Fudim, Marat

Abstract Background Cardiovascular inflammation is thought to play a central role in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF), but no therapies specifically targeting inflammation in this setting are currently available. Purpose Here we describe the rationale and design of two clinical trials (ATHENA and HERMES) investigating ziltivekimab, a human monoclonal antibody directed against the IL-6 ligand, in patients with HFpEF/HFmrEF and cardiovascular inflammation. Methods ATHENA and HERMES are international, multicenter, double-blind, placebo-controlled trials randomizing adults with HFpEF/HFmrEF and cardiovascular inflammation to ziltivekimab 15 mg or placebo, both administered subcutaneously once-monthly on top of standard of care. Eligible participants have a left ventricular ejection fraction >40%, elevated NTproBNP and serum high sensitivity C reactive protein ≥2 mg/L. The primary endpoint in ATHENA (n=680) is the change in Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score at 12 months. The primary endpoint in HERMES (n=4900) is the composite of CV death, hospitalization for HF or urgent HF visit. The study is event-driven and will target 845 primary events (Figure 1). Conclusions ATHENA and HERMES will investigate the effect of ziltivekimab in HFpEF/HFmrEF and cardiovascular inflammation. ATHENA will determine the effect of ziltivekimab on health status. HERMES will determine the efficacy and safety of ziltivekimab on morbidity and mortality.Fig 1.ATHENA and HERMES trial designsFor image description, please refer to the figure legend and surrounding text.

Abstract Aims We hypothesized that targeting interleukin-6—a cytokine central to NOD-like receptor protein 3 (NLRP3) inflammasome activation that is associated with both the onset and progression of heart failure (HF)—may be beneficial in patients with HF and circulating evidence of cardiovascular inflammation but without overtly reduced ejection fraction (EF). We describe the rationale and design of two clinical trials (ATHENA and HERMES) investigating ziltivekimab, a human monoclonal antibody directed against the interleukin-6 ligand, in patients with HF and mildly reduced or preserved EF (HFmrEF/HFpEF) and cardiovascular inflammation. Methods ATHENA (n = 673) and HERMES (n = 4900) are international, multi-centre, double-blind, placebo-controlled trials randomizing adults with HFpEF/HFmrEF and cardiovascular inflammation (high-sensitivity C-reactive protein ≥2 mg/l) to ziltivekimab 15 mg or placebo, administered subcutaneously once monthly on top of standard of care. Eligible participants have a left ventricular EF >40%, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), and serum high-sensitivity C-reactive protein ≥2 mg/l. The primary endpoint in ATHENA is the change in Kansas City Cardiomyopathy Questionnaire—Clinical Summary Score at 12 months. The primary endpoint in HERMES is time to first composite of cardiovascular death, hospitalization for HF, or urgent HF visit. ATHENA has a fixed duration of 12 months, whereas the HERMES trial is event driven (∼845 adjudicated primary events) with a minimum exposure of 6 months from randomization to the last treatment visit. Conclusion ATHENA and HERMES will investigate the effect of ziltivekimab in HFpEF/HFmrEF and cardiovascular inflammation. ATHENA will determine the effect of ziltivekimab on health status. HERMES will determine the efficacy and safety of ziltivekimab on morbidity and mortality.

ABSTRACT Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with heart failure (HF), independent of shared risk factors. Our aim was to describe the incidence of HF in patients with biopsy-proven MASLD. Methods and results We followed patients with biopsy-proven MASLD from the prospective Duke NAFLD Biorepository and Clinical Database from liver biopsy (2007–2013) until death or 5 January 2023. Clinical and echocardiographic data were abstracted via manual chart review. Incident HF was defined as one of the following: (1) hospitalization for HF, (2) medical record diagnosis of HF, (3) ≥1 sign/symptom of HF and elevated natriuretic peptide, or (4) diastolic dysfunction on transthoracic echocardiography with ≥1 sign/symptom of HF. Univariable and multivariable logistic regression models were evaluated. Overall, 570 patients with biopsy-proven MASLD were included. The mean age was 49.5 years, 42.5% were male and 87.0% were non-Hispanic White. Ten patients (1.8%) had baseline HF, leaving 560 patients to assess for incident HF. Over a median follow up of 4009 days (11.0 years) (interquartile range 2270–4672 days), 100 (17.9%) patients developed incident HF while 268 (47.9%) met criteria for HF suspicion. In a multivariable model, increasing age (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02–1.08, p < 0.001) and female sex (OR 1.85, 95% CI 1.12–3.04, p = 0.02) were associated with incident HF. Conclusions We found a high incidence of HF in patients with biopsy-proven MASLD. Despite nearly half of patients having suspected HF, very few carried a chart diagnosis. Screening for HF in high-risk patients and establishment of formal care pathways to address early HF may reduce morbidity and mortality.

AbstractThe intricate role of the autonomic nervous system (ANS) in regulating cardiac physiology has long been recognized. Aberrant function of the ANS is central to the pathophysiology of cardiovascular diseases. It stands to reason, therefore, that neuroscience‐based cardiovascular therapeutics hold great promise in the treatment of cardiovascular diseases in humans. A decade after the inaugural edition, this White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology and pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases. image

ImportanceGreater splanchnic nerve ablation may improve hemodynamics in patients with heart failure and preserved ejection fraction (HFpEF).ObjectiveTo explore the feasibility and safety of endovascular right-sided splanchnic nerve ablation for volume management (SAVM).Design, Setting, and ParticipantsThis was a phase 2, double-blind, 1:1, sham-controlled, multicenter, randomized clinical trial conducted at 14 centers in the US and 1 center in the Republic of Georgia. Patients with HFpEF, left ventricular ejection fraction of 40% or greater, and invasively measured peak exercise pulmonary capillary wedge pressure (PCWP) of 25 mm Hg or greater were included. Study data were analyzed from May 2023 to June 2024.InterventionSAVM vs sham control procedure.Main Outcomes and MeasuresThe primary efficacy end point was a reduction in legs-up and exercise PCWP at 1 month. The primary safety end point was serious device- or procedure-related adverse events at 1 month. Secondary efficacy end points included HF hospitalizations, changes in exercise function and health status through 12 months, and baseline to 1-month change in resting, legs-up, and 20-W exercise PCWP.ResultsA total of 90 patients (median [range] age, 71 [47-90] years; 58 female [64.4%]) were randomized at 15 centers (44 SAVM vs 46 sham). There were no differences in adverse events between groups. The primary efficacy end point did not differ between SAVM or sham (mean between-group difference in PCWP, −0.03 mm Hg; 95% CI, −2.5 to 2.5 mm Hg; P = .95). There were also no differences in the secondary efficacy end points. There was no difference in the primary safety end point between the treatment (6.8% [3 of 44]) and sham (2.2% [1 of 46]) groups (difference, 4.6%; 95% CI, −6.1% to 15.4%; P = .36). There was no difference in the incidence of orthostatic hypotension between the treatment (11.4% [5 of 44]) and sham (6.5% [3 of 46]) groups (difference, 4.9%; 95% CI, −9.2% to 18.8%; P = .48).Conclusions and RelevanceResults show that SAVM was safe and technically feasible, but it did not reduce exercise PCWP at 1 month or improve clinical outcomes at 12 months in a broad population of patients with HFpEF.Trial RegistrationClinicalTrials.gov Identifier: NCT04592445

Abstract Aims Quantitative methods have shown clinically significant heterogeneity in blood volume (BV) profiles across heart failure (HF) phenotypes. These profiles extend from hypovolaemia to normal BV and to variable degrees of BV hypervolaemia, frequently with similar clinical presentations. However, a comprehensive survey of BV profiles providing practical clinical guidance for the interpretation and management of quantitative plasma volume (PV) and red blood cell (RBC) mass findings has not been reported. The intent of this study is to advance this concept through a multicentre analysis. Methods and results A retrospective analysis of clinical and BV data was undertaken in stable NYHA class II–III HF patients (N = 546). BV was quantitated using established nuclear medicine indicator-dilution methodology. Differing combinations of PV and RBC mass were identified contributing to marked heterogeneity in overall BV profiles. A quantitatively normal BV was identified in 32% of the cohort but of these only ~1/3 demonstrated a true normal BV (i.e., normal PV + normal RBC mass). The remaining portion of normal BV profiles reflected balanced combinations of compensatory PV expansion with RBC mass deficit (anaemia) (14% of cohort) and PV contraction with RBC mass excess (erythrocythemia) (6% of cohort). Main contributors to BV hypervolaemia were PV excess with a normal RBC mass (21% of cohort; 23% female) and PV excess with erythrocythemia (24% of cohort; 26% female). Hypovolaemia was predominately defined by RBC mass deficit with a normal PV (6% of cohort; 57% female) or RBC mass deficit with PV contraction (5% of cohort; 48% female). Conclusions Findings support the clinical relevance of identifying and accurately interpreting the varying combinations of PV and RBC mass in patients with chronic HF. This in turn helps guide appropriate individualized patient management strategies. A practical volume-based guideline is provided in an effort to aid clinician interpretation.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is associated with heart failure with preserved ejection fraction (HFpEF), independent of shared risk factors. The aim of this study was to determine the prevalence, clinical, and echocardiographic (TTE) features of HFpEF in patients with biopsy-proven NAFLD. Methods: We performed a retrospective single-center cohort study of patients with biopsy-proven NAFLD in the Duke NAFLD Biorepository and Clinical Database. Study entry was at the time of liver biopsy and patients were followed until death or 5/1/2023. Clinical and echocardiographic data were abstracted via manual chart review. HFpEF was defined as: at least one TTE characteristic (left atrial volume index ≥ 29 ml/m 2 , septal wall thickness ≥ 1 cm, or evidence of diastolic dysfunction) and signs or symptoms of heart failure (diagnosis of heart failure on problem list, hospitalization for heart failure, elevated NT pro-BNP level, jugular venous distention, use of loop diuretics, pulmonary or peripheral edema, fatigue, or exertional symptoms). Descriptive statistics were evaluated. Results: A total of 742 patients were included in the study. The mean age of the cohort was 50 +/- 12 years, and 83% were White. 95 (13%) had TTE both prior to study entry and during follow up, while 279 patients (38%) had TTE only during follow up. A total of 185 patients met criteria for HFpEF during follow up. After removing patients with TTE evidence of HFpEF prior to study entry, there were 132 cases of incident HFpEF over a mean follow up of 9.1 years, representing 47% of those with TTE after liver biopsy, and 18% of the overall cohort. Considering only TTE criteria, 142 patients had incident HFpEF. During follow up, 12 patients were hospitalized for heart failure. Conclusions: HFpEF is common in patients with NAFLD and a small percentage of patients do not have a chart diagnosis despite meeting echocardiographic criteria, suggesting that HFpEF may be under-recognized. Screening for HFpEF and/or formal care pathways to address early heart failure will be important to prevent morbidity and mortality in this population.

Background Nonalcoholic fatty liver disease (NAFLD) and heart failure with preserved ejection fraction (HFpEF) share common risk factors, including obesity and diabetes. They are also thought to be mechanistically linked. The aim of this study was to define serum metabolites associated with HFpEF in a cohort of patients with biopsy‐proven NAFLD to identify common mechanisms. Methods and Results We performed a retrospective, single‐center study of 89 adult patients with biopsy‐proven NAFLD who had transthoracic echocardiography performed for any indication. Metabolomic analysis was performed on serum using ultrahigh performance liquid and gas chromatography/tandem mass spectrometry. HFpEF was defined as ejection fraction >50% plus at least 1 echocardiographic feature of HFpEF (diastolic dysfunction, abnormal left atrial size) and at least 1 heart failure sign or symptom. We performed generalized linear models to evaluate associations between individual metabolites, NAFLD, and HFpEF. Thirty‐seven out of 89 (41.6%) patients met criteria for HFpEF. A total of 1151 metabolites were detected; 656 were analyzed after exclusion of unnamed metabolites and those with >30% missing values. Fifty‐three metabolites were associated with the presence of HFpEF with unadjusted P value <0.05; none met statistical significance after adjustment for multiple comparisons. The majority (39/53, 73.6%) were lipid metabolites, and levels were generally increased. Two cysteine metabolites (cysteine s‐sulfate and s‐methylcysteine) were present at significantly lower levels in patients with HFpEF. Conclusions We identified serum metabolites associated with HFpEF in patients with biopsy‐proven NAFLD, with increased levels of multiple lipid metabolites. Lipid metabolism could be an important pathway linking HFpEF to NAFLD.