Ray KK, Clarke N, Thornton P
… +17 more, Miles AE, Digby Z, Davies MJ, Gorman M, Mullen B, Reader V, Magill M, Johnstone H, Ariti C, Sattar N, Marx N, Navar AM, Hernandez AF, George JT, Watt AP, Butler J, Ridker PM
J Am Coll Cardiol
· 2026 May · PMID 42187339
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BACKGROUND: The NLRP3 inflammasome is a key sensor of diverse exogenous stimuli linked to non-communicable diseases including atherosclerotic cardiovascular disease. Early clinical data with the oral NLRP3 inhibitor ruvo...BACKGROUND: The NLRP3 inflammasome is a key sensor of diverse exogenous stimuli linked to non-communicable diseases including atherosclerotic cardiovascular disease. Early clinical data with the oral NLRP3 inhibitor ruvonoflast suggested lowering of biomarkers of systemic and central nervous system inflammation. OBJECTIVES: To assess anti-inflammatory efficacy and safety of ruvonoflast in participants with residual inflammatory risk and high ASCVD risk. METHODS: In a double-blind Phase 1b trial, we randomly allocated individuals with hsCRP ≥2.5 mg/L and BMI ≥30 to ≤40 kg/m2, plus dyslipidemia, hypertension or type 2 diabetes, to oral ruvonoflast (225mg twice daily; N=40) or matching placebo (N=23). Both groups were maintained on a 2000 kcal/day diet. The primary endpoint was change in hsCRP at Day 28 (ratio to baseline), analyzed using a Bayesian analysis of covariance. Additionally, change in hsCRP ratio to baseline over time was analyzed using a mixed-effects model with repeated measures (MMRM). Change from baseline in inflammatory biomarkers and body weight were secondary endpoints analyzed with MMRM and ANCOVA, respectively. Safety and tolerability were analyzed descriptively. RESULTS: Of 63 participants (mean age=52.6 years; 71.4% female; 69.8% white) randomized, 59 completed the study. Median hsCRP at baseline was 5.7 mg/L (IQR=3.9-9.8). The primary endpoint of hsCRP reduction was met with a posterior probability of >99% for superiority of ruvonoflast over placebo at Day 28. Between-group differences favoring ruvonoflast were significant from Day 3 onwards (p≤0.001); at Day 28, geometric least-squares mean reduction in hsCRP was 82.2% (95% CI=75.9-86.8) with ruvonoflast versus 37.2% (95% CI=7.0-57.6) with placebo. hsCRP returned to baseline 7 days post-treatment discontinuation. Ruvonoflast significantly lowered key secondary biomarkers IL-6 and fibrinogen versus placebo at Day 28 (p<0.001). Treatment groups had comparable mean percentage body weight reductions at Day 28. Serious treatment-emergent adverse advents (TEAEs) were similar between groups, but four (10%) ruvonoflast-treated participants discontinued treatment due to transient, reversible TEAEs, versus none in placebo. CONCLUSIONS: Oral NLRP3 inhibition with ruvonoflast significantly reduced hsCRP with concurrent reductions in inflammatory biomarkers in participants with elevated inflammatory risk. Ongoing Phase 2 trials of larger size and longer duration will further characterize the therapeutic potential of ruvonoflast.
Konstam MA, Udelson JE, Mann DL
… +24 more, DiCarlo L, Butler J, Ardell J, De Ferrari GM, Klein HU, Filippatos G, Metra M, Anand I, Close N, Saville BR, Detry MA, Paulon G, Khandwala F, Bosse A, KenKnight B, Mindrebo S, Rice P, Trifunovic N, Popescu MI, Apostolovic S, Adler A, Parker JD, Teerlink JR, ANTHEM-HFrEF Investigators
J Am Coll Cardiol
· 2026 Jun · PMID 42159539
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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 tri...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).
Stroeks SLVM, Bart NK, Rossano J
… +36 more, Claggett B, Beelen NJ, Buchan RJ, Day S, Fornaro A, Halliday BP, Wheeler MT, Hammersley DJ, Helms A, Heymans ABM, Ho CY, Khan SS, Lin K, Lota A, Merlo M, Mestroni L, Olivotto I, Owens A, Seidman CE, Shore S, Sinnette C, Sinagra G, Stevenson LW, Stewart GC, Theotakis P, Venner MFGHM, Ware JS, Taylor MRG, Verdonschot JAJ, Wilsbacher L, Prasad S, Heymans SR, Parikh VN, Tayal U, Lakdawala NK, DCM/ACM SHaRe Investigators
J Am Coll Cardiol
· 2026 Jun · PMID 42159538
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BACKGROUND: Dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) are progressive cardiac muscle disorders with phenotypic and genetic overlap. Although a male predominance is noted in DCM/ACM, it remains...BACKGROUND: Dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) are progressive cardiac muscle disorders with phenotypic and genetic overlap. Although a male predominance is noted in DCM/ACM, it remains unclear whether this extends to specific genetic subtypes or reflects variation in disease stage and whether sex influences age-dependent disease onset across pediatric and adult groups. OBJECTIVES: The aim of this study was to define sex-based differences in genetic architecture and age at diagnosis of DCM/ACM across pediatric and adult populations. METHODS: Genetically tested adult and pediatric DCM/ACM patients and asymptomatic genotype-positive relatives enrolled in the multicenter SHaRe (Sarcomeric Human Cardiomyopathy Registry) were analyzed. Sex distribution across 27 DCM- and ACM-associated genes was evaluated using logistic regression. Age at diagnosis was compared across sex and genes using Kaplan-Meier cumulative incidence estimates. RESULTS: Among 3,410 patients, a 61% male predominance was present across subgroups of genotype positive, genotype negative, and variants of uncertain significance (P = 0.008), with significant gene-specific variation. TTN truncating variants (TTNtv) were less common in females (OR: 0.42 [95% CI: 0.33-0.54]; P < 0.01), while DSP (OR: 3.3 [95% CI: 2.35-4.78]; P < 0.01) and grouped non-TTN sarcomeric variants (ACTC1, TNNT2, MYH7, TNNC1, TNNI3, and TPM1) were more common (OR: 1.68 [95% CI: 1.15-2.47]; P < 0.001) in females compared with males with DCM/ACM. Age at diagnosis was comparable between sexes, except in TTNtv carriers, among whom males exhibited earlier disease onset compared with females (median age 45 years [Q1-Q3: 33-55 years] vs 51 years [Q1-Q3: 38-60 years]; P = 0.003). Pediatric-onset (diagnosis at <18 years) cases (n = 174) also demonstrated a male predominance (60% male) but had distinct genetic characteristics, with non-TTN sarcomeric and PKP2 variants being more prevalent compared with adult-onset disease (non-TTN sarcomeric OR: 5.5 [95% CI: 3.3-8.9; P < 0.01]; PKP2 OR: 2.8 [95% CI: 1.1-5.2; P < 0.05]) and a bimodal age at onset peaking in infancy and adolescence. CONCLUSIONS: Gene-specific sex differences influence disease prevalence and age at onset in DCM/ACM. TTNtv are more common with earlier onset in males, whereas DSP and non-TTN sarcomeric variants predominate in females. Pediatric-onset DCM/ACM is genetically distinct and caused predominantly by non-TTN sarcomeric variants, especially during infancy. These findings support age- and sex-informed surveillance strategies and prioritize future research into the mechanisms of observed sex-based differences.
Manzato M, Kalhor P, Nogami K
… +4 more, Pinna A, Montone RA, Lerman LO, Lerman A
J Am Coll Cardiol
· 2026 May · PMID 42159534
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BACKGROUND: Coronary endothelial dysfunction (ED) represents an early stage of coronary artery disease (CAD). Several factors may induce ED. Air pollution, more specifically particulate matter <2.5 μm (PM), has emerged a...BACKGROUND: Coronary endothelial dysfunction (ED) represents an early stage of coronary artery disease (CAD). Several factors may induce ED. Air pollution, more specifically particulate matter <2.5 μm (PM), has emerged as a major nontraditional cardiovascular risk factor contributing to early vascular injury, but its impact on coronary ED remains poorly defined. OBJECTIVES: In this study, we sought to identify an association between chronic PM exposure and epicardial endothelial dysfunction (EED) determined by means of invasive coronary vasoreactivity testing, the criterion standard technique to assess EED. METHODS: This observational study included prospectively enrolled patients with angina and nonobstructive CAD who underwent coronary reactivity testing at Mayo Clinic from 2000 to 2023. Residential addresses at the time of testing were geocoded to derive monthly PM exposure at a 0.01° × 0.01° spatial resolution, averaged over the 2 years preceding testing. EED was defined as percentage change of less than -20% in coronary artery diameter in response to acetylcholine infusion. Associations between continuous PM and EED were assessed according to a generalized propensity score with a gamma-distributed model to derive stabilized inverse probability weights, applied in multivariable logistic regression. RESULTS: A total of 1,485 patients with a median age of 51.7 years (Q1-Q3: 42.7-60.1 years) were included in the analysis. Individuals exposed to PM above environmental protection agency standards (9 μg/m) were younger and had less cardiovascular comorbidities, although they had worse lipid profiles. In weighted multivariable logistic regression, each 1 μg/m increase in PM was associated with increased odds of EED (OR: 1.078; 95% CI: 1.021-1.139; P = 0.007), adjusted for age, sex, body mass index, and cardiovascular comorbidities. CONCLUSIONS: Chronic PM exposure is associated with epicardial coronary ED, suggesting a potential biological link between PM and CAD.
Hatherley J, Dakshi A, Collinson P
… +20 more, Miller G, Bailey L, Davies S, Fearon H, Meah N, Frost F, Raj R, Ensor E, Fisher M, Goulden C, Noori Z, Salmon T, Rawat A, Hornby R, Lambert A, Sekulska K, Ingram T, Fitzgerald G, Shaw M, Khand A
J Am Coll Cardiol
· 2026 May · PMID 42159533
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BACKGROUND: For suspected acute coronary syndrome (ACS), guidelines recommend using high-sensitivity troponins (hs-cTn) in accelerated diagnostic pathways (ADPs) with 0/1-hour recommended over 0/3-hour ADP. However, impl...BACKGROUND: For suspected acute coronary syndrome (ACS), guidelines recommend using high-sensitivity troponins (hs-cTn) in accelerated diagnostic pathways (ADPs) with 0/1-hour recommended over 0/3-hour ADP. However, implementation of these ADPs, with universal use of hs-cTns, has not been directly compared in randomized trials OBJECTIVES: This study sought to compare the efficiency and safety of the European Society of Cardiology (ESC) 0/1-hour and a 0/3-hour ADP when implemented in real-world clinical practice. METHODS: This pragmatic, randomized, noninferiority implementation trial compared the safety and efficiency of clinician decision making using these 2 pathways. To prevent incorporation bias, an independent hs-cTnI was used for formal adjudication using the fourth universal definition of myocardial infarction (MI). Efficiency was judged by the proportion of patients discharged within 4 hours. The safety endpoint was major adverse cardiac events (MACE) within 30 days (adjudicated index or representation type 1 MI, cardiovascular death, and urgent coronary revascularization) for those who were considered not to have ACS and discharged. The noninferiority margin, for absolute difference in sensitivity, between the ESC 0/1-hour and the 0/3-hour ADP was set at 3%, assessed with a 1-sided 97.5% CI. RESULTS: From December 2021 to July 2024, of 13,983 screened 3,543 individual patients with suspected ACS were recruited and consented from 2 major emergency departments in North-West England, with 100% follow-up achieved for all representations to any national hospital. The median age was 60 years (IQR: 49.5-70.5 years), 53% were men, 6.7%, and 7.6% had adjudicated index type 1 MI and MACE within 30 days, respectively. The turnaround time from sample to result for central laboratory hs-cTnT was 81 minutes (IQR: 69-101 minutes). The proportion of patients discharged within 4 hours was relatively low and did not differ substantially (21.8% vs 19.2%, P = 0.07). In addition, the 0/1-hour pathway was noninferior for safety, in patients discharged, compared with the 0/3-hour pathway, absolute difference in sensitivity was +4.2% (1-sided 97.5% CI: -2.5) in favor of the 0/1-hour pathway. The calculated sensitivities were 93.7% (95% CI: 88.4%-97.1%) vs 89.5% (95% CI: 82.7%-94.3%), respectively. CONCLUSIONS: Implementation of the ESC 0/1-hour pathway failed to discharge significantly more patients within 4 hours of presentation compared with the 0/3-hour ADP. In addition, The ESC 0/1-hour was noninferior to the 0/3-hour hs-cTn pathway for safety of discharge, although safety for both pathways was less than that imputed by observational studies. This trial demonstrates that perceived benefits to emergency department efficiency of a reduced sampling interval are mitigated by central laboratory turnaround times as well as system constraints. (Pragmatic Randomised Trial of the ESC 0/1 Versus 0/3 Hour Troponin Pathway [MACROS2]; NCT05322395).