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.

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

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.

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

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

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

Congenital heart disease (CHD) occurs in over half of individuals with 22q11.2 deletion syndrome (22q11.2DS) and the types of lesions range from mild to severe. To determine the basis of variation in cardiac phenotypes we analyzed demographic data from 3,016 unrelated individuals with 22q11.2DS from centers in the Northeast US, Canada, Europe, South America, Israel and Australia. Most individuals in this cohort had a 3 million base pair hemizygous deletion between low copy repeat, LCR22 A-D (87.2%), while a minority had nested proximal deletions (1.5 Mb, A-B, 5.4%; 1.8 Mb, A-C, 1.8%). By univariable analysis methods, we found several demographic features contributed to phenotypic variation, which may in part be due to collection site heterogeneity. To disentangle these effects, we performed multivariable mixed-effects logistic regression and uncovered significant differences between CHD phenotypes and these features. Individuals with the A-D deletion had a lower risk of persistent truncus arteriosus (OR = 0.37, 95% CI 0.18-0.75) but a higher risk of septal defects (OR = 4.7, 95% CI 1.7-12.8) compared to those with the smaller A-B deletion, suggesting distinct developmental pathways sensitive to 22q11.2 gene dosage. In addition, genome-wide genetic principal components (PCs) were associated with specific CHD subtypes, including reduced risk of pulmonary stenosis or atresia with other heart lesions with increasing PC2 (OR = 0.73, 95% CI 0.61-0.87) and increased risk of abnormal origin of the subclavian arteries with PC4 (OR = 2.6, 95% CI 1.4-4.9), indicating that background genetic variation may modify lesion-specific susceptibility. Together, these results suggest that both deletion size and background genetic variation shape the highly variable cardiac phenotypes in 22q11.2DS.

BackgroundPatients with repaired coarctation of the aorta (CoAo) remain at risk for left ventricular hypertrophy (LVH) even in the absence of hypertension. Alterations in wave reflection and the timing of reflected pressure waves may contribute to ventricular remodeling beyond pressure load alone. MethodsWe performed a cross-sectional analysis of patients with repaired CoAo. Office and ambulatory blood pressure (ABPM), non-invasive central hemodynamics, and echocardiographic indices of left ventricular structure were assessed. Linear and multivariable regression models evaluated associations with posterior wall thickness (PWTd) and interventricular septal thickness (IVSTd). Computational simulations were conducted to examine the impact of heart rate on ventricular remodeling. ResultsFifty-seven patients (median post-repair follow-up 11 years) were included. LVH prevalence was 15.2% (95% CI: 4.8-25.6). Although 42% met criteria for hypertension based on ABPM, no patients exhibited elevated central blood pressure. Adjusted augmentation index (AIX@75) was inversely associated with PWTd and remained independently associated after multivariable adjustment (R2 = 0.40, p < 0.01). Replacing AIX@75 by heart rate improved model performance (R2 = 0.44), with lower heart rate independently associated with greater PWTd. Simulation modeling showed that a 10% increase in heart rate reduced mean PWTd and decreased posterior wall hypertrophy prevalence from 30.9% to 2.4% (OR =0.10; 95% CI: 0.01-0.44). ConclusionsVentricular remodeling occurs despite normal central blood pressure in CoAo. A lower heart rate associates with increased ventricular mass. Heart rate-mediated modulation of wave reflection timing represents a potential mechanistic and therapeutic target.

BackgroundLong-term electrocardiogram (ECG) monitoring with wearable devices enables large-scale characterisation of cardiac rhythms, but population-based evidence remains limited. The UK Biobank Cardiac Monitoring Study integrates 14-day patch-based ECG monitoring with accelerometry and detailed phenotypic and lifestyle data. Here, we report the acquisition protocol, data processing, and initial findings from 27,658 participants. MethodsParticipants in the UK Biobank imaging study were invited to undergo 14-day cardiac monitoring using a Zio XT (pilot phase; 2015-18) or BodyGuardian MINI (main phase; 2019- ongoing) monitor. ECGs were analysed by certified technicians and automated algorithms to identify atrial, ventricular, and conduction arrhythmias. In parallel, beat-to-beat RR intervals were derived using in-house algorithms, and physical activity from calibrated triaxial accelerometer data. Analyses assessed wear time, arrhythmia prevalence, circadian patterns, and repeatability. FindingsIn total, 27,658 participants (mean age 71 years; 49.9% women) were analysed, including 7,795 from the pilot phase and 21,141 from the main phase; 1,353 (4.9%) had repeat recordings. In the main phase, median wear time was 13.2 days (IQR 11.9-13.9), and undiagnosed atrial fibrillation (AF) was detected more frequently in men than women (3.2% vs 1.7%; p<0.001); 68% was paroxysmal, with 27.4% detected during week two. Ventricular tachycardia occurred in 12.1% (8.4% in women), with sustained episodes rare (0.4%) but observed. Arrhythmia timing varied markedly with activity, with AF peaking during nocturnal inactivity and ventricular ectopy increasing during activity, peaking at midday. Repeat assessments showed strong reproducibility of diurnal heart rate and activity profiles, with more modest arrhythmia consistency. InterpretationExtended ECG monitoring enables detection of subclinical arrhythmias and long-term physiological rhythms in older adults. Linkage to imaging, multi-omics, and clinical outcomes in UK Biobank will enable unprecedented evaluation of the natural history of asymptomatic rhythm disturbances and their impact on brain health. FundingBritish Heart Foundation and Wellcome Trust.

Background: Acute heart failure (AHF) exhibits marked heterogeneity in diastolic hemodynamics, yet comprehensive echocardiographic assessment of diastolic function (DF) and filling pressure (FP) is often infeasible. We evaluated whether artificial intelligence-enabled electrocardiography (AI-ECG) could provide scalable DF grading and FP estimation in hospitalized AHF patients. Methods: We retrospectively studied adults hospitalized for AHF across Mayo Clinic sites (2013-2023) who received 1 dose of intravenous loop diuretic and had paired 12-lead ECG and TTE. The previously validated AI-ECG DF model was applied without retraining to generate four DF grades and a continuous FP probability. Clinical outcomes were all-cause mortality and heart failure rehospitalization. Associations with clinical severity markers and echocardiographic indices were examined. Kaplan-Meier survival analysis and adjusted multivariable Cox proportional hazards models were performed. Exploratory analyses examine the kinetics of change in FP probability and impact on mortality. Results: Among 11,513 patients (median age 75 years, 39% female), AI-ECG DF grading was feasible in 100%, whereas echocardiographic DF was indeterminate in 44% of clinically eligible patients. In 2,582 patients with determinate echocardiographic DF, AI-ECG FP probability discriminated TTE Grade 2-3 dysfunction with AUC 0.85 (95% CI 0.83 - 0.86). Higher AI-ECG DF grades were associated with higher comorbidity burden, worse NYHA class, elevated NT-proBNP, higher MAGGIC scores, elevated PCWP, and more advanced structural remodeling. After multivariable adjustment, AI-ECG DF remained independently associated with mortality (hazard ratio [HR] 1.25, 95% CI 1.16-1.35 for Grade 2; HR 1.44, 95% CI 1.33-1.56 for Grade 3 versus Normal/Grade 1). Combining AI-ECG DF with MAGGIC scores yielded ordered risk gradients, with highest mortality in patients with both high MAGGIC and Grade 2-3 DF. Among patients with serial ECGs, improvement in FP probability was independently associated with lower mortality (HR 0.85, 95% CI 0.79-0.91), whereas worsening did not show a consistent adverse gradient beyond baseline DF. Conclusions: In a large, geographically diverse AHF cohort, AI-ECG DF grading was universally feasible, correlated with established hemodynamic severity markers, and provided independent prognostic information beyond established risk factors, supporting its role as a pragmatic, scalable diastolic biomarker in AHF.

Background and aims Iron deficiency (ID) and myocardial iron depletion (MID) are causally linked to heart failure (HF) in the general population and in preclinical models. ID is common amongst pregnant women, but its impact on cardiac adaptations to pregnancy is unknown. This study examines that impact, and its potential relevance to peripartum cardiomyopathy (PPCM). Methods. We provided female mice with iron-replete or iron-deficient diets, and monitored cardiac function and morphology longitudinally in pregnancy and postpartum. In women with no HF (n=64), we explored the associations between antenatal iron parameters and echocardiographic parameters in late pregnancy and at 6-12 months postpartum. We also performed a case (n=55), control (n=170) study comparing iron markers and assessing their association with PPCM risk. Results In mice, ID prevented postpartum reversal of pregnancy-induced hypertrophy, reduced postpartum LVEF, and caused profound MID. In women with no HF, low hepcidin, high transferrin and low serum iron were respectively associated with higher LVESV, lower LVEF and higher CMR T1-mapping (lower myocardial iron) in postpartum. In the PPCM study, serum iron, hepcidin and haemoglobin were significantly lower in cases than controls, and were independently associated with risk of PPCM. Mechanistically, myocardial proteomics revealed that ID caused sustained postpartum activation of pyruvate dehydrogenase kinase 4, a master cardiometabolic switch enzyme with a well-recognised role in HF. Conclusions This study links antenatal maternal ID to postpartum systolic dysfunction, and implicates MID and cardiometabolic switching as potential mechanisms. It suggests these links may potentially contribute to the pathophysiology of PPCM

BackgroundLeft atrial (LA) remodeling, a hallmark of chronically elevated LA pressure, is characterized by enlargement and functional impairment. While global and reservoir LA functions are well described, the role of LA booster function and its failure remains poorly defined. ObjectivesTo characterize LA booster function using cardiac computed tomography angiography (CCTA) and to evaluate the relationship between LA preload, booster performance, remodeling, and clinical outcomes. MethodsWe retrospectively analyzed 975 patients who underwent spiral CCTA between 2010 and 2018. Phasic LA and LV volumes were obtained, from which LA reservoir and booster functions were derived. LA performance curve was constructed by plotting LA pre-A volume (preload) against LA booster stroke volume. Clinical outcomes (heart failure, stroke, or cardiovascular death) were analyzed based on the LA performance curve. ResultsLA pre-A volume strongly correlated with LA end-systolic volume (r=0.92, p<0.001). The LA booster stroke volume displayed an inverted U-shaped relation to LA pre-A volume (linear coefficient 0.64, P<0.0001; squared coefficient-0.0029, P<0.0001). The atrial booster function curve reached its vertex at 107 mL (95% CI 90 to 113 mL), indicating that the booster pump response for the increased preload is exhausted at this point. Booster dysfunction was associated with impaired reservoir function (r=0.77, p<0.001) and reduced LA systolic flow rates (-0.79, P<0.001). Patients with increased LA pre-A volume but reduced booster volume ("LA failure") exhibited the highest event rate of the combined endpoint of heart failure, stroke or cardiovascular mortality (43.2%, 95% CI 33.6-54.2%). ConclusionsLA enlargement predominantly serves to increase LA pre-A volume to sustain booster function. LA contractile dysfunction affects global LA function via a concomitant reduction in LA reservoir volume. LA failure can be defined as reduced booster contraction despite elevated preload, portending poor clinical outcomes.

BackgroundScreening for atherosclerosis focuses on identifying Standard Modifiable Risk Factors (SMuRFs), including diabetes, hypertension, hyperlipidaemia, and smoking. PurposeTo compare the extracardiac thoracoabdominal atherosclerotic plaque burden, as measured by computed tomography angiography (CTA), among heart transplant candidates with ischemic or non-ischemic cardiomyopathy (ICM, NICM), and evaluate potential associations between plaque burden and SMuRFs. MethodsThis retrospective study identified heart transplant candidates with ICM or NICM matched for age and sex, undergoing thoracoabdominal CTA. Patients were classified as with SMuRFs or SMuRF-less. Extracardiac thoracoabdominal non-calcified and calcified atherosclerotic plaque was classified as present or absent across 78 arterial segments per patient. ResultsAmong included patients (n=167, median [interquartile range] age 58 [53-63] years, 16% female, 51% NICM), 40 patients (24%) were SMuRF-less (ICM: 16/82 (20%), NICM: 24/85 (28%), age 56 [50-67] years). Overall, out of 13,026 arterial segments analysed, 1,746 (13%) were affected by atherosclerotic plaque (9 [4-15] segments per patient). ICM had a higher total plaque burden than NICM (11 [7-18] vs 6 [3-11] segments per patient, p<0.001). SMuRF-less patients showed no difference in non-calcified, calcified, or total plaque burden compared to patients with SMuRFs, among all patients (ICM+NICM, p>0.17) and within the ICM and NICM groups, respectively (p>0.30). ConclusionsThe burden of extracardiac thoracoabdominal atherosclerotic plaque is higher among heart transplant candidates with ICM. However, it does not differ between SMuRF-less or those with SMuRFs, regardless of underlying ICM or NICM. The prevalence of SMuRFs is not an effective marker to determine the need to screen for extracardiac atherosclerotic plaque among heart transplant candidates. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/26347056v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1aff6b1org.highwire.dtl.DTLVardef@16cfb07org.highwire.dtl.DTLVardef@1d4894corg.highwire.dtl.DTLVardef@81e9d3_HPS_FORMAT_FIGEXP M_FIG C_FIG

PurposeDespite strong evidence, real-world adoption of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) remains suboptimal. The Get With The Guidelines-Heart Failure (GWTG-HF) program was designed to close gaps in care. We evaluated whether hospital participation in GWTG-HF is associated with greater GDMT intensity and improved outcomes. MethodsWe conducted a retrospective analysis (2013-2021) of Medicare beneficiaries with Part A and Part D hospitalized with HFrEF. Using a multiple baseline time series design, we compared changes in GDMT prescribing and outcomes at hospitals before and after GWTG-HF enrollment with hospitals that never participated. The primary outcome was a 90-day post-discharge prescription-fill GDMT score summarizing use and dose of beta blockers, renin-angiotensin system inhibitors (RASI; ACE inhibitor/ARB/ARNI), and mineralocorticoid receptor antagonists (MRA). Secondary outcomes included class-specific medication fills, achievement of [&ge;]50% target doses, and 30-day, 90-day, and 1-year all-cause and HF readmission and mortality. We adjusted for baseline hospital performance, patient characteristics, and temporal trends. ResultsAmong 1,274,863 Medicare beneficiaries hospitalized for HFrEF, 53.5% were treated at hospitals that never participated in GWTG-HF and 9.6% at hospitals that joined GWTG-HF before hospitalization. Unadjusted median GDMT scores increased from 3.0 in both groups to 4.0 in non-participating hospitals and 4.5 in GWTG-HF hospitals at 90 days (p<0.001). Hospital enrollment was associated with a higher 90-day GDMT score (+0.15 points; 95% CI 0.12-0.18; p<0.001), and greater use of beta blockers, RASI, and MRA, but not ARNI. HF readmission did not differ significantly; however, GWTG-HF participation was associated with lower all-cause mortality at 30 days (OR 0.95; 95% CI:0.92-0.98), 90 days (OR: 0.97; 95% CI: 0.95-0.99), and 1 year (0.97; 95% CI: 0.95-.0.99; all p<0.05). ConclusionHospital participation in GWTG-HF was associated with higher GDMT intensity and lower mortality, supporting structured quality programs to improve HFrEF care.

Background and AimSedentary lifestyle and obesity are considered to be significant risk factors that create a pathway for the appearance of the sedentary cardiac phenotype consisting of cardiac atrophy, myocardial stiffening, and altered haemodynamics. Although exercise training has the potential to reverse this detrimental process, the literature data on the magnitude of improvements and the certainty of evidence are inconsistent. This systematic review and meta-analysis aimed to evaluate the effects of exercise interventions on cardiac morphology, systolic/diastolic function, and haemodynamics in sedentary and obesity-prone individuals. MethodIn accordance with the PRISMA guidelines, the study was conducted by searching the PubMed, Web of Science, and Scopus databases from 1990 to 2025 without applying any filters, using Covidence software. As a result of this comprehensive search, 15 randomised controlled trials (RCTs; N=559) comparing exercise training with a control group in sedentary individuals were included in the analysis. Data were pooled using the Standardised Mean Difference (SMD) and a random-effects model. Publication bias and methodological robustness of the results were tested using the Egger regression test, the Trim-and-Fill method, and Leave-One-Out sensitivity analysis. The certainty of the evidence was graded using the GRADE system. ResultsExercise training was associated with a significant reduction in resting HRs and SBPs, which was a strong improvement in the haemodynamic profile. The improvements in SV and LVEF, although on the statistical threshold in the primary analysis, were statistically significant and methodologically stable in the Leave-One-Out sensitivity analysis, which excluded confounding studies. The exercise training was associated with a marked improvement in the E/A ratio and S wave, and the triggering of a physiological athletes heart-like eccentric hypertrophy, defined by improvements in LVMass and LVEDV. The exercise training was associated with diastolic adaptation and mass increase, with HIIT being the most superior method for diastolic adaptation and mass increase, and aerobic exercise being the most effective method for blood pressure reduction. Importantly, the meta-regression analyses revealed two important findings: first, the improvement in blood pressure and diastolic function was independent of weight loss; second, the improvement in structure and function was linearly related to improvements in body composition. ConclusionExercise acts as a cardiac polypill reversing the sedentary phenotype by improving hemodynamics and diastolic function independently of weight loss, while linking structural remodeling to BMI optimization; our data prioritize HIIT for structural/diastolic gains and Aerobic training for blood pressure control.

BackgroundAmiodarone is a widely used antiarrhythmic which frequently induces thyroid dysfunction, including both amiodarone-induced hypothyroidism (AIH) and thyrotoxicosis (AIT). Whether genetic factors contribute to these adverse drug reactions is unknown. In this study, we aimed to identify genetic variants that influence the risk of amiodarone-induced thyroid dysfunction and to evaluate their potential to support genotype-guided risk screening. MethodsThis pharmacogenetic study comprised two genome-wide meta-analyses of AIH and AIT using five datasets (Copenhagen Hospital Biobank, The Danish Blood Donor Study, Estonian Biobank, deCODE genetics, and Mass General Brigham Biobank). Key measures included the odds ratio (OR) per risk allele, the variants effects on spontaneous thyroid disease and biomarkers, and their clinical predictive ability, assessed by the area under the receiver operating curve (AUC), positive and negative predictive values (PPV and NPV). FindingsThe AIH meta-analysis (880 cases, 4,031 controls) identified three genome-wide significant loci in: FOXE1 (rs36052460; OR 2.58, allele frequency [AF] = 64.3%, P = 2.55 x 10-44), FOXA2 (rs2424459; OR 1.67, AF = 71.3%, P = 2.59 x 10-14), and ADAM32 (rs12681571; OR 1.49, AF = 61.8%, P = 3.05 x 10-9). The AIT meta-analysis (385 cases, 4,936 controls) identified one locus in CAPZB (rs867355; OR 1.63, AF = 66.1%, P = 3.49 x 10-8). In risk prediction models, a polygenic risk score (PRS) of the AIH variants increased the AUC by 9.2% (95% CI 6.6 - 11.9%), which outperformed a genome-wide hypothyroidism PRS (1.5% AUC increase, 95%CI 0.0 - 2.9%). Similarly, the CAPZB variant improved AIT prediction (AUC increase of 4.0%, 95% CI 0.4 - 7.5%) beyond a hyperthyroidism PRS (0.2% AUC increase, 95%CI -0.8 - 1.2%). Genotype-guided screening would identify individuals at low risk (NPVs ranging from 90-95% and PPVs 2-20%). InterpretationWe identified genetic variants that influence the risk of developing amiodarone-induced thyroid dysfunction. Genotype-guided screening offers a potential complement to current strategies and personalize pre-treatment risk assessment for patients initiating amiodarone therapy.