Exercise training for chronic heart failure (ExTraMATCH II): individual participant data meta-analysis of randomised controlled trials

This is the author accepted manuscript. The final version is available from NIHR Journals Library via the DOI in this record.Background: Current national and international guidelines on the management of heart failure (HF) recommend exercise-based cardiac rehabilitation (ExCR), but do not differentiate this recommendation according to patient subgroups. Objective(s): (1) to obtain definitive estimates of the impact of ExCR interventions versus control (no exercise intervention) on mortality, hospitalisation, exercise capacity, and health-related quality of life (HRQoL) in HF patients; (2) to determine the differential (subgroup) effects of ExCR in HF patients according to their age, gender, ejection fraction, aetiology, New York Heart Association (NYHA) class, and baseline exercise capacity; (3) to assess whether the change in exercise capacity mediates for the impact of the ExCR on final outcomes (mortality, hospitalisation, and HRQoL) and is an acceptable surrogate endpoint. Design: Individual participant data (IPD) meta-analysis Setting: An international literature review Participants: HF patients in randomised controlled trials (RCTs) of ExCR Interventions: ExCR for at least 3 weeks compared with no exercise control with 6 months follow-up Main outcome measures: mortality (all cause and HF-specific), hospitalisation (all-cause & HF-specific), exercise capacity, and HRQoL Data sources: Individual participant data from eligible RCTs 3 Review methods: RCTs from ExTraMATCH IPD meta-analysis and 2014 Cochrane systematic review of ExCR Results: Out of the 23 eligible RCTs (4,398 patients), 19 RCTs (3,990 patients) contributed data to this IPD meta-analysis. There was a wide variation in exercise programme prescriptions across included studies. Compared with control, there was no statistically significant difference in pooled time to event estimates in favour of ExCR although confidence intervals were wide: all-cause mortality: hazard ratio (HR) 0.83 (95% confidence interval (CI): 0.67 to 1.04), HF-related mortality: HR 0.84 (95% CI: 0.49 to 1.46), all-cause hospitalisation: HR 0.90 (95% CI: 0.76 to 1.06), and HF-related hospitalisation: HR 0.98 (95% CI: 0.72 to 1.35). There was a statistically significant difference in favour of ExCR for exercise capacity and HRQoL. Compared to control, at 12-months follow-up, improvements were seen in the six-minute walk test (6MWT) (mean: 21.0 metres, 95% CI: 1.57 to 40.4, and Minnesota Living with HF Questionnaire score (mean: -5.94, 95% CI: -1.0 to -10.9, lower scores indicate improved HRQoL). No strong evidence for differential intervention effects across patient characteristics was found for any outcomes. Moderate to good levels of correlation (R2 trial>50% & ρ>0.50) between peak oxygen uptake (VO2peak) or 6MWT with mortality and HRQoL were seen. Estimated surrogate threshold effect (STE) was an increase of 1.6 to 4.6 ml/kg/min for VO2peak. Limitations: Lack consistency in how included RCTs defined and collected the outcomes; we were unable to obtain IPD from all includable trials for all outcomes; and we did not seek patient level on exercise adherence. . Conclusions: In comparison to no exercise control, participation in ExCR improves the exercise and HRQoL in HF patients but appears to have no effect on their mortality or hospitalisation. No strong evidence was found of differential intervention effects of ExCR across patient characteristics. VO2peak and 6MWT may be suitable surrogate endpoints for the treatment effect of ExCR on mortality and HRQoL in HF.NIHR Health Technology Assessment programm

Desmin is essential for the structure and function of the sinoatrial node:implications for increased arrhythmogenesis

Our objective was to investigate the effect of desmin depletion on the structure and function of the sinoatrial pacemaker complex (SANcl) and its implication in arrhythmogenesis. Analysis of mice and humans (SANcl) indicated that the sinoatrial node exhibits high amounts of desmin, desmoplakin, N-cadherin, and β-catenin in structures we call “lateral intercalated disks” connecting myocytes side by side. Examination of the SANcl from an arrhythmogenic cardiomyopathy model, desmin-deficient (Des-/-) mouse, by immunofluorescence, ultrastructural, and Western blot analysis showed that the number of these lateral intercalated disks was diminished. Also, electrophysiological recordings of the isolated compact sinoatrial node revealed increased pacemaker systolic potential and higher diastolic depolarization rate compared with wild-type mice. Prolonged interatrial conduction expressed as a longer P wave duration was also observed in Des-/mice. Upregulation of mRNA levels of both T-type Ca2+ current channels, Cav3.1 and Cav3.2, in the Des-/- myocardium (1.8- and 2.3-fold, respectively) and a 1.9-fold reduction of funny hyperpolarization-activated cyclic nucleotide-gated K+ channel 1 could underlie these functional differences. To investigate arrhythmogenicity, electrocardiographic analysis of Des-deficient mice revealed a major increase in supraventricular and ventricular ectopic beats compared with wild-type mice. Heart rate variability analysis indicated a sympathetic predominance in Des-/- mice, which may further contribute to arrhythmogenicity. In conclusion, our results indicate that desmin elimination leads to structural and functional abnormalities of the SANcl. These alterations may be enhanced by the sympathetic component of the cardiac autonomic nervous system, which is predominant in the desmin-deficient heart, thus leading to increased arrhythmogenesis

Exercise-Based Cardiac Rehabilitation in Twelve European Countries Results of the European Cardiac Rehabilitation Registry

AIM: Results from EuroCaReD study should serve as a benchmark to improve guideline adherence and treatment quality of cardiac rehabilitation (CR) in Europe. METHODS AND RESULTS: Data from 2.054 CR patients in 12 European countries were derived from 69 centres. 76% were male. Indication for CR differed between countries being predominantly ACS in Switzerland (79%), Portugal (62%) and Germany (61%), elective PCI in Greece (37%), Austria (36%) and Spain (32%), and CABG in Croatia and Russia (36%). A minority of patients presented with chronic heart failure (4%). At CR start, most patients already were under medication according to current guidelines for the treatment of CV risk factors. A wide range of CR programme designs was found (duration 3 to 24weeks; total number of sessions 30 to 196). Patient programme adherence after admission was high (85%). With reservations that eCRF follow-up data exchange remained incomplete, patient CV risk profiles experienced only small improvements. CR success as defined by an increase of exercise capacity >25W was significantly higher in young patients and those who were employed. Results differed by countries. After CR only 9% of patients were admitted to a structured post-CR programme. CONCLUSIONS: Clinical characteristics of CR patients, indications and programmes in Europe are different. Guideline adherence is poor. Thus, patient selection and CR programme designs should become more evidence-based. Routine eCRF documentation of CR results throughout European countries was not sufficient in its first application because of incomplete data exchange. Therefore better adherence of CR centres to minimal routine clinical standards is requested

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)

Secondary prevention through comprehensive cardiovascular rehabilitation : from knowledge to implementation. 2020 update. A position paper from the Secondary Prevention and Rehabilitation Section of the European Association of Preventive Cardiology

©The European Society of Cardiology 2020. Article reuse guidelines : sagepub.com/journals-permissionsSecondary prevention through comprehensive cardiac rehabilitation has been recognized as the most cost-effective intervention to ensure favourable outcomes across a wide spectrum of cardiovascular disease, reducing cardiovascular mortality, morbidity and disability, and to increase quality of life. The delivery of a comprehensive and ‘modern’ cardiac rehabilitation programme is mandatory both in the residential and the out-patient setting to ensure expected outcomes. The present position paper aims to update the practical recommendations on the core components and goals of cardiac rehabilitation intervention in different cardiovascular conditions, in order to assist the whole cardiac rehabilitation staff in the design and development of the programmes, and to support healthcare providers, insurers, policy makers and patients in the recognition of the positive nature of cardiac rehabilitation. Starting from the previous position paper published in 2010, this updated document maintains a disease-oriented approach, presenting both well-established and more controversial aspects. Particularly for implementation of the exercise programme, advances in different training modalities were added and new challenging populations were considered. A general table applicable to all cardiovascular conditions and specific tables for each clinical condition have been created for routine practice.info:eu-repo/semantics/publishedVersio

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

Pro-HEART — A randomized clinical trial to test the effectiveness of a high protein diet targeting obese individuals with heart failure: Rationale, design and baseline characteristics

There is ample research to support the potential benefits of a high protein diet on clinical outcomes in overweight/obese, diabetic subjects. However, nutritional management of overweight/obese individuals with heart failure (HF) and type 2 diabetes mellitus (DM) or metabolic syndrome (MS) is poorly understood and few clinical guidelines related to nutritional approaches exist for this subgroup. This article describes the design, methods, and baseline characteristics of study participants enrolled in Pro-HEART, a randomized clinical trial to determine the short term and long term effects of a high protein diet (30% protein [~110 g/day], 40% carbohydrates [150 g/day], 30% fat [~50 g/day]) versus a standard protein diet (15% protein [~55 g/day], 55% carbohydrates [~200 g/day], 30% fat [~50 g/day]) on body weight and adiposity, cardiac structure and function, functional status, lipid profile, glycemic control, and quality of life. Between August, 2009 and May, 2013, 61 individuals agreed to participate in the study; 52 (85%) - mean age 58.2 ± 9.8 years; 15.4% Blacks; 57.7% Whites; 19.2% Hispanics; 7.7% Asians; 73.1% male; weight 112.0 ± 22.6 kilograms- were randomized to a 3-month intensive weight management program of either a high protein or standard protein diet; data were collected at baseline, 3 months, and 15 months. This study has the potential to reveal significant details about the role of macronutrients in weight management of overweight/obese individuals with HF and DM or MS

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