The ability of the heart to compensate for and adapt to a superimposed environmental stress determines whether the heart will maintain preserved structure and function or decompensate and fail. In mammalian tissues, sterile tissue injury activates a suite of stress-activated programs that integrate cytoprotective stress responses that are tightly coupled with carefully regulated and precisely timed inflammatory signaling, thereby promoting tissue repair while simultaneously limiting collateral damage. Although the terminology for this phenomenon is still evolving, the recently described concept of "disease tolerance" has been proposed to explain tissue-intrinsic cell autonomous molecular programs that couple cytoprotective stress responses with tightly regulated inflammatory signaling that minimizes collateral damage while also activating tissue repair mechanisms. Emerging evidence reviewed here suggests that sterile cardiac injury (e.g., myocardial ischemia or hemodynamic pressure overload) elicits an acquired stress-tolerant state that sustains cytoprotective programs in cardiac myocytes and constrains collateral immune-mediated tissue injury. However, these stress-activated pathways are highly context-dependent and are shaped by the magnitude and duration of the ensuing inflammatory response. When tissue injury-induced inflammation is sustained and/or excessive, it can also lead to unwanted collateral tissue damage and cardiac decompensation.

Background Excess adiposity, most commonly indexed through body mass index (BMI), is strongly associated with the development of heart failure (HF). Weight loss therapies improve outcomes in patients with obesity and HF with preserved left ventricular ejection fraction (LVEF), but their effects in HF with reduced LVEF remain unclear. Objectives The aim of this work is to determine whether higher BMI is associated with adverse clinical outcomes in patients with HF and whether there is effect modification by LVEF subgroup. Methods Two-sample Mendelian randomization (MR) was used, with genome-wide significant loci associated with BMI as instrumental variables and outcome data from a genome-wide association study (GWAS) of time-to-event clinical outcomes in patients with HF. A total of 50,636 individuals of European ancestry with established HF from 22 cohorts were included in the genetic analysis: 12 HF trials, 1 prospective case-cohort study, 9 cohorts nested within non-HF cardiovascular trials, and 1 population-based cohort derived from the UK Biobank.The exposure was genetically predicted BMI and the outcome measures were all-cause mortality and a composite of cardiovascular mortality or HF hospitalization. Genetic associations for the outcomes were derived from our GWAS and MR was used to estimate the unbiased association of genetically predicted BMI with these clinical outcomes. Results The mean BMI was 29.2 ± 5.8 kg/m2. Over a median follow-up of 27.0 months, all-cause mortality occurred in 11,454 patients (23%), and 11,360 participants (22%) experienced the composite endpoint. Genetically predicted BMI was associated with an increased rate of both all-cause mortality (HR per SD [4.8 BMI units] 1.21; 95% CI: 1.13-1.29; P = 9 × 10-8) and the composite outcome (HR 1.29; 95% CI: 1.20-1.38; P = 8 × 10-13). Associations were consistent across LVEF ≤40% and >40%: for all-cause mortality, HR: 1.16 (95% CI: 0.99-1.37) and 1.20 (95% CI: 0.94-1.53); and for the composite outcome, HR: 1.30 (95% CI: 1.15-1.48) and 1.57 (95% CI: 1.29-1.91), respectively. Conclusions Among patients with HF, higher BMI was associated with increased all-cause mortality and cardiovascular death or HF hospitalization, supporting the potential role of weight-management strategies across the ejection fraction spectrum.

BACKGROUND:Vagal nerve stimulation (VNS) may reverse autonomic dysfunction in heart failure (HF). This paper describes results from a pivotal trial, while addressing challenges investigators face following premature trial termination. OBJECTIVES:We report VNS actions in patients with HF with reduced ejection fraction and investigators response to early discontinuation. METHODS:Randomization was 2:1 to VNS or control. Entry required NYHA functional class II or III, left ventricular ejection fraction (LVEF) ≤35%, and N-terminal pro-B-type natriuretic peptide ≥800 pg/mL. Primary efficacy endpoint was time to cardiovascular death or HF hospitalization. Secondary endpoints included LVEF, 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire. Adaptive sample sizing targeted ≤1,000 patients. P values are 1-sided. RESULTS:After randomizing 532 patients, the sponsor terminated enrollment, unrelated to futility or efficacy. The primary efficacy endpoint was not met (HR: 0.84; 95% CI: 0.62-1.12; P = 0.115). The primary safety endpoint achieved 96.7% freedom from procedure- or device-related serious adverse events. Autonomic engagement persisted long-term. Findings were favorable, although inconclusive, for the primary endpoint, HF hospitalization, Kansas City Cardiomyopathy Questionnaire, NYHA functional class, and 6-minute walk distance. LVEF was unchanged. The still-blinded investigators, seeking to extend data reporting while maintaining scientific integrity, had prespecified a single exploratory outcomes-symptoms win ratio. Results were favorable although merely hypothesis-generating, given primary endpoint neutrality, multiplicity, subjective bias, and marginal statistical significance. CONCLUSIONS:Early termination outside Data Monitoring Committee processes challenged investigators to maintain scientific and ethical integrity and transparency, while optimizing data reporting. The underpowered primary endpoint was neutral. Data documented feasibility, safety, and autonomic engagement. Trends favoring outcomes, symptoms, and function were inconclusive although hypothesis-generating. Importantly, we provide guidance for investigators facing trial discontinuation. (ANTHEM-HFrEF Pivotal Study [Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure with Reduced Ejection Fraction]; NCT03425422).

Importance:Accurate patient understanding of prognosis is essential for informed decision-making to pursue therapies for advanced heart failure (HF). Objectives:To evaluate (1) patient characteristics associated with overestimating survival with HF and (2) whether overestimation is associated with mortality. Design, Setting, and Participants:This prospective cohort study was an exploratory secondary analysis of data from the multicenter US Registry Evaluation of Vital Information for Ventricular Assist Devices (VADs) in Ambulatory Life (REVIVAL) study. Participants were high-risk ambulatory patients with HF with reduced ejection fraction enrolled from July 2015 to June 2016. Data were analyzed from December 1, 2024, to December 16, 2025. Exposures:Patient characteristics (eg, age) and estimation index (EI), defined as the ratio of patient-estimated life expectancy to Seattle Heart Failure Model (SHFM)-estimated mean survival (EI <0.5, discordantly pessimistic; 0.5 to <1.5, concordant; and ≥1.5, discordantly optimistic). Main Outcomes and Measures:Primary outcomes were EI and 2-year all-cause mortality. Factors associated with EI were estimated using ordered logistic regression. Association between EI and mortality was assessed using a cause-specific Cox proportional hazards regression model with VAD and heart transplant as censoring events. Results:A total of 296 high-risk, ambulatory patients with chronic HF were included; 223 (75.3%) were male, and mean (SD) age was 60.1 (11.5) years. The median SHFM-estimated survival was 8.2 years (IQR, 5.1-12.1 years), and median patient-estimated life expectancy was 7.0 years (IQR, 5.0-10.0 years). In all, 98 patients (33.1%) were discordantly optimistic. Increasing EI was associated with increased mortality in the univariable model, which was attenuated with multivariable adjustment (adjusted hazard ratio [AHR] for concordant optimism, 1.21 [95% CI, 0.49-2.99] and for discordant optimism, 2.23 [95% CI, 0.94-5.33] vs discordant pessimism). Compared with discordantly pessimistic or concordantly optimistic estimates (EI <1.5), discordant optimism was associated with increased hazard of 2-year mortality (AHR, 1.98; 95% CI, 1.04-3.77) but a similar hazard for a VAD or heart transplant compared with discordant pessimism (HR, 1.24; 95% CI, 0.64-2.41) in a post hoc analysis. Conclusions:In this cohort study, discordant optimism regarding life expectancy compared with model estimates was common and associated with mortality that was not due to a lower probability of receiving a heart transplant or VAD. The findings suggest clinicians should objectively evaluate HF risk when considering advanced therapies, rather than relying primarily on patient-reported symptoms.

A panoply of different stimuli activates endogenous signaling pathways that confer cardioprotection in the heart; however, it is unclear whether these stimuli engage similar or distinct biological pathways. We showed that tissue injury induced by isoproterenol (ISO), or pretreatment with the Toll-like receptor 4 agonist lipopolysaccharide (LPS), protects the heart against the myopathic effects of a subsequent exposure to ISO. Here, we used a multiomic approach to examine ISO- and LPS-treated hearts to identify shared and distinct biological themes. Bulk RNA sequencing showed that ISO and LPS elicited upregulation of distinct stress response signatures that featured interferon (IFN) signaling, while converging on the widespread downregulation of pathways related to metabolism or cell growth. Multiome (RNA + ATAC) sequencing revealed that ISO-treated hearts underwent distinct chromatin remodeling, with more regions showing decreased accessibility than increased accessibility. IFN-related pathways were consistently enriched across many cell types in the heart, including endocardial cells, TNK cells, myeloid cells, and endothelial cells. Analysis of cell-cell interactions using CellChat showed that ISO stimulation enhanced communication between myeloid cells with fibroblasts, TNK cells, and pericytes. Remarkably, cell-cell interactions for cardiac myocytes were restricted to myeloid cells. Bulk ATAC sequencing of bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) demonstrated that ISO and LPS stimulation predominantly resulted in decreased chromatin accessibility in HSPCs and bone marrow stromal cells. Viewed together, these studies show that although ISO and LPS engage distinct upstream signaling pathways, both converge on IFN signaling and a shared suppression of energy-intensive pathways.NEW & NOTEWORTHY This study shows that isoproterenol and lipopolysaccharide establish cardioprotection through the activation of distinct upstream signaling and cell-cell communication networks that converge on interferon signaling in the heart. Viewed together, these studies suggest an important role for immune-mediated cardioprotection as a mechanism for enhancing cardiac resilience in response to stress.

We examined current evidence regarding the effects of anti-inflammatory therapies in patients with acute heart failure (AHF) on the risk of cardiovascular outcomes, inflammatory markers, natriuretic peptides, and renal function. Despite growing evidence that inflammation plays a pivotal role in both the development and progression of heart failure, including AHF, only a few trials have been conducted to date in patients with AHF. A systematic literature search of PubMed, Medline, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov was conducted in November 2024 to identify randomized controlled trials (RCTs) evaluating anti-inflammatory therapies in adult patients with AHF. Meta-analyses were conducted to estimate effects on clinical outcomes (death, HF readmission, or worsening HF) and inflammatory and other markers. Five RCTs were identified that enrolled a total of 289 patients to an anti-inflammatory intervention and 273 to a control. Prednisone was examined in two RCTs, anakinra in two, and colchicine in one. Three of the five trials required elevated C-reactive protein (CRP) level for entry. Anti-inflammatory therapy was associated with a reduced risk of the composite outcome (hazard ratio 0.55 [95

BACKGROUND:N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with heart failure (HF) hospitalizations and death when measured during a myocardial infarction (MI). However, NT-proBNP concentrations change following the initial ischemic insult and less is known about the prognostic importance of NT-proBNP in the early convalescent phase. METHODS:PARADISE-MI randomized 5661 patients with MI complicated by LVEF ≤40% and/or pulmonary congestion to sacubitril/valsartan or ramipril. Patients with available week 2 NT-proBNP concentrations and without-incident HF between randomization and week 2 (n = 1062) were analyzed. Associations of week 2 NT-proBNP with subsequent clinical outcomes were evaluated in landmark analyses using Cox models adjusted for clinical characteristics, including LVEF, baseline NT-proBNP and atrial fibrillation. RESULTS:Median 2-week NT-proBNP concentration was 1391 [676-2507] ng/L. Patients in the highest NT-proBNP quartile (≥2507 ng/L) were older, had lower left ventricular ejection fraction (LVEF) and estimated glomerular filtration rate (eGFR), higher Killip class, and more atrial fibrillation. Higher NT-proBNP concentrations were independently associated with greater risk of cardiovascular death or incident HF (adjusted hazard ratio [aHR], 1.65 per doubling of NT-proBNP; 95% confidence interval [CI], 1.31-2.09), HF hospitalization (aHR, 1.87; 95% CI, 1.38-2.54), recurrent myocardial infarction (aHR, 1.46; 95% CI, 1.09-1.95) and all-cause death (aHR, 1.85; 95% CI, 1.35-2.53). CONCLUSIONS:Patients with elevated NT-proBNP concentrations approximately 2 weeks after a high-risk myocardial infarction are at heightened risk of incident HF, recurrent coronary events, and death independent of baseline NT-proBNP concentrations and clinical characteristics. Elevations in NT-proBNP concentrations in the early convalescent phase may assist in risk stratification and the identification of patients in need of more advanced preventive treatment approaches.

AIMS:Although the ability of the heart to adapt to environmental stress has been studied extensively, the molecular and cellular mechanisms responsible for cardioprotection are not yet fully understood. In this study, we sought to elucidate these mechanisms for cytoprotection using a model of stress-induced cardiomyopathy. METHODS AND RESULTS:We administered Toll-like receptor (TLR) agonists or diluent to wild-type mice and assessed for cardioprotection against injury from a high intraperitoneal dose of isoproterenol (ISO) administered 7 days later. Cardioprotective effects were analysed through serum cardiac troponin I levels, immune profiling via flow cytometry, echocardiography, and multiomic single-nuclei RNA/ATAC sequencing. Pretreatment with the TLR4 agonist lipopolysaccharide (LPS), but not TLR1/2 or TLR3 agonists, conferred cardioprotection, as demonstrated by reduced cardiac troponin I leakage, decreased inflammation, preserved cardiac structure and function, and improved survival. Remarkably, LPS-induced tolerance was reversed by β-glucan treatment. Multiomic analysis showed that LPS-tolerized hearts had greater chromatin accessibility and up-regulated gene expression vs. hearts treated with LPS and β-glucan (reverse-tolerized). LPS tolerance was associated with up-regulation of interferon response pathways across various cell types, including cardiac myocytes and stromal cells. Blocking both Type 1 and 2 interferon signalling eliminated LPS-induced tolerance against ISO, while pretreatment with recombinant Type 1 and 2 interferons conferred cardiac protection. Multiomic sequencing further revealed enhanced cytoprotective signalling in interferon-treated hearts. Analysis of cell-cell communication networks indicated increased autocrine signalling by cardiac myocytes, as well as greater paracrine signalling between stromal cells and myeloid cells, in LPS-tolerized vs. reverse-tolerized hearts. CONCLUSION:LPS pretreatment confers cardiac protection against ISO-induced injury through TLR4-mediated Type 1 and 2 interferon signalling, consistent with trained innate immune tolerance. The observation that LPS-induced protection in cardiac myocytes involves both cell-autonomous and non-cell-autonomous mechanisms underscores the complexity of innate immune tolerance in the heart, warranting further investigation into this cardioprotective phenotype.

Phase II clinical trials play an important role in drug development, providing key data that guide decision-making for promising therapeutic candidates. An important objective of phase II is to establish proof of concept by demonstrating that the drug produces its intended biological effects in the target population. Phase II trials also evaluate pharmacokinetics, pharmacodynamics, safety, and dose-response relationships. Ultimately, the goal is to generate the evidence needed to inform go/no-go decisions for further development. However, as we will discuss, phase II studies have inherent limitations and cannot fully predict phase III outcomes. In this JACC: Basic to Translational Science and Heart Failure Collaboratory position paper, we examine the value and constraints of phase II programs, using prior examples of heart failure trials, with the goal of providing insights that will help investigators and sponsors to derisk go/no-go decisions.