Divergent cardiac and renal effects of miR-181c-5p inhibition in a rodent heart failure model.

Aims: MiR-181c-5p overexpression associates with heart failure (HF) and cardiac damage, but the underlying pathophysiology remains unclear. This study investigated the effect of miR-181c-5p inhibition on cardiac function and fibrosis in a rodent model of diastolic dysfunction, and evaluated additional effects on kidney as relevant comorbid organ. Methods and results: Diastolic dysfunction was induced in male C57/BL6J mice (n = 20) by combining high-fat diet, L-NG-nitroarginine methyl ester, and angiotensin II administration, and was compared to sham controls (n = 18). Mice were randomized to subcutaneous miR-181c-5p antagomiR (INH) or scrambled antagomiR injections (40 mg/kg/week). HF mice demonstrated diastolic dysfunction and increased fibrosis, which was attenuated by INH treatment. Remarkably, HF + INH animals had a threefold higher mortality rate (60%) compared to HF controls (20%). Histological examination revealed increased glomerular damage in all INH treated mice, and signs of thrombotic microangiopathy (TMA) in mice who died prematurely. Quantitative polymerase chain reaction demonstrated a miR-181c-5p-related downregulation of cardiac but not renal Tgfbr1 in HF + INH mice, while INH treatment reduced renal but not cardiac Vegfa expression in all mice. Conclusion: This study demonstrates cardiac anti-fibrotic effects of miR-181c-5p inhibition in a rodent HF model through targeting of Tgfbr1 in the heart. Despite improved diastolic function, HF + INH mice had higher mortality due to increased predisposition for TMA, increased renal fibrosis and glomerular damage, associated with Vegfa downregulation in kidneys.

Circulating MicroRNA as Biomarkers of Anthracycline-Induced Cardiotoxicity: JACC: CardioOncology State-of-the-Art Review.

Close monitoring for cardiotoxicity during anthracycline chemotherapy is crucial for early diagnosis and therapy guidance. Currently, monitoring relies on cardiac imaging and serial measurement of cardiac biomarkers like cardiac troponin and natriuretic peptides. However, these conventional biomarkers are nonspecific indicators of cardiac damage. Exploring new, more specific biomarkers with a clear link to the underlying pathomechanism of cardiotoxicity holds promise for increased specificity and sensitivity in detecting early anthracycline-induced cardiotoxicity. miRNAs (microRNAs), small single-stranded, noncoding RNA sequences involved in epigenetic regulation, influence various physiological and pathological processes by targeting expression and translation. Emerging as new biomarker candidates, circulating miRNAs exhibit resistance to degradation and offer a direct pathomechanistic link. This review comprehensively outlines their potential as early biomarkers for cardiotoxicity and their pathomechanistic link.

Heart failure with severely reduced ejection fraction after liver transplantation: a case report and review of the literature.

BACKGROUND: Liver transplantation (LT) is a strenuous event for the cardiovascular system. Cardiovascular events (CVE), including heart failure (HF), arrhythmias and myocardial ischemia, are important causes of peri- and post-liver transplantation morbidity and mortality. CASE PRESENTATION: We describe the case of a 45-year-old male patient who developed heart failure with severely reduced ejection fraction (HFrEF) after receiving liver transplantation (LT) for end-stage post-alcoholic liver cirrhosis. Preoperative transthoracic echocardiography (TTE) demonstrated borderline left ventricular ejection fraction (LVEF) of 50% and diastolic dysfunction grade 2. On coronary angiography, the patient had no coronary stenoses. Persistent vasopressor need, increasing creatinine levels and progressive pleural effusion characterized the early postoperative period. TTE on postoperative day 6 revealed a new finding of a markedly reduced LVEF of 15%, accompanied by a discrete increase in hs-TnI and CK-MB without electrocardiographic (ECG) ST-T abnormalities. LVEF did not recover completely (EF 45%) during follow-up. The patient had a sudden death 4.5 months post-liver transplantation. CONCLUSION: Our case demonstrates that the risk of post-LT systolic dysfunction is not excluded by preoperative resting examinations within normal range and highlights the need for preoperative cardiac stress assessment (e.g. dobutamine echocardiography or stress cardiac magnetic resonance imaging) before LT. In addition, patients on a liver-transplant waiting list with cardiac dysfunction should be followed by a multidisciplinary team including a dedicated cardiology team experienced in managing liver-related cardiac pathology.

Fluorescent In Situ Hybridization for miRNA Combined with Staining of Proteins.

The last decades have illustrated the importance of microRNAs (miRNAs) in various biological and pathological processes. The combined visualization of miRNAs using fluorescent in situ hybridization (FISH) and proteins using immunofluorescence (IF) can reveal their spatiotemporal distribution in relation to the cell and tissue morphology and can provide interesting insights into miRNA-protein interactions. However, standardized protocols for co-localization of miRNAs and proteins are currently lacking, and substantial technical obstacles still need to be addressed. In particular, the incompatibility of protein IF protocols with steps required for miRNA FISH, such as proteolytic pretreatments and ethylcarbodiimide post-fixation, as well as hurdles related to low signal intensity of low-copy miRNAs, remains challenging. Our technique may considerably enhance miRNA-based research, as current detection techniques lack the ability to elucidate cellular and subcellular localization. Here, we describe an optimized 2-day protocol for combined detection of low-abundant miRNAs and proteins in cryosections of cardiac tissue, without the need for protease-dependent pretreatment or post-fixation treatment. We successfully demonstrate endothelial-specific localization of low-abundant miR-181c-5p in cardiac tissue. © 2023 Wiley Periodicals LLC. Basic Protocol: Fluorescent in situ hybridization for miRNA combined with staining of proteins.

Webtool to enhance the accuracy of diagnostic algorithms for HFpEF: a prospective cross-over study.

AIMS: Diagnosis of heart failure with preserved ejection fraction (HFpEF) can be challenging. This study aimed to evaluate the potential of a webtool to enhance the scoring accuracy when applying the complex HFA-PEFF and H2 FPEF algorithms, which are commonly used for diagnosing HFpEF. METHODS AND RESULTS: We developed an online tool, the HFpEF calculator, that enables the automatic calculation of current HFpEF algorithms. We assessed the accuracy of manual vs. automatic scoring, defined as the percentage of correct scores, in a cohort of cardiologists with varying clinical experience. Cardiologists scored eight online clinical cases using a triple cross-over design (i.e. two manual-two automatic-two manual-two automatic). Data were analysed in study completers (n = 55, 29% heart failure specialists, 42% general cardiologists, and 29% cardiology residents). Manually calculated scores were correct in 50% (HFA-PEFF: 50% [50-75]; H2 FPEF: 50% [38-50]). Correct scoring improved to 100% using the HFpEF calculator (HFA-PEFF: 100% [88-100], P < 0.001; H2 FPEF: 100% [75-100], P < 0.001). Time spent on clinical cases was similar between scoring methods (±4 min). When corrections for faulty algorithm scores were displayed, cardiologists changed their diagnostic decision in up to 67% of cases. At least 67% of cardiologists preferred using the online tool for future cases in clinical practice. CONCLUSIONS: Manual calculation of HFpEF diagnostic algorithms is often inaccurate. Using an automated webtool to calculate HFpEF algorithms significantly improved correct scoring. This new approach may impact the eventual diagnostic decision in up to two-thirds of cases, supporting its routine use in clinical practice.

Left ventricular functional recovery after atrial fibrillation catheter ablation in heart failure: a prediction model.

AIMS: Management of patients with atrial fibrillation (AF) and concomitant heart failure (HF) remains complex. The Antwerp score, based on four parameters [QRS >120 ms (2 points), known aetiology (2 points), paroxysmal AF (1 point), severe atrial dilation (1 point)] adequately estimated the probability of left ventricular ejection fraction (LVEF) recovery after AF ablation in a single-centre cohort. The present study aims to externally validate this prediction model in a large European multi-centre cohort. METHODS AND RESULTS: A total of 605 patients (61.1 ± 9.4 years, 23.8% females, 79.8% with persistent AF) with HF and impaired LVEF (<50%) undergoing AF ablation in 8 European centres were retrospectively identified. According to the LVEF changes at 12-month echocardiography, 427 (70%) patients fulfilled the '2021 Universal Definition of HF' criteria for LVEF recovery and were defined as 'responders'. External validation of the score yielded good discrimination and calibration {area under the curve 0.86 [95% confidence interval (CI) 0.82-0.89], P < .001; Hosmer-Lemeshow P = .29}. Patients with a score < 2 had a 93% probability of LVEF recovery as opposed to only 24% in patients with a score > 3. Responders experienced more often positive ventricular remodelling [odds ratio (OR) 8.91, 95% CI 4.45-17.84, P < .001], fewer HF hospitalizations (OR 0.09, 95% CI 0.05-0.18, P < .001) and lower mortality (OR 0.11, 95% CI 0.04-0.31, P < .001). CONCLUSION: In this multi-centre study, a simple four-parameter score predicted LVEF recovery after AF ablation in patients with HF and discriminated clinical outcomes. These findings support the use of the Antwerp score to standardize shared decision-making regarding AF ablation referral in future clinical studies.

Effect of Training on Vascular Function and Repair in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Exercise training improves peak oxygen uptake (V.O2peak) 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 = 180) to HIIT, MICT, or guideline control. At baseline, 3, and 12 months, the authors measured peripheral arterial tonometry (valid baseline measurement in n = 109), flow-mediated dilation (n = 59), augmentation index (n = 94), and flow cytometry (n = 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 V.O2peak 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).

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.

Peak O2 -pulse predicts exercise training-induced changes in peak V̇O2 in heart failure with preserved ejection fraction.

AIMS: Exercise training (ET) has been consistently shown to increase peak oxygen consumption (V̇O2 ) in patients with heart failure with preserved ejection fraction (HFpEF); however, inter-individual responses vary significantly. Because it is unlikely that ET-induced improvements in peak V̇O2 are significantly mediated by an increase in peak heart rate (HR), we aimed to investigate whether baseline peak O2 -pulse (V̇O2  × HR-1 , reflecting the product of stroke volume and arteriovenous oxygen difference), not baseline peak V̇O2 , is inversely associated with the change in peak V̇O2 (adjusted by body weight) following ET versus guideline control (CON) in patients with HFpEF. METHODS AND RESULTS: This 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 V̇O2 (%) was analysed as a function of baseline peak V̇O2 and its determinants (absolute peak V̇O2 , peak O2 -pulse, peak HR, weight, haemoglobin) using robust linear regression analyses. Mediating effects on change in peak V̇O2 through changes in peak O2 -pulse, peak HR and weight were analysed by a causal mediation analysis with multiple correlated mediators. Change in submaximal exercise tolerance (V̇O2 at the ventilatory threshold, VT1) was analysed as a secondary endpoint. Among 158 patients with HFpEF (66% female; mean age, 70 ± 8 years), changes in peak O2 -pulse explained approximately 72% of the difference in changes in peak V̇O2 between ET and CON [10.0% (95% CI, 4.1 to 15.9), P = 0.001]. There was a significant interaction between the groups for the influence of baseline peak O2 -pulse on change in peak V̇O2 (interaction P = 0.04). In the ET group, every 1 mL/beat higher baseline peak O2 -pulse was associated with a decreased mean change in peak V̇O2 of -1.45% (95% CI, -2.30 to -0.60, P = 0.001) compared with a mean change of -0.08% (95% CI, -1.11 to 0.96, P = 0.88) following CON. None of the other factors showed significant interactions with study groups for the change in peak V̇O2 (P > 0.05). Change in V̇O2 at VT1 was not associated with any of the investigated factors (P > 0.05). CONCLUSIONS: In patients with HFpEF, the easily measurable peak O2 -pulse seems to be a good indicator of the potential for improving peak V̇O2 through exercise training. While changes in submaximal exercise tolerance were independent of baseline peak O2 -pulse, patients with high O2 -pulse may need to use additional therapies to significantly increase peak V̇O2 .

Exercise Systolic Reserve and Exercise Pulmonary Hypertension Improve Diagnosis of Heart Failure With Preserved Ejection Fraction.

AIMS: Diastolic stress testing (DST) is recommended to confirm heart failure with preserved ejection fraction (HFpEF) in patients with exertional dyspnea, but current algorithms do not detect all patients. We aimed to identify additional echocardiographic markers of elevated pulmonary arterial wedge pressure during exercise (exPAWP) in patients referred for DST. METHODS AND RESULTS: We identified candidate parameters in 22 patients referred for exercise right heart catheterization with simultaneous echocardiography. Elevated exPAWP (≥25 mmHg) was present in 14 patients, and was best identified by peak septal systolic annular velocity <9.5 cm/s [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 ≥3.2 mmHg/L [mPAP/CO, AUC 0.88 (0.72-1.0)]. We propose a decision tree to identify patients with elevated exPAWP. Applying this decision tree to 326 patients in an independent non-invasive DST cohort showed that patients labeled as "high probability of HFpEF" (n = 85) had reduced peak oxygen uptake [13.0 (10.7-15.1) mL/kg/min, p < 0.001 vs. intermediate/low probability], high H2FPEF score [53 (40-72) %, p < 0.001 vs. intermediate/low probability], and typical clinical characteristics. The diagnostic yield of DST increased from 11% using exercise E/e', to 62% using the decision tree. CONCLUSION: In 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 number of inconclusive results.

Heart failure with preserved ejection fraction: recent concepts in diagnosis, mechanisms and management.

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.

Plasma-Derived microRNAs Are Influenced by Acute and Chronic Exercise in Patients With Heart Failure With Reduced Ejection Fraction.

Background: Exercise training improves VO2peak in heart failure with reduced ejection fraction (HFrEF), but the effect is highly variable as it is dependent on peripheral adaptations. We evaluated changes in plasma-derived miRNAs by acute and chronic exercise to investigate whether these can mechanistically be involved in the variability of exercise-induced adaptations. Methods: Twenty-five male HFrEF patients (left ventricular ejection fraction < 40%, New York Heart Association class ≥ II) participated in a 15-week combined strength and aerobic training program. The effect of training on plasma miRNA levels was compared to 21 male age-matched sedentary HFrEF controls. Additionally, the effect of a single acute exercise bout on plasma miRNA levels was assessed. Levels of 5 miRNAs involved in pathways relevant for exercise adaptation (miR-23a, miR-140, miR-146a, miR-191, and miR-210) were quantified using RT-qPCR and correlated with cardiopulmonary exercise test (CPET), echocardiographic, vascular function, and muscle strength variables. Results: Expression levels of miR-146a decreased with training compared to controls. Acute exercise resulted in a decrease in miR-191 before, but not after training. Baseline miR-23a predicted change in VO2peak independent of age and left ventricular ejection fraction (LVEF). Baseline miR-140 was independently correlated with change in load at the respiratory compensation point and change in body mass index, and baseline miR-146a with change in left ventricular mass index. Conclusion: Plasma-derived miRNAs may reflect the underlying mechanisms of exercise-induced adaptation. In HFrEF patients, baseline miR-23a predicted VO2peak response to training. Several miRNAs were influenced by acute or repeated exercise. These findings warrant exploration in larger patient populations and further mechanistic in vitro studies on their molecular involvement.

miR-181c level predicts response to exercise training in patients with heart failure and preserved ejection fraction: an analysis of the OptimEx-Clin trial.

AIMS: In 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 RESULTS: We 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, ß = -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. CONCLUSIONS: Circulating 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.

Clinical phenogroups are more effective than left ventricular ejection fraction categories in stratifying heart failure outcomes.

AIMS: Heart failure (HF) guidelines place patients into 3 discrete groups according to left ventricular ejection fraction (LVEF): reduced (<40%), mid-range (40-49%), and preserved LVEF (≥50%). We assessed whether clinical phenogroups offer better prognostication than LVEF. METHODS AND RESULTS: This was a sub-study of the Patient-Centered Care Transitions in HF trial. We analysed baseline characteristics of hospitalized patients in whom LVEF was recorded. We used unsupervised machine learning to identify clinical phenogroups and, thereafter, determined associations between phenogroups and outcomes. Primary outcome was the composite of all-cause death or rehospitalization at 6 and 12 months. Secondary outcome was the composite cardiovascular death or HF rehospitalization at 6 and 12 months. Cluster analysis of 1693 patients revealed six discrete phenogroups, each characterized by a predominant comorbidity: coronary heart disease, valvular heart disease, atrial fibrillation (AF), sleep apnoea, chronic obstructive pulmonary disease (COPD), or few comorbidities. Phenogroups were LVEF independent, with each phenogroup encompassing a wide range of LVEFs. For the primary composite outcome at 6 months, the hazard ratios (HRs) for phenogroups ranged from 1.25 [95% confidence interval (CI) 1.00-1.58 for AF] to 2.04 (95% CI 1.62-2.57 for COPD) (log-rank P < 0.001); and at 12 months, the HRs for phenogroups ranged from 1.15 (95% CI 0.94-1.41 for AF) to 1.87 (95% 1.52-3.20 for COPD) (P < 0.002). LVEF-based classifications did not separate patients into different risk categories for the primary outcomes at 6 months (P = 0.69) and 12 months (P = 0.30). Phenogroups also stratified risk of the secondary composite outcome at 6 and 12 months more effectively than LVEF. CONCLUSION: Among patients hospitalized for HF, clinical phenotypes generated by unsupervised machine learning provided greater prognostic information for a composite of clinical endpoints at 6 and 12 months compared with LVEF-based categories. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02112227.

Comprehensive multicomponent cardiac rehabilitation in cardiac implantable electronic devices recipients: a consensus document from the European Association of Preventive Cardiology (EAPC; Secondary prevention and rehabilitation section) and European Heart Rhythm Association (EHRA).

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.

Circulating microRNA as predictors for exercise response in heart failure with reduced ejection fraction.

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 <6%, respectively. First, unsupervised clustering analysis of the miRNA pattern was performed. Second, differential expression of miRNA in ER and ENR was analysed and related to percent change in VO2peak. Third, a gene set enrichment analysis was conducted to detect targeted genes and pathways. Baseline characteristics and training volume were similar between ER and ENR. Unsupervised clustering analysis of miRNAs distinguished ER from ENR with 83% accuracy. A total of 57 miRNAs were differentially expressed in ENR vs. ER. A panel of seven miRNAs up-regulated in ENR (Let-7b, miR-23a, miR-140, miR-146a, miR-191, miR-210, and miR-339-5p) correlated with %changeVO2peak (all P < 0.05) and predicted ENR with area under the receiver operating characteristic curves ≥0.77. Multiple pathways involved in exercise adaptation processes were identified. 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.

Comprehensive multicomponent cardiac rehabilitation in cardiac implantable electronic devices recipients: a consensus document from the European Association of Preventive Cardiology (EAPC; Secondary prevention and rehabilitation section) and European Heart Rhythm Association (EHRA).

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.

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.

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.