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Background: Cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3 ) and Sorbin and SH3 domain-containing protein 2 (Sorbs2, encoded by SORBS2 ) are critical sarcomeric components that maintain cardiac structure and function. MYBPC3 and SORBS2 are linked to hypertrophic and dilated cardiomyopathies. But the relationship between Sorbs2 and cMyBP-C regulation, and their roles in the pathogenesis of atrial fibrotic cardiomyopathy (AFCM), remains unclear. Hypothesis: Sorbs2 acts as a cytoskeletal and RNA-binding protein that regulates cMyBP-C expression in atrial myocardium. Methods: We created the cardiac-specific Sorbs2 knockout ( c-Sorbs2 KO mice. We used next-generation RNA sequencing, molecular biology techniques, and in silico analysis to study how Sorbs2 regulates cMyBP-C expression in the atria of c-Sorbs2 KO mice. Results: Compared to age-matched wild-type (WT) mice at 8-9 months of age, the c-Sorbs2 KO male exhibited significant left atrial (LA) enlargement (diameter: 2.41±0.11 mm vs 1.82 ± 0.05 mm in WT; n = 8; p < 0.001) and severe atrial fibrosis (fibrotic area: 12.29±1.73 vs 2.83 ± 0.41% in WT; p < 0.001), accompanied by marked reductions in both mRNA and protein levels of cMyBP-C in LA. In vitro knock-down of Sorbs2 by 60% via shRNA led to an 86.3% decrease in cMyBP-C protein levels, while a 3-fold Sorbs2 overexpression via adenoviral transduction resulted in a 1.4-fold increase in cMyBP-C protein levels in HL-1 cells . cMyBP-C mRNAs were identified in the ribonucleoprotein complexes immunoprecipitated with anti-Sorbs2 antibodies from cardiomyocyte lysates. Loss of Sorbs2 significantly reduced the half-life of cMyBP-C mRNA (from 2.1 hrs in WT to 1.2 hrs in KO). Co-immunoprecipitation with truncated Sorbs2 constructs showed that the C-terminal SH3 domains of Sorbs2, but not the N-terminal SoHo domain, interacted with cMyBP-C protein. Molecular docking and modeling showed hydrophobic interactions and hydrogen bonds between residues H906 and G907 in the SH3 domain of Sorbs2 and residue A954, P955 and T957 in the SH3-binding motif (949-MA P GA P VT-957) of cMyBP-C with a weighted score of -1036 using ClusPro online service. Conclusions: Sorbs2 regulates cMyBP-C expression through direct interaction with both cMyBP-C mRNA and protein. Loss of Sorbs2 results in reduced cMyBP-C expression, atrial fibrosis, and chamber enlargement, revealing a novel Sorbs2/cMyBP-C axis underlying AFCM pathogenesis.

Background: Cardiac radioablation (CRA) is emerging as a treatment modality for refractory ventricular tachycardia (VT). This study aimed to evaluate the effects of radiation on the coronary arteries in a swine model of proton beam CRA. Methods: Eighteen domestic swine underwent 30–40 Gy pencil-beam scanning proton therapy in a single-fraction targeting the left ventricle with no attempt to spare coronary arteries and were euthanized 12-40 weeks later. Contrast-enhanced cardiac computed tomography (CT) was performed at baseline for treatment planning and at study end. Using dose-volume histograms, the maximum point (D max ), mean (D mean ) doses and the minimal doses received by the highest irradiated volumes of 0.01 cc (D 0.01cc ) for the left main, left anterior descending, circumflex, and right coronary artery, as well as the large diagonal and obtuse marginal branches were calculated. The D max location for each artery was mapped from the baseline planning CT onto the follow-up CT using deformable registration. Coronary artery segments were harvested from the D max sites for histological analysis. Receiver operating characteristic (ROC) analysis was performed to identify dose thresholds for predicting histologically severe coronary stenoses (≥75%). Results: Ninety-six coronary artery segments were analyzed. No stenoses were observed by CT imaging before irradiation. By histological analysis post-euthanasia, 25/96 (26%) coronary segments sampled at the Dmax site per artery had ≥75% stenosis. The median D max was 4.7 Gy for the <75% stenosis group and 29.7 Gy for the ≥75% stenosis group (p<0.001). The AUC-ROC for the association between D max and severe stenosis was 92.2%. A D max value of 20.1 Gy in a single fraction best predicted severe stenosis, with sensitivity of 92.3% and specificity of 87.1%. The AUC-ROC for the association between severe stenosis versus D mean and D 0.01cc was 84.8% and 91.6%, respectively. Based on histopathologic analysis, intimal hyperplasia was the most common coronary artery abnormality at the D max sites. Conclusion: In this pre-clinical model of proton beam CRA, coronary stenoses occurred in a dose-dependent manner, with D max being a better dosimetric predictor of stenosis than D mean and D 0.01cc . These data provide for the first time radiation dose constraint information for the epicardial coronary arteries that can be considered in treatment planning for CRA and radiation for thoracic malignancies.

Background: Sudden cardiac death (SCD) is a leading cause of mortality in the U.S., with emerging evidence pointing to racial disparities and the impact of social vulnerability. Yet, geographic patterns integrating race and county-level vulnerability remain underexplored. Objective: To identify U.S. counties where socially vulnerable communities, stratified by race/ethnicity, experience disproportionate burdens of SCD-related mortality. Methods: We analyzed county-level data (1999-2020), integrating age-adjusted mortality rates (AAMR) for SCD with the 2020 CDC Social Vulnerability Index (SVI). Counties were categorized into SVI quartiles (Q1: Low to Q4: High Social Vulnerability). Analyses were stratified by race/ethnicity: Black or African American, Hispanic/Latino, White, American Indian/Alaska Native (AI/AN), and Asian/Pacific Islander (API). We used RStudio (v2023.06.1) for data cleaning, ANOVA testing, and descriptive analysis. “Unreliable” mortality values were handled as missing or set to zero, with only valid AAMR > 0 included. Hotspot counties were identified by selecting the top decile of AAMR SCD within Q4 SVI counties. Results: Significant disparities emerged across SVI quartiles for Black (p = 0.0003), Hispanic (p < 0.0001), and White (p < 0.0001) groups. Mean AAMR more than doubled from low to high SVI counties in Black communities (17.0 to 39.4 per 100,000). White and Hispanic groups showed smaller but consistent increases. API (p = 0.60) or AI/AN (p = 0.63) groups showed no significant trends. Madison Parish, LA appeared in the top-10 highest-burden counties across all groups. Black populations faced extreme rates in some SVI counties (e.g., Madison Parish, LA: 351.4 per 100,000), while API groups had low AAMR even in vulnerable areas. Data misclassification limited interpretation in the Hispanic group. Conclusions: Black, Hispanic, and White populations showed significant differences in SCD mortality tied to social vulnerability. Black populations in the most vulnerable areas experienced more than twice the rate of mortality compared to those in less vulnerable areas, suggesting a strong correlation between social vulnerability and SCD mortality in Black communities. API and AI/AN groups showed no significant associations, likely due to small sample sizes. Madison Parish, LA reflects the compounded impact of structural disadvantage. Findings support targeted interventions in socially and racially vulnerable counties to reduce preventable cardiac deaths.

Background: An increasing recognition of angina and nonobstructive coronary artery disease (ANOCA) underscores the importance of this patient group. While inflammation is a well-established key driver in the initiation and progression of atherosclerosis, its role in early stage is less clear. The current study was designed to assess the predictive value of monocyte-lymphocyte ratio(MLR) in comparison with hs-CRP in these patients. Method: This observational cohort study included patients with chest pain and nonobstructive coronary artery disease <40% stenosis in major coronary arteries on clinically indicated elective coronary angiography who underwent invasive physiological coronary reactivity testing for evaluation of coronary vasomotor function between 1997-2021. Preprocedural MLR was categorized as high (≥0.30) or low (<0.30) using the best cutoff value for predicting major adverse cardiovascular and cerebrovascular events (MACCE) determined by ROC curves. Preprocedural Hs-CRP levels ≥1 and <1 mg/L were classified as high or low, respectively. MACCE comprised cardiovascular death, nonfatal myocardial infarction, heart failure, stroke, and late revascularization. Kaplan-Meier plots, Log-rank test, and Cox regression analysis were used for analysis. Result: Among 892 patients (median age 52 [IQR: 43- 61] years, 69% females), 40% had high MLR and 49% had high hs-CRP, respectively. Over a 10-year follow-up, 125 patients (14%) experienced MACCE. In univariable analysis, high MLR level ( p < 0.001 ) and high hs-CRP ( p = 0.045) were associated with worse outcomes. (Figure 1) In multivariate Cox regression after adjusting for age, body mass index, creatinine, hypertension, hyperlipidemia, and diabetes mellitus, MLR remained a significant predictor of MACCE (HR=1.75, 95% CI=1.20- 2.55, p = 0.004), whereas hs-CRP lost its significance (HR=1.26, 95% CI=0.857- 1.848, p=0.241). Stratifying patients into four groups of high MLR/high hs-CRP (21%), high MLR/low hs-CRP (19%), low MLR/high hs-CRP (28%), and low MLR/low hs-CRP (32%) revealed that high MLR was associated with increased MACCE in both groups with high and low hs-CRP, while in both high MLR and low MLR groups, hs-CRP levels made no difference in MACCE incidences. (Figure 2). Conclusion: elevated MLR is a strong independent predictor of MACCE in patients with ANOCA, superior to hs-CRP. These findings highlight the potential of MLR as a valuable, readily available marker for risk stratification in early atherosclerosis.

Background: Whether oral anticoagulation (OAC) can be discontinued after the resolution of left ventricular thrombus (LVT) remains controversial, particularly in patients without risk factors such as left ventricular aneurysms. This study aimed to identify patients who may safely discontinue OAC. Methods: We conducted a retrospective cohort study of patients with LVT resolution who completed their anticoagulation course and excluded patients with left ventricular (LV) aneurysm. Clinical and echocardiographic factors were compared between patients who experienced LVT recurrence (n = 22) and those without recurrence during follow-up (n = 94). Results: The cohort had a mean age of 64.5 ± 15.0 years, and half (50%) were male. Most had an ischemic cardiomyopathy (64.6%). LVT recurred in 19% (22/116) of patients following initial resolution. Patients with recurrence were older (mean age 71.3 ± 11.9 vs. 63.4 ± 15.7 years, p = 0.03) and were more likely to have prior ischemic stroke and arterial thromboembolism (18.2% vs. 4.3%, p = 0.02 for both). At the time of thrombus resolution, LVEF was significantly lower among patients who had recurrence (33.4 ± 13.6% vs. 42.5 ± 15.5%, p = 0.012). Stroke, systemic embolism, and mortality rates were similar regardless of recurrence status. Recurrence risk by presence or absence of stroke and LEVF >50% on the LVT resolution echocardiogram is shown in Figure 1. Notably, no recurrences were observed among patients with both LVEF > 50% and no history of stroke (0/32), which was statistically significant compared to each other category. Conclusion: Among patients without left ventricular aneurysm who discontinued oral anticoagulation after LVT resolution, those with preserved LVEF (>50%) and no prior history of stroke had a very low risk of recurrence, with no events observed in this subgroup. These findings suggest that some patients may safely discontinue anticoagulation after LVT resolution.

Background: Severe mitral regurgitation (MR) in cardiogenic shock (CS) presents unique therapeutic challenges, especially in patients with prohibitive surgical risk. Transcatheter edge-to-edge repair (TEER) with MitraClip offers a less invasive alternative, yet optimal strategies for hemodynamic support in this setting remain unclear. Methods: We conducted a retrospective study of patients undergoing MitraClip implantation for severe MR and CS between 2018 and 2024 at a tertiary academic center. Of 440 screened cases, 47 met CS criteria and were stratified based on receipt of periprocedural Impella support. Clinical, procedural, and survival outcomes were compared between Impella-supported and unsupported cohorts using appropriate statistical methods. Results: Among the 47 patients, 24 received Impella support and 23 did not. The Impella group had greater illness severity, including higher rates of preprocedural intubation (75.0% vs. 43.5%) and SCAI stage D shock (50.0% vs. 13.0%). Despite these differences, procedural success was 100% in both groups. In-hospital (8.3% vs. 8.7%), 30-day (12.5% vs. 8.7%), and 1-year mortality (25.0% vs. 26.0%) were similar between Impella and non-Impella patients, respectively. Impella recipients had longer hospital stays (median 18 vs. 11 days; p=0.032) and higher 1-year readmission rates (55.0% vs. 21.7%; p=0.024), reflecting baseline acuity. There were no differences in major procedural complications or re-intervention rates. Conclusions: MitraClip implantation in CS patients supported with Impella is feasible and safe. Despite significantly worse hemodynamic profiles, outcomes were comparable to those without mechanical support. These findings suggest a potential role for tailored Impella use in expanding TEER to critically ill patients and underscore the need for prospective studies to guide support strategies in high-risk MR intervention.

Background: Papillary Muscle (PM) related ventricular arrhythmia ablation is associated with lower acute success and suboptimal long-term outcomes due to complex anatomy, variable arrhythmogenic sites and dynamic exit points. Objective: To evaluate clinical and procedural outcomes of patients undergoing PM vs non-PM ablation. Methods: A retrospective analysis of adults (≥18 years) undergoing PVC ablation at Mayo Clinic (2019–2024) matched PM PVC ablations to controls (1:2) using propensity scoring based on age, sex, comorbidities and baseline LVEF. Chi-square and t-tests compared baseline and procedural characteristics. Logistic regression estimated odds ratios for immediate procedural success, PVC burden reduction and LVEF improvement at 3 months. Results: Of the 720 ablations, 392 cases were included after propensity matching: 132 PM and 260 non-PM. Patients in the PM group exhibited higher rates of complicated diabetes (9.8% vs 4.6%, p =0.045) and prior MI (18.2% vs 9.2%, p =0.011). Preprocedural ECG PVCs in the PM group showed a shorter intrinsicoid deflection (89.1 ± 35.0 msec vs 100.7 ± 24.3 msec, p <0.001) and longer coupling intervals (532.7 ± 100.3 vs 512.2 ± 81.4 msec, p =0.048).Moderate-to-severe MR was more prevalent in the PM group (17.4% vs 10.0%, p =0.036). Intraoperatively, the PM group had higher total energy delivery times (1939 ± 1336 sec vs 1227 ± 1033 sec, p <0.001) and more frequent cryoablation use (46.2% vs 7.3%, p <0.001). During post-ablation testing, non-clinical PVC was inducible in 39.5% of the cases in PM group compared to 25.7% in non-PM group ( p =0.005). More patients in the PM group were discharged on atleast one antiarrhythmic drug (AAD)(35.9% vs 18.5%, p <0.001) and AAD use persisted at 3 months (31.3% vs 18.4%, p =0.004). Outcomes were similar between groups, with no significant differences observed in immediate ablation success (aOR 0.64, p = 0.063, CI = 0.40-1.03), or >5% improvement in LVEF (aOR 0.76, p = 0.29) and PVC burden reduction (aOR 0.93, p = 0.81) at 3 months follow up. Conclusion: Patients undergoing PM ablation exhibited higher baseline rates of comorbidities. Intraoperatively they required greater energy delivery times, and an increased use of cryoablation. Postoperatively, a larger proportion of PM ablation patients required antiarrhythmic drug therapy. Despite these complexities, PM ablation showed no significant differences in PVC burden reduction, LVEF improvement, or procedural success compared to non-PM ablation.

Background: Among cardiac amyloidosis subtypes, transthyretin cardiac amyloidosis (ATTR) has gained increased recognition with the development of disease-specific therapies. Tafamidis, a selective oral stabilizer of the transthyretin tetramer, has emerged as an effective treatment. In the broader heart failure landscape, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have become cornerstone therapies across the ejection fraction spectrum, improving survival and reducing hospitalizations in both HFrEF and HFpEF. However, the clinical benefit of combining Tafamidis with SGLT2i in ATTR remains largely unknown. Hypothesis: Combination therapy with Tafamidis and SGLT2i provides added clinical benefits in patients with ATTR cardiac amyloidosis. Methods: This retrospective cohort study included adults with confirmed ATTR cardiac amyloidosis diagnosed via 99mTc-pyrophosphate scintigraphy and treated with Tafamidis alone or with an SGLT2i across three academic centers from January 2019 to February 2025. Baseline characteristics and outcomes were collected from medical records. The primary endpoint was all-cause mortality. Kaplan-Meier analysis and multivariable Cox proportional hazards modeling were used, adjusting for age, sex, atrial fibrillation, diabetes, hypertension, hyperlipidemia, ejection fraction (EF), and glomerular filtration rate (GFR). Results: Among the 1,211 patients included in the 3-year follow-up analysis,946 received Tafamidis monotherapy and 265 received a combination of Tafamidis and an SGLT2i. The mean age of the cohort was 71.9 years (SD ±9.4), and 87.3% were male. A total of 142 mortality events occurred, with a higher cumulative mortality rate observed in the tafamidis-only group (16.3%) compared to the combination group (9.4%) (log-rank p = 0.042). In the multivariable Cox proportional hazards model, combination therapy with Tafamidis and an SGLT2i was independently associated with a significantly lower risk of mortality (adjusted HR =0.576, 95% CI:0.334–0.992, p =0.04). Additionally, increasing age (HR =1.049, 95% CI:1.024–1.074, p < 0.001) was associated with higher mortality, while EF(HR =0.971, 95% CI:0.958–0.984, p< 0.001) and GFR (HR =0.975, 95% CI:0.965-0.985, p< 0.001) were with lower mortality. Conclusion: Combination therapy with Tafamidis and SGLT2i was associated with improved survival compared to Tafamidis alone in ATTR cardiac amyloidosis. Further prospective trials are needed to validate these findings and guide therapy optimization.

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.