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Background: Long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy that stems primarily from pathogenic variants in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3) and is characterized by prolongation of the cardiac action potential duration (APD) at the cellular level. Despite current therapeutic options, there is a pressing need for novel, precision medicine-based, effective pharmacological therapies for LQTS, particularly for LQT2 and LQT3. Goal: To develop a high-throughput drug screening platform to identify novel therapeutics for LQTS using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Methods: iPSC-CMs were made for patients with LQT2 (p.G604S) or LQT3 (p.P1332L). Voltage dye assays were performed using a kinetic image cytometer (KIC) in a 96 well format. The APD at 90% repolarization (APD90) was measured in treated/untreated iPSC-CMs. Cyteseer image analysis software was used for optical APD analysis. SCN5A-P1332L iPSC-CMs were treated with 10 uM mexiletine (MEX) as a positive control. 114 compounds from a commercially available library of FDA-approved drugs were tested in triplicate to assess their APD shortening efficacy. Whole-cell patch clamp was used to confirm the lead compound’s effect in KCNH2-G604S iPSC-CMs. Results: MEX significantly shortened the APD90 of SCN5A-P1332L iPSC-CMs by 13% (669 ± 5 to 586 ± 10 ms; p<0.0001; n=50). Of the 114 tested compounds, 6 shortened the APD90 of SCN5A-P1332L iPSC-CMs by greater than 20%. The lead compound shortened the APD90 of SCN5A-P1332L iPSC-CMs by 32% (571 ± 2 ms; n=314, to 387 ± 4 ms; n=80; p<0.0001). All 6 candidate compounds also shortened the APD90 of KCNH2-G604S iPSC-CMs by greater than 20% in KIC screening assays. Whole-cell patch clamp confirmed APD shortening by the lead compound in KCNH2-G604S iPSC-CMs (759 ± 35 ms; n=13, to 599 ± 89 ms; n=9; p<0.03). Conclusion: The high-throughput KIC screen confirmed mexiletine’s APD shortening effects in SCN5A-P1332L iPSC-CMs, validating the assay's potential for efficient, large-scale drug screening. In a pilot screen, we identified 6 novel LQTS drug candidates which shortened the APD90 in SCN5A-P1332L (LQT3) and KCNH2-G604S (LQT2) iPSC-CMs more than mexiletine. The lead compound’s APD shortening effects in KCNH2-G604S iPSC-CMs were confirmed with whole cell patch clamp. The KIC platform offers a robust method for identifying novel QT shortening compounds by enabling reproducible APD measurements in a high-throughput format.

Introduction: Valvular heart disease (VHD) poses a growing global burden, particularly in aging populations. While transcatheter interventions have expanded rapidly over the past two decades, the extent to which trial populations reflect real-world demographics—especially age and sex—is unclear. Understanding enrollment trends and representation gaps is essential to ensure equitable, generalizable evidence for clinical decision-making. Methods: We systematically reviewed VHD interventional trials (2000–2024) indexed in PubMed. Surgical and percutaneous trials across aortic, mitral, tricuspid, and pulmonic valves were included. Trial characteristics, demographics, and interventions were analyzed using descriptive and nonparametric statistics. Results: We included 487 trials enrolling 87,412 participants (45% women). Median trial size increased over time (z = 4.98, p < 0.01), and the mean age of participants also rose significantly (z = 10.08, p < 0.01). Trials involving percutaneous (11% to 45%), bioprosthetic (22% to 53%), aortic valve (27% to 62%), and multinational (2% to 16%) interventions increased over time. Older participants were more commonly enrolled in percutaneous, industry-funded, multinational, bioprosthetic, and aortic valve trials. Female representation remained unchanged across time (median 47%, z = -0.48, p = 0.63), but trials enrolling older participants tended to include more women (ρ = 0.196, p < 0.01). Female representation was highest in mitral (59%) and tricuspid (59%) valve trials, and more common in percutaneous (52%) than surgical (42%) interventions. Conclusion: Over the past two decades, VHD trials have expanded in size and geographic scope, with increased enrollment of older adults, particularly in percutaneous and industry-sponsored studies. However, sex disparities and demographic variability persist. Future trials should prioritize inclusive designs to ensure equitable, generalizable evidence for evolving valve interventions.

Background: Impella 5.5 is a temporary MCS device FDA-approved for use up to 14 days. Limited data suggest it may be safe beyond this. We aim assess outcomes based on the duration of Impella 5.5 support in heart failure cardiogenic shock (HFCS) patients at our institution. Methods: We retrospectively reviewed all HFCS patients supported with Impella 5.5 at our institution between 2020-2024. Patients supported for >14 days were compared with those supported for ≤14 days. Categorical variables were analyzed with chi-square tests, continuous variables with t-tests or Mann-Whitney U. Logistic regression identified factors linked to clinical outcomes. Results: 154 patients were included: 38 (25%) with support ≤14 days, 116 (75%) with >14 days. Median support duration was 10 (6–12) vs 31 (22–45) days, respectively. Median support duration was 10 (6-12) days for the ≤14 cohort and 31 days (22-45) days for the >14 cohort. Baseline characteristics, comorbidities, LVEF 18% (15-23) and hemodynamics show no statistical differences. Patients supported for >14 days were more likely to undergo heart transplant compared to those supported ≤14 days (91% vs 74%, p=0.009). In contrast, myocardial recovery was more likely in the ≤14 day cohort (8% vs 1%, p=0.018). One patient suffered stroke post-transplant in the ≤14 day group and two had brachial plexus injuries in the >14 days group. Mortality during the impella-supported period was slightly higher in the ≤14 day group (8% vs 5%, p=0.535) but comparable overall, 13% in both groups, p=0.971. Support >14 days was associated with transplant outcome (OR 3.41, 95% CI 1.32–8.84, p=0.012), and remained significant after adjusting for age, gender, GFR, and EF (OR 4.05, 95% CI 1.31–12.54, p=0.015). Support duration <14 days was associated with recovery or LVAD outcomes (OR 5.01, 95% CI 1.49–16.89, p=0.009), and remained significant after adjustment (OR 5.43, 95% CI 1.11–26.45, p=0.036). No association was observed between duration of support and LVAD/mortality outcomes or with EcPella use. Conclusion: Shorter Impella support duration was independently associated with early myocardial recovery or LVAD candidacy, likely reflecting rapid clinical decision-making. Prolonged Impella support was associated with increased likelihood of transitioning to heart transplantation, likely reflecting clinical stabilization over time. Our multidisciplinary, single-center data suggests Impella 5.5 can be used beyond FDA-approved 14 days in HFCS patients.

Introduction: Patients with variant transthyretin (TTR) amyloid cardiomyopathy (ATTRv-CM) experience early onset disease, rapid progression, and poor outcomes due to amyloid aggregated from destabilized tetrameric TTR. Acoramidis, a highly selective, oral TTR stabilizer, achieves ≥90% TTR stabilization and is approved in the USA, EU, Japan, and UK for adults with wild-type (ATTRwt-CM) or ATTRv-CM. In the phase 3 ATTRibute-CM study and its open-label extension (OLE), acoramidis reduced both the risk of all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) through Month 30 and risk of ACM through Month 42 by 36%. Research Question: Is acoramidis efficacy in ATTRv-CM consistent with that observed in the overall ATTRibute-CM population? Methods: In ATTRibute-CM, participants with ATTR-CM were randomized 2:1 to acoramidis HCl 800 mg or PBO, twice daily (BID) for 30 months. After Month 30, all participants enrolled in the OLE received acoramidis HCl 800 mg BID. Genotype (ATTRwt-CM or ATTRv-CM) was captured at randomization; efficacy was analyzed separately in ATTRv-CM. Time-to-event analyses used a stratified Cox model with terms for treatment, baseline 6MWT, genotype, genotype×treatment interaction, stratified by randomization NT-proBNP and eGFR levels. ACM was analyzed at Month 42 (ATTRibute-CM 30 months + OLE 12 months). Results: The ATTRv-CM group comprised 59 patients (39 acoramidis, 20 PBO). Baseline characteristics were mostly similar in both groups ( Table ). The three most common variants reported were p.V142I (n=35), p.I88L (n=7), and p.T80A (n=5). Compared with PBO, acoramidis reduced the risk of ACM/first CVH through Month 30 by 59% (acoramidis, 46.2%; PBO, 75.0%; HR 0.41; 95% CI 0.21–0.81; P =0.011; Fig 1 ) and ACM through Month 42 by 59% (continuous acoramidis, 30.8%; PBO to acoramidis, 60.0%; HR 0.41; 95% CI 0.19–0.93; P =0.032; Fig 2 ) , with Kaplan–Meier curves separating at Months 5 and 10, respectively. Conclusions: In ATTRibute-CM, acoramidis use was associated with clinical benefit in the ATTRv-CM group as demonstrated by a 59% risk reduction in both ACM/first CVH at Month 30, and ACM at Month 42 compared to PBO. These previously unreported findings support the hypothesis that near complete TTR stabilization observed experimentally with acoramidis across multiple TTR mutations translates into improvement in long-term outcomes. Further validation by individual TTR variant is warranted.

Background: Susceptibility to cardiometabolic diseases (CDs) is shaped by genetic, socio-environmental, and lifestyle factors. We evaluated the associations of disease-specific polysocial risk scores (PSSs)— derived from social determinants of health (SDOH) and lifestyle factors—and genetic risk factors with six CDs, across self-identified race/ethnicity (SIRE) groups in the eMERGE IV cohort. Methods: The six CDs included: atrial fibrillation, coronary heart disease, chronic kidney disease, hyperlipidemia, obesity, and type 2 diabetes. Disease-specific PSSs were developed using machine-learning models based on 65 SDOH and lifestyle factors. Participants were grouped based on their SIRE as Asian, Black, Hispanic/Latino, and White. We evaluated PSS distributions across SIRE groups. Genetic risk was assessed through disease-specific polygenic risk scores (PRSs), monogenic etiologies, and family history (FamHx). High PSS and high PRS were defined as the top 5th percentile. Associations were tested using multivariable logistic regression; model performance was assessed using the C-statistic. Results: Among 20178 participants (50±15 years, 68% female, 40% non-White), the most frequently associated PSS components were physical activity, sleep, self-perceived health, and income. PSS distributions varied across SIRE groups, with Whites having the lowest and Black and Hispanic/Latinos the highest scores for most CDs (Figure 1). All PSSs were significantly associated with their respective CDs, independent of confounders (OR per 1 SD increase: 1.19–2.68; Figure 2-A). No significant interactions were observed between PSSs and PRSs or monogenic etiologies. However, significant interactions were noted between PSSs and FamHx for CKD and obesity. PSS and PRS effects on the odds of CDs were independent (Figure 2-B) and additive (Figure 2-C). Incorporating PSSs into models that included clinical and genetic risk factors improved predictive performance of risk prediction models (Figure 3). Conclusion: PSSs, reflecting socio-environmental and lifestyle disadvantage, varied significantly across SIRE groups and were associated with risk of six CDs, independent of and additive to PRS. Given the substantial variation in socio-environmental and lifestyle risks across SIRE groups, integrating these factors into risk prediction models for CDs may help address health disparities and enhance preventive efforts, especially in marginalized populations.

Background: We investigated the impact of genetic risk factors for coronary heart disease (CHD) -polygenic risk score (PRS), familial hypercholesterolemia (FH), and family history (FamHx)- on CHD risk estimates, across the age spectrum, in two diverse cohorts of US adults -eMERGE IV (eIV) and All of Us (AoU). Methods: CHD was defined as myocardial infarction, unstable angina, and coronary revascularization. Self-identified race/ethnicity (SIRE) was used as a population descriptor. We calculated a PRS for CHD (PRS CHD , PGS004698), ascertained FH as the presence of pathogenic/likely pathogenic variants in FH genes, and defined FamHx as early-onset CHD in first-degree relatives. We employed Pooled Cohort Equations (PCE) to estimate the 10y risk of CHD for adults ≥40y and modeled the association of conventional risk factors with CHD in adults <40y. AoU served as the training set, and eIV as the testing set. We analyzed the impact of PRS CHD and FamHx on CHD risk estimates by a) using multivariable logistic regression and Cox proportional hazard models, assessing discrimination and the extent of risk reclassification; and b) net benefit analysis and decision curves to assess the performance of prediction models across actionable thresholds. Results: We analyzed data for 19348 participants from eIV (age 50±15, 68% female, 41% non-White) and 239645 participants from AoU (age 55±17, 61% female, 48% non-White). Genetic risk factors were significantly associated with CHD. PRS CHD performance varied by SIRE groups, while FamHx was consistent. The effects of PRS CHD and FamHx on CHD were independent and additive (Figure 1). In adults ≥40y, incorporating PRS CHD and FamHx into PCE improved discrimination (C-statistic increased from 0.719 to 0.753; P -diff=9.1×10 -3 , Figure 2) and reclassified risk in 19% and 20% of participants at the 7.5% and 10% 10y CHD risk thresholds, respectively. Between the 7.5% and 10% 10y CHD risk thresholds, incorporating PRS CHD and FamHx into the PCE improved the net benefit of the risk prediction models across White, Black, and Hispanic/Latino groups (Figure 3). Conclusion: PRS CHD and FamHx were independently and additively associated with CHD in two large diverse cohorts in the US. Incorporating PRS CHD and FamHx into PCE improved risk discrimination, reclassified risk in a significant portion of participants, and improved net benefit of the PCE across all three major SIRE groups, motivating the addition of these factors to clinical risk calculators.

Background: Congenital long QT syndrome (LQTS) is characterized by a prolongation of the heart rate-corrected QT interval (QTc) and an increased risk of syncope, seizure and sudden cardiac arrest/death (SCA/SCD). Genome-wide association studies have identified numerous QT interval-influencing loci of small effect sizes. Herein, we sought to investigate whether a polygenic background for the QT interval contributes to the phenotypic heterogeneity in patients with genotype-positive LQTS. Methods: We used summary statistics from a recent genome-wide meta-analysis for QT interval (n = 117,532) to derive 160 different polygenic scores for QT interval (PGS QT ) using LDpred2-grid, each comprising ~1.4 million common variants with varying assumptions of the underlying genetic architecture. Next, we applied these PGS QT to predict the QTc value in a genetically unrelated, European ancestry subset of the ‘All of Us’ cohort with available electrocardiogram and genetic data (n=6,404), where the best performing PGS QT was determined based on explained variance. Next, using 225 patients with genetically confirmed LQTS who were evaluated in the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic, we tested the effect of the best performing PGS QT on QTc duration and LQTS-associated cardiac events (defined as a composite of syncope, seizures, sustained ventricular arrhythmia, appropriate ICD shocks, and SCA/SCD) using Bayesian regression models. Results: Overall, the best performing PGS QT explained 11.8% of the variance in the QTc in the ‘All of Us’ cohort. Among patients with genotype-positive LQTS (n [%]; KCNQ1 125 [55.6], KCHN2 76 [33.8], SCN5A 21 [9.3], Other 3 [1.3]), those with higher PGS QT had a higher QTc (predicted mean QTc [95% uncertainty interval], 95 th percentile vs 50 th percentile for PGS QT , 478 ms [464-491] vs 459 ms [449-468]). In comparison to the median PGS, those LQTS patients with a PGS QT >95 th percentile were more than twice as likely to have experienced a LQTS-associated cardiac event (Odds ratio [95% UI], 95 th percentile vs 50 th percentile for PGS QT ; 2.16 [1.02-5.41]), ( Figure ). Conclusions: Individuals with genotype-positive LQTS who have high polygenic susceptibility for QTc prolongation are more likely to phenotypically exhibit a higher QTc value and experience potentially life-threatening LQTS-associated cardiac events. Accounting for polygenic background may refine risk stratification strategies for patients with genotype-positive LQTS

Introduction: Cardiovascular risks following SARS-CoV-2 infection are incompletely defined. We evaluated evolving cardiovascular outcomes across COVID-19 variant eras using a large community-based cohort to inform risk stratification and clinical care. Methods: We conducted a retrospective cohort study of 162,471 adults with COVID-19 between March 2020 and December 2023 using the Rochester Epidemiology Project. Patients were stratified by variant era (Pre-Delta, Delta, and Omicron). Cardiovascular outcomes included major adverse cardiovascular events (MACE: myocardial infarction, stroke, death), ischemic and inflammatory heart disease, thrombotic events, and dysrhythmias. Diagnoses were identified using ICD-10 codes and validated in a subset. Cumulative incidence was estimated using Kaplan-Meier and competing risk models. Cox proportional hazards regression was used to assess differences by era and age. Results: MACE occurred in 4,922 patients, primarily in those ≥80 (2-year incidence: 17%). Event rates peaked within 30 days post-infection, with marked variation by variant. In patients ≥80, 30-day MACE risk was highest in the Pre-Delta (HR 3.85; 95% CI, 3.14–4.71) and Delta (HR 2.72; 95% CI, 2.13–3.47) eras versus Omicron. After 30 days, event rates fell and era differences narrowed. Thrombotic events (n=2,090; 1.4%) decreased across eras. Ischemic and inflammatory heart disease rates were stable. Myocarditis/pericarditis were rare (0.1%) without age trends. Dysrhythmias affected 6,765 patients (2-year incidence: 4.9%) and rose with age (2.0% in <40 vs. 19.9% in ≥80). Within 30 days, risk was higher in the Pre-Delta and Delta eras for age ≥40, especially ≥80 (Delta HR 3.08; 95% CI, 2.08–4.56) and 60–79 (HR 2.23; 95% CI, 1.75–2.85). Among those 40–59, Delta posed the highest risk (HR 2.74; 95% CI, 1.94–3.86 vs. Pre-Delta HR 1.77; 95% CI, 1.26–2.49). No differences were observed in <40. Beyond 30 days, risk converged across variants. Conclusion: Cardiovascular risk after SARS-CoV-2 infection was concentrated in the first 30 days, with attenuation thereafter. While MACE and thrombotic event rates declined over time, early dysrhythmia risk varied by variant and age, especially in older adults. These findings define a time-sensitive, variant-specific risk window and support short-term, risk-stratified post-COVID monitoring. This work informs targeted follow-up protocols by infection era and age, with implications for quality improvement, resource use, and equitable care.

Background: Heart failure (HF) is a complex syndrome marked by adverse cardiac remodeling and natriuretic peptide (NP) deficiency, which drives disease progression despite current therapies. NPs exert cardioprotective effects via particulate guanylate cyclase receptors GC-A and GC-B, which generate cGMP. Activation of GC-A by ANP or BNP induces arteriodilation, natriuresis, antihypertrophic effects, and inhibits the renin-angiotensin-aldosterone system, while GC-B activation by CNP mediates antifibrotic, lusitropic, venodilatory, and anti-inflammatory actions. Existing drugs target either GC-A or GC-B, but none target both. We developed RT-A1, a unimolecular peptide activating both GC-A and GC-B, hypothesizing it will attenuate myocardial remodeling in a preclinical model of HF with preserved systolic function. Methods: RT-A1 was engineered by rational drug design. HEK293 cells expressing human GC-A or GC-B, human cardiac myocytes (CMs) and fibroblasts (CFs) were treated with RT-A1 (10-100nM) and cGMP was measured. In vivo, mice underwent mild transverse aortic constriction (TAC) or sham surgery. After 3 weeks, LV hypertrophy (LVH) was confirmed by echo. TAC mice were then randomized to vehicle (Veh) or RT-A1 (50pmol/kg/min) via subcutaneous osmotic pumps for 3 weeks. Endpoints included LV/body weight ratio, myocyte cross-sectional area (CSA), plasma cGMP, and RNA-seq. Data are mean±SEM. P<0.05 was significant. Results: RT-A1 dose-dependently increased cGMP in HEK293 cells expressing GC-A or GC-B, confirming dual activation, and elevated cGMP in human CMs and CFs. TAC induced significant LV wall thickening with preserved systolic function versus sham. After three weeks, RT-A1 normalized LV/body weight (3.14±0.14 vs. 3.82±0.29, P=0.03) and reduced myocyte CSA (348±16 vs. 506±17, P=0.0005) compared to Veh. Plasma cGMP was higher in TAC+RT-A1 versus TAC+Veh (85±8 vs 54±8 pmol/ml, P=0.01), confirming target engagement. RNA-seq showed reduced LV BNP expression and downregulation of hypertrophy, fibrosis, and inflammation pathways with RT-A1 treatment vs. Veh following TAC. Conclusions: RT-A1 is a novel dual GC-A/GC-B peptide activator that elevates plasma cGMP and reduces adverse cardiac remodeling in experimental HF by downregulating hypertrophy, fibrosis, and inflammation pathways. Dual GC-A/GC-B activation via RT-A1 represents a promising anti-remodeling therapeutic strategy for HF with preserved systolic function warranting further study.

Background: Pathogenic/likely pathogenic (P/LP) variants in the RBM20-encoded RNA-binding protein motif 20 splicing factor result in a penetrant form of arrhythmogenic/dilated cardiomyopathy (ACM/DCM) characterized by ventricular arrhythmias (VA) and early-onset heart failure. The role of cardiac magnetic resonance (CMR) imaging in characterizing RBM20 cardiomyopathy and guiding risk stratification remains inadequately defined. Objectives: To characterize CMR phenotypes in patients with RBM20 cardiomyopathy and explore associations between variant type, CMR phenotype, and VA risk. Methods: Retrospective analysis of 1,061 genotype-positive ACM/DCM patients was used to identify individuals with P/LP arginine/serine-rich domain-localizing missense (RBM20msv) or truncating (RBM20tv) variants in RBM20. Clinical outcomes, including major VA (MVA; sudden cardiac arrest, sustained ventricular arrhythmia, or appropriate ICD therapy) events, were compared between RBM20msv and RBM20tv-positive patients. When available, CMR findings were also analyzed by variant type and correlated with MVA events. Results: Overall, 64 of 1,061 (6%) ACM/DCM patients possessed an RBM20msv or RBM20tv. Of those, 35 (mean age 38±16 years, 54% female, 94% Caucasian) underwent CMR. Late gadolinium enhancement (LGE) was present in 9/35 (26%), typically in a mid-myocardial septal or inferolateral pattern. Left ventricular (LV) noncompaction was noted in 9/35 (26%). Within the CMR subgroup, RBM20msv accounted for 29/35 (83%) of cases, while RBM20tv was observed in 6/35 (17%). No significant difference in LV ejection fraction (36±7% vs. 42±13%, p=0.358), LV end-diastolic volume index (100±32 mL/m2 vs. 118±44 mL/m2, p=0.342), or LGE prevalence (1/6 [17%] vs. 8/29 [28%], p=1.000) was observed between RBM20tv- and RBM20msv-positive patients. However, MVA events were more frequent among RBM20tv-positive patients in the CMR subset (3/6 [50%] vs. 2/29 [7%], p=0.026) and the overall cohort (7/15 [47%] vs. 6/49 [12%], p=0.008). Conclusions: RBM20tv-positive patients experienced a higher rate of MVA events despite similar rates of LGE and structural remodeling compared to those with RBM20msv. Future studies are needed to determine whether mechanisms independent of fibrosis/re-entry drive arrhythmogenesis in RBM20tv-positive patients and to establish if RBM20tv represents an independent risk factor for MVA events that merits incorporation into genotype-specific risk stratification strategies.