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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

Background: Patients with low gradient non-severe aortic stenosis (AS) at rest, in the context of reduced left ventricular ejection fraction (LVEF) (less than 50%), occasionally undergo dobutamine stress echocardiogram (DSE). However, limited data is available in the literature regarding the utility of DSE in this context. Methods: We conducted a retrospective study on patients with non-severe AS and LVEF less than 50% at rest who underwent DSE after Institutional Review Board approval. Retrospective data was extracted including rest and DSE parameters using an internal database. Only patients greater than 18 years old, who had an LVEF less than 50%, mean gradient (MG) less than 40 mmHg, and valve area greater than or equal to 1 cm 2 at rest were included in the study. Univariate and multivariate regression methods were used to identify which resting variables were associated with severe AS (MG greater than 40 mm Hg and valve area less than 1 cm 2 ) with DSE. Results: A total of 124 patients were included in the study. The mean age of patients was 78 years (±9) and 84% were male. The mean resting LVEF was 34% (±8%) while it was 40% (±12%) with DSE, mean stroke volume index at rest was 39 mL/m2 (±9) while it was 45 mL/m2 (±10) with DSE, MG at rest was 20 mmHg (±7) while it was 31 mmHg (±10) with DSE, and mean aortic valve area at rest was 1.27 cm 2 (±0.27) while it was 1.24 cm 2 (±0.29) with DSE. Of the 124 patients with non-severe AS at rest, 13 (10.5%) patients had severe AS with DSE. MG at rest was associated with severe AS (OR 1.3; 95% Cl: 1.1 - 1.5; p < 0.001) in a multivariate logistic regression model after adjusting for age, sex, LVEF at rest, SV index at rest. Resting aortic valve mean gradient also showed the highest AUC in relation to likelihood of having severe AS (0.87) (figure 1). Conclusion: Our study indicated that DSE remains useful in identifying severe AS in certain patients (up to 10%) who exhibit non-severe AS at rest in the setting of reduced LVEF. Additionally, MG at rest is the most reliable parameter to determine those who may benefit from undergoing DSE. This is one of the first studies to our knowledge in the literature suggesting that DSE may still be useful in identifying severe AS patients despite non-severe AS (i.e., valve area greater than or equal to 1 cm 2 ) at rest with reduced LVEF. Further research is warranted to validate our findings.

Background: Several studies have described anteroapical displacement of the anterolateral papillary muscle (PM) in patients with hypertrophic cardiomyopathy (HCM), implying a role in left ventricular outflow tract obstruction. Some surgeons address PM position during myectomy, but no quantitative imaging measures of abnormal versus normal PM anatomy exist. Objective: To quantify PM anatomy in HCM using cardiac magnetic resonance imaging (CMR) and determine if differences in PM anatomy alter myectomy outcomes. Methods: 143 patients with HCM (median age 58 (IQR 48-65) years, 64% male) who had undergone CMR were compared to 50 healthy controls (median age 32 (IQR 28-50) years, 40% male). The HCM cohort included 50 patients with non-obstructive HCM, 50 with obstructive HCM requiring transaortic myectomy, and 43 with obstructive HCM requiring transapical myectomy. Six independent measurements of PM anatomy were performed (Figure), comprising both established and novel measurements. Intergroup comparisons were made, and correlative analysis of PM measurements was performed using echocardiographic data and surgical outcomes. Results: There was significant variability in PM anatomy in all patients. The SXAd measurement was smaller (26.76 +/- 6.10 mm vs 32.10 +/- 4.85 mm, p < 0.001) in HCM patients versus controls. The 4Cd measurement was smaller in patients with apical HCM than in all other groups (p < 0.001). D_PM, d_apex, and the ratio between these measurements were consistent among all groups. No PM quantification in HCM patients correlated to pre-, intra-, or postoperative LVOT obstruction, NYHA class, or postoperative length of stay. Conclusions: Although there were some statistically significant differences between healthy patients and those with HCM, analysis of six different PM measurements yielded no associations with LVOT obstruction or outcomes of septal myectomy.

Background: Sex differences in coronary physiology have been reported, particularly with regard to higher resting coronary flow in women. Resting flow is independently associated with clinical outcomes, irrespective of the presence of coronary microvascular dysfunction (CMD), but its sex-specific prognostic significance remains unclear. Aims: This study aimed to compare the prognostic implications of resting flow and CMD between sexes among patients with angina and non-obstructive coronary arteries (ANOCA). Methods: We studied 1194 patients with ANOCA undergoing coronary reactivity testing. Endothelium-independent microvascular function was assessed by coronary flow reserve (CFR) during adenosine-induced hyperemia, and endothelium-dependent function by coronary blood flow (CBF) increase during intracoronary acetylcholine infusion. Endothelium-dependent CMD was defined as <50% CBF increase, and endothelium-independent CMD as CFR <2.5. Cardiovascular events were defined as a composite of all-cause death, myocardial infarction and heart failure. Results: The median age of the study population was 52 years, and 71.1% were women. Resting average peak velocity (rAPV) and baseline CBF (bCBF) were significantly higher in women (p<0.001 and p=0.006, respectively). Survival analysis revealed that both elevated rAPV and bCBF were significantly associated with worse outcomes in men (p<0.001 and p=0.036, respectively, Figure 1), whereas no such associations were observed in women. In Cox proportional hazard analysis, sex showed a significant interaction effect with elevated rAPV (interaction p=0.014). Furthermore, endothelium-independent CMD was significantly associated with adverse outcomes in both men and women (p=0.011 and p=0.004, respectively), whereas endothelium-dependent CMD was significantly associated with prognosis only in men (p=0.006). Among men with endothelium-dependent CMD, the subtype characterized by higher bCBF was particularly associated with worse prognosis (p=0.001, Figure 2). Conclusions: In patients with ANOCA, men had lower resting coronary flow than women. However, its association with adverse outcomes was observed only in men, especially in those with impaired endothelial function. These results suggest that coronary physiology should be interpreted differently by sex, and that clinical decisions should be adjusted accordingly.

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.

A 44-year-old recent heart transplant recipient supported by VA-ECMO presented to the operating room (OR) for left ventricular (LV) vent removal. She had a history of double-inlet LV with right atrioventricular valve atresia and transposition of great arteries, status post fenestrated Fontan complicated by end-stage heart failure. Three days ago, she underwent a fourth sternotomy and orthotopic heart transplant complicated by coagulopathy and severe bi-ventricular dysfunction necessitating initiation of central VA-ECMO. Due to massive blood product transfusion and ventricular dilatation, an apical LV vent was inserted. Postoperatively the arterial line waveform remained non-pulsatile. The patient was brought to the OR for mediastinal debridement and removal of the LV vent for the purpose of assessing ventricular function and improving arterial pulsatility. Pulse pressure remained negligible at an ECMO flow of 4.5 L/min. Transeosphageal echocardiography (TEE) demonstrated extensive thrombosis of the aortic root, particularly involving the right and non-coronary sinuses (Fig 1a). The aortic valve (AV) did not open. Patency of the left main coronary ostium was evident by color Doppler (Fig 1b) although no right coronary artery (RCA) flow could be visualized. The tip of LV vent was seen tenting the anterior leaflet of mitral valve (MV) causing significant regurgitation. (Fig. 2a-d) After vent removal, LV contraction gradually increased and the AV began to open. This progressively dislodged thrombus from the aortic root. At the conclusion of imaging, there was a highly mobile, bi-lobed thrombus attached to the sinotubular junction (Fig 1c-d). Right ventricular (RV) function remained severely reduced. Moderate mitral regurgitation persisted, arising from A2 leaflet prolapse. This patient subsequently underwent transcatheter thrombectomy and aspiration of the aortic root with cerebral protection device. Coronary angiogram confirmed proximal RCA occlusion (Fig. 3). Attempts to remove RCA thrombus were only partially successful. She eventually required a second heart transplant due to RV infarction. Discussion: This case illustrates a TEE-detected complication of excessive LV venting during VA-ECMO support, namely aortic root thrombosis associated with lack of AV opening. TEE also demonstrated the associated complications of RCA occlusion and iatrogenic mitral valve injury. Unfortunately, these complications were not detected soon enough to avoid RV infarction.

Introduction: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) typically have low serum transthyretin (sTTR) levels, worsening heart failure, and increased mortality. A recent study has shown the association of sTTR levels ≥20mg/dL with reduced risk of all-cause mortality and cardiovascular mortality (CVM). It has also been shown that regardless of baseline sTTR level, greater increases in sTTR levels are associated with greater improvements in cardiovascular outcomes. Acoramidis, a near-complete (≥90%) TTR stabilizer, demonstrated a rapid and sustained increase from baseline in sTTR by Day 28 and reduced risk of cardiovascular outcomes in patients with ATTR-CM. Hypothesis: Acoramidis-mediated early increase in sTTR levels ≥20 mg/dL (lower limit of normal) at Day 28 reduces risks of CVM and cardiovascular-related hospitalizations (CVH) in patients with ATTR-CM. Methods: Analyses were conducted in the ATTRibute-CM modified intention-to-treat (mITT) population (acoramidis: 409; placebo: 202). The sTTR concentrations (normal range is 20-40 mg/dL) were assessed using an immunoturbidimetric method (Abbott ARCHITECT system) in a central laboratory. The proportion of participants with sTTR levels below normal at baseline and Day 28 were determined. The relationship between sTTR levels <20 or ≥20 mg/dL, at Day 28 across the pooled acoramidis and placebo treatment groups, and subsequent risk of CVM and of CVH over 30 months were analyzed using a stratified log-rank test. Results: At baseline about 25% of study participants had sTTR levels below normal in both treatment groups. At Day 28, less than 2% of participants had sTTR levels <20 mg/dL in the acoramidis arm compared with 26% in the placebo arm ( Table 1 ). When acoramidis and placebo treatment groups were pooled based on sTTR levels <20 or ≥20 mg/dL at Day 28, participants with sTTR ≥20 mg/dL were associated with a lower risk of the composite endpoint of CVM or first CVH at Month 30 in comparison with <20 mg/dL ( p <0.0001) ( Figure 1A ). Comparable findings were observed for the individual components (CVM, first CVH) ( Figure 1B and C ). Conclusion: Across treatment groups, sTTR levels above normal range (≥20 mg/dL) at Day 28 were associated with a lower risk of cardiovascular outcomes at Month 30, when compared with sTTR levels below normal range (<20 mg/dL). Thus, these observations demonstrate that higher sTTR levels over time may have the potential for clinical benefits in both CVM and CVH.

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: Tricuspid regurgitation (TR) is associated with significant morbidity, but individualized treatment and timing of intervention are yet to be defined. We previously proposed and validated artificial intelligence electrocardiography (AI-ECG) scores for various diseases. Whether incorporating AI-ECG information adds to risk stratification above and beyond classical clinical parameters is unknown. Objectives: To identify AI-ECG scores independently associated with all-cause mortality in chronic TR and to create a composite AI-ECG risk score. Methods: Patients with a first echocardiographic diagnosis of ≥moderate TR between 2005-2016 and an ECG within ±15 days were included. The Tricuspid Regurgitation Impact on Outcome (TRIO) score was calculated as previously described based on 8 simple parameters (age, sex, severe TR, heart failure, lung disease, heart rate, creatinine and AST). AI-ECG probabilities of low ejection fraction, aortic stenosis, amyloid, cirrhosis, atrial fibrillation and hypertrophic cardiomyopathy were estimated by existing algorithms; the first 4 were associated with all-cause mortality and a composite AI-ECG risk score was calculated (0-4; 1 point for each AI-ECG above specific threshold). Results: A total of 12,377 pts were included (age 72±13 yrs, 55% women). Over a median follow-up of 1.3 yrs (IQR 0.1 to 4.4), 7,121 pts (58%) died. Mortality risk increased significantly with higher composite AI-ECG risk score (Fig. 1A). On multivariable analysis (proportional hazards method), the composite AI-ECG risk score remained independently associated with death, even after adjusting for age, sex, high NT-proBNP levels (>2,500 pg/mL), right ventricular systolic pressure (RVSP), diuretic use and TRIO risk score category (Fig. 1B). Conclusions: Patients with ≥moderate TR show progressively worse survival with increasing composite AI-ECG risk score. Incorporating AI-derived information from a simple and inexpensive ECG may identify patients with the highest risk of mortality beyond clinical risk scores as TRIO or classical clinical, laboratory and echocardiographic parameters. Prospective validation of this approach needs to be tested in future trials.

Background: Syncope is a leading cause of transient loss of consciousness, especially in older adults. Post-syncopal driving restrictions are widely recommended, but the required duration varies by state. The impact of these policies on motor vehicle crash outcomes remains unclear. Methods: We conducted a cross-sectional analysis of 45 U.S. states, comparing crash and fatality data between states requiring < 6 months vs. ≥ 6 months of driving restriction following a syncopal episode. Data were obtained from Fatality Analysis Reporting System, National Highway Traffic Safety Administration, state Department of Motor Vehicles, and medical boards. Crash rates were normalized by licensed drivers and population. Statistical comparisons were made using Welch’s t-tests. Results: States with ≥ 6-month restrictions had significantly lower crash rates among older drivers (0.0171 vs. 0.0256, p = 0.0076). Relative crash ratios comparing older to younger drivers were also lower (0.220 vs. 0.306, p = 0.067). Overall crash rates trended lower in states with ≥ 6-month restrictions in both per licensed driver ( p = 0.054) and per population ( p = 0.099). No significant differences were observed in fatality rates. Conclusions: Longer post-syncope driving restriction durations (≥ 6 months) are associated with reduced crash risk among older drivers and a narrowing of age-related disparities in crash rates. These findings suggest potential public health value in adopting more uniform, evidence-based restriction policies following syncopal events for older drivers.