Journal of the American College of Cardiology

BACKGROUNDPeak oxygen uptake (pVO2) is a strong, independent predictor of adverse cardiovascular outcomes, supporting cardiopulmonary exercise testing as a primary end point assessing efficacy of novel drug therapies in obstructive hypertrophic cardiomyopathy (oHCM) clinical trials. However, characterizing changes in pVO2 that patients perceive as beneficial or meaningful (ie, minimal important difference [MID]) has not been determined. METHODSData from patients with symptomatic oHCM enrolled in SEQUOIA-HCM and MAPLE-HCM were pooled. A total of 282 patients were randomized 1:1 to aficamten (5-20 mg daily) or matching placebo in SEQUOIA-HCM, and 175 patients were randomized 1:1 to aficamten (5-20mg daily) or to metoprolol (50-200 mg) in MAPLE-HCM; follow-up in both trials was 24 weeks. Primary outcome was change from baseline to week 24 ({Delta}) in pVO2 using Patient Global Impression of Change with anchor-based analysis to define MID. RESULTSAt week 24, {Delta}pVO2 (mL/kg/min) that corresponded to no change, one-category improvement, and one-category worsening were -0.05 (95% CI, -0.58 to 0.48), +0.35 (95% CI, -0.22 to 0.91), and -0.61 (95% CI, -1.36 to 0.13), respectively. Similarly, minute ventilation to carbon dioxide production ratio (VE/VCO2) slope that corresponded to no change, one-category improvement, and one-category worsening were 0.16 (95% CI, -0.59 to 0.90), -1.15 (95% CI, - 1.89 to -0.42), and 0.88 (95% CI, -0.42 to 2.19), respectively. In a responder analysis using this new threshold for pVO2, 60% of patients receiving aficamten achieved a {Delta}pVO2 [&ge;]0.35 versus 31% of patients on placebo or metoprolol (odds ratio, 3.4 [95% CI, 2.3-4.9], P<0.001). Consistent findings were seen with VE/VCO2 responder analysis. CONCLUSIONSChanges in pVO2 of +0.35 and -0.61 mL/kg/min were associated with a small but perceptible clinical improvement and worsening, respectively, in patients with oHCM. Applying this newly defined threshold resulted in excellent differentiation of treatment effect in a clinical trial. These novel data provide a measure of clarity to patients and clinicians regarding the interpretation of changes in pVO2 following therapeutic interventions, with potential impact on HCM management strategies and future clinical trials. Clinical Trial RegistrationSEQUOIA-HCM (NCT05186818; https://clinicaltrials.gov/study/NCT05186818?term=sequoia-hcm&rank=1); MAPLE-HCM (NCT05767346; https://clinicaltrials.gov/study/NCT05767346?term=maple-hcm&rank=1) Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIUsing pooled data from over 440 patients with symptomatic obstructive hypertrophic cardiomyopathy enrolled in two phase 3 clinical trials, we define, for the first time, the minimally important difference for peak oxygen uptake (pVO2) and ventilatory efficiency (VE/VCO2) using patient-anchored and distribution-based methodologies. C_LIO_LIA change in pVO2 of +0.35 mL/kg/min and a change in VE/VCO2 of -1.15 represent the minimal thresholds associated with patient-perceived clinical improvement. C_LIO_LIResponder analyses using these thresholds demonstrated robust differentiation between aficamten and placebo/metoprolol, with an odds ratio exceeding 3 for achieving a meaningful improvement in pVO2. C_LI What Are the Clinical Implications?O_LIThese newly defined thresholds bridge the gap between statistically significant changes in cardiopulmonary exercise testing measures and clinically meaningful benefit as perceived by patients with obstructive hypertrophic cardiomyopathy. C_LIO_LIClinicians can use these benchmarks to contextualize individual patient responses to medical therapy, informing shared decision-making regarding treatment continuation or modification. C_LIO_LIThese data provide a standardized, patient-centered framework for designing and interpreting primary end points in future hypertrophic cardiomyopathy clinical trials. C_LI

BackgroundElevated resting heart rate (HR) and atrial cardiopathy are each linked to higher mortality risk, yet their interrelationship and joint prognostic value remain unclear. MethodsWe analyzed 7,326 adults (mean age 59 {+/-} 13 years) without cardiovascular disease from the Third National Health and Nutrition Examination Survey with available electrocardiograms. Atrial cardiopathy was defined by electrocardiogram as abnormal P-wave axis or deep terminal P-wave negativity in V1. Multivariable logistic regression assessed cross-sectional associations between HR categories and atrial cardiopathy. Cox proportional hazards models evaluated independent and joint associations of HR categories and atrial cardiopathy with all-cause mortality. ResultsAtrial cardiopathy was present in 1,833 participants (13.5%). After adjustment, sinus tachycardia ([&ge;]100 bpm) was associated with higher odds of atrial cardiopathy (OR 1.76, 95% CI 1.06-2.92), whereas sinus bradycardia ([&le;]50 bpm) was associated with lower odds (OR 0.61, 95% CI 0.43-0.84). Each 10-bpm HR increase corresponded to 25% higher odds of atrial cardiopathy. Over a median 13.8-year follow-up, 2,415 deaths (33.0%) occurred. Sinus tachycardia (HR 3.58, 95% CI 2.61-4.91) and atrial cardiopathy (HR 1.27, 95% CI 1.16-1.39) were independently associated with mortality. Individuals with both conditions had the highest risk (HR 4.11, 95% CI 2.63-6.41). Associations varied by age and race. ConclusionsElevated resting HR is associated with higher odds of atrial cardiopathy, and their coexistence confers markedly increased mortality risk. Integrating resting HR into atrial cardiopathy metrics may enable granular population-level risk profiling.

AimsCardiac myosin inhibitors (CMIs) have emerged as an alternative to septal reduction therapy (SRT) for obstructive hypertrophic cardiomyopathy (oHCM). However, comparative data on the time-trajectory of myocardial functional adaptation after septal myectomy (SM), alcohol septal ablation (ASA), and CMI are lacking. We compared temporal changes in echocardiographic parameters including LV global longitudinal strain (LVGLS) and LA reservoir strain (LASr) across these treatment strategies. Methods and ResultsIn this single-center retrospective cohort, symptomatic oHCM patients treated with SM (n=22), ASA (n=11), or CMI (n=47) underwent serial echocardiography with deep-learning-based automated strain analysis. Primary outcomes were temporal changes in LVGLS and LASr. Mixed-effects models adjusted for baseline clinical and echocardiographic variables were used to assess time-trajectories for up to 24 months. Treatment success rates were 86.4% (SM), 72.7% (ASA), and 93.6% (CMI). LVOT gradients were similarly reduced across groups. LVEF showed a subtle early decline after CMI (adjusted P-for-interaction=0.019). LVGLS gradually improved after SM and ASA but remained unchanged with CMI. LASr significantly improved after SM, showed minimal change after ASA, and demonstrated late attenuation beyond 9-12 months in the CMI group (adjusted P=0.029). ConclusionsDespite comparable LVOT gradient reduction, myocardial functional adaptation differed across therapies. Conventional SRT was associated with progressive improvement in LV and LA strain, whereas CMI therapy showed stable LVGLS with subtle early LVEF decline and late attenuation of LASr. These findings underscore the importance of longitudinal deformation imaging during CMI therapy and support reappraisal of SRT in selected patients requiring durable long-term management.

Background and AimsDespite advances in reperfusion and medical therapy, survivors of acute myocardial infarction (AMI) remain at risk for adverse left ventricular remodeling (LVR), a precursor to heart failure. Building on prior work outlining 12-month biomarker trajectories linked to early ventricular dysfunction, we aimed to assess whether these circulating biomarkers predict long-term adverse LVR. MethodsWe prospectively enrolled 155 patients experiencing their first AMI. Clinical, biochemical, and echocardiographic data were obtained at pre-percutaneous coronary intervention (pre-PCI), 24 h post-PCI, discharge (day 3), 6 months, and 12 months. Adverse LVR was defined as an increase of [&ge;]15 % in left ventricular end-systolic volume at 12 months. ResultsAdverse LVR occurred in 34 % of patients and was associated with cardiometabolic dysregulation (higher glucose, triglycerides, BMI, HOMA-IR; lower HDL-C). Among the six baseline biomarkers, only insulin-like growth factor-binding protein 2 (IGFBP-2) differed significantly between groups (p = 0.021) and remained independently associated in multivariable analysis (p = 0.036). Inclusion of IGFBP-2 increased the predictive models area under the receiver-operating characteristic curve from 0.735 to 0.801. ConclusionsIGFBP-2 is an independent predictor of adverse LVR following AMI, highlighting the interplay between metabolic dysfunction and maladaptive remodeling. Incorporating IGFBP-2 into clinical risk models could improve stratification and guide precision therapies for high-risk patients.

AimsLeft bundle branch block (LBBB) is associated with mechanical dyssynchrony, heterogeneous perfusion, and adverse left ventricular (LV) remodeling. However, not all patients with LBBB develop cardiomyopathy, and dyssynchrony can occur without conduction defects. The role of microvascular dysfunction remains uncertain. We aimed to assess how mechanical dyssynchrony and perfusion heterogeneity relate to LV remodeling and function in patients with and without LBBB. Methods and resultsWe retrospectively analyzed 233 patients with isolated LBBB and 932 matched controls who underwent PET myocardial perfusion imaging, assessing mechanical dyssynchrony (phase entropy), myocardial blood flow (MBF), coronary vascular resistance (CVR), myocardial flow reserve (MFR), septal-to-lateral MBF ratio (SLR) for perfusion heterogeneity, LV volumes, and ejection fraction (EF). Compared to controls, patients with LBBB had greater dyssynchrony (56% vs. 40%), larger LV volumes, and lower EF (54% vs. 67%) (all p<0.001), and had higher stress CVR (37 vs. 34 mmHg/mL{middle dot}min-{superscript 1}{middle dot}g-{superscript 1}), lower stress MBF (2.4 vs. 2.6 mL/min/g), reduced MFR (2.4 vs. 2.6), and lower SLR (0.95 vs. 1.00) (all p<0.05). Among patients with dyssynchrony, SLR<1.0 identified those with more adverse remodeling. In multivariable regression, phase entropy and SLR independently predicted LV volumes and EF, with adverse effects of SLR reduction amplified in LBBB (interaction p<0.01). In the Cox proportional hazards analysis, phase entropy (HR:1.02, p=0.01), MFR (HR:0.62, p<0.001), and LVEF (HR:0.97, p<0.001) were independently associated with mortality and heart failure hospitalization, whereas LBBB was not. ConclusionsMechanical dyssynchrony and perfusion heterogeneity independently predict adverse LV remodeling, irrespective of LBBB. Integrated imaging enhances cardiomyopathy stratification.

BACKGROUNDDilated cardiomyopathy (DCM) presents a highly heterogeneous spectrum, including a familial subset with elevated arrhythmic risk. Traditional demographic and imaging markers, such as late gadolinium enhancement, have been inadequate for identifying high-risk patients before arrhythmic events. Remodelling of the interventricular septum--central to ventricular mechanics and conduction--may offer improved risk stratification. OBJECTIVESTo identify differences in left ventricular (LV) morphology between arrhythmic and idiopathic dilated cardiomyopathy (aDCM vs iDCM), and to identify LV remodeling patterns that link to adverse outcomes. METHODSThree-dimensional LV shape models were constructed from end diastolic cardiovascular magnetic resonance images of 102 individuals subdivided by their idiopathic or arrhythmic subgroup allocation. A statistical shape model was built using principal component analysis. A linear discriminant analysis determined shape features of the arrhythmic subgroup and increased composite arrhythmic outcome of sudden cardiac death, aborted sudden cardiac death, and sustained ventricular tachycardia. RESULTSThe idiopathic DCM group displayed larger mass, length, diameter, mass to volume ratio, and a mild spiral pattern of thicker septal walls (p=0.004). The arrhythmic DCM group displayed a more conical (wider basal and mid wall to apical diameter) LV, and the lack of the spiral septal morphology was the most significant feature (p=0.006) to identify subjects that had the composite arrhythmic outcome. CONCLUSIONThe LV morphology derived suggests a differentiation of arrhythmic DCM patients beyond size, function and LGE presence. This was distinctive and captured shape features that suggest alternate mechanisms for arrhythmic risk linked to a pattern of remodeling. Graphical AbstractAssessing LV morphology signature of arrhythmic DCM phenotype O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/26346514v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1f47f7aorg.highwire.dtl.DTLVardef@dd5d08org.highwire.dtl.DTLVardef@106ef07org.highwire.dtl.DTLVardef@36eb76_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundMyocardial 18fluorodeoxyglucose (18FDG)-avidity is frequently seen in patients with genetic cardiomyopathy (CMP), as well as a growing "idiopathic 18FDG-avidity" group of genotype-negative patients who do not clearly have cardiac sarcoidosis (CS). ObjectivesTo determine the prognostic implications of 18FDG-avidity in patients with and without genetic CMP, and the effects of immunosuppression in the latter. MethodsThis multicenter, retrospective study included all patients who were referred for both 18FDG-PET and CMP genetic testing. Patients with acute myocarditis, biopsy-proven sarcoidosis or extracardiac 18FDG-avidity were excluded. We investigated heart failure (HF) composite (left ventricular assist device, heart transplant, HF hospitalization, death) and arrhythmia composite (sustained ventricular arrhythmias (VT/VF), atrio-ventricular block, death) outcomes using survival analysis including Cox proportional hazards modeling and inverse probability of treatment weighting (IPWT). ResultsAmong 372 patients, 142 (38%) were 18FDG-avid. Prevalence of genetic CMP among 18FDG-avid patients (12%) was similar to that of 18FDG-negative patients (19%, p=0.07). 18FDG-avidity was associated with increased risk of HF composite (HR 1.69 (1.04-2.75), p=0.034) and arrhythmia composite (HR 1.63 (1.1-2.4), p=0.014) outcomes compared to 18FDG-negative patients. However, these associations were present only in genotype-negative patients, and not in genetic CMP. After IPWT, immunosuppression of 18FDG-avid patients (n=49) was not associated with a reduction in HF (HR 3.31 (1.25, 8.77), p=0.016) or arrhythmia composite outcomes (HR 1.61 (0.79, 3.25), p=0.19) compared with those who were not immunosuppressed (n=93). ConclusionsMyocardial-only 18FDG-avidity is only associated with adverse HF and arrhythmia outcomes in genotype-negative patients who do not clearly have CS. IST does not seem to modify the disease course, suggesting that not all myocardial 18FDG uptake reflects clinically significant inflammation.

1ObjectiveTo assess the effects of SGLT2 inhibitors on cardiovascular outcomes in HFpEF/HFmrEF. DesignSystematic review, random-effects meta-analysis using Hartung-Knapp, and trial sequential analysis (TSA). Data sourcesMEDLINE, Embase, and CENTRAL; searches updated through August 13, 2025. Eligibility criteriaParallel-group randomized trials enrolling adults with LVEF 40% (HFmrEF 40-49%; HFpEF 50%). Main outcome measuresTime-to-event composite of cardiovascular death or first heart failure hospitalization (primary); Kansas City Cardiomyopathy Questionnaire (KCCQ-TSS), components, and safety (secondary). ResultsTwo dedicated HFpEF trials (n=12,251) reported the primary outcome. The pooled hazard ratio was 0.80 (95% CI 0.73-0.87; I2=0%; 2 0; 95% prediction interval 0.67-0.96). TSA crossed efficacy boundaries and exceeded the diversity-adjusted required information size, indicating conclusive evidence for the composite. Effects were consistent in patients with and without diabetes and across EF 40-49% vs 50% (no significant interactions). KCCQ improved (+2.3 points, 95% CI 1.0-3.6; responders 5 pts: 42% vs 38%). Safety showed more genital mycotic infections, with no increase in serious adverse events or acute kidney injury. ConclusionsSGLT2 inhibitors robustly reduce cardiovascular death/heart failure hospitalization and improve health status in HFpEF/HFmrEF, supporting their role as foundational therapy, irrespective of diabetes status; effects on mortality alone remain imprecise. RegistrationPROSPERO CRD420251167908. Data and code: https://doi.org/10.5281/zenodo.18409428 PROSPEROCRD420251167908 Data availabilityhttps://doi.org/10.5281/zenodo.18409428

BackgroundHypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease associated with increased risks of heart failure, sudden cardiac death (SCD), and stroke. Over 1,400 pathogenic variants, primarily in MYH7 and MYBPC3, have been identified, yet the prognostic significance of genetics remains unclear. Recent studies suggest genotype-positive (G+) HCM is linked to earlier diagnosis, greater disease severity, and poorer outcomes, necessitating further research to clarify the relationship between genotype, disease progression, and clinical management. ObjectivesO_LIExamine the association between genetic mutations (MYBPC3, MYH7, TNNT2, TNNI3) and both clinical outcomes (AF, syncope, ventricular arrhythmias, SCD, stroke) and structural cardiac characteristics (left atrial/ventricular thickness, LVEF) in HCM patients. C_LIO_LIConduct a systematic review and meta-analysis to evaluate the prognostic significance of genotype-positive HCM, aiming to inform clinical risk stratification and management strategies. C_LI MethodsA systematic literature search in PubMed for English-language articles from 2000 onward using relevant Medical Subject Headings (MeSH) terms identified six studies meeting inclusion criteria. G+ HCM was defined as mutations in MYBPC3, MYH7, TNNT2, or TNNI3. Data analysis employed the Cochrane Database of Systematic Reviews, assessing outcomes via risk ratios and mean differences with random-effects models. Heterogeneity was evaluated using appropriate statistical methods. ResultsG+ HCM showed significantly increased risk of AF (RR 1.20, p = 0.02) and ventricular arrhythmias (RR 1.56, p = 0.04), with greater left atrial thickness (p = 0.004). No significant differences were found in syncope (p = 0.33), stroke (p = 0.98), or SCD (p = 0.22), left ventricular thickness (p = 0.13), or LVEF (p = 0.10) between G+ and G-patients. These findings underscore the impact of genetic mutations on arrhythmic risk and structural remodeling in HCM. ConclusionsGenetic mutations in MYBPC3, MYH7, TNNT2, and TNNI3 increase AF, ventricular arrhythmias, and left atrial remodeling risks in HCM patients, but do not significantly affect stroke, SCD, syncope, or left ventricular structure. Genetic status is crucial in risk assessment, necessitating close arrhythmia monitoring in G+ patients and further research to refine risk stratification and management strategies in HCM.

BackgroundElevated resting heart rate is associated with increased mortality, but the underlying mechanisms remain incompletely understood. Subclinical myocardial injury (SCMI), defined by a Cardiac Infarction/Injury Score (CIIS) [&ge;]10, represents silent cardiac damage that predicts poor cardiovascular (CV) outcomes and may partially explain this association. MethodsWe analyzed 7,152 participants from NHANES III who underwent ECG recording and were free of cardiovascular disease. Heart rate was categorized as bradycardia ([&le;]50 bpm), normal (>50-<100 bpm), or tachycardia ([&ge;]100 bpm). Mortality was assessed through National Death Index linkage. Logistic and Cox regression models evaluated associations with SCMI and mortality, respectively, and attenuation was assessed by change in hazard ratios after adjusting for SCMI. ResultsSCMI was present in 1,744 (24.3%) participants. Tachycardia was associated with increased odds of SCMI (adjusted OR 2.34, 95% CI 1.42-3.88). Over 13.9 years median follow-up, 2,311 (32.3%) died from all causes and 933 (13.1%) from CV causes. Tachycardia was associated with increased all-cause mortality (HR 3.58, 95% CI 2.63-4.88) and CV mortality (HR 2.05, 95% CI 1.06-3.79). Adjustment for SCMI attenuated the tachycardia-CV mortality association by 8.6% and all-cause mortality by 5%. Bradycardia was not associated with SCMI or mortality. ConclusionThese findings suggest that SCMI partially mediates the heart rate-mortality relationship and that ECG-based assessment of SCMI may enhance risk stratification in individuals with elevated resting heart rate.

BackgroundCardiovascular health (CVH) and genetic susceptibility to adverse left ventricular (LV) remodeling are each linked to cardiovascular diseases (CVD); however, their combined role remains unclear. MethodsFramingham Heart Study participants [n=1,255 Offspring-Exam 8 (2005-2008), n=2,835 Generation 3-Exam 1 (2002-2005)] had assessment of modifiable risk factors comprising the American Heart Associations Lifes Essential 8 (LE8) score with higher scores indicating better CVH health. A Polygenic Risk Score (PRS) for LV mass index (LVMI) was also calculated based on published PRS(PGS003427). We created 9 groups combining LE8 and PRS tertiles (high LE8+low PRS served as referent group reflecting optimal risk) and related these groups to presence of LVMI, LV ejection fraction (LVEF), and the ratio of the peak early diastolic mitral inflow velocity (E wave) to the peak early diastolic mitral annular velocity (e wave; E/e; separate model for each outcome), and incident cardiovascular disease (CVD; a composite of coronary heart disease [CHD], heart failure, stroke, peripheral arterial disease). We applied linear mixed regression and Cox regression models to evaluate the relation of LE8-PRS groups with all outcomes mentioned above. ResultsParticipants (56% women, mean age 47 years) had mean LE8 score 70 (SD=13), indicating intermediate CV health and normal LVMI and systolic function (LVMI 76{+/-}13 g/m{superscript 2}, LVEF 65{+/-}5%, E/e 6 {+/-}1.8 cm/s). Over 19 years of follow-up, composite CV events and CHD occurred in n=188 and n=99, respectively, of Offspring and n=83 and n=49 respectively, of Gen 3 participants. Compared to the referent group, individuals in the low LE8-high PRS group had high LVMI, E/e, and over three-fold higher risks for CVD and CHD, with incidence rates of approximately 1.84 versus 4.06 per 1,000 person-year, respectively. ConclusionLower LE8 scores (indicating worse CVH) combined with high genetic risk confer higher conjoint risks for adverse LV structure, function, and CVD development.

BackgroundPremature coronary artery disease (PCAD) continues to impose a disproportionate burden on younger adults in the United States, yet recent patterns across sex, region, race, and urbanization remain poorly defined. MethodsUsing CDC WONDER data from 1999-2023, we examined PCAD-related age-adjusted mortality rates (AAMR) for males <45 years and females <55 years, stratified by region, race/ethnicity, and urbanization. Temporal trends were assessed using Joinpoint regression to estimate annual percent change (APC) and average annual percent change (AAPC). ResultsThe combined AAMR for PCAD in the U.S. is approximately 8.5 deaths per 100,000 population. Both sexes demonstrated overall declines in PCAD mortality since 1999 (AAPC males -0.84%; females -1.07%), interrupted by a transient rise during 2018-2021 (APC = 7.85%; 95% CI 5.41-9.32), followed by a sharp post-pandemic decline (APC = -7.39%; 95% CI -10.64 to -4.53). Females consistently exhibited higher mean AAMRs than males (8.74 vs. 8.34; p<0.00001). Regional analyses showed that mortality rates were highest in the South (males 9.86; females 10.96) and Midwest (8.97; 9.36), with intermediate rates in the Northeast (males 7.09, females 6.77), and the lowest rates in the West (6.35; 6.16). Non-metropolitan residents carried a 1.5-1.7-fold greater mortality burden than metropolitan populations (males 12.20 vs. 7.74; females 13.31 vs. 8.06). Black/African Americans had the highest rates (males: 12.17, females: 15.98), followed by American Indian/Alaska Natives (8.49, 9.02) and Whites (8.0, 8.0), while Asian/Pacific Islanders had the lowest (about 2.4-4.3). ConclusionsNational PCAD mortality has decreased, but disparities persist and are growing by region, race, sex, and urbanization. Concentration in the Southern and Midwestern states and among certain races highlights the need for further research using modern molecular methods and improved health care resources. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/25342435v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@5fa12dorg.highwire.dtl.DTLVardef@4eb887org.highwire.dtl.DTLVardef@34b48forg.highwire.dtl.DTLVardef@3a2be1_HPS_FORMAT_FIGEXP M_FIG C_FIG Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LIThe combined AAMR for PCAD in the U.S. is approximately 8.5 deaths per 100,000 population. C_LIO_LIPremature coronary artery disease-related mortality rates are higher in the Southern and Midwestern states, among non-Hispanic Black, Native American, and non-metro populations. C_LI What are the Clinical Implications?O_LIThe geographic and demographic clustering of cases strongly suggest contributions from underlying genetic, environmental, and dietary factors that warrant further investigation. C_LIO_LIEarly identification of at-risk individuals through precision-medicine approaches and the implementation of targeted, evidence-based preventive strategies could mitigate these regional and racial disparities. C_LI

BackgroundDiastolic dysfunction is a major driver of morbidity in congenital heart disease (CHD), but its mechanisms are poorly understood. It remains unknown whether left ventricular (LV) diastolic dysfunction in borderline left heart patients is caused by a defect in active relaxation or in passive compliance. ObjectivesWe sought to apply gold-standard pressure-volume (PV) loop analysis to define the primary mechanism of diastolic dysfunction in patients with borderline LV (bLV). MethodsWe analyzed invasive PV loop data from pediatric patients with bLV (n =13) and a comparison group of patients with congenitally corrected transposition of the great arteries (ccTGA, presumed no diastolic dysfunction; n=14). PV loops were generated during transient preload reduction and augmentation. Active relaxation was assessed by the isovolumic relaxation time-constant ({tau}) and maximal rate of pressure decline (dP/dtmin) indexed to peak-systolic pressure (PSP). Passive compliance was quantified by the chamber stiffness constant ({beta}), derived from the multi-beat end-diastolic PV relationship (EDPVR). To account for size differences, {beta} was (1) calculated using indexed ventricular volumes (i{beta}), and (2) converted to a dimensionless stiffness constant ({beta}W) by multiplying {beta} by ventricular wall volume. ResultsActive relaxation measures were similar between groups, indicating normal lusitropy in bLV ({tau} bLV: 28 [23.5-29.5] vs ccTGA: 24 [21-28] msec, p=0.10; dP/dtmin/PSP bLV: -10.6 [-11.0, -9.4] vs. ccTGA: -9.9 [-10.5, -8.7] s-1, p=0.17). In contrast, patients with bLV had markedly abnormal passive compliance. The EDPVR was shifted sharply upward and to the left, and the stiffness constants were significantly higher in the bLV group (i{beta} bLV: 0.10 [0.04-0.35] vs. ccTGA: 0.03 [0.02-0.04] m2/mL, p=0.003); {beta}W bLV: 4.08 [1.60-7.52] vs. ccTGA: 1.21 [0.95-1.77], p=0.002). ConclusionsThe primary mechanism of diastolic dysfunction in bLV is impaired passive ventricular compliance, and not impaired active relaxation. These findings suggest a limited role for lusitropic medications and therapeutic strategies that focus on mitigating ventricular stiffness (such as surgical endocardial fibroelastosis resection) may be more valuable. Condensed abstractPressure-volume loop analysis with preload alteration in pediatric congenital heart disease shows that in borderline left heart patients left ventricular diastolic dysfunction is caused by impaired passive compliance, with preserved active relaxation. This mechanistic insight suggests that interventions targeting ventricular stiffness such as surgical endocardial fibroelastosis resection may be more beneficial than the use of lusitropic medications to improve outcomes.

BackgroundBoth acute myocardial infarction (AMI) and acute myocarditis are characterised by cardiac troponin release as a marker of cardiomyocyte injury. While peak troponin is widely accepted as a surrogate marker for infarct size in AMI, its relationship with myocardial injury in acute myocarditis is unclear. This study aimed to quantify and compare the association between peak high-sensitivity cardiac troponin and cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) extent in patients with AMI versus acute myocarditis. MethodsPatients undergoing CMR imaging and measurement of high-sensitivity cardiac troponin I during hospital admission were retrospectively included. LGE extent was quantified in grams using the semi-automated expectation-maximization weighted intensity algorithm (EWA). ResultsCompared to patients with acute myocarditis (n=47), patients with AMI (n=49) had higher peak troponin levels (median [interquartile range] 32,470 [3,109-104,699] vs 7,295 [1,857-22,550] ng/L, p=0.002), larger LGE extent (25 [13-56] vs 10 [6-17] g, p<0.001), and lower left ventricular ejection fraction (45 [36- 52] vs 55 [49-58] %, p<0.001). Peak troponin was moderately positively correlated with LGE extent in both AMI (rho=0.56, p<0.001) and acute myocarditis (rho=0.58, p<0.001). However, the ratio of peak troponin to LGE mass was higher in AMI compared to acute myocarditis (1,299 [419-3233] vs 909 [310-1446] ng/L/g, p=0.02). ConclusionsPeak cardiac troponin correlates positively with LGE extent in both AMI and acute myocarditis, but the magnitude of LGE and LV systolic dysfunction is greater in AMI. Also, AMI typically has an approximately 40% greater amount of troponin release per unit LGE mass compared to acute myocarditis. This suggest that troponin-based estimates of myocardial injury size estimated by LGE are not directly interchangeable between ischaemic and inflammatory myocardial diseases.

We performed a systematic review and meta-analysis of randomized controlled trials evaluating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus placebo in adults with heart failure (HF), searching PubMed, Cochrane CENTRAL, and ClinicalTrials.gov through February 2026. The primary outcome was the composite of cardiovascular death and first HF hospitalization. Random-effects meta-analysis used restricted maximum likelihood estimation with Hartung-Knapp-Sidik-Jonkman adjustment. We included 14 studies (6 dedicated HF trials and 8 cardiovascular outcomes trial HF subgroup analyses) encompassing 18,558 patients, of whom 2,499 were randomized in dedicated HF trials. The primary composite did not reach statistical significance (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.73-1.01; P=0.067; I2=47%). GLP-1 RAs significantly reduced all-cause mortality (HR 0.87, 95% CI 0.81-0.93; P<0.001; I2=0%), major adverse cardiovascular events (HR 0.83, 95% CI 0.73-0.95; P=0.019), and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (+7.4 points, 95% CI 6.3-8.5) and 6-minute walk distance (+17.6 m, 95% CI 13.4-21.7). Excluding the FIGHT trial (acute HFrEF) yielded a significant primary composite (HR 0.83, P=0.011). The mortality signal was driven primarily by CVOT subgroups; the largest dedicated HFpEF trial (SUMMIT) showed numerically higher mortality (HR 1.25). The strongest evidence supports GLP-1 RAs in HFpEF with obesity. HighlightsO_LIPrimary composite of CV death + HHF was not significant (HR 0.86, P=0.067) C_LIO_LIGLP-1 RAs reduced all-cause mortality (HR 0.87) with no heterogeneity C_LIO_LIKCCQ-CSS improved by 7.4 points and 6MWD by 17.6 m in HFpEF trials C_LIO_LIMortality benefit driven by CVOT subgroups, not dedicated HF trials C_LIO_LIStrongest evidence supports GLP-1 RAs in HFpEF with obesity C_LI

BackgroundTranscatheter aortic valve replacement (TAVR) has rapidly evolved into a standardized treatment for severe aortic stenosis, particularly in patients at increased surgical risk. The fifth-generation SAPIEN 3 Ultra RESILIA (S3UR) valve notably incorporates RESILIA-treated tissue as well as an enhanced external skirt in order to reduce structural valve deterioration (SVD) and paravalvular leak (PVL). However, real-world data on its clinical performance remains limited. ObjectivesTo evaluate procedural, hemodynamic, and short-term clinical outcomes of the S3UR valve compared to earlier-generation SAPIEN 3 (S3) and SAPIEN 3 Ultra (S3U) platforms in Ronald Raegan UCLA medical center. Methods513 patients who underwent transfemoral TAVR at Ronald Reagan UCLA Medical Center between 2022 and 2024 were analyzed. Of these, 216 received the S3UR valve and 297 received S3U/S3 valves. Propensity-score matching (1:1) yielded 181 well-balanced patient pairs. Primary endpoints included device success per VARC-3 criteria, with secondary endpoints encompassing 30-day safety, echocardiographic performance, and procedural complications. ResultsThe S3UR group demonstrated significantly lower post-procedural and 30-day mean aortic valve gradients (7.45 {+/-} 3.37 mmHg and 9.06 {+/-} 2.94 mmHg, respectively; p < 0.001) compared to the S3U/S3 group. Rates of moderate or greater PVL were 0% in the S3UR group versus 8.9-10.1% in S3U/S3 patients (p < 0.001). Procedural success exceeded 98% in both groups, with no significant differences in stroke, mortality, or new pacemaker implantation. Readmission rates trended lower in the S3UR cohort (7.8% vs. 13.9%), though not statistically significant. ConclusionsThe SAPIEN 3 Ultra RESILIA valve demonstrated superior hemodynamic performance and significantly reduced PVL compared to earlier-generation balloon-expandable valves, while maintaining comparable safety and procedural success. These findings support the S3UR as a preferred TAVR platform in contemporary clinical practice, with ongoing follow-up needed to evaluate long-term durability.

Dilated cardiomyopathy (DCM) is a major driver of heart failure and transplantation. Despite its strong genetic basis, clinical genetic testing identifies pathogenic/likely pathogenic (P/LP) variants in only about one-third of cases. Genome-wide association studies (GWAS) indicate that common variants also contribute to genetic risk, but utility of polygenic risk score (PRS) for diagnostic testing is unclear. We derived a DCM PRS from a large GWAS and applied it to 113 Australian Genomics Health Alliance (AGHA) participants of genetically determined European ancestry with clinically diagnosed DCM, with most having a family history of disease. Genetic testing identified a P/LP variant in 34% of patients. Using 450,280 UK Biobank participants of European ancestry as a reference, we selected the best performing PRS (SBayesRC; odds ratio per SD increase in PRS = 1.72, 95% CI 1.58-1.88). We compared the PRS of individuals with a P/LP variant in the TTN gene (TTN_G+) or other genes (nonTTN_G+), and in those without any P/LP or variants of unknown significance identified (G-). Relative to the UK Biobank reference, median PRS values were significantly higher in G- and TTN_G+ groups. Twenty-six percent of G- and 25% of TTN_G+ cases were in the top decile, versus 11% of nonTTN_G+ cases. Notably, TTN_G+ cases were absent from the lowest four deciles. These findings support a substantial polygenic contribution in DCM patients without identifiable monogenic variants as well as in TTN-related DCM. Incorporating PRS alongside routine genetic testing could increase diagnostic yield and inform risk management for patients and families.

Whether the cumulative evidence for remote patient monitoring (RPM) in heart failure (HF) has reached a definitive threshold -- and whether benefits extend to geographically underserved populations -- remains uncertain. We conducted a systematic review, meta-analysis, and trial sequential analysis (TSA) of 65 RCTs (59 poolable; [~]23,000 participants) across four databases through February 2026, encompassing structured telephone support (15 trials), non-invasive telemonitoring (33), and invasive hemodynamic monitoring (11). Random-effects meta-analysis used REML with Hartung-Knapp-Sidik-Jonkman adjustment. RPM significantly reduced all-cause mortality (RR 0.890, 95% CI 0.819-0.966; P=0.007; I2=2.3%; k=41; NNT 84/year; prediction interval 0.820-0.965). TSA confirmed that accrued evidence exceeded the required information size, establishing firm evidence that additional RPM-versus-control trials are unlikely to overturn the mortality benefit. HF hospitalization was reduced (RR 0.782, 95% CI 0.711-0.859; P<0.001; k=39; NNT 17/year), though the prediction interval crossed 1.0 (0.589-1.038), indicating that in some settings the effect may be attenuated. No interaction by RPM type was observed (Pinteraction=0.15-0.24). GRADE certainty was moderate for mortality and low for HF hospitalization. A pre-specified geographic access analysis revealed that only 2 of 59 trials reported rural/urban subgroups -- a critical evidence gap that precludes conclusions about whether RPM differentially benefits underserved populations. HighlightsO_LITrial sequential analysis confirms firm evidence for RPM mortality benefit C_LIO_LIAll-cause mortality reduced 11% (NNT 84/yr, prediction interval excludes null) C_LIO_LIHF hospitalization reduced 22% (NNT 17/yr), though prediction interval crosses 1.0 C_LIO_LINo differential benefit by RPM type (STS vs TM vs invasive; Pinteraction=0.24-0.34) C_LIO_LIOnly 2 of 59 trials reported rural/urban subgroups -- a critical geographic evidence gap C_LI

AbstracO_ST_ABSBackgroundC_ST_ABSSodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in heart failure (HF), yet comparative effectiveness between individual agents in heart failure with mildly reduced ejection fraction (HFmrEF) remains limited. MethodsWe conducted a retrospective cohort study using the TriNetX Global Collaborative Network electronic health record database. Adults ([&ge;]18 years) with HF and left ventricular ejection fraction (LVEF) 41-49% initiating empagliflozin or dapagliflozin between September 2021 and December 2025 were included. Propensity score matching (1:1) balanced demographics, comorbidities, medications, and laboratory values, yielding 1,466 patients per group. Outcomes were assessed over 1 year after treatment initiation and included all-cause mortality, hospitalization, HF exacerbation, and urinary tract infection (UTI). Risk analyses and Kaplan-Meier survival analyses with hazard ratios (HRs) were performed. ResultsIn the matched cohort, empagliflozin was associated with lower all-cause mortality (HR 0.75, 95% CI 0.59-0.96), substantially fewer hospitalizations (HR 0.61, 95% CI 0.55-0.67), and HF exacerbations (HR 0.64, 95% CI 0.57-0.73) compared to dapagliflozin. Rates of UTI were similar between groups (HR 0.81, 95% CI 0.65-1.01). ConclusionsIn this large real-world HFmrEF population, empagliflozin was associated with lower mortality, hospitalization, and HF exacerbation compared with dapagliflozin, with no significant difference in UTI risk. These findings suggest potential heterogeneity in clinical effectiveness among SGLT2 inhibitors in HFmrEF and warrant confirmation in prospective comparative studies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=146 HEIGHT=200 SRC="FIGDIR/small/26343819v1_ufig1.gif" ALT="Figure 1000"> View larger version (46K): org.highwire.dtl.DTLVardef@1a0ce4corg.highwire.dtl.DTLVardef@481df6org.highwire.dtl.DTLVardef@a71830org.highwire.dtl.DTLVardef@25114a_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundHeart failure (HF) is an increasingly common complication among patients with type 2 diabetes (T2D), yet its early detection remains challenging, especially in those with concomitant chronic kidney disease (CKD). NT-proBNP is a key biomarker for diagnosing and prognosticating HF, but its reference thresholds are influenced by renal function, age, and ethnicity. Current guideline cutoffs, largely derived from Western populations, may not apply to Asian patients. MethodsThis retrospective cohort study included 10,587 adults with T2D who underwent NT-proBNP testing between 2006 and 2021 at the National Taiwan University Hospital. Patients with prior HF were excluded. Generalized additive models identified NT-proBNP thresholds associated with HF hospitalization, and Kaplan-Meier analysis validated outcome separation. Subgroup analyses were stratified by age, sex, body mass index (BMI), and estimated glomerular filtration rate (eGFR). ResultsDuring a mean follow-up of 3.5 years, 1,892 (17.9%) patients were hospitalized for HF. NT-proBNP levels of 179 pg/mL (outpatient) and 728 pg/mL (emergency) marked inflection points for rising event risk (log-rank p < 0.0001). Age-specific analyses showed progressive increases in optimal thresholds: from 85 (<50 years old), 150 (50-74 years old) and 290 pg/mL ([&ge;]75 years old) in outpatients, and from 310, 600 and 1,165 pg/mL, respectively, in emergency settings. In the BMI-stratified analysis, NT-proBNP thresholds demonstrated an inverse relation with BMI. Considering renal function, the optimal cutoffs were 100, 310, and 935 pg/mL for eGFR > 60, 30-60, and < 30 mL/min/1.73 m{superscript 2}, respectively; in the emergency cohort, the corresponding thresholds were 290, 835, and 3,905 pg/mL. ConclusionsThis large Asian cohort defines setting- and renal function-specific NT-proBNP thresholds for predicting HF hospitalization in patients with T2D. The lower optimal cutoffs compared with Western guidelines highlight the need for ethnicity-adjusted diagnostic criteria to improve early identification and risk stratification of HF in clinical practice. What is new?O_LIIn a large real-world Asian cohort of patients with type 2 diabetes, we identified setting-specific NT-proBNP thresholds (179 pg/mL outpatient; 728 pg/mL emergency) associated with heart failure hospitalization risk. C_LIO_LIAge-, BMI-, and kidney function-stratified cutoffs revealed substantial heterogeneity in optimal NT-proBNP thresholds. C_LIO_LICompared with guideline-recommended values, Asian-specific thresholds were consistently lower ([~]30-40%), supporting ethnic differences in natriuretic peptide biology. C_LIO_LIA generalized additive model (GAM) captured nonlinear biomarker-risk relationships, enabling data-driven and clinically interpretable cutoff identification. C_LI What are the clinical implications?O_LIUse of ethnicity- and context-specific NT-proBNP thresholds may improve early detection of heart failure in Asian patients with type 2 diabetes. C_LIO_LIIncorporating kidney function and BMI into NT-proBNP interpretation enhances risk stratification, particularly in patients with CKD. C_LIO_LIReliance on Western guideline cutoffs may underestimate heart failure risk in Asian populations. C_LIO_LIThese findings support a precision medicine approach to biomarker interpretation and highlight the need for population-specific guideline refinement. C_LI