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Effects of Exercise on Metabolic Markers and Biomarkers of Inflammation in Hypertensive cases: A Randomized Controlled Trial.

Byline: Sikiru Lamina, Shmaila Mustapha Hanif and Chuba Goddy Okoye

Abstract

Background: Hypertension has been hypothesized to be a part of inflammatory disorder and elevated low density lipoproteins or total cholesterol, and reduced high density lipoproteins, increase the risk of coronary events in these patients.

Objectives: To determine the effects of exercise (interval training program) on metabolic markers and biomarkers of inflammation in black African men with essential hypertension.

Subjects and Methods: A total of 245 male patients having mild to moderate essential hypertension (systolic BP between 140-179 and diastolic BP between 90-109 mmHg) were age and gender matched into experimental and control groups. The experimental group was put to exercise for 8 weeks using interval training (60-79% HR max reserve) program ranging between 45minutes to 60 minutes, while control group remained sedentary. Cardiovascular parameters (systolic blood pressure, diastolic blood pressure) and VO2max, biomarkers of inflammation (C-reactive protein, white blood cell) and metabolic makers (fasting blood sugar), total cholesterol, triglyceride, high density lipoprotein, low density lipoprotein and artherogenic index) were assessed. Analysis of co-variance (ANCOVA) and Pearson correlation tests were used in data analysis.

Results: Of 254 subjects, the experimental group had 140 cases whose ages ranged from 58.9+-7.3 years) while 114 were controls of similar age. There was significant effect of interval training program on VO2 max, systolic blood pressure, diastolic blood pressure, C-reactive protein, white blood cell, fasting blood sugar, total cholesterol, triglyceride, high density lipoprotein, low density lipoprotein and artherogenic index (p less than 0.05). Changes in VO2 max significantly correlated with all other variables (p less than 0.05).

Conclusions: Therapeutic role of interval training program in the reduction of blood pressure could be through the suppression of systemic inflammation and abnormal metabolic markers.

Key words: Hypertension, biomarkers of inflammation, metabolic markers, lipid profile, artherogenic, exercise.

Introduction

Research into the etiology of hypertension has yielded an important array of lifestyle, dietary, psychosocial factors and biochemical markers of inflammation1. It has been hypothesized and confirmed that hypertension may be a part of chronic inflammatory disorder2 where white blood cell (WBC) derived macrophages and other phagocytes contribute to vascular injury, endothelial dysfunction, and atherosclerotic disease progression3. About 40% of hypertensive patients also have high blood cholesterol levels. Factors that increase the risk for coronary events in hypertensive cases include; elevated low density lipoprotein cholesterol (LDL) or total cholesterol (TC), smoking, impaired glucose tolerance and reduced high density lipoprotein (HDL)4.

Ability of exercise to alter inflammatory markers has provided mixed results where as in general population there is an inverse association between WBC, C-reactive protein (CRP) levels and self-reported physical activity or physical fitness5. These studies suggested that regular physical exercise might lower CRP levels by an anti-inflammatory action. On the contrary, non beneficial effect of exercise on CRP has also been reported6.

Most previous studies were done on older population using white, caucasian and other mixed black subjects. However, the role of genes, heredity, race, ethnicity, environmental factors and gene-environmental interaction in the aetiology and biomarkers of inflammation in hypertension has also been stressed7. Bouchard et al8 reported genetics plays a major role in a person's VO2 max and heredity can account for up to 25-50% of the variance between individuals. This interpersonal and interracial difference clearly indicates the needs for study on pure black African population.

For this study, 3 hypotheses were formulated and tested:

(1) There would be significant correlation between baseline VO2max and other variables of interest such as: Blood Pressure (BP), systolic blood pressure (SBP) and diastolic blood pressure (DBP), biomarkers of inflammation (CRP and WBC), metabolic markers [(fasting blood sugar (FBS), total cholesterol (TC), triglyceride (TG), high density lipoproteins (HDL), low density lipoproteins (LDL)] and artherogenic index (AI)).

(2) There would be significant difference between experimental and control groups in blood pressure, biomarkers of inflammation, metabolic markers, lipid profile and VO2max.

(3) Changes in VO2max would significantly correlate with changes in BP, biomarkers of inflammation and metabolic markers.

Subjects and Methods

Study population were males with essential hypertension who were attending the hypertensive clinic of Murtala Muhammed Specialist Hospital Kano Nigeria. Subject were informed about the experimental procedures, risk and protocol. Only those who consented to participate in the study were recruited. Subjects between the age range of 45 and 70 years having chronic mild to moderate stable hypertension for 1 year duration were selected. Hypertension was defined as systolic blood pressure between 140-179 and diastolic blood pressure between 90-109 mmHg. Only those cases who volunteered to stop taking antihypertensive drugs or were on a single antihypertensive medication were recruited. All subjects were sedentary workers and had no history of psychiatry or psychological disorders or abnormalities.

Obese or underweight (BMI between 20 and 30 kg/m2), smokers, alcoholics, diabetics and those with cardiac, renal or respiratory disease were excluded along with those who were involved in vigorous physical activities and above average physically fit (VO2max greater than27 and greater than33 ml/kg.min for over 60 and 50 years old respectively).

A total of 323 hypertensives satisfied the study criteria, they were age matched and randomly grouped into experimental (162) and control (161) groups. They were informed about the experimental procedures, risk and protocol and only those who gave informed consent in accordance with the American College of Sports Medicine (ACSM)9 guidelines were included in the study. Ethical approval was granted by the Ethical Committee/Board of Kano State Hospitals Management Board.

Pretest procedure

All subjects who were taking antihypertensive drugs were asked to stop their medication. Both experimental group and controls were given placebo tablets (consisted of mainly lactose and inert substance) in a double blind method for a week as "Wash out period" to get rid of the effects of previously taken antihypertensive medications. During this period all subjects reported to the hypertensive clinic for daily blood pressure monitoring and general observation. The pretest procedure was conducted on the last day of wash out period in the department of physiotherapy Murtala Mohammed Specialist Hospital (MMSH), Kano between 8-10:00 am.

Subject's resting systolic and diastolic blood pressures were measured daily in the right arm as described by Musa et al10 using an automated digital electronic BP monitor (Omron digital BP monitor, Medel 11 EM 403c; Tokyo Japan). Venous blood samples were also taken between 8-10:00 am after 12 hour overnight fast (fasting blood sample). Five ml blood was taken where 1 ml was transferred into a heprinised container (heparin, 75U/ml) for WBC count while remaining 4ml was allowed to coagulate (clot) at room temperature for one hour and later centrifuged to separate serum which was stored at -80oC until analysis.

Serum C-reactive protein was determined qualitatively and semi-quantitatively using commercial latex agglutination method (by Dialab Producktion und Vertrieb Von Chemisch, Gesellschatt M.B.H), WBC count was analyzed using Turks method11, blood sugar and serum lipids by commercial enzymatic method (Randox kits and manuals by Randox Laboratory, Antrim, United Kingdom), LDL was estimated indirectly using Friedwald et al formula12 (LDL = TC- (TG/5)-HDL). Artherogenic index was estimated from the ratio of TC and HDL (TC/HDL)10.

The Young Men Christian Association (YMCA) submaximal cycle ergometry test protocol was used to assess subject's aerobic power9. The protocol uses two to four 3-minutes stages of continuous exercise. Two steady heart rates of between 110 and 150 beat/min were marked and these two rates were plotted against the respective workload on the YMCA graph sheet. A straight line was drawn through the two points and extended to the subjects predicted maximum hear rate (220 minus age). The point at which the diagonal line intersects the horizontal line predicts the hear rate and max line represents the maximal working capacity for the subject. A perpendicular line was dropped from this point to the baseline where the maximal physical workload capacity was read in kg.m.min-1, which was used to predict the subjects VO2 max. This procedure was done for both pre and posttest stress test.

Table 1: Groups mean(X) and standard deviation (SD) for pre and posttest values. (N=245)

Variables###Interval group###Control group

###X+-SD###X+-SD

###Pretest###Posttest###Pretest###Posttest

SBP(mmHg)###166.05+-14.10###150.00+-16.67###160.87=-13.33###163.47+-14.88

DBP(mmHg)###96.80+-3.38###94.98+-5.04###97.17+-1.43###96.10+-2.67

VO2max(ml/kg/min)###23.62+-9.15###37.46+-7.42###21.23+-5.76###22.82+-7.44

CRP(mg/L)###0.16+-0.05###0.12+-0.4###0.13+-0.04###0.13=-0.05

WBC (X10mm)###7.61+-1.17###7.62+-1.38###7.13+-1.30###8.21+-1.60

FBS (mg/dl)###78.64+-23.41###46.82+-11.58###85.27+-21.49###85.33+-22.10

TC (mg/dl)###162.00+-49.31###134.10+-43.91###163.20+-36.61###169.40+-35.47

TG (mg/dl)###109.90+-30.99###96.95+-31.08###102.00+-20.41###113.07+-19.14

HDL (mg/dl)###24.60+-8.51###33.81+-6.38###29.53+-6.55###29.54+-6.57

LDL (mg/dl)###107.45+-41.52###87.11+-37.86###121.73+-33.35###125.40+-33.05

AI (mg/dl)###7.25+-3.31+-3.31###4.16+-1.77###5.62+-1.10###5.84+-1.06

Test procedures

The test procedures were conducted in the department of physiotherapy of Murtala Mohammed Specialist Hospital (MMSH), Kano. Following stress test and prior to the exercise training, all subjects in control and experimental groups were assessed by the physician and were prescribed with methyldopa (500mg-1g daily in divided doses of 2 to 4 times) based on individual's response and tolerance to therapy. Methyldopa was preferred because it does not alter normal haemodynamic responses to exercise13 and is a well-tolerated and most prescribed antihypertensive drug in Africa14,15.

Subjects used this drug with regular medical consultation and observation through-out the period of exercise training.

Subjects in the experimental group exercised on a bicycle ergometer at a low intensity of between 60-79% of their heart rate max reserve that was estimated from 220 minus the age of a subject as recommended by ACSM9. The starting workload was 100 kgm (17 watts) which was increased at a pedal speed of 50 rpm to obtain a heart rate max reserve 60% in the first two weeks to and level up at 79% heart rate max reserve throughout the remaining part of the training period at a work/rest ratio of 1:1of 6 minutes each. The initial of exercise session

Table 2: Changed score values and ANOVA test. (N = 245)

###Groups changed score values (X+-SD)###ANOVA results

Variables###Interval group###Control group###F-values p-values

SBP###-16.40+-13.16###2.61+-7.85###137.220###0.000

DBP###-4.01+-4.34###-1.07+-0.17###42.059###0.000

VO2max###13.85+-9.94###1.59+-3.54###199.262###0.000

CRP###-0.03+-0.05###0.01+-0.03###22.261###0.000

WBC###0.02+-1.67###1.09+-1.89###34.289###0.029

FBS###-30.08+-18.72###0.14+-0.40###511.463###0.000

TC###-22.71+-28.59###6.20+-7.94###160.104###0.000

TG###11.69+-7.58###0.07+-8.72###532.172###0.000

HDL###8.70+-12.15###0.01+-0.33###28.181###0.000

LDL###-19.80+-12.15###3.67+-3.42###171.679###0.000

AI###-3.11+-3.61###0.22+-0.30###58.065###0.000

significant p less than 0.05

was increased from 45 minutes in the first two weeks and leveled up at 60 minutes throughout the remaining part of the training. Exercise session was three times per week for 8 weeks in the experimental or interval group. Subjects in the control group were instructed not to undertake any vigorous physical activity during the 8 weeks period of study.

Posttest procedure

At the end of the 8 weeks, all subjects were asked to stop methyldopa and were prescribed placebo tablets in a single blinded method for a week to wash out the effect of the methyldopa. Immediately after the post training wash out period, fasting blood samples were collected again. All pre and post test measurements were recorded on a data sheet Following data collection, the variables were statistically analyzed. The descriptive statistics (Means and standard deviations) of the subjects' physical characteristics, estimated VO2max, BP, CRP, WBC, FBS and lipid profile were determined. Analysis of co-variance (ANCOVA) was used to assess the outcome variables; in the ANCOVA, the posttest values were the outcome variables and the co-covariates were the age and pretest (baseline) values. Pearson product moment correlation tests were computed for the variables of interest.

In the correlation tests, the difference between subjects post-training and pre-training measurements (changed score) were used as dependent measures. The score changed was the difference between the posttest and pretest values. All statistical analysis was performed on a Toshiba compatible microcomputer using the statistical package for the social science (SPSS), (Windows Version 16.0 Chicago IL, USA). The probability level for all the above tests was set at 0.05 to indicate significance.

Results

Two hundred and fifty seven subjects (140 experimental, and 105 controls) completed the 8 weeks training program while data of 78 subjects (22 experimental and 56 controls) was not used because they either dropped or were non-compliant, unfavorable responses to methyldopa and exercise training or due to incomplete data. The final analysis was done on the data of 245 subjects (Figure-1).

The ages of the subjects ranged between 45 and 70 years. In the experimental or interval group the mean age was 58.40+-6.91years, height 167.78+-7.81cm, weight 70.18+-11.37kg, BMI 24.96+-3.88 kg.m-2 and % BF+-SD of 17.69+-17.69+- 6.50%. In the control group these were 58.27+-6.24years, 167.89+-5.31cm, 68.47+-17.07 kg, 24.16+-4.91 kg.m-2 and 22.27+- 9.82% respectively. There was no significant difference in the age between the two groups (t=.156, p=.876).

Table-1 shows pretest versus and posttest mean BP, CRP, WBC, FBS, HDL and VO2max for the exercise group and controls.

Table-2 shows a significant reduction in in both systolic and diastolic blood pressure, CRP, WBC, FBS; TC, TG, HDL, LDL, AI and VO2 max in the exercise groups over control group (p less than 0.05).

Significant positive correlation was seen in the baseline VO2 max and other variables (SBP, DBP, CRP, WBC) (Figure-2). Training or exercise significantly changed (p less than 0.01)VO2max negatively and positively and it correlated with training changes in other parameters too like systolic blood pressure (-.304); diastolic blood pressure (r=-.289); C reactive protein (-.444); WBC (-.379); Fasting sugar(r=-0.225); Total cholersterol (r=-232); TG (-0.190); LDL (-.197); AI (-.283) and HDL (.232) (Figure-3, 4 and 5).

Discussion

To our knowledge, this is the first randomized, controlled trial examining the simultaneous impact of interval, moderate intensity, aerobic training on blood pressure, biomarkers of inflammation and metabolic markers in pure black African hypertensives. The study showed a significant correlation between baseline VO2max and other variables like BP (SBP and DBP), biomarkers of inflammation (CRP and WBC), metabolic markers (FBS, TC, TG, HDL, LDL and AI). It also showed a significant difference between experimental and control groups in BP(SBP and DBP), biomarkers of inflammation (CRP and WBC), metabolic markers (TC, TG, HDL, LDL and AI) and VO2max. The changes in VO2max significantly correlated with changes in BP (SBP and DBP), biomarkers of inflammation (CRP and WBC), metabolic markers (FBS, TC, TG, HDL, LDL and AI) but there was no significant correlation between baseline VO2max and FBS.

VO2max

Our findings are similar to the report of Mughal et al16, who studied the effect of aerobic exercise in patients with essential hypertension. Dengel and associates17 also conducted a study on the effect of physical training on maximum aerobic capacity and reported a significant increase in maximal aerobic capacity (VO2max:18.3+-3.8 versus output of 20.7+-4.2ml/kg/min, at p less than 0.017). Both these studies showed outstanding results with exercise but had limitation of lacking control group.

The present study showed a significant decrease in blood pressure in the experimental groups over placebo group. These favorable from aerobic training on blood pressure were also reported by others18,19.

A significant reduction in CRP and WBC was seen in the present study in the interval group over control. Kullo et al20 also reported similar findings and showed inverse correlation with VO2max (r=-0.40, p=0.001) and IL-6 (r=-0.38, p=0.001). Effects of long-term exercise intervention on two biomarkers of inflammation (C-reactive protein (CRP) interleukin-6 [IL-6]) and WBC were studied by workers who reported no significant differences in CRP and WBC21.

The effect of exercise and weight loss on FBS in hypertensives reported a significant reduction in FBS exercise cases as compared to controls22. Effect of mild exercise reported a significant reduction in FBS and insulin levels23.

The changes in the lipid profile seen in the present study are in agreement with other study24 who used a treadmill exercise program. They reported significant reductions in clinic and ambulatory BP, plasma TC, LDL and triglyceride along with elevation of HDL. However, others have reported contrary findings25. The differences in findings could be attributed to the differences in exercise intensities, subjects' health status and pre (baseline) lipid profile status.

It was concluded from the present study that physical activity and fitness are related to lower levels of the inflammatory marker and various metabolic markers. Interval training program is an effective adjunct non-pharmacological multipurpose management of hypertension; and that the therapeutic role of interval training program in the reduction of blood pressure may be through the suppression of systemic inflammation and abnormal metabolic markers.

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Department of Biomedical Technology, School of Health Technology, Federal University of Technology1, Owerri, Department of Physiotherapy, Bayero University2, Kano, Department of Medical Rehabilitation, University of Nigeria3, Enugu Campus, Enugu Nigeria.

Corresponding Author: Sikiru Lamina Department of Biomedical Technology School of Health Technology, Federal University of Technology, Owerri, Nigeria., Email: siklam_86@yahoo.co.uk
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Publication:Pakistan Journal of Medical Research
Article Type:Report
Geographic Code:6NIGR
Date:Sep 30, 2012
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