Heart failure (HF) is a syndrome affecting all organ systems. While some organ interactions have been studied intensively in HF (such as the cardiorenal interaction), the endocrine gut has to some degree been overlooked. However, there is growing evidence of direct cardiac effects of several hormones secreted from the gastrointestinal tract. For instance, GLP-1 (glucagon-like peptide-1), an incretin hormone secreted from the distal intestine following food intake, has notable effects on the heart, impacting heart rate and contractility. GLP-1 may even possess cardioprotective abilities, such as inhibition of myocardial ischemia and cardiac remodeling. While other gut hormones have been less studied, there is evidence suggesting cardiostimulatory properties of several hormones. Moreover, it has been reported that patients with HF have altered bioavailability of numerous gastrointestinal hormones, which may have prognostic implications. This might indicate an important role of gut hormones in cardiac physiology and pathology, which may be of particular importance in the failing heart. We present an overview of the current knowledge on gut hormones in HF, focusing on HF with reduced ejection fraction, and discuss how these hormones may be regulators of cardiac function and central hemodynamics. Potential therapeutic perspectives are discussed, and knowledge gaps are highlighted herein.

Pregnancy imposes significant cardiovascular adaptations, including progressive increases in plasma volume and cardiac output. For most women, this physiological adaptation resolves at the end of pregnancy, but some women develop pathological dilatation and ultimately heart failure late in pregnancy or in the postpartum period, manifesting as peripartum cardiomyopathy (PPCM). Despite the mortality risk of this form of heart failure, the molecular mechanisms underlying PPCM have not been extensively examined in human hearts.

Medical record review by a physician clinical events committee is the gold standard for identifying cardiovascular outcomes in clinical trials, but is labor-intensive and poorly reproducible. Automated outcome adjudication by artificial intelligence (AI) could enable larger and less expensive clinical trials, but has not been validated in global studies. We developed a novel model for automated AI-based heart failure adjudication ("HF-NLP") using hospitalizations from three international clinical outcomes trials. This model was tested on potential heart failure hospitalizations from the DELIVER trial, a cardiovascular outcomes trial comparing dapagliflozin with placebo in 6063 patients with heart failure with mildly reduced or preserved ejection fraction. AI-based adjudications were compared with adjudications from a clinical events committee that followed FDA-based criteria. AI-based adjudication agreed with the clinical events committee in 83% of events. A strategy of human review for events that the AI model deemed uncertain (16%) would have achieved 91% agreement with the clinical events committee while reducing adjudication workload by 84%. The estimated effect of dapagliflozin on heart failure hospitalization was nearly identical with AI-based adjudication (hazard ratio 0.76 [95% CI 0.66-0.88]) compared to clinical events committee adjudication (hazard ratio 0.77 [95% CI 0.67-0.89]). The AI model extracted symptoms, signs, and treatments of heart failure from each medical record in tabular format and quoted sentences documenting them. AI-based adjudication of clinical outcomes has the potential to improve the efficiency of global clinical trials while preserving accuracy and interpretability.

Invasive exercise right heart catheterization is a gold standard in diagnosing heart failure with preserved ejection fraction (HFpEF). Body positions during the test influence hemodynamics. However, the discrepancy in HFpEF diagnosis between exercise testing in supine versus upright position is unknown.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition that can lead to atrial fibrillation, heart failure, and sudden cardiac death in many individuals but mild clinical impact in others. The mechanisms underlying this phenotypic heterogeneity are not well defined. The aim of this study was to use plasma proteomic profiling to help illuminate biomarkers that reflect or inform the heterogeneity observed in HCM.

Mavacamten is the only cardiac myosin inhibitor approved by the US FDA for treatment of symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy (HCM) patients. Under the risk evaluation and mitigation strategy (REMS) program for mavacamten, patients are required to be monitored for development of systolic heart failure, and reduction of left ventricular ejection fraction (LVEF) to <50%. We report results from the mavacamten REMS database (28-Apr-2022 to 27-Feb-2024). Data on healthcare providers and pharmacy certification, patient monitoring (from Patient Status Forms, based partly on echocardiograms), and screening for drug interactions prior to each dispense were collected. Of 6,299 patients who received ≥1 dose of mavacamten, 60.0% were women; 64.6% were >60 years of age. Of 5,573 patients with submitted Patient Status Forms, 256 (4.6%) developed LVEF <50% and 71 (1.3%) experienced heart failure requiring hospitalization (HFH). On the 29,111 status forms in these patients, each representing an assessment of an echocardiogram, LVEF <50% was reported on 276 (0.9%) and HFH was reported on 86 (0.3%). Of 1,929 patients with ≥1 year of treatment, 78 (4.0%) had an LVEF reduction to <50% and 4 (0.2%) experienced LVEF <50% + HFH but later resumed treatment. Of 3,228 patients initiated on 5 mg/day mavacamten and were treated for at least 6 months, 2,391 (74.1%) remained at 5 or 10 mg/day. At 3- and 6-months following mavacamten treatment initiation, 57.2% and 70.3%, respectively, demonstrated post-Valsalva LV outflow tract gradient <30 mmHg. We describe the feasibility and experience of the first 22 months of the REMS program for prescribing mavacamten in >6,000 symptomatic obstructive HCM patients. The need for temporary interruption for LVEF <50% was low, including for patients on therapy ≥1 year, with even fewer LVEF reductions associated with HFH.

Distinguishing hypertrophic cardiomyopathy (HCM) from other cardiomyopathies with left ventricular hypertrophy (LVH), such as hypertensive LVH, transthyretin amyloid cardiomyopathy (ATTR-CM), and aortic stenosis (AS), is sometimes challenging. Using plasma proteomics profiling, we aimed to identify circulating biomarkers and dysregulated signaling pathways specific to HCM. In this multicenter case-control study, plasma proteomics profiling was performed in cases with HCM and controls with hypertensive LVH, ATTR-CM, and AS. Two-thirds of patients enrolled earlier in each disease group were defined as the training set, and the remaining one-third as the test set. Protein concentrations in HCM were compared with those in hypertensive LVH (comparison 1), ATTR-CM (comparison 2), and AS (comparison 3). Candidate proteins that meet the following 2 criteria were selected: (1) Higher abundance in HCM throughout all 3 comparisons or lower abundance in HCM throughout all 3 comparisons with univariable P<0.05 and |log(fold change)| >0.5 in both the training and test sets and (2) Independently associated with HCM with multivariable P<0.05 after adjusting for clinical parameters significantly different between HCM and controls. Using the selected candidate proteins, a logistic regression model to distinguish HCM from controls was developed in the training set and applied to the test set. Finally, pathway analysis was performed in each comparison using proteins with different abundance. Overall, 4,979 proteins in 1,415 patients (HCM, n=879; hypertensive LVH, n=331; ATTR-CM, n=169; AS, n=36) were analyzed. Of those, 5 proteins were selected as candidate proteins. The logistic regression model with these 5 proteins had an area under the receiver-operating-characteristic curve of 0.86 (95% CI 0.82-0.89) in the test set. The MAPK and HIF-1 pathways were dysregulated in HCM throughout the 3 comparisons. This study identified circulating biomarkers that distinguish HCM from other cardiomyopathies with LVH independently from confounders and revealed signaling pathways associated with HCM.

Fewer than 20% of eligible patients with heart failure with reduced ejection fraction receive all 4 pillars of guideline-directed medical therapy. Understanding disparities by race, ethnicity, sex, and adverse social determinants of health is necessary to equitably optimize quadruple therapy.

Currently, there are no therapies targeting specific pathogenic pathways in myocarditis. IL (interleukin)-1 blockade has shown promise in preclinical studies and case reports. We hypothesized that blockade of IL1RAP (IL-1 receptor accessory protein), a shared subunit of the IL-1, IL-33, and IL-36 receptors, could be more efficient than IL-1 blockade alone.

Cardiorenal dysfunction with impaired cyclic GMP (cGMP) response is common in patients presenting with acute heart failure (HF). Type V phosphodiesterase (PDEV) is known to be upregulated in HF and may explain the dysfunction of renal response. The aim of this study was to determine whether B-type natriuretic peptide (BNP) alone or in combination with PDEV inhibition improves renal function and increases urinary sodium and cGMP excretion in acute HF.

Pulmonary arterial hypertension (PAH) is a disease of progressive right ventricular (RV) failure with high morbidity and mortality. Our goal is to investigate proteomic features and pathways associated with RV-focused outcomes including mortality, RV dilation, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in PAH.