Effect of exercise training on the renin-angiotensin-aldosterone system: a meta-analysis.

Blood pressure (BP) management reduces the risk of cardiovascular disease (CVD). The renin-angiotensin-aldosterone system (RAAS) plays an important role in regulating and maintaining blood volume and pressure. This analysis aimed to investigate the effect of exercise training on plasma renin, angiotensin-II and aldosterone, epinephrine, norepinephrine, urinary sodium and potassium, BP and heart rate (HR). We systematically searched PubMed, Web of Science, and the Cochrane Library of Controlled Trials until 30 November 2022. The search strategy included RAAS key words in combination with exercise training terms and medical subject headings. Manual searching of reference lists from systematic reviews and eligible studies completed the search. A random effects meta-analysis model was used. Eighteen trials with a total of 803 participants were included. After exercise training, plasma angiotensin-II (SMD -0.71; 95% CI -1.24, -0.19; p = 0.008; n = 9 trials), aldosterone (SMD -0.37; 95% CI -0.65, -0.09; p = 0.009; n = 8 trials) and norepinephrine (SMD -0.82; 95% CI -1.18, -0.46; p < 0.001; n = 8 trials) were reduced. However, plasma renin activity, epinephrine, and 24-h urinary sodium and potassium excretion remained unchanged with exercise training. Systolic BP was reduced (MD -6.2 mmHg; 95% CI -9.9, -2.6; p = 0.001) as was diastolic BP (MD -4.5 mmHg; 95% CI -6.9, -2.1; p < 0.001) but not HR (MD -3.0 bpm; 95% CI -6.0, 0.4; p = 0.053). Exercise training may reduce some aspects of RAAS and sympathetic nervous system activity, and this explains some of the anti-hypertensive response.

An evidence-based guide to the efficacy and safety of isometric resistance training in hypertension and clinical implications.

More than 30 randomized controlled trials, supported by individual patient-level and group-level meta-analyses and a Delphi analysis of expert opinion, unequivocally show isometric resistance training (IRT) elicits antihypertensive benefits in healthy people and those with chronic illness. We aim to provide efficacy and safety evidence, and a guide for IRT prescription and delivery. Recommendations are made for the use of IRT in specific patient populations and appropriate methods for IRT delivery. Published data suggest IRT consistently elicits mean blood pressure reductions of 7.4/3.3 mmHg systolic blood pressure/diastolic blood pressure, equivalent to antihypertensive medication monotherapy. Blood pressure reductions of this size are associated with an approximate 13% to 22% reduction in major cardiovascular events. Moreover, IRT is safe in a range of patient populations. We suggest that IRT has the greatest potential benefit when used as an antihypertensive therapy in individuals unwilling and/or unable to complete aerobic exercise, or who have had limited adherence or success with it; individuals with resistant or uncontrolled hypertension, already taking at least two pharmacological antihypertensive agents; and healthy or clinical populations, as an adjunct to aerobic exercise and dietary intervention in those who have not yet attained control of their hypertension. IRT is efficacious and produces clinically meaningful blood pressure reductions (systolic blood pressure, 7 mmHg; diastolic blood pressure, 3 mmHg). IRT is safe and typical program delivery requires only about 17 min weekly. IRT should be used as an adjunct to other exercise modalities, in people unable to complete other types of exercise, or in resistant hypertension.

Safety, efficacy and delivery of isometric resistance training as an adjunct therapy for blood pressure control: a modified Delphi study.

Uncontrolled hypertension remains the major risk factor for cardiovascular disease. Isometric resistance training (IRT) has been shown to be a useful nonpharmacological therapy for reducing blood pressure (BP); however, some exercise physiologists and other health professionals are uncertain of the efficacy and safety of IRT. Experts' consensus was sought in light of the current variability of IRT use as an adjunct treatment for hypertension. An expert consensus-building analysis (Delphi study) was conducted on items relevant to the safety, efficacy and delivery of IRT. The study consisted of 3 phases: (1) identification of items and expert participants for inclusion; (2) a two-round modified Delphi exercise involving expert panelists to build consensus; and (3) a study team consensus meeting for a final item review. A list of 50 items was generated, and 42 international experts were invited to join the Delphi panel. Thirteen and 10 experts completed Delphi Rounds 1 and 2, respectively, reaching consensus on 26 items in Round 1 and 10 items in Round 2. The study team consensus meeting conducted a final item review and considered the remaining 14 items for the content list. A final list of 43 items regarding IRT reached expert consensus: 7/10 items on safety, 11/11 items on efficacy, 10/12 items on programming, 8/10 items on delivery, and 7/7 on the mechanism of action. This study highlights that while experts reached a consensus that IRT is efficacious as an antihypertensive therapy, some still have safety concerns, and there is also ongoing conjecture regarding optimal delivery.

Resistance training in heart failure patients: a systematic review and meta-analysis.

Aerobic training (AT) has been the primary mode of exercise training in cardiac rehabilitation. Historically, the reason for the prescription of AT was that it was speculated that although RT may be beneficial for some clinical outcomes, it may have an adverse effect on ventricular structure and function. However, RT has now made its way into current cardiac rehabilitation guidelines, including those directed towards patients with HF, albeit differences exist across institutions and guidelines. A systematic search of PubMed, EMBASE and Cochrane Trials Register on April 30, 2021, was conducted for exercise-based rehabilitation trials in HF. Randomised and controlled trials that reported on resistance training versus usual care or trials that directly compared RT to an AT intervention were included. Resistance training versus controls improves parameters of lower (SMD 0.76 (95%CI 0.26, 1.25, p = 0.003] and upper extremity muscle strength (SMD 0.85 (95%CI 0.35, 1.35), p = 0.0009], both key parameters of physical function throughout the lifespan. Importantly, RT in isolation, versus control, improves VO2peak [MD: 2.64 ml/kg/min (95%CI 1.67, 3.60), p < 0.00001] and 6MWD [MD: 49.94 m (95%CI 34.59, 65.29), p < 0.00001], without any detrimental effect on left ventricular parameters. Resistance training in HF patients is safe and improves parameters of physical function and quality of life. Where people with HF are unable to, or are not inclined to, partake in aerobic activity, RT alone is appropriate to elicit meaningful benefit.

The effect of remote ischaemic conditioning on blood pressure response: A systematic review and meta-analysis.

BACKGROUND: Previous work has evaluated the effect of remote ischaemic conditioning (RIC) in a number of clinical conditions (e.g. cardiac surgery and acute kidney injury), but only one analysis has examined blood pressure (BP) changes. While individual studies have reported the effects of acute bouts and repeated RIC exposure on resting BP, efficacy is equivocal. We conducted a systematic review and meta-analysis to evaluate the effects of acute and repeat RIC on BP. METHODS: A systematic search was performed using PubMed, Web of Science, EMBASE, and Cochrane Library of Controlled Trials up until October 31, 2020. Additionally, manual searches of reference lists were performed. Studies that compared BP responses after exposing participants to either an acute bout or repeated cycles of RIC with a minimum one-week intervention period were considered. RESULTS: Eighteen studies were included in this systematic review, ten examined acute effects while eight investigated repeat effects of RIC. Mean differences (MD) for outcome measures from acute RIC studies were: systolic BP 0.18 mmHg (95%CI -0.95, 1.31; p = 0.76), diastolic BP -0.43 mmHg (95%CI -2.36, 1.50; p = 0.66), MAP -1.73 mmHg (95%CI -3.11, -0.34; p = 0.01) and HR -1.15 bpm (95%CI -2.92, 0.62; p = 0.20). Only MAP was significantly reduced. Repeat RIC exposure showed non-significant change in systolic BP -3.23 mmHg (95%CI -6.57, 0.11; p = 0.06) and HR -0.16 bpm (95%CI -7.08, 6.77; p = 0.96) while diastolic BP -2.94 mmHg (95%CI -4.08, -1.79; p < 0.00001) and MAP -3.21 mmHg (95%CI -4.82, -1.61; p < 0.0001) were significantly reduced. CONCLUSIONS: Our data suggests repeated, but not acute, RIC produced clinically meaningful reductions in diastolic BP and MAP.

Blood pressure control in older adults with hypertension: A systematic review with meta-analysis and meta-regression.

BACKGROUND: Managing blood pressure reduces CVD risk, but optimal treatment thresholds remain unclear as it is a balancing act to avoid hypotension-related adverse events. OBJECTIVES: This systematic review, meta-analysis and meta-regression evaluated the benefits of intensive BP treatment in hypertensive older adults. METHODS: We systematically searched PubMed, MEDLINE, EMBASE, and the Cochrane Library of Controlled Trials until January 31, 2020. Studies comparing different BP treatments/targets and/or active BP against placebo treatment, with a minimum 12 months follow-up, were included. Risk ratios (RR) and 95% CIs were calculated using a random effects model. The primary outcome was RR of major cardiovascular events (MCEs); secondary outcomes included myocardial infarction (MI), stroke, heart failure (HF), cardiovascular (CV) mortality, and all-cause mortality. RESULTS: We included 16 studies totaling 65,890 hypertensive participants (average age 69.4 years) with a follow-up period from 1.8 to 4.9 years. Intensive BP treatment significantly reduced the relative risk of MCEs by 26% (RR:0.74, 95%CI 0.64-0.86, p = 0.000; I 2 = 79.71%). RR of MI significantly reduced by 13% (RR:0.87, 95%CI 0.76-1.00, p = 0.052; I 2 = 0.00%), stroke by 28% (RR:0.72, 95%CI 0.64-0.82, p = 0.000; I 2  = 32.45%), HF by 47% (RR:0.53, 95% CI 0.43-0.66, p = 0.000; I 2 = 1.23%), and CV mortality by 24% (RR:0.76, 95%CI 0.66-0.89, p = 0.000; I 2 = 39.74%). All-cause mortality reduced by 17% (RR:0.83, 95%CI 0.73-0.93, p = 0.001; I 2 = 53.09%). Of the participants - 61% reached BP targets and 5% withdrew; with 1 hypotension-related event per 780 people treated. CONCLUSIONS: Lower BP treatment targets are optimal for CV protection, effective, well-tolerated and safe, and support the latest hypertension guidelines.

An evidence-based analysis of managing hypertension with isometric resistance exercise-are the guidelines current?

Exercise guidelines for managing hypertension maintain aerobic exercise as the cornerstone prescription, but emerging evidence of the antihypertensive effects of isometric resistance training (IRT) may necessitate a policy update. We conducted individual patient data (IPD) meta-analyses of the antihypertensive effects of IRT. We utilized a one-step fitted mixed effects model and a two-step model with each analyzed trial using a random effects analysis. We classified participants as responders if they lowered their systolic blood pressure (SBP) by ≥5 mmHg, diastolic (DBP) or mean arterial blood pressure (MAP) by ≥3 mmHg. Twelve studies provided data on 326 participants. IRT produced significant reductions in SBP, DBP, and MAP. The SBP responder rates for both groups, or the absolute risk reduction (ARR) between groups, was 28.1% in favor of the IRT group. The number needed to treat (NNT) to achieve one 5 mmHg reduction in SBP was 3.56, 95% CI [2.56, 5.83], or four people. The ARR for DBP was 20.0% in favor of IRT. Therefore, the NNT to achieve one 3 mmHg decrease in DBP was five people, 95% CI [3.22, 11.10]. The ARR for MAP was 28.2% in favor of IRT. Therefore, the NNT to achieve one 3 mmHg reduction in MAP was four people, 95% CI [2.80, 7.42]. Our analyses demonstrated that IRT (three times per week for a total of 8 min of squeezing activity) is able to reduce the participants' SBP by 6-7 mmHg, equating to a 13% reduction in the risk for myocardial infarction and 22% for stroke.

Effect of vitamin D supplementation on endothelial function - An updated systematic review with meta-analysis and meta-regression.

BACKGROUND AND AIMS: Atherogenesis and endothelial dysfunction contribute to cardiovascular risk and vitamin D has been implemented in endothelial repair. This systematic review, meta-analysis and meta-regression aims to establish the effect of vitamin D supplementation on endothelial function. METHODS AND RESULTS: To conduct the systematic review we searched the Cochrane Library of Controlled Trials, PubMed, ProQuest and EMBASE for randomized controlled trials that investigated the effects of vitamin D supplementation on flow-mediated dilation (FMD%), pulse wave velocity (PWV), and central augmentation index (AIx). Meta-analysis was based on a random effects model and inverse-variance methods to calculate either mean difference (MD) or standardized mean difference (SMD) as effects sizes. This was followed by meta-regression investigating the effect of baseline vitamin D concentrations, vitamin D dosing and study duration. Risk of bias was assessed using the JADAD scale and funnel plots. We identified 1056 studies of which 26 studies met inclusion criteria for quantitative analysis. Forty-two percent of the 2808 participants had either deficient or insufficient levels of vitamin D. FMD% (MD 1.17% (95% CI -0.20, 2.54), p = 0.095), PWV (SMD -0.09 m/s (95% CI -0.24, 0.07), p = 0.275) and AIx (SMD 0.05% (95% CI -0.1, 0.19), p = 0.52) showed no improvement with vitamin D supplementation. Sub-analysis and meta-regression revealed a tendency for AIx and FMD% to increase as weekly vitamin doses increased; no other significant relationships were identified. CONCLUSIONS: Vitamin D supplementation showed no improvement in endothelial function. More evidence is required before recommendations for management of endothelial dysfunction can be made.

Reported methods for handling missing change standard deviations in meta-analyses of exercise therapy interventions in patients with heart failure: A systematic review.

BACKGROUND: Well-constructed systematic reviews and meta-analyses are key tools in evidenced-based healthcare. However, a common problem with performing a meta-analysis is missing data, such as standard deviations (SD). An increasing number of methods are utilised to calculate or impute missing SDs, allowing these studies to be included in analyses. The aim of this review was to investigate the methods reported and utilised for handling missing change SDs in meta-analyses, using the topic of exercise therapy in heart failure patients as a model. METHODS: A systematic search of PubMed, EMBASE and Cochrane Library from 1 January 2014 to 31st March 2018 was conducted for meta-analyses of exercise based trials in heart failure. Studies were eligible to be included if they performed a meta-analysis of change in exercise capacity in heart failure patients after a training intervention. RESULTS: Twenty two publications performed a meta-analysis on the effect of exercise therapy on exercise capacity in heart failure patients. Eleven (50%) publications did not directly report the approach for dealing with missing change SDs. Approaches reported and utilised to deal with missing change SDs included imputation, actual and approximate algebraic recalculation using study level summary statistics and exclusion of studies. CONCLUSION: Change SDs are often not reported in trial papers and while in the first instance meta-analysts should attempt to obtain missing data from trial authors, this information is frequently not forthcoming. Meta-analysts are then forced to make a decision on how these trials and missing data are to be handled. Whilst not one approach is favoured for dealing with this matter, authors need to clearly report the approach to be utilised for missing change SDs. Where change SDs are imputed meta-analyst are encouraged to explore several options and have a sound rationale as to the choice, and where data is imputed, sensitivity analysis should be conducted.

Effect of exercise therapy on established and emerging circulating biomarkers in patients with heart failure: a systematic review and meta-analysis.

Background: Biomarkers are important in the diagnosis, risk stratification and management of patients with heart failure (HF). The established biomarkers of myocardial stretch, brain natriuretic peptide (BNP) and amino (N) portion of BNP (NT-proBNP) have been extensively studied, and early analyses have demonstrated response to exercise training. Several other biomarkers have been identified over the last decade and may provide valuable and complementary information which may guide treatment strategies, including exercise therapy. Methods: A systematic search of PubMed, EMBASE and Cochrane Trials Register to 31 October 2017 was conducted for exercise-based rehabilitation trials in HF. Randomised and controlled trials that reported biomarkers, BNP, NT-proBNP, soluble ST2, galectin-3, mid-regional atrial natriuretic peptide, mid-regional adrenomedullin and copeptin, were included. Results: Forty-three studies were included in the systematic review, with 27 studies suitable for meta-analyses. Data pooling was only possible for NT-proBNP and BNP. Meta-analyses of conventional training studies demonstrated a statistically significant improvement in NT-proBNP (pmol/L); mean difference (MD) -32.80 (95% CI -56.19 to -9.42), p=0.006 and in BNP (pmol/L); MD -17.17 (95% CI -29.56 to -4.78), p=0.007. Pooled data of non-conventional training failed to demonstrate any statistically significant improvements. Conclusion: Pooled data indicated a favourable effect of conventional exercise therapy on the established biomarkers, NT-proBNP and BNP; however, this was in contrast to a number of studies that could not be pooled. Limited evidence exists as to the effect of exercise training on emerging biomarkers.

Exercise-based cardiac rehabilitation improves exercise capacity and health-related quality of life in people with atrial fibrillation: a systematic review and meta-analysis of randomised and non-randomised trials.

Objective: The aim of this study was to undertake a contemporary review of the impact of exercise-based cardiac rehabilitation (CR) targeted at patients with atrial fibrillation (AF). Methods: We conducted searches of PubMED, EMBASE and the Cochrane Library of Controlled Trials (up until 30 November 2017) using key terms related to exercise-based CR and AF. Randomised and non-randomised controlled trials were included if they compared the effects of an exercise-based CR intervention to a no exercise or usual care control group. Meta-analyses of outcomes were conducted where appropriate. Results: The nine randomised trials included 959 (483 exercise-based CR vs 476 controls) patients with various types of AF. Compared with control, pooled analysis showed no difference in all-cause mortality (risk ratio (RR) 1.08, 95% CI 0.77 to 1.53, p=0.64) following exercise-based CR. However, there were improvements in health-related quality of life (mean SF-36 mental component score (MCS): 4.00, 95% CI 0.26 to 7.74; p=0.04 and mean SF-36 physical component score: 1.82, 95% CI 0.06 to 3.59; p=0.04) and exercise capacity (mean peak VO2: 1.59 ml/kg/min, 95% CI 0.11 to 3.08; p=0.04; mean 6 min walk test: 46.9 m, 95% CI 26.4 to 67.4; p<0.001) with exercise-based CR. Improvements were also seen in AF symptom burden and markers of cardiac function. Conclusions: Exercise capacity, cardiac function, symptom burden and health-related quality of life were improved with exercise-based CR in the short term (up to 6 months) targeted at patients with AF. However, high-quality multicentre randomised trials are needed to clarify the impact of exercise-based CR on key patient and health system outcomes (including health-related quality of life, mortality, hospitalisation and costs) and how these effects may vary across AF subtypes.