Isometric Resistance Exercise on Accelerated Atherosclerosis in Hypertension

1. IntroductionHypertension (HT) is the most common condition worldwide predisposing toatherosclerotic diseases (stroke, heart attack and peripheral vascular disease),apart from other traditional risk factors [1‐3]. However, most HT patients havesuboptimal BP control despite anti‐HT medications [4]. On this issue, aerobic anddynamic exercise are effective in BP‐reduction, but HT‐patients often have poorcompliance with exercise, mainly because of requirement of additional time, skilltraining, venue and equipments [5‐6]. Isometric resistance exercised (IRE) (e.g.wall squat) may improve BP control, characterized by sustained muscle contractionswith minimal change in muscle length and joint angle. However, most randomizedtrials of IRE have short duration and their long‐term effect on BP‐reduction,mechanisms and atherosclerosis complications, particularly in the Chinese, remainunknown [7‐11].Much advance in noninvasive vessel‐imaging has been witnessed in past few decades.Brachial flow‐mediated dilation (FMD) and carotid intima‐media thickness (IMT), havebeen advocated as surrogate markers for the documentation of early atherosclerosisand evaluation of preventive measures (12‐20). Both brachial FMD and carotid IMT cannow be measured accurately with high reproducibility, and have been related tocardiovascular outcomes. In clinical context, a 0.1mm increase in carotid IMT hasbeen associated with 41% increase in stroke and 43% increase in acute myocardialinfarction over a follow‐up period of 2‐7 years. [17] An 8% difference in carotidIMT was approximately similar to the kind of difference seen between diabetes andnon‐diabetes Chinese adults [21). 2. Aims and Hypotheses to be TestedSystemic hypertension has been proven accelerating atherosclerotic process. Tofurther test this initial hypothesis, this interventional substudy aims:(i) To evaluate the impact of IRE on Clinic and Ambulatory BP (AMBP) in Hong Kong.(ii) To evaluate the impact of IRE on atherosclerotic surrogates (brachial FMD andcarotid IMT).(iii) To evaluate the impact of IRE on mechanisms of BP and atherogenesisreductions, including endothelial function FMD, carotid IMT and arterial wallstiffness (cfPWV), and inflammatory parameters. 3. Plan of Investigation The brachial FMD and carotid IMT before and after IREintervention will be compared between the wall‐squat and control interventiongroups.3.1 The impact of Isometric resistance exercise (IRE) Intervention on brachial FMD andcarotid IMT.Subjects:200 HT adults, aged 18‐75yr with SBP 135‐160mmHg on AMBP will be recruited. Those withincapacitating osteoarthritis of knee and secondary HT will be excluded.3.2 Methods: These HT participants will be randomized to practise IRE (100 adults) 14mins per session, (2 mins IRE x 4sets, 2 mins rest in between), 3 sessions per week, orusual standard care & stretching (yoga) exercise (100 adults).Week‐0 Health Examination, Randomization (IRE vs Yoga), Vascular Study (FMD & IMT),Blood Test, and Arterial wall stiffness (cfPWV)Week‐13 Compliance (adhenence) checkingWeek‐24 Health Examination, vascular study (FMD & IMT), blood tests, and arterial wallstiffness (cfPWV)One Year Compliance (adherence) checking, vascular study (FMD & IMT), vessel wallstiffness, and blood Tests ‐ Collection of health data: 1. Questionnaire ‐ All adult subjects will be interviewed and required to complete a detailed questionnaire regarding their individual and family history of cardiovascular diseases, hypertension, diabetes and current use of medications. Information on socio‐economic status, tobacco use and lifestyle will be collected. 2. Health examination ‐ Each participant will receive a health examination and their weight and height, blood pressures, body mass index (BMI) and wait‐hip circumference ratio (WHR) will be measured (light clothing and no shoes). 3. Blood tests: 10ml of fasting blood will be taken for WBC platelet, fasting glucose, HgbA1C, low density lipoprotein cholesterol, hsC‐reactive protein, fibrinogen and IL‐6. ‐ Vascular Studies:Endothelial function, flow‐mediated dilation (FMD) of the brachial artery and carotid IMTwill be studied by using high resolution ultrasound.(i) Endothelial function, (brachial flow‐mediated dilation, FMD) will be studied by usinghigh resolution ultrasound, as described previously. [12,22‐24] In brief, the diameter ofthe brachial artery will be measured on B‐mode ultrasound images, using a linear arraytransducer (HF L38) with a median frequency of 13‐6MHz and a standard Sonosite(MicroMaxx) system. Forearm tourniquet cuff placement will be applied to induce reactivehyperemia on deflation. Scans of brachial artery 10cm proximal to elbow will be acquiredat rest, during reactive hyperemia (to induce flow‐mediated endothelium‐dependentdilation, FMD). FMD will be expressed as % of dilation from baseline vessel diameternormalized with vessel strain. Hyperemia is calculated as the % increase in blood flowafter cuff deflation compared with baseline.(ii) Carotid intima‐media thickness (CIMT) measurement ‐ B‐mode ultrasound examinationswill be performed using a 10‐5 probe, with a 7.5 MHz scanning frequency linear arraytransducer. All carotid scans will be performed by a single operator after apredetermined, standardized scanning protocol for the right and left carotid arteries asdescribed by Salonen and Salonen [16] and Touboul et al [19], using images of the farwall of the distal 10 mm of the common carotid arteries. All scans will be recorded onsuper‐VHS videotape for subsequent off‐line analysis for intima‐media thickness (IMT),using a verified automatic edge‐detecting and measurement software package as describedpreviously. [19‐24] The intra‐observer variability of mean IMT is 0.003 to 0.011mm (CV0.998%).3.3 Outcomes3.3.1 Primary outcomes: (i) Daytime ambulatory SBP and DBP (mean and BP variability)(mmHg) at baseline, 24 weeks and 1 year (ii) Vascular Parameters: Brachial FMD (%) andCarotid IMT (mm) at baseline, 24 weeks and 1 year.3.3.2 Secondary outcomes: (i) Clinic BP and Ambulatory BP parameters (mmHg) at baseline,24 weeks and 1 year.(ii) Carotid femoral pulse wave velocity, cfPWV (mm/sec) at baseline and 24 weeks.(iii) Other important traditional atherosclerosis risk factors: BMI (weight kg/ heightm^2), glucose (mmol/l), lipid profiles (mmol/l), HgbA1‐C (%), creatinine (umol/L),haemoglobin (g/dl), hsCRP (mg/l), Fibrinogen (mg/dl) and IL‐6 (pg/ml) at baseline, 24weeks and 1 year.3.3.3 Safety profiles (if any) including CVS event and hospitalization at 1 year,4. Compliance with Declaration of Helsinki. The design, methodology and conduction ofproject are in compliance with Declaration of Helsinki.5. Data processing and analysis:(5.1) Power Calculation: The Proc Power in the STS 9.2 statistical packages (SASInstitute Inc. Cary. NC, US) was used to calculate the sample size for FMD and carotidIMT. Data from our previous studies on Chinese adults in Hong Kong reported FMD was in6‐8% +/‐ 1.3%, and carotid IMT was 0.55‐0.68mm +/‐ 0.1mm. On the assumption of post IREbrachial FMD will improve to 6.7‐8.7 +/‐ 1.4%, and carotid IMT will reduce to 0.51‐0.61mm+/‐ 0.11mm, recruitment of 200 Chinese adults (100 in each group) will be adequatelypowered (85%) to detect a group difference in brachial FMD of 1.2% and in carotid IMT of0.06mm (12%), at 1 year between the two treatment groups.(5.2). Data Analysis: Statistical Analysis System SPSS version 28 (SAS Institute Inc.,Cary, NC, US) will be used for all statistical analyses. Descriptive methods will be usedto describe characteristics of cardiovascular risks. The primary endpoints are AMBP,brachial FMD and carotid IMT; serological inflammatory biomarkers (Neutrophil/ monocyteratio and Platelet), hsCRP, fibrinogen and IL‐6 are secondary endpoints. Students'T‐tests will be used to detect the group differences in brachial FMD and carotid IMT.Multivariable linear and logistic regressions will be used to calculate the riskmagnitude by IRE vs usual care and stretching exercise interventions, and to controlpotential confounders such as traditional cardiovascular risk factors.