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BACKGROUND Exercise training improves peak oxygen uptake (_VO2peak) in heart failure with preserved ejection fraction (HFpEF). Multiple adaptations have been addressed, but the role of circulating endothelium-repairing cells and vascular function have not been well defined. OBJECTIVES The authors investigated effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on vascular function and repair in HFpEF. METHODS This study is a subanalysis of the OptimEx-Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure) study randomizing patients with HFpEF (n 1/4 180) to HIIT, MICT, or guideline control. At baseline, 3, and 12 months, the authors measured peripheral arterial tonometry (valid baseline measurement in n 1/4 109), flow -mediated dilation (n 1/4 59), augmentation index (n 1/4 94), and flow cytometry (n 1/4 136) for endothelial progenitor cells and angiogenic T cells. Abnormal values were defined as outside 90% of published sex-specific reference values. RESULTS At baseline, abnormal values (%) were observed for augmentation index in 66%, peripheral arterial tonometry in 17%, flow-mediated dilation in 25%, endothelial progenitor cells in 42%, and angiogenic T cells in 18%. These parameters did not change significantly after 3 or 12 months of HIIT or MICT. Results remained unchanged when confining analysis to patients with high adherence to training. CONCLUSIONS In patients with HFpEF, high augmentation index was common, but endothelial function and levels of endothelium-repairing cells were normal in most patients. Aerobic exercise training did not change vascular function or cellular endothelial repair. Improved vascular function did not significantly contribute to the _VO2peak improvement after different training intensities in HFpEF, contrary to previous studies in heart failure with reduced ejection fraction and coronary artery disease. (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure [OptimEx-Clin]; NCT02078947) (J Am Coll Cardiol HF 2023;11:454-464) (c) 2023 by the American College of Cardiology Foundation.

Background: MiR-181c-5p is described to induce heart failure (HF), while its role in renal pathology is undetermined. Renal dysfunction is present in 40-60% of HF patients and associated with poor prognosis. This study is the first of its kind to investigate the role of miR-181c-5p in a mouse model of cardiorenal disease (CRD). Our hypothesis states a protective effect of miR-181c-5p inhibition on HF development. Methods: CRD was induced by feeding male C57BL/6J mice (n=20) a high-fat diet (HFD) and L-NAME in drinking water (5g/L) for 6 weeks, angiotensin-II was co-administered via osmotic minipumps (1000ng/kg/min) during the final 2 weeks. Healthy controls (n=16) underwent sham-surgery. Mice were randomly assigned to weekly injections (40mg/kg) with miR-181c-5p antagomiR (INH) or scrambled control for the duration of the study. We assessed cardiac function (echocardiography, hemodynamics), renal function (plasma creatinine), target expression (RT-qPCR), and histology. Results: CRD animals showed mild systolic and diastolic cardiac dysfunction compared to healthy controls, with cardiac fibrosis (2.5±0.3 vs 1.8±0.2% area; p=0.0004) and hypertrophy (0.11±0.03 vs 0.08±0.01g/cm; p=0.005). Renal dysfunction presents with kidney atrophy (0.07±0.006 vs 0.09±0.01g/cm; p=0.02), increased plasma creatinine (21±6 vs 10±5; p=0.01), renal fibrosis (0.26±0.22 vs 0.005±0.21 % area; p=0.036) and glomerular abnormalities (glomerulosclerosis, hypertrophy/atrophy, mesangial matrix expansion, reduced podocyte number). CRD+INH animals had comparable cardiac phenotype to CRD (p>0.05). Their renal phenotype was exacerbated with elevated glomerular damage (26±3 vs 18±9;p=0.04) and significantly increased mortality rate (50%) (Kaplan-Meier p=0.01) compared to healthy controls (0%) or CRD (20%), associated with increased occurrence of tubular atrophy, endothelial swelling and systemic thrombotic microangiopathy (TMA). qPCR analysis identified Vegf as potential target of miR-181c-5p. Conclusion: This study demonstrates a detrimental effect of miR-181c-5p inhibition on renal function in a CRD mouse model, driven by glomerular damage and TMA through Vegf signaling. Cardiac function was unaffected.

©The European Society of Cardiology 2020. Article reuse guidelines : sagepub.com/journals-permissions, Secondary 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.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021, Cardiac rehabilitation (CR) is a multidisciplinary intervention including patient assessment and medical actions to promote stabilization, management of cardiovascular risk factors, vocational support, psychosocial management, physical activity counselling, and prescription of exercise training. Millions of people with cardiac implantable electronic devices live in Europe and their numbers are progressively increasing, therefore, large subsets of patients admitted in CR facilities have a cardiac implantable electronic device. Patients who are cardiac implantable electronic devices recipients are considered eligible for a CR programme. This is not only related to the underlying heart disease but also to specific issues, such as psychological adaptation to living with an implanted device and, in implantable cardioverter-defibrillator patients, the risk of arrhythmia, syncope, and sudden cardiac death. Therefore, these patients should receive special attention, as their needs may differ from other patients participating in CR. As evidence from studies of CR in patients with cardiac implantable electronic devices is sparse, detailed clinical practice guidelines are lacking. Here, we aim to provide practical recommendations for CR in cardiac implantable electronic devices recipients in order to increase CR implementation, efficacy, and safety in this subset of patients.

Exercise training (ET) has been consistently shown to increase peak oxygen consumption (V̇OThis was a secondary analysis of the OptimEx-Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure, NCT02078947) trial, including all 158 patients with complete baseline and 3 month cardiopulmonary exercise testing measurements (106 ET, 52 CON). Change in peak V̇OIn patients with HFpEF, the easily measurable peak O

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., European Journal of Preventive Cardiology, 29 (17), ISSN:2047-4873, ISSN:2047-4881

International audience; It is estimated that half of all patients with heart failure (HF) have HF with preserved ejection fraction (HFpEF). Yet this form of HF remains a diagnostic and therapeutic challenge. Differentiating HFpEF from other causes of dyspnoea may require advanced diagnostic methods, such as exercise echocardiography, invasive haemodynamics and investigations for ‘HFpEF mimickers’. While the classification of HF has relied heavily on cut-points in left ventricular ejection fraction (LVEF), recent evidence points towards a gradual shift in underlying mechanisms, phenotypes and response to therapies as LVEF increases. For example, among patients with HF, the proportion of hospitalisations and deaths due to cardiac causes decreases as LVEF increases. Medication classes that are efficacious in HF with reduced ejection fraction (HFrEF) have been less so at higher LVEF ranges, decreasing the risk of HF hospitalisation but not cardiovascular or all-cause death in HFpEF. These observations reflect the burden of non-cardiac comorbidities as LVEF increases and highlight the complex pathophysiological mechanisms, both cardiac and non-cardiac, underpinning HFpEF. Treatment with sodium-glucose cotransporter 2 inhibitors reduces the risk of composite cardiovascular events, driven by a reduction in HF hospitalisations; renin-angiotensin-aldosterone blockers and angiotensin-neprilysin inhibitors result in smaller reductions in HF hospitalisations among patients with HFpEF. Comprehensive management of HFpEF includes exercise as well as treatment of risk factors and comorbidities. Classification based on phenotypes may facilitate a more targeted approach to treatment than LVEF categorisation, which sets arbitrary cut-points when LVEF is a continuum. This narrative review summarises the pathophysiology, diagnosis, classification and management of patients with HFpEF.

The benefit of regular physical activity and exercise training for the prevention of cardiovascular and metabolic diseases is undisputed. Many molecular mechanisms mediating exercise effects have been deciphered. Personalised exercise prescription can help patients in achieving their individual greatest benefit from an exercise-based cardiovascular rehabilitation programme. Yet, we still struggle to provide truly personalised exercise prescriptions to our patients. In this position paper, we address novel basic and translational research concepts that can help us understand the principles underlying the inter-individual differences in the response to exercise, and identify early on who would most likely benefit from which exercise intervention. This includes hereditary, non-hereditary and sex-specific concepts. Recent insights have helped us to take on a more holistic view, integrating exercise-mediated molecular mechanisms with those influenced by metabolism and immunity. Unfortunately, while the outline is recognisable, many details are still lacking to turn the understanding of a concept into a roadmap ready to be used in clinical routine. This position paper therefore also investigates perspectives on how the advent of 'big data' and the use of animal models could help unravel inter-individual responses to exercise parameters and thus influence hypothesis-building for translational research in exercise-based cardiovascular rehabilitation. The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: TSB is supported by a Medical Research Council UK New Investigator award (MR/S025472/1). EMVC is supported by Fund for Scientific Research Flanders (Senior Clinical Investigator fellowship) and Koning Boudewijnstichting (Fund Joseph Oscar Waldmann-Berteau 2015). NK receives project-specific funding from the German Centre for Cardiovascular Research (DZHK; 81X2100238 and 81X2100243), the German Foundation of Heart Research (F/39/17) and the German Diabetes Foundation (FP-0421-2018). ABG, VA, MB, VC, MD, DH, HMCK and PL do not receive funding pertinent to this work.

AimsIn patients with heart failure with preserved ejection fraction (HFpEF), exercise training improves the quality of life and aerobic capacity (peakV·O2). Up to 55% of HF patients, however, show no increase in peakV·O2 despite adequate training. We hypothesized that circulating microRNAs (miRNAs) can distinguish exercise low responders (LR) from exercise high responders (HR) among HFpEF patients.Methods and resultsWe selected HFpEF patients from the Optimizing Exercise Training in Prevention and Treatment of Diastolic HF (OptimEx) study which attended ≥70% of training sessions during 3 months (n = 51). Patients were defined as HR with a change in peakV·O2 above median (6.4%), and LR as below median (n = 30 and n = 21, respectively). Clinical, ergospirometric, and echocardiographic characteristics were similar between LR and HR. We performed an miRNA array (n = 377 miRNAs) in 14 age- and sex-matched patients. A total of 10 miRNAs were upregulated in LR, of which 4 correlated with peakV·O2. Validation in the remaining 37 patients indicated that high miR-181c predicted reduced peakV·O2 response (multiple linear regression, β = −2.60, P = 0.011), and LR status (multiple logistic regression, odds ratio = 0.48, P = 0.010), independent of age, sex, body mass index, and resting heart rate. Furthermore, miR-181c decreased in LR after exercise training (P-group = 0.030, P-time = 0.048, P-interaction = 0.037). An in silico pathway analysis identified several downstream targets involved in exercise adaptation.ConclusionsCirculating miR-181c is a marker of the response to exercise training in HFpEF patients. High miR-181c levels can aid in identifying LR prior to training, providing the possibility for individualized management.

The myocardium is a highly structured tissue consisting of different cell types including cardiomyocytes, endothelial cells, fibroblasts, smooth muscle cells, inflammatory cells, and stem cells. Microvascular endothelial cells are the most abundant cell type in the myocardium and play crucial roles during cardiac development, in normal adult myocardium, and during myocardial diseases such as heart failure. In the last decade, epigenetic changes have been described regulating cellular function in almost every cell type in the organism. Here, we review recent evidence on different epigenetic changes that regulate intercellular communication in normal myocardium and during myocardial diseases, including cardiac remodeling. Epigenetic changes influence many intercellular communication signaling systems, including the nitric oxide, angiotensin, and endothelin signaling systems. In this review, we go beyond discussing classic endothelial function (for instance nitric oxide secretion) and will discuss epigenetic regulation of intercellular communication.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com, A proper determination of the exercise intensity is important for the rehabilitation of patients with cardiovascular disease (CVD) since it affects the effectiveness and medical safety of exercise training. In 2013, the European Association of Preventive Cardiology (EAPC), together with the American Association of Cardiovascular and Pulmonary Rehabilitation and the Canadian Association of Cardiac Rehabilitation, published a position statement on aerobic exercise intensity assessment and prescription in cardiovascular rehabilitation (CR). Since this publication, many subsequent papers were published concerning the determination of the exercise intensity in CR, in which some controversies were revealed and some of the commonly applied concepts were further refined. Moreover, how to determine the exercise intensity during resistance training was not covered in this position paper. In light of these new findings, an update on how to determine the exercise intensity for patients with CVD is mandatory, both for aerobic and resistance exercises. In this EAPC position paper, it will be explained in detail which objective and subjective methods for CR exercise intensity determination exist for aerobic and resistance training, together with their (dis)advantages and practical applications.

AimsDiastolic stress testing (DST) is recommended to confirm heart failure with preserved ejection fraction (HFpEF) in patients with exertional dyspnea, but algorithms lack sensitivity. We aimed to identify additional echocardiographic markers of elevated pulmonary arterial wedge pressure during exercise (exPAWP) in patients referred for DST.Methods and ResultsWe analyzed 22 patients referred for exercise right heart catheterization with simultaneous echocardiography. We identified candidate parameters in patients with exPAWP ≥25 mmHg. Elevated exPAWP was present in 14 patients, and was best identified by peak septal systolic annular velocity on color Doppler (exS’, area under the receiver operating characteristic curve (AUC) 0.97, 95% confidence interval 0.92-1.0) and mean pulmonary artery pressure/cardiac output slope (mPAP/CO, AUC 0.88 [0.72-1.0]). We propose a three-step decision tree to identify patients with elevated exPAWP. Applying this decision tree to 376 patients in an independent non-invasive DST cohort showed that patients labeled as ‘high probability of HFpEF’ had reduced peak oxygen uptake (12.8 (10.5-15.9) mL/kg/min, pConclusionIn DST for suspected HFpEF, exS’ was the most accurate echocardiographic parameter to identify elevated PAWP. We propose a decision tree including exS’ and mPAP/CO for interpretation of DST. Application of this decision tree revealed typical HFpEF characteristics in patients labeled as high probability of HFpEF, and substantially reduced the amount of inconclusive results.

Aims Exercise training is a powerful adjunctive therapy in patients with heart failure with reduced ejection fraction (HFrEF), but ca. 55% of patients fail to improve VO2peak. We hypothesize that circulating microRNAs (miRNAs), as epigenetic determinants of VO2peak, can distinguish exercise responders (ER) from exercise non-responders (ENR). Methods and results We analysed 377 miRNAs in 18 male HFrEF patients (9 ER and 9 ENR) prior to 15 weeks of exercise training using a miRNA array. ER and ENR were defined as change in VO2peak of >20% or Conclusion A fingerprint of seven miRNAs involved in exercise adaptation processes is highly correlated with VO2peak trainability in HFrEF, which holds promise for the prediction of training response and patient-targeted exercise prescription.

The myocardium is a highly structured pluricellular tissue which is governed by an intricate network of intercellular communication. Endothelial cells are the most abundant cell type in the myocardium and exert crucial roles in both healthy myocardium and during myocardial disease. In the last decade, microRNAs have emerged as new actors in the regulation of cellular function in almost every cell type. Here, we review recent evidence on the regulatory function of different microRNAs expressed in endothelial cells, also called endothelial microRNAs, in healthy and diseased myocardium. Endothelial microRNA emerged as modulators of angiogenesis in the myocardium, they are implicated in the paracrine role of endothelial cells in regulating cardiac contractility and homeostasis, and interfere in the crosstalk between endothelial cells and cardiomyocytes.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com., This Delphi consensus by 28 experts from the European Association of Preventive Cardiology (EAPC) provides initial recommendations on how cardiovascular rehabilitation (CR) facilities should modulate their activities in view of the ongoing coronavirus disease 2019 (COVID-19) pandemic. A total number of 150 statements were selected and graded by Likert scale [from -5 (strongly disagree) to +5 (strongly agree)], starting from six open-ended questions on (i) referral criteria, (ii) optimal timing and setting, (iii) core components, (iv) structure-based metrics, (v) process-based metrics, and (vi) quality indicators. Consensus was reached on 58 (39%) statements, 48 'for' and 10 'against' respectively, mainly in the field of referral, core components, and structure of CR activities, in a comprehensive way suitable for managing cardiac COVID-19 patients. Panelists oriented consensus towards maintaining usual activities on traditional patient groups referred to CR, without significant downgrading of intervention in case of COVID-19 as a comorbidity. Moreover, it has been suggested to consider COVID-19 patients as a referral group to CR per se when the viral disease is complicated by acute cardiovascular (CV) events; in these patients, the potential development of COVID-related CV sequelae, as well as of pulmonary arterial hypertension, needs to be focused. This framework might be used to orient organization and operational of CR programmes during the COVID-19 crisis.