Comparison of exercise training modalities and change in peak oxygen consumption in heart failure with preserved ejection fraction: a secondary analysis of the OptimEx-Clin trial.

AIMS: Exercise training (ET) is an effective therapy in heart failure with preserved ejection fraction (HFpEF), but the influence of different ET characteristics is unclear. We aimed to evaluate the associations between ET frequency, duration, intensity [% heart rate reserve (%HRR)] and estimated energy expenditure (EEE) with the change in peak oxygen consumption (V̇O2) over 3 months of moderate continuous training (MCT, 5×/week) or high-intensity interval training (HIIT, 3×/week) in HFpEF. METHODS AND RESULTS: ET duration and heart rate (HR) were recorded with a smartphone application. EEE was calculated using the HR data during ET and the individual HR-V̇O2 relationships during cardiopulmonary exercise testing. Differences between groups and associations between ET characteristics and peak V̇O2 change were assessed with linear regression analyses. Peak V̇O2 improved by 9.2 ± 13.2% after MCT and 8.7 ± 15.9% after HIIT (P = 0.67). The average EEE of 1 HIIT session was equivalent to ∼1.42 MCT sessions and when adjusted for EEE, the mean difference between MCT and HIIT was -0.1% (P = 0.98). For both MCT and HIIT, peak V̇O2 change was positively associated with ET frequency (MCT: R2 = 0.103; HIIT: R2 = 0.149) and duration/week (MCT: R2 = 0.120; HIIT: R2 = 0.125; all P < 0.05). Average %HRR was negatively associated with peak V̇O2 change in MCT (R2 = 0.101; P = 0.034), whereas no significant association was found in HIIT (P = 0.234). Multiple regression analyses explained ∼1/3 of the variance in peak V̇O2 change. CONCLUSION: In HFpEF, isocaloric HIIT and MCT seem to be equally effective over 3 months. Within each mode, increasing ET frequency or duration/week may be more effective to improve peak V̇O2 than increasing ET intensity.

In heart failure with preserved ejection fraction, endurance exercise training is one of the most effective treatment options to improve exercise tolerance, however, the influence of different exercise training characteristics such as training frequency, duration, intensity and energy expenditure have not yet been evaluated. A high-intensity interval training session of 38 min was associated with a ∼42% higher energy expenditure compared with a moderate continuous training session of 40 min. After taking into account the different energy expenditure, both training modes had equal effects on exercise tolerance. Therefore, patient preferences should be considered when planning an exercise program to improve treatment adherence. A higher number of exercise sessions per week or a higher weekly duration of exercise were more closely related to an increase in exercise tolerance than a higher exercise intensity. Therefore, increasing the frequency or weekly duration of exercise may be more effective in improving exercise tolerance than increasing exercise intensity.

Exercise training in left ventricular assist device patients: Protocol of an individual participant data meta-analysis.

AIMS: Although left ventricular assist device (LVAD) implantation improves prognosis of advanced heart failure patients still suffer from impaired exercise capacity and quality of life (QoL). Exercise training may improve both; however, the available evidence about exercise training effects in LVAD patients remains inconclusive due to small and monocentric randomized controlled trials. This study aims to aggregate the individual participant data (IPD) to perform meta-analysis on the safety and efficacy of exercise training on exercise capacity and QoL over standard care in LVAD patients. METHODS: Randomized controlled trials comparing exercise training and standard care (no supervised training) will be identified through database searching. Corresponding authors of eligible randomized controlled trials will be invited to share IPD. All IPD will be checked, recalculated to validate findings in initial reports, merged in a single dataset and stored in a secured encrypted database server. The merged IPD will be screened for quality, risk of bias, and heterogeneity of the included trials. Random effects meta-analyses will be conducted using one-stage and two-stage approaches, in particular with a view to subgroup analyses. RESULTS: Based on findings of the individual randomized trials, we expected to obtain superior effects of exercise training on submaximal exercise capacity and QoL and similar effects on maximal aerobic capacity when compared with standard care. CONCLUSIONS: Our study will be the first to harmonize IPD in meta-analysis to demonstrate the effects of exercise training on exercise performance and QoL over standard care in LVAD patients. PROSPERO REGISTRATION NUMBER: CRD42023480119.

Converting PROMIS®-29 v2.0 profile data to SF-36 physical and mental component summary scores in patients with cardiovascular disorders.

BACKGROUND: Health-related quality of life (HRQL) has become an important outcome parameter in cardiology. The MOS 36-ltem Short-Form Health Survey (SF-36) and the PROMIS-29 are two widely used generic measures providing composite HRQL scores. The domains of the SF-36, a well-established instrument utilized for several decades, can be aggregated to physical (PCS) and mental (MCS) component summary scores. Alternative scoring algorithms for correlated component scores (PCSc and MCSc) have also been suggested. The PROMIS-29 is a newer but increasingly used HRQL measure. Analogous to the SF-36, physical and mental health summary scores can be derived from PROMIS-29 domain scores, based on a correlated factor solution. So far, scores from the PROMIS-29 are not directly comparable to SF-36 results, complicating the aggregation of research findings. Thus, our aim was to provide algorithms to convert PROMIS-29 data to well-established SF-36 component summary scores. METHODS: Data from n = 662 participants of the Berlin Long-term Observation of Vascular Events (BeLOVE) study were used to estimate linear regression models with either PROMIS-29 domain scores or aggregated PROMIS-29 physical/mental health summary scores as predictors and SF-36 physical/mental component summary scores as outcomes. Data from a subsequent assessment point (n = 259) were used to evaluate the agreement between empirical and predicted SF-36 scores. RESULTS: PROMIS-29 domain scores as well as PROMIS-29 health summary scores showed high predictive value for PCS, PCSc, and MCSc (R2 ≥ 70%), and moderate predictive value for MCS (R2 = 57% and R2 = 40%, respectively). After applying the regression coefficients to new data, empirical and predicted SF-36 component summary scores were highly correlated (r > 0.8) for most models. Mean differences between empirical and predicted scores were negligible (|SMD|<0.1). CONCLUSIONS: This study provides easy-to-apply algorithms to convert PROMIS-29 data to well-established SF-36 physical and mental component summary scores in a cardiovascular population. Applied to new data, the agreement between empirical and predicted SF-36 scores was high. However, for SF-36 mental component summary scores, considerably better predictions were found under the correlated (MCSc) than under the original factor model (MCS). Additionally, as a pertinent byproduct, our study confirmed construct validity of the relatively new PROMIS-29 health summary scores in cardiology patients.

Reduced dynamic changes in pulmonary artery compliance during isometric handgrip exercise in patients with heart failure.

Exercise intolerance is a debilitating symptom in heart failure (HF), adversely affecting both quality of life and long-term prognosis. Emerging evidence suggests that pulmonary artery (PA) compliance may be a contributing factor. This study aims to non-invasively assess PA compliance and its dynamic properties during isometric handgrip (HG) exercise in HF patients and healthy controls, using cardiovascular magnetic resonance (CMR). We prospectively enrolled 36 subjects, comprising 17 HF patients (NYHA class II and III) and 19 healthy controls. Participants performed an HG test, and we assessed changes in PA compliance and hemodynamic flow parameters using advanced CMR techniques. We also explored the relationship between CMR-derived PA compliance metrics and established clinical indicators, ensuring the validity of our findings through intra- and interobserver agreements. HF patients had significantly lower resting PA compliance compared to controls (28.9% vs. 50.1%, p < 0.01). During HG exercise, HF patients exhibited a dampened adaptability in PA compliance. Hemodynamic responses, including heart rate and blood pressure, were not significantly different between the groups. Further analyses revealed a significant correlation between changes in PA compliance and functional capacity, and an inverse relationship with NYHA class. Our study demonstrates a marked difference in PA vascular responses during HG exercise between HF patients and healthy controls. The compromised adaptability in PA compliance in HF patients is correlated with diminished functional capacity. These findings have significant clinical implications and may guide future interventional strategies in HF management.

Tricuspid Regurgitation in Patients With Heart Failure and Preserved Ejection Fraction: JACC State-of-the-Art Review.

Heart failure with preserved ejection fraction (HFpEF) is associated with high morbidity and mortality. Important risk factors for the development of HFpEF are similar to risk factors for the progression of tricuspid regurgitation (TR), and both conditions frequently coexist and thus is a distinct phenotype or a marker for advanced HF. Many patients with severe, symptomatic atrial secondary TR have been enrolled in current transcatheter device trials, and may represent patients at an advanced stage of HFpEF. Management of HFpEF thus may affect the pathophysiology of TR, and the physiologic changes that occur following transcatheter treatment of TR, may also impact symptoms and outcomes in patients with HFpEF. This review discusses these issues and suggests possible management strategies for these patients.

Transition from asymptomatic to symptomatic systolic chronic heart failure: rationale and design of TransitionCHF.

AIMS: Chronic systolic heart failure (CHF) is a major health burden. A relevant number of patients shows asymptomatic left ventricular dysfunction (ALVSD) before symptomatic CHF or becomes asymptomatic after initiating heart failure therapy. Clinical course, prognosis, and response to pharmacological and device-based treatment are largely unknown in these two distinct groups of patients. Current pharmacological and interventional therapies do neither properly address the underlying pathophysiology nor prevent malignant loss of function. New therapeutic paradigms are needed to stop the progression from asymptomatic to symptomatic heart failure. Key questions are what causes progression of clinically asymptomatic New York Heart Association (NYHA) I heart failure to overt heart failure (>NYHA I) in some but not all patients and the underlying reasons for this transition. This requires the identification of disease mechanisms and biomarkers that predict outcome in well-defined cohorts for innovative preclinical and clinical trials. METHODS AND RESULTS: TransitionCHF is a prospective, multicentre, longitudinal pathophysiological evaluation cohort study in patients with asymptomatic systolic dysfunction NYHA I and left ventricular ejection fraction ≤40%. The cohort comprises both incidental findings and patients who had become asymptomatic after a previous symptomatic event. TransitionCHF has recruited 1000 patients with ALVSD caused by various aetiologies in 20 university heart failure clinics across Germany. Both patients with and without comorbidities at study entry will be recruited. Patients will be systematically investigated and followed up annually over the course of the study. The primary composite endpoint is time to hospitalization for heart failure and cardiovascular death. The secondary endpoints assess time to all-cause mortality, to cardiovascular mortality, to heart failure mortality, to all-cause hospitalization, to heart failure hospitalization, and to recurrent heart failure hospitalizations, as well as time to assist device implantation/transplantation. Additional investigations focusing on biomarkers, comorbidities, gender aspects, nutrition, and functional parameters including quality of life will be performed. CONCLUSIONS: TransitionCHF will provide a more thorough pathophysiological understanding of the progression of asymptomatic systolic dysfunction into symptomatic heart failure that will help develop therapies tailored to prevent progressive heart failure.

Heart failure with preserved ejection fraction: diagnosis, risk assessment, and treatment.

The aetiology of heart failure with preserved ejection fraction (HFpEF) is heterogenous and overlaps with that of several comorbidities like atrial fibrillation, diabetes mellitus, chronic kidney disease, valvular heart disease, iron deficiency, or sarcopenia. The diagnosis of HFpEF involves evaluating cardiac dysfunction through imaging techniques and assessing increased left ventricular filling pressure, which can be measured directly or estimated through various proxies including natriuretic peptides. To better narrow down the differential diagnosis of HFpEF, European and American heart failure guidelines advocate the use of different algorithms including comorbidities that require diagnosis and rigorous treatment during the evaluation process. Therapeutic recommendations differ between guidelines. Whilst sodium glucose transporter 2 inhibitors have a solid evidence base, the recommendations differ with regard to the use of inhibitors of the renin-angiotensin-aldosterone axis. Unless indicated for specific comorbidities, the use of beta-blockers should be discouraged in HFpEF. The aim of this article is to provide an overview of the current state of the art in HFpEF diagnosis, clinical evaluation, and treatment.

Proteomic profiles of left atrial volume and its influence on response to spironolactone: Findings from the HOMAGE trial and STANISLAS cohort.

AIMS: High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables. METHODS AND RESULTS: In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m2). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population-based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m2). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase-2 (MMP-2), insulin-like growth factor binding protein-2 (IGFBP-2) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP-2 and NT-proBNP, regardless of baseline LAVi (pinteraction > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C-terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (pinteraction > 0.10). CONCLUSION: In individuals without heart failure, LAVi was associated with MMP-2, IGFBP-2 and NT-proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size.

Diuretic use and outcomes in patients with heart failure with reduced ejection fraction: Insights from the VICTORIA trial.

AIMS: In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a worsening heart failure (WHF) event. We examined clinical outcomes and efficacy of vericiguat as it relates to background use of loop diuretics in patients with WHF. METHODS AND RESULTS: We calculated the total daily loop diuretic dose equivalent to furosemide dosing at randomization and categorized these as: no loop diuretic, 1-39, 41-80, 40, and >80 mg total daily dose (TDD). The primary composite outcome of CVD/HFH and its components were evaluated based on TDD loop diuretic and expressed as adjusted hazard ratios with 95% confidence intervals. Post-randomization rates of change in TDD were also examined. Of 4974 patients (98% of the trial) with diuretic dose information available at randomization, 540 (10.8%) were on no loop diuretic, 647 (13.0%) were on 1-39, 1633 (32.8%) were on 40, 1185 (23.8%) were on 41-80, and 969 (19.4%) were on >80 mg TDD. Patients with higher TDD had a higher rate of primary and secondary clinical outcomes. There were no significant interactions with TDD at randomization and efficacy of vericiguat versus placebo for any outcome (all pinteraction > 0.5). Post-randomization diuretic dose changes for vericiguat and placebo showed similar rates of up-titration (19.6 and 20.2/100 person-years), down-titration (16.8 and 18.1/100 person-years), and stopping diuretics (22.9 and 24.2/100 person-years). CONCLUSIONS: Loop diuretic TDD at randomization was independently associated with worse outcomes in this high-risk population. The efficacy of vericiguat was consistent across the range of diuretic doses.

An altered plasma lipidome-phenome network characterizes heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial, multisystemic syndrome that involves alterations in lipid metabolism. This study aimed to test whether distinct plasma lipid profiles or lipid entities or both are associated with clinical and functional echocardiographic parameters in HFpEF. METHODS AND RESULTS: We examined the human plasma lipidome in HFpEF patients (n = 18) with left ventricular ejection fraction ≥50% and N-terminal pro-brain natriuretic peptide (NT-proBNP) >125 pg/mL and control subjects (n = 12) using mass spectrometry-based shotgun lipidomics. The cohort included 8 women and 22 men with average age of 67.8 ± 8.6 SD. The control and disease groups were not significantly different with respect to age, body mass index, systolic and diastolic blood pressure, and waist-to-hip ratio. The disease group experienced more fatigue (P < 0.001), had more often coronary artery disease (P = 0.04), and received more medications (beta-blockers, P < 0.001). The disease group had significantly different levels of HFpEF-relevant parameters, including NT-proBNP (P < 0.001), left ventricular mass index (P = 0.005), left atrial volume index (P = 0.001), and left ventricular filling index (P < 0.001), and lower left ventricular end-diastolic diameter (P = 0.014), with no difference in left ventricular ejection fraction. Significant differences in lipid profiles between HFpEF patients and controls could not be detected, including no significant differences in abundance of circulating lipids binned by carbon chain length or by double bonds, nor at the level of individual lipid species. However, there was a striking correlation between selected lipids with smoking status that was independent of disease status, as well as between specific lipids and hyperlipidaemia [with corresponding significance of either false discovery rate (FDR) <0.1 or FDR < 0.01]. In an exploratory network analysis of correlations, we observed significantly stronger correlations within the HFpEF group between individual lipids from the cholesterol ester and phosphatidylcholine (PC) classes and clinical/echocardiographic parameters such as left atrial volume index, left ventricular end-diastolic diameters, and heart rate (FDR < 0.1). In contrast, the control group showed significantly stronger negative correlations (FDR < 0.1) between individual species from the PC and sphingomyelin classes and left ventricular mass index or systolic blood pressure. CONCLUSIONS: We did not find significant direct associations between plasma lipidomic parameters and HFpEF and therefore could not conclude that any specific lipids are biomarkers of HFpEF. The validation in larger cohort is needed to confidently conclude the absence of first-order associations.

[Diagnosis of heart failure with preserved ejection fraction]. / Diagnostik der Herzinsuffizienz mit erhaltener Pumpfunktion.

Heart failure with preserved ejection fraction (HFpEF) currently causes about half of the heart failure related hospitalizations. With the aging of the population and increasing prevalence of risk factors and comorbidities, such as arterial hypertension, diabetes mellitus and obesity, HFpEF prevalence is expected to increase as well. With regards to quality of life, overall morbidity, and mortality, HFpEF patients have a similarly adverse prognosis as patients with heart failure with reduced ejection fraction. The leading symptoms of exertional dyspnea and exercise intolerance with concomitant clinical signs of heart failure should, therefore, prompt diagnostic tests to exclude or confirm HFpEF. Considering the main pathophysiological mechanisms, echocardiography is crucial to non-invasively identify signs of left ventricular (LV) hypertrophy, impaired myocardial relaxation, and elevated filling pressures. Elevated NT-proBNP may furthermore indicate increased LV wall stress and volume overload. If the results of these investigations are inconclusive, parameters of elevated filling pressures can be measured invasively by right or left heart catheterization. High pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) may confirm a HFpEF diagnosis. Ongoing studies are investigating potential distinct phenotypes within the HFpEF patient group.

Phenotyping patients with ischaemic heart disease at risk of developing heart failure: an analysis of the HOMAGE trial.

AIMS: We aim to characterize the clinical and proteomic profiles of patients at risk of developing heart failure (HF), with and without coronary artery disease (CAD) or prior myocardial infarction (MI). METHODS AND RESULTS: HOMAGE evaluated the effect of spironolactone on plasma and serum markers of fibrosis over 9 months of follow-up in participants with (or at risk of having) CAD, and raised natriuretic peptides. In this post hoc analysis, patients were classified as (i) neither CAD nor MI; (ii) CAD; or (iii) MI. Proteomic between-group differences were evaluated through logistic regression and narrowed using backward stepwise selection and bootstrapping. Among the 527 participants, 28% had neither CAD or MI, 31% had CAD, and 41% had prior MI. Compared with people with neither CAD nor MI, those with CAD had higher baseline plasma concentrations of matrix metalloproteinase-7 (MMP-7), galectin-4 (GAL4), plasminogen activator inhibitor 1 (PAI-1), and lower plasma peptidoglycan recognition protein 1 (PGLYRP1), whilst those with a history of MI had higher plasma MMP-7, neurotrophin-3 (NT3), pulmonary surfactant-associated protein D (PSPD), and lower plasma tumour necrosis factor-related activation-induced cytokine (TRANCE). Proteomic signatures were similar for patients with CAD or prior MI. Treatment with spironolactone was associated with an increase of MMP7, NT3, and PGLYRP1 at 9 months. CONCLUSIONS: In patients at risk of developing HF, those with CAD or MI had a different proteomic profile regarding inflammatory, immunological, and collagen catabolic processes.

Noninvasive evaluation of pulmonary artery stiffness in heart failure patients via cardiovascular magnetic resonance.

Heart failure (HF) presents manifestations in both cardiac and vascular abnormalities. Pulmonary hypertension (PH) is prevalent in up 50% of HF patients. While pulmonary arterial hypertension (PAH) is closely associated with pulmonary artery (PA) stiffness, the association of HF caused, post-capillary PH and PA stiffness is unknown. We aimed to assess and compare PA stiffness and blood flow hemodynamics noninvasively across HF entities and control subjects without HF using CMR. We analyzed data of a prospectively conducted study with 74 adults, including 55 patients with HF across the spectrum (20 HF with preserved ejection fraction [HFpEF], 18 HF with mildly-reduced ejection fraction [HFmrEF] and 17 HF with reduced ejection fraction [HFrEF]) as well as 19 control subjects without HF. PA stiffness was defined as reduced vascular compliance, indicated primarily by the relative area change (RAC), altered flow hemodynamics were detected by increased flow velocities, mainly by pulse wave velocity (PWV). Correlations between the variables were explored using correlation and linear regression analysis. PA stiffness was significantly increased in HF patients compared to controls (RAC 30.92 ± 8.47 vs. 50.08 ± 9.08%, p < 0.001). PA blood flow parameters were significantly altered in HF patients (PWV 3.03 ± 0.53 vs. 2.11 ± 0.48, p < 0.001). These results were consistent in all three HF groups (HFrEF, HFmrEF and HFpEF) compared to the control group. Furthermore, PA stiffness was associated with higher NT-proBNP levels and a reduced functional status. PA stiffness can be assessed non-invasively by CMR. PA stiffness is increased in HFrEF, HFmrEF and HFpEF patients when compared to control subjects.Trial registration The study was registered at the German Clinical Trials Register (DRKS, registration number: DRKS00015615).

Protocol of the Berlin Long-term Observation of Vascular Events (BeLOVE): a prospective cohort study with deep phenotyping and long-term follow up of cardiovascular high-risk patients.

INTRODUCTION: The Berlin Long-term Observation of Vascular Events is a prospective cohort study that aims to improve prediction and disease-overarching mechanistic understanding of cardiovascular (CV) disease progression by comprehensively investigating a high-risk patient population with different organ manifestations. METHODS AND ANALYSIS: A total of 8000 adult patients will be recruited who have either suffered an acute CV event (CVE) requiring hospitalisation or who have not experienced a recent acute CVE but are at high CV risk. An initial study examination is performed during the acute treatment phase of the index CVE or after inclusion into the chronic high risk arm. Deep phenotyping is then performed after ~90 days and includes assessments of the patient's medical history, health status and behaviour, cardiovascular, nutritional, metabolic, and anthropometric parameters, and patient-related outcome measures. Biospecimens are collected for analyses including 'OMICs' technologies (e.g., genomics, metabolomics, proteomics). Subcohorts undergo MRI of the brain, heart, lung and kidney, as well as more comprehensive metabolic, neurological and CV examinations. All participants are followed up for up to 10 years to assess clinical outcomes, primarily major adverse CVEs and patient-reported (value-based) outcomes. State-of-the-art clinical research methods, as well as emerging techniques from systems medicine and artificial intelligence, will be used to identify associations between patient characteristics, longitudinal changes and outcomes. ETHICS AND DISSEMINATION: The study was approved by the Charité-Universitätsmedizin Berlin ethics committee (EA1/066/17). The results of the study will be disseminated through international peer-reviewed publications and congress presentations. STUDY REGISTRATION: First study phase: Approved WHO primary register: German Clinical Trials Register: https://drks.de/search/de/trial/DRKS00016852; WHO International Clinical Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00016852. Recruitment started on July 18, 2017.Second study phase: Approved WHO primary register: German Clinical Trials Register DRKS00023323, date of registration: November 4, 2020, URL: http://www.drks.de/ DRKS00023323. Recruitment started on January 1, 2021.

Repurposing the ß3-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial.

Importance: Left ventricular (LV) hypertrophy contributes to the onset and progression of heart failure (HF), particularly for patients with pre-HF (stage B) for whom no treatment has yet proven effective to prevent transition to overt HF (stage C). The ß3-adrenergic receptors (ß3ARs) may represent a new target, as their activation attenuates LV remodeling. Objective: To determine whether activation of ß3ARs by repurposing a ß3AR agonist, mirabegron, is safe and effective in preventing progression of LV hypertrophy and diastolic dysfunction among patients with pre- or mild HF. Design, Setting, and Participants: The Beta3-LVH prospective, triple-blind, placebo-controlled phase 2b randomized clinical trial enrolled patients between September 12, 2016, and February 26, 2021, with a follow-up of 12 months. The trial was conducted at 10 academic hospitals in 8 countries across Europe (Germany, Poland, France, Belgium, Italy, Portugal, Greece, and the UK). Patients aged 18 years or older with or without HF symptoms (maximum New York Heart Association class II) were screened for the presence of LV hypertrophy (increased LV mass index [LVMI] of ≥95 g/m2 for women or ≥115 g/m2 for men) or maximum wall thickness of 13 mm or greater using echocardiography. Data analysis was performed in August 2022. Intervention: Participants were randomly assigned (1:1) to mirabegron (50 mg/d) or placebo, stratified by the presence of atrial fibrillation and/or type 2 diabetes, for 12 months. Main Outcomes and Measures: The primary end points were LVMI determined using cardiac magnetic resonance imaging and LV diastolic function (early diastolic tissue Doppler velocity [E/e'] ratio assessed using Doppler echocardiography) at 12 months. Patients with at least 1 valid measurement of either primary end point were included in the primary analysis. Safety was assessed for all patients who received at least 1 dose of study medication. Results: Of the 380 patients screened, 296 were enrolled in the trial. There were 147 patients randomized to mirabegron (116 men [79%]; mean [SD] age, 64.0 [10.2] years) and 149 to placebo (112 men [75%]; mean [SD] age, 62.2 [10.9] years). All patients were included in the primary intention-to-treat analysis. At 12 months, the baseline and covariate-adjusted differences between groups included a 1.3-g/m2 increase in LVMI (95% CI, -0.15 to 2.74; P = .08) and a -0.15 decrease in E/e' (95% CI, -0.69 to 0.4; P = .60). A total of 213 adverse events (AEs) occurred in 82 mirabegron-treated patients (including 31 serious AEs in 19 patients) and 215 AEs occurred in 88 placebo-treated patients (including 30 serious AEs in 22 patients). No deaths occurred during the trial. Conclusions: In this study, mirabegron therapy had a neutral effect on LV mass or diastolic function over 12 months among patients who had structural heart disease with no or mild HF symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT02599480.

Treatment response to spironolactone in patients with heart failure with preserved ejection fraction: a machine learning-based analysis of two randomized controlled trials.

BACKGROUND: Whether there is a subset of patients with heart failure with preserved ejection fraction (HFpEF) that benefit from spironolactone therapy is unclear. We applied a machine learning approach to identify responders and non-responders to spironolactone among patients with HFpEF in two large randomized clinical trials. METHODS: Using a reiterative cluster allocating permutation approach, patients from the derivation cohort (Aldo-DHF) were identified according to their treatment response to spironolactone with respect to improvement in E/e'. Heterogenous features of response ('responders' and 'non-responders') were characterized by an extreme gradient boosting (XGBoost) algorithm. XGBoost was used to predict treatment response in the validation cohort (TOPCAT). The primary endpoint of the validation cohort was a combined endpoint of cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization. Patients with missing variables for the XGboost model were excluded from the validation analysis. FINDINGS: Out of 422 patients from the derivation cohort, reiterative cluster allocating permutation identified 159 patients (38%) as spironolactone responders, in whom E/e' significantly improved (p = 0.005). Within the validation cohort (n = 525) spironolactone treatment significantly reduced the occurrence of the primary outcome among responders (n = 185, p log rank = 0.008), but not among patients in the non-responder group (n = 340, p log rank = 0.52). INTERPRETATION: Machine learning approaches might aid in identifying HFpEF patients who are likely to show a favorable therapeutic response to spironolactone. FUNDING: See Acknowledgements section at the end of the manuscript.

Supervised exercise training in patients with advanced heart failure and left ventricular assist device: A multicentre randomized controlled trial (Ex-VAD trial).

AIMS: Small studies and observations suggested that exercise training may improve peak oxygen consumption (peakVO2 ) in patients with advanced heart failure and left ventricular assist device (LVAD). We investigated whether in this patient group a supervised exercise training can improve exercise capacity. METHODS AND RESULTS: In this multicentre, prospective, randomized, controlled trial, patients with stable heart failure and LVAD were randomly assigned (2:1) to 12 weeks of supervised exercise training or usual care, with 12 weeks of follow-up. The primary endpoint was the change in peakVO2 after 12 weeks (51 patients provided a power of 90% with an expected group difference in peakVO2 of 3 ml/kg/min). Secondary endpoints included changes in submaximal exercise capacity and quality of life. Among 64 patients enrolled (97% male, mean age 56 years), 54 were included in the analysis. Mean difference in the change of peakVO2 after 12 weeks was 0.826 ml/min/kg (95% confidence interval [CI] -0.37, 2.03; p = 0.183). There was a positive effect of exercise training on 6-min walk distance with a mean increase in the intervention group by 43.4 m (95% CI 16.9, 69.9; p = 0.0024), and on the Kansas City Cardiomyopathy Questionnaire physical domain score (mean 14.3, 95% CI 3.7, 24.9; p = 0.0124), both after 12 weeks. The overall adherence was high (71%), and there were no differences in adverse events between groups. CONCLUSION: In patients with advanced heart failure and LVAD, 12 weeks of exercise training did not improve peakVO2 but demonstrated positive effects on submaximal exercise capacity and physical quality of life.

De Novo Lipogenesis-Related Monounsaturated Fatty Acids in the Blood Are Associated with Cardiovascular Risk Factors in HFpEF Patients.

De novo lipogenesis (DNL)-related monounsaturated fatty acids (MUFAs) in the blood are associated with incident heart failure (HF). This observation's biological plausibility may be due to the potential of these MUFAs to induce proinflammatory pathways, endoplasmic reticulum stress, and insulin resistance, which are pathophysiologically relevant in HF. The associations of circulating MUFAs with cardiometabolic phenotypes in patients with heart failure with a preserved ejection fraction (HFpEF) are unknown. In this secondary analysis of the Aldosterone in Diastolic Heart Failure trial, circulating MUFAs were analysed in 404 patients using the HS-Omega-3-Index® methodology. Patients were 67 ± 8 years old, 53% female, NYHA II/III (87/13%). The ejection fraction was ≥50%, E/e' 7.1 ± 1.5, and the median NT-proBNP 158 ng/L (IQR 82-298). Associations of MUFAs with metabolic, functional, and echocardiographic patient characteristics at baseline/12 months follow-up (12 mFU) were analysed using Spearman's correlation coefficients and linear regression analyses, using sex/age as covariates. Circulating levels of C16:1n7 and C18:1n9 were positively associated with BMI/truncal adiposity and associated traits (dysglycemia, atherogenic dyslipidemia, and biomarkers suggestive of non-alcoholic-fatty liver disease). They were furthermore inversely associated with functional capacity at baseline/12 mFU. In contrast, higher levels of C20:1n9 and C24:1n9 were associated with lower cardiometabolic risk and higher exercise capacity at baseline/12 mFU. In patients with HFpEF, circulating levels of individual MUFAs were differentially associated with cardiovascular risk factors. Our findings speak against categorizing FA based on physicochemical properties. Circulating MUFAs may warrant further investigation as prognostic markers in HFpEF.

Standardised Exercise Prescription for Patients with Chronic Coronary Syndrome and/or Heart Failure: A Consensus Statement from the EXPERT Working Group.

Whereas exercise training, as part of multidisciplinary rehabilitation, is a key component in the management of patients with chronic coronary syndrome (CCS) and/or congestive heart failure (CHF), physicians and exercise professionals disagree among themselves on the type and characteristics of the exercise to be prescribed to these patients, and the exercise prescriptions are not consistent with the international guidelines. This impacts the efficacy and quality of the intervention of rehabilitation. To overcome these barriers, a digital training and decision support system [i.e. EXercise Prescription in Everyday practice & Rehabilitative Training (EXPERT) tool], i.e. a stepwise aid to exercise prescription in patients with CCS and/or CHF, affected by concomitant risk factors and comorbidities, in the setting of multidisciplinary rehabilitation, was developed. The EXPERT working group members reviewed the literature and formulated exercise recommendations (exercise training intensity, frequency, volume, type, session and programme duration) and safety precautions for CCS and/or CHF (including heart transplantation). Also, highly prevalent comorbidities (e.g. peripheral arterial disease) or cardiac devices (e.g. pacemaker, implanted cardioverter defibrillator, left-ventricular assist device) were considered, as well as indications for the in-hospital phase (e.g. after coronary revascularisation or hospitalisation for CHF). The contributions of physical fitness, medications and adverse events during exercise testing were also considered. The EXPERT tool was developed on the basis of this evidence. In this paper, the exercise prescriptions for patients with CCS and/or CHF formulated for the EXPERT tool are presented. Finally, to demonstrate how the EXPERT tool proposes exercise prescriptions in patients with CCS and/or CHF with different combinations of CVD risk factors, three patient cases with solutions are presented.