tests.
After providing a detailed explanation of the study design and protocol, written informed consent was obtained from each participant, as approved by the Institutional Review Board of Pusan University (protocol no. PNU IRB/2014_19_HR). An 80% compliance with the exercise program was set as the criterion for completing the study.
Physiological measurement and exercise test
Before and after training, BP and resting HR were measured using an automatic digital BP monitor (HEM-7080IT; Omron digital BP monitor, Tokyo, Japan). After a quiet rest for at least 5 min, three consecutive measurements were performed at 2 min intervals, with the participant in a sitting position. The average of the three readings was recorded as the representative BP value.
In this study, stress test was conducted as a screening process to evaluate the abnormal symptoms or signs related to the exercise in the participants. The participants underwent symptom-limited exercise stress testing on a programmed treadmill (GE CASE T2100; GE Medical Systems, Milwaukee, WI) according to the Bruce protocol. 17 BP was measured using an automated BP monitor (Suntech Tango; Suntech Medical, Morrisville, NC) throughout the treadmill test. HR and 12-lead electrocardiogram (ECG) were continuously monitored, and ECG, BP and HR measurements were recorded at the end of each stage during the test. Exercise testing was stopped when participants experienced volitional fatigue or when the HR exceeded 95% of the predicted maximum (220 − age).
Measurement of FMD and EFT
FMD was measured in the brachial artery according to current guidelines. 18 Measurements of FMD baseline were performed on the left arm of the participants after 10–20 min of rest in the supine position. Two-dimensional ultrasonography (Vivid 7; General Electric, Horten, Norway) was performed using a 10-MHz probe. After recording baseline images, hyperemia was induced by inflation of a pneumatic cuff to 180–200 mmHg (50 mmHg higher than SBP) for 5 min on the forearm. The peak diameter of the brachial artery was recorded after 40–60 sec after sudden deflation of the cuff. Percent FMD induced by reactive hyperemia was expressed as the relative change from baseline (%FMD = 100 × [(diameter after hyperemia − baseline diameter)/baseline diameter]). Each diameter was measured three times during two heartbeats, and the average values were used for the final analysis. Each diameter was measured at the peak of the R wave of the surface electrocardiogram. It may be ∼40–60 sec. The intra- and interobserver variabilities of FMD were 3.5% and 6.2%, respectively.
EFT was identified as an echo-free space between the outer wall of the myocardium and the visceral layer of the pericardium. Standard two-dimensional echocardiography was performed using a 3.5-MHz transducer (Philips iE33; Philips Medical Systems, Bothell, WA) according to standard techniques provided by the American Society of Echocardiography. 19 The EFT was measured at end-diastole on the free wall of the right ventricle. Measurements of EFT and FMD were performed by two independent cardiologists (B.J.K. and K.-I.C.) who did not have access to the clinical data of the participants.
Blood samples
For glucose, lipid, and NO assay, blood samples (4 mL) were drawn into an EDTA tube and immediately centrifuged at 2200 rpm for 20 min at 4°C. The serum was stored at −80°C until assayed. Glucose, triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol were analyzed by standard methods using a Dimension RXL Max automatic analyzer (Dade Behring, Newark, DE). NO level was indirectly assessed by measuring NO metabolites (NOx), nitrite (NO2 −) and nitrate (NO3−), using an assay kit (#KGE001; R&D Systems, Minneapolis, MN) and analyzed by spectrophotometry.
Measurement of circulating EPCs
Peripheral blood samples (3 mL) were drawn into heparinized tubes. Peripheral blood mononuclear cells (PBMCs) were separated by density gradient centrifugation using Ficoll (Histopaque-1077; Sigma-Aldrich, St. Louis, MO) and stored at 4°C until the cells were analyzed. For flow cytometry analysis, the PBMCs were double stained with the following antibodies: CD34-FITC (348053; BD Pharmingen, San Diego, CA) and KDR-PE (FAB357P; R&D Systems), CD34-FITC and CD117-PE (555714; BD Pharmingen), and CD34-FITC and CD133-PE (130-080-801; Miltenyi Biotec, Bergisch Gladbach, Germany). A negative control was also stained with FITC mouse IgG1 isotype control (555909; BD Pharmingen) and PE mouse IgG1 isotype control (349043; BD Pharmingen) antibodies. Thirty thousand cells per sample were analyzed using the FACS Vantage SE flow sorter (BD Biosciences, San Jose, CA). Data were analyzed using CellQuest Pro software (BD Biosciences). CD34+/KDR+, CD34+/CD117+, and CD34+/CD133+ double-positive cells were defined as circulating EPCs after gating on the lymphocyte population.
Exercise training
Participants from both HIIT and MICT groups performed an aerobic exercise program on a treadmill 3 days/week for 8 weeks under supervision of an exercise specialist. Exercise intensity was determined by the Karvonen method [Target HR = exercise intensity × (HRmax − resting HR) + resting HR]. The estimated HRmax was calculated as 220 − the age of the participant. Exercise intensity was calculated to promote the same CV workload for all patients in the HIIT and MICT groups. The HIIT consisted of a 5 min warm-up at 40% of HR reserve (HRR) and 5 min warm-up at 60% of HRR with light jogging, followed by five 3 min intervals at 80% of HRR, with a 3 min active recovery at 40% of HRR between each interval. The MICT consisted of a 5 min warm-up at 40% of HRR, followed by 35 min of continuous running at 60% of HRR. The HR was recorded during each session using an HR monitor (Polar RS400sd; Madison Heights, MI). In addition, Borg scale was measured during each exercise session. Participants were excluded if they did not perform more than 80% of the exercise sessions.
Statistics
After data collection, the measured and derived variables were statistically analyzed. The descriptive statistics (mean and standard deviation) of the physical characteristics and other parameters of the participants were determined. Paired t-test was used to compare the before and after training within groups. A two-way ANOVA (group × time) with repeated measures was used to compare the data. Bonferroni post hoc analysis was performed to evaluate the differences among groups. Data were analyzed using SPSS version 12.0 (SPSS, Inc., Chicago, IL). P values less than 0.5 were considered statistically significant.
Results
During the experimental period, three participants were unable to complete the training program: one from the HIIT group for personal reasons, one from the MICT group owing to insufficient attendance, and one from the MICT group owing to incomplete post-tests. Thus, a total of 34 participants were included in our data analyses. The baseline characteristics of the participants are presented in Table 2. Baseline of all parameters was similar between the groups before training.
Weight, body mass index, and resting HR
Despite no diet alterations during the training period, participants from the HIIT and MICT group showed a slight reduction of 1.1% and 1.7% in body weight (both P < 0.01, with no difference between HIIT and MICT) and body mass index (BMI), respectively (both P < 0.01) (Table 3). However, resting HR was significantly reduced in the HIIT group (P < 0.01), but not in the MICT group (P = 0.057; between-group difference, P < 0.05) (Table 3).
Parameters Related to Hypertensive Metabolic Syndrome Before and After Training
Data are presented as mean ± SD.
Significantly different pre- and post-training values within the groups (P < 0.05).
Significantly different pre- and post-training values within the groups (P < 0.01).
BMI, body mass index; DBP, diastolic blood pressure; HDL, high-density lipoprotein; HIIT, high-intensity interval training; HR, heart rate; LDL, low-density lipoprotein; MICT, moderate-intensity continuous training; SBP, systolic blood pressure; SD, standard deviation.
Blood pressure
SBP was reduced by both HIIT (by 9.4 mmHg, 6.6%; P < 0.05) and MICT (by 10.6 mmHg, 7.7%; P < 0.01); DBP was also reduced by both HIIT (by 7.1 mmHg, 8.2%; P < 0.01) and MICT (by 7.8 mmHg, 9.0%; P < 0.01) (Table 3). There was no difference in changes in BP between the two exercise groups.
Endothelial function (FMD, EPCs, and NOx)
No change in the diameter of the brachial artery (resting) after training was observed in either of the groups. However, participants in the HIIT and MICT groups showed improved brachial artery diameters (peak) by an average of 0.6 mm (P < 0.01) and 0.3 mm (P < 0.01), and FMD by an average of 6.1% (P < 0.001) and 2.9% (P < 0.01), respectively. In addition, there was a significant difference in increase in the brachial artery diameter (peak) and FMD (both P < 0.05; Table 4) between the groups.
Parameters Related to Endothelial Function and Epicardial Fat Thickness Before and After Training
Data are presented as mean ± SD.
Significantly different pre- and post-training values within the groups (P < 0.05).
Significantly different pre- and post-training values within the groups (P < 0.01).
Significantly different pre- and post-training values within the groups (P < 0.001).
EFT, epicardial fat thickness; FMD, flow-mediated dilation; NOx, nitrite/nitrate.
Furthermore, after the 8-week intervention, only participants in the HIIT group exhibited statistically significant increases in circulating CD34+/KDR+ (P < 0.01), CD34+/CD117+ (P < 0.05), and CD34+/CD133+ (P < 0.05) compared with baseline measurements, whereas those in the MICT group did not show changes in the circulation levels of these EPCs (Table 4). However, there were no differences in changes in circulating EPCs between the groups. We also observed increased availability of NOx level after HIIT (P < 0.05), but not after MICT (P = 0.27, with no difference between HIIT and MICT; Table 4).
Epicardial fat thickness
Changes in EFT after training are shown in Table 4. EFT decreased significantly in both the groups. Before and after training, participants in the HIIT and MICT groups showed significant decreases in EFT from 6.12 ± 2.0 to 4.92 ± 1.3 mm (P < 0.001) and from 5.59 ± 1.7 to 4.98 ± 1.4 mm (P < 0.01), respectively. However, compared to participants in the MICT group, those in the HIIT group showed a greater reduction in EFT (P < 0.05).
Discussion
The results of the present study indicate that both HIIT and MICT effectively reduce BMI, resting BP, and EFT and improve FMD. However, HIIT appears to be superior to MICT for improving EFT, FMD, and resting HR in patients with hypertensive MS.
Elevated resting HR has been associated with poor prognosis in both the general population and patients with CV disease. 20 In the Framingham study, the predictive power of HR for all-cause mortality was equal to that of smoking, 21 and in the NHANES I epidemiologic follow-up study, the risks of death from all causes, CV diseases, and non-CV diseases increased with elevated pulse rate, independent of other risk factors. 22 On the contrary, exercise training is known to be effective in reducing resting HR. Although no effect was observed on resting HR in the MICT group in this study, the superior impact of HIIT on reducing resting HR was observed. The decrease in resting HR may be explained by increased stroke volume, cardiorespiratory fitness, 23 and improved cardiac autonomic function 24 owing to the effects of CV adaptation elicited by aerobic exercise. Therefore, the superiority of HIIT for reducing resting HR has important clinical implications for improving cardiorespiratory fitness and reducing CV risk factors in this study.
It is well known that aerobic exercise decreases BP, and typical traditional MICT exerts significant reduction of BP in adults with hypertension. 25 Recently, a few studies have analyzed the effect of different exercise modes (HIIT vs. MICT) on change in BP. Only one study on rats with MS demonstrated that HIIT brings about a superior reduction of BP. 26 The effects of different exercise intensities on BP reduction remain controversial. 13,27 –30 In this study, 8-week programs of HIIT and MICT were equally effective at reducing SBP and DBP. Several factors are involved in exercise-mediated reduction in BP. Decrease in sympathetic nervous system activity, 31 improvement in baroreflex control, 32 and increase in endothelial function (NO production) 33 are probably involved in the antihypertensive effects of exercise.
Exercise-induced shear stress, that stimulates the endothelium to produce NO, contributes to endothelium-dependent vasodilation (FMD). In addition, endothelial NO synthase (eNOS) and vascular endothelial growth factor (VEGF) seem to play a key role in the increased mobilization of EPCs by exercise. Exercise training promotes higher VO2 and blood flow in skeletal muscle, leading to an increase in hypoxia and shear stress, respectively, subsequently causing elevated VEGF and eNOS production. Higher VEGF and eNOS muscle levels induced by exercise training might create a local chemokine gradient, dictating the directional responses of enhancement of EPCs to angiogenesis. 34
In this study, we analyzed CD34+/KDR+, which is a typical marker of EPCs, and CD34+/CD133+ and CD34+/CD117+, which are known as major cells for neovascularization. 35,36 Although there was no significant interaction between the two groups, NO and EPCs (CD34+/KDR+, CD34+/CD117+ and CD34+/CD133+) improved only in the HIIT group. In addition, HIIT was superior to MICT in improving FMD. The exact reason for this superiority of HIIT in improving endothelial function is not fully understood; however, the alternative low- and high-intensity exercise programs likely affect the larger changes in shear stress on the vascular wall differently during exercise training, leading to differences in molecular responses. 13,28,29 However, the 8-week aerobic exercise of this study did not change the baseline of artery diameters. Robinson et al. 37 have shown that 8 weeks of aerobic training changes the baseline diameter of overweight and obese people. Maybe there was a difference in the subject, so the change in diameter may not have occurred in this study. This may be due to the higher burden of disease or the difference in gender ratios.
Recently, epicardial fat tissue has been reported to reflect visceral fat composition and has been suggested to be a more effective cardiometabolic risk factor than general fat-accumulation disease. 38 Although physical exercise is established as the first-line treatment for MS with elevated adipose accumulation, 39 there are limited data on exercise-induced changes in EFT in patients with MS. Several studies have shown that exercise training decreased EFT in postmenopausal women with MS 40 and in obese individuals. 41 However, no changes were observed in epicardial fat reduction in patients with type 2 diabetes mellitus (DM) after 6 months of exercise training. 42
Meanwhile, some studies have investigated the effect of HIIT and MICT on change in visceral fat. Only two studies reported the greater effect of HIIT than MICT on visceral fat adiposity in overweight women 43 and postmenopausal women with type 2 DM. 44 Because of the mechanical factors associated with mitochondrial adaptation, fat and body fat loss can differ between HIIT and MICT exercise. 45 In this study, HIIT was more effective than MICT in reducing EFT, probably owing to the difference in physiological adaptation required for HIIT compared with MICT. Despite the equal energy consumption in both the exercise programs, HIIT was more effective in reducing EFT. This may be partly attributed to the greater elevation of postexercise metabolic rate and associated fat expenditure in HIIT, because the magnitude and duration of the elevated O2 expended after exercise are reported to be greater after high-intensity exercise than after moderate exercise. 46 This might explain the differences in physiological responses between the groups. In addition, differences in exercise intensity may affect hormone responses-related energy intake, which in turn may have affected body composition. 47
Study limitations
The number of patients in our study was small. Also, our indirect estimation of cardiorespiratory fitness via resting HR is a limitation of this study. However, elevated resting HR is associated with a lower level of cardiorespiratory fitness and is a well-known and widely accepted marker of cardiorespiratory fitness. In addition, shear stress was not considered in FMD measurement. This was a major limitation. We will include this aspect in our follow-up study. Finally, we failed to evenly distribute participants by sex across the two groups when we randomly assigned them to the exercise programs. In this study, HIIT was more effective than MICT in reducing EFT, but it is not clear if the different proportion of men and women do not interfered on the results. Moreover, this result may be due a numeric difference before the intervention. Future studies are warranted to investigate the mechanisms underlying endothelial function and improvements in EFT after HIIT by controlling for the effects of different medications and age.
Conclusion
We found that both the HIIT and MICT programs are effective at decreasing EFT, resting HR, and BP, and at increasing FMD. However, HIIT is more effective than MICT at decreasing resting HR and EFT and improving FMD. These results suggest the possibility that HIIT may have a greater improvement on epicardial fat and endothelial function than MICT. Furthermore, the superiority of HIIT for reducing resting HR has important clinical implications for improving cardiorespiratory fitness and reducing CV risk factors; therefore, HIIT could be recommended for patients with hypertensive MS.
Footnotes
Author Disclosure Statement
No competing financial interests exist.
Funding Information
This study was supported by Korean Society of Cardio Metabolic Syndrome and Future Leading Research Supporting Program of Kosin University College of Medicine (2016).
