Validation of Exercise Capacity as a Surrogate Endpoint in Exercise-Based Rehabilitation for Heart Failure: A Meta-Analysis of Randomized Controlled Trials

This is the final version. Available on open access from Elsevier via the DOI in this recordObjectives: This study sought to validate exercise capacity (EC) as a surrogate for mortality, hospitalization, and health-related quality of life (HRQOL). Background: EC is often used as a primary outcome in exercise-based cardiac rehabilitation (CR) trials of heart failure (HF) via direct cardiorespiratory assessment of maximum oxygen uptake (VO2peak) or through submaximal tests, such as the 6-min walk test (6MWT). Methods: After a systematic review, 31 randomized trials of exercise-based CR compared with no exercise control (4,784 HF patients) were included. Outcomes were pooled using random effects meta-analyses, and inverse variance weighted linear regression equations were fitted to estimate the relationship between the CR on EC and all-cause mortality, hospitalization, and HRQOL. Spearman correlation coefficient (ρ), R2 at trial level, and surrogate threshold effect (STE) were calculated. STE represents the intercept of the prediction band of the regression line with null effect on the final outcome. Results: Exercise-based CR is associated with positive effects on EC measured through VO2peak (+3.10 ml/kg/min; 95% confidence interval [CI]: 2.01 to 4.20) or 6MWT (+41.15 m; 95% CI: 16.68 to 65.63) compared to control. The analyses showed a low level of association between improvements in EC (VO2peak or 6MWT) and mortality and hospitalization. Moderate levels of correlation between EC with HRQOL were seen (e.g., R2 <52%; |ρ| < 0.72). Estimated STE was an increase of 5 ml/kg/min for VO2peak and 80 m for 6MWT to predict a significant improvement in HRQOL. Conclusions: The study results indicate that EC is a poor surrogate endpoint for mortality and hospitalization but has moderate validity as a surrogate for HRQOL. Further research is needed to confirm these findings across other HF interventions.National Institute for Health Research (NIHR)University of Exete

Impact of exercise-based cardiac rehabilitation in patients with heart failure (ExTraMATCH II) on mortality and hospitalisation:an individual-patient data meta-analysis of randomised trials

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordAIMS: To undertake an individual patient data (IPD) meta-analysis to assess the impact of exercise-based cardiac rehabilitation (ExCR) in patients with heart failure (HF) on mortality and hospitalisation, and differential effects of ExCR according to patient characteristics: age, sex, ethnicity, New York Heart Association functional class, ischaemic aetiology, ejection fraction, and exercise capacity. METHODS AND RESULTS: Randomised trials of exercise training for at least 3 weeks compared with no exercise control with 6-month follow-up or longer, providing IPD time to event on mortality or hospitalisation (all-cause or HF-specific). IPD were combined into a single dataset. We used Cox proportional hazards models to investigate the effect of ExCR and the interactions between ExCR and participant characteristics. We used both two-stage random effects and one-stage fixed effect models. IPD were obtained from 18 trials including 3912 patients with HF with reduced ejection fraction. Compared to control, there was no statistically significant difference in pooled time to event estimates in favour of ExCR although confidence intervals (CIs) were wide [all-cause mortality: hazard ratio (HR) 0.83, 95% CI 0.67-1.04; HF-specific mortality: HR 0.84, 95% CI 0.49-1.46; all-cause hospitalisation: HR 0.90, 95% CI 0.76-1.06; and HF-specific hospitalisation: HR 0.98, 95% CI 0.72-1.35]. No strong evidence was found of differential intervention effects across patient characteristics. CONCLUSION: Exercise-based cardiac rehabilitation did not have a significant effect on the risk of mortality and hospitalisation in HF with reduced ejection fraction. However, uncertainty around effect estimates precludes drawing definitive conclusions.This work is supported by UK National Institute for Health Research funding (HTA 15/80/30)

Epigenetics in the primary and secondary prevention of cardiovascular disease: influence of exercise and nutrition

Increasing evidence links changes in epigenetic systems, such as DNA methylation, histone modification, and non-coding RNA expression, to the occurrence of cardiovascular disease (CVD). These epigenetic modifications can change genetic function under influence of exogenous stimuli and can be transferred to next generations, providing a potential mechanism for inheritance of behavioural intervention effects. The benefits of exercise and nutritional interventions in the primary and secondary prevention of CVD are well established, but the mechanisms are not completely understood. In this review, we describe the acute and chronic epigenetic effects of physical activity and dietary changes. We propose exercise and nutrition as potential triggers of epigenetic signals, promoting the reshaping of transcriptional programmes with effects on CVD phenotypes. Finally, we highlight recent developments in epigenetic therapeutics with implications for primary and secondary CVD prevention

British randomised controlled trial of AV and VV optimization ("BRAVO") study:rationale, design, and endpoints

Background Echocardiographic optimization of pacemaker settings is the current standard of care for patients treated with cardiac resynchronization therapy. However, the process requires considerable time of expert staff. The BRAVO study is a non-inferiority trial comparing echocardiographic optimization of atrioventricular (AV) and interventricular (VV) delay with an alternative method using non-invasive blood pressure monitoring that can be automated to consume less staff resources. Methods/Design BRAVO is a multi-centre, randomized, cross-over, non-inferiority trial of 400 patients with a previously implanted cardiac resynchronization device. Patients are randomly allocated to six months in each arm. In the echocardiographic arm, AV delay is optimized using the iterative method and VV delay by maximizing LVOT VTI. In the haemodynamic arm AV and VV delay are optimized using non-invasive blood pressure measured using finger photoplethysmography. At the end of each six month arm, patients undergo the primary outcome measure of objective exercise capacity, quantified as peak oxygen uptake (VO2) on a cardiopulmonary exercise test. Secondary outcome measures are echocardiographic measurement of left ventricular remodelling, quality of life score and N-terminal pro B-type Natriuretic Peptide (NT-pro BNP). The study is scheduled to complete recruitment in December 2013 and to complete follow up in December 2014. Discussion If exercise capacity is non-inferior with haemodynamic optimization compared with echocardiographic optimization, it would be proof of concept that haemodynamic optimization is an acceptable alternative which has the potential to be more easily implemented

Identification of molecular signatures specific for distinct cranial sensory ganglia in the developing chick

Background The cranial sensory ganglia represent populations of neurons with distinct functions, or sensory modalities. The production of individual ganglia from distinct neurogenic placodes with different developmental pathways provides a powerful model to investigate the acquisition of specific sensory modalities. To date there is a limited range of gene markers available to examine the molecular pathways underlying this process. Results Transcriptional profiles were generated for populations of differentiated neurons purified from distinct cranial sensory ganglia using microdissection in embryonic chicken followed by FAC-sorting and RNAseq. Whole transcriptome analysis confirmed the division into somato- versus viscerosensory neurons, with additional evidence for subdivision of the somatic class into general and special somatosensory neurons. Cross-comparison of distinct ganglia transcriptomes identified a total of 134 markers, 113 of which are novel, which can be used to distinguish trigeminal, vestibulo-acoustic and epibranchial neuronal populations. In situ hybridisation analysis provided validation for 20/26 tested markers, and showed related expression in the target region of the hindbrain in many cases. Results One hundred thirty-four high-confidence markers have been identified for placode-derived cranial sensory ganglia which can now be used to address the acquisition of specific cranial sensory modalities.</p

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Ischaemic preconditioning protects against myocardial dysfunction caused by ischaemia in isolated hypertrophied rat hearts

Although ischaemic preconditioning (PC) has been shown to protect normal hearts from a subsequent ischaemic insult, its protective effect on the hypertrophied myocardium has not been widely studied. This study was designed to investigate whether ischaemic preconditioning protects hearts with hypertrophy (HYP). Cardiac HYP was produced in rats by suprarenal abdominal aortic constriction of 5 weeks’ duration, and was defined as left ventricular weight: body weight [LVW: BW(mg/g)] ratio over 3.0. Isolated rat hearts were perfused with a modified Krebs-Henseleit buffer at 37 degrees C in a Langendorff preparation. Hearts from sham-operated animals (NORM) and those with HYP underwent a PC protocol consisting of 3 min of global zero flow ischaemia, 5 min of reperfusion followed by 5 min of ischaemia and 5 min of reperfusion. This was followed by 20 min ischaemia and 45 min reperfusion. Control hearts in the HYP and NORM groups were not subjected to the PC protocol. There were, thus, four experimental groups: NORM control (n = 9), NORM, PC (n = 9), HYP control (n = 9), HYP, PC (n = 11). The recovery of function after ischaemia was evaluated by recovery of left ventricular developed pressure (LVDP) expressed as % of the initial value (LVDP%). The LVW: BW ratio for the HYP groups was 3.4 (SEM 0.08). LVDP% was higher (p &lt; 0.01) in preconditioned groups as compared with controls. In NORM control recovery was 49.3 (6.1), NORM, PC 76.5 (3.4), HYP control 39.8 (4.6) HYP, PC 70.1 (4.1). These data indicate that the ability of preconditioning to protect against ischaemic ventricular dysfunction is preserved in this model of cardiac hypertrophy

Body mass and survival in patients with chronic heart failure without cachexia: the importance of obesity.

Background: Cachexia in chronic heart failure carries a poor prognosis, but little is known about the influence of body mass on the prognosis of noncachectic heart failure patients. Methods: We studied 589 consecutive chronic heart failure patients followed for at least a year, in whom there were accurate baseline data for body mass. Results: Average age was 64.5 ± 12.4 years, left ventricular ejection fraction (LVEF) 30.9 ± 0.73%. Cachexia was present in 64. Noncachectic patients were divided into quintiles of body mass index (BMI), Q1 (BMI 22.2 ± 1.5) to Q5 (BMI 34.1 ± 2.8). There was no difference among the 5 groups in age, exercise capacity or LVEF. Survival was greatest in Q4 (1-year survival [95% confidence interval (CI)]) 0.91 (0.85-0.96) and 3-year survival 0.81 (0.73-0.89). Relative risks compared with Q4 were Q1: 2.3 (1.4-3.8); Q2: 1.7 (1.1-2.9); Q3: 1.8 (1.1-3.0); and Q5: 1.5 (0.9-2.5). In multivariate analysis of 1 year follow-up, peak oxygen consumption (hazard ratio with 95% CI) (0.89 [0.82-0.97]; P = .006), LVEF (0.94 [0.91-0.97]; P = .0002) and BMI (0.90 [0.82-0.98]; P = .02) independently predicted 1-year survival with a combined X2 value of 42.4. Age (1.01 [0.98-1.05] and diagnosis (1.56 [0.78-3.11]) was not a predictor of survival. Conclusion: In patients with chronic heart failure, increasing BMI is not an adverse prognostic feature. Thinner patients appear to have a poorer prognosis