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Abstract 4370972: Impact of Aortic Annular Area on Outcomes Following Balloon-Expandable vs. Self-Expandable Valve-in-Valve Transcatheter Aortic Valve Replacement
Danesh, Sina , Sawma, Tedy, Banivaheb, Behrooz , Herrera, Harrison, Todd, Austin , Sawma, Tedy , Herrera, Harrison, Tang, Paul C.

Circulation | November 3, 2025 | Volume: 152 | Issue: Suppl_3 | Pages: No page available

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Background: Valve-in-valve transcatheter aortic valve replacement (ViV-TAVR) is an increasingly preferred strategy for managing failed surgical bioprosthetic valves, especially in high-risk patients. However, limited data exist comparing outcomes between balloon-expandable (BE) and self-expandable (SE) transcatheter heart valves (THVs) in this setting. The influence of aortic annular area on outcomes by valve type remains poorly understood. This study evaluated the impact of annular area on clinical outcomes following ViV-TAVR with BE vs. SE valves. Methods: We conducted a retrospective, single-center analysis of 353 patients who underwent ViV-TAVR between 2012 and 2024. All had prior surgical bioprosthetic AVR and received either BE (n=267) or SE (n=86) valves. Preprocedural multidetector CT was used to quantify aortic annular area. Transthoracic echocardiography was performed before and after the procedure to assess transvalvular gradients and hemodynamics. The primary endpoint was all-cause mortality. Penalized spline regression was used to model the nonlinear relationship between annular area and mortality and assess interaction by valve type. Results: Median age was 79 (IQR: 72–83) in the BE group and 80 (IQR: 76–85) in the SE group (p=0.07). Female sex was more common in the SE group (32% vs. 22%, p=0.047). Median annular area was 374 mm2 (IQR: 316–440) for BE and 365 mm2 (IQR: 308–432) for SE (p=0.081). Preprocedural gradient and effective orifice area index were 36 mm Hg (IQR: 28–46) and 0.6 cm2/m2 (IQR: 0.5–0.9), respectively, with no significant differences. Median hospital stay was 2 vs. 3 days (p=0.68). Thirty-day mortality was low (1 per group, p=0.36). Median follow-up was 4.0 years (IQR: 1.6–6.4). One- and 5-year survival rates were 94.75% and 61.7%, respectively (p=0.20). Penalized spline analysis showed a nonlinear association between annular area and mortality. The hazard ratio for BE valves declined with increasing annular area and fell below SE valves beyond ~400 mm2. Conclusion: ViV-TAVR is a safe and effective treatment for failed surgical bioprostheses. Smaller annular areas were associated with higher mortality. Outcomes with BE valves improved in larger annuli, suggesting annular area could guide valve selection. Further studies are warranted to validate these observations.
Abstract 4369970: Predictive Value of Coronary Artery Calcification on the baseline PET/CT or Chest CT for MACE and Mortality in Lung Cancer
ARDILA, MARIA F. GOMEZ, Muslera, Eduardo Brenner, Nuques, Maria Jose Perez, Pallares, Eduardo Villa, Tellez‐Garcia, Eduardo , Foley, T. Raymond , Villarraga, Hector R. , ARDILA, MARIA F. GOMEZ, Cajigas, Héctor , Foley, Thomas

Circulation | November 3, 2025 | Volume: 152 | Issue: Suppl_3 | Pages: No page available

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Background: Lung cancer is classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC – including adenocarcinoma, squamous cell, and large cell carcinoma). The incidence of major adverse cardiovascular events (MACE)—defined as acute myocardial infarction, acute coronary syndrome/ischemic heart disease requiring revascularization, stroke, and cardiovascular death—have not been well defined in lung cancer patients following treatment. Coronary artery calcifications (CAC) and aortic calcifications (CA) are known cardiovascular risk markers in non-cancer populations. Purpose: To determine whether the presence of CAC or CA, as identified on baseline PET-CT (Positron Emission Tomography–Computed Tomography) or chest CT imaging, is predictive of MACE and all-cause mortality (ACM) in patients with lung cancer. Methods: We conducted a retrospective cohort study of patients diagnosed with SCLC or NSCLC who received chemotherapy, between January 1, 2010, and December 31, 2024. The baseline PET-CT or chest CT scans were reviewed for the presence of CAC and/or CA. Patients were excluded if they lacked baseline imaging or had experienced a MACE before treatment. Univariate and multivariate adjusted Cox regression models were employed to assess associations between CAC/CA and MACE or ACM. The Kaplan-Meier survival analyses was performed to evaluate event-free survival. Results: A total of 385 patients were included (mean age: 74 years, IQR: 67–79), predominantly female (158 [55%]) and white (279 [96.2%]). NSCLC was found in 255 (88%) and SCLC in 35 (12%). CAC was identified in 172 (60%) and CA in 87 (30%). Among patients with NSCLC, the presence of CAC was significantly associated with MACE (HR: 2.84 [95% CI: 1.6–4.8], p=0.0001) (Fig. a), particularly in those with adenocarcinoma (Fig. b). In SCLC, (HR: 1.56 [95% CI: 0.1–14.0], p=ns). On multivariable analysis, CAC remained the strongest predictor of MACE after adjusting for age, hypertension, diabetes, dyslipidemia, and smoking status (HR: 2.6 [95% CI: 1.5–4.4], p=0.0008) (Fig. d). No significant association was found between CA and MACE in either group (p>0.05). ACM was similar for SCLC, squamous cell, and NSCLC (Fig. c). Conclusion: In patients with NSCLC especially lung adenocarcinoma, the presence of CAC in the baseline PET/CT was an independent predictor of MACE. This finding supports the value of CAC as a non-invasive cardiovascular risk marker.
Abstract 4369930: Disparities in Editorial Leadership of Highly Cited Cardiology Journals by Gender and Country Income Classification
Estrada-Mendizabal, Ricardo, Shama, Saiyara, Osorio-Godoy, Ruben, Rodriguez-Riascos, Juan, Leon, Lizbeth Romo-De, Saldana-Fraire, Veronica, García, Judith Estela Guzmán, Castillo-Ivon, Alfonso, Gomez, Patricio, Allende, Ricardo, Estrada-Mendizabal, Ricardo, Shama, Saiyara, Osorio-Godoy, Ruben, Rodriguez-Riascos, Juan, Leon, Lizbeth Romo-De, Saldana-Fraire, Veronica, García, Judith Estela Guzmán, Castillo-Ivon, Alfonso, Gomez, Patricio, Allende, Ricardo

Circulation | November 3, 2025 | Volume: 152 | Issue: Suppl_3 | Pages: No page available

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Background: Journal editors influence the visibility and direction of scientific research and should have adequate gender and geographic representation. Research Question: Are there disparities in gender and institutional country affiliation among editors of highly cited cardiology and cardiovascular disease journals? Methods: In May 2025, we used Scimago Journal Rankings to identify the 50 top-cited cardiology and cardiovascular disease journals worldwide from 2022 to 2024. Due to the large volume of members, general editorial board listings without defined roles were excluded. Editors’ genders and country of institutional affiliation were extracted independently and in duplicate by eight sub-investigators. An additional sub-investigator resolved any discrepancies. Gender was determined using institutional profiles and publicly available pronouns on academic or professional platforms. Country affiliation was based on the editor’s primary institution and categorized by World Bank income classification 2025, which divides countries into high-income (HIC), upper-middle income (UMIC), lower-middle income (LMIC), and low-income countries (LIC). Key journal characteristics, such as country, impact factor, and article processing charges, were also extracted in duplicate. Results: All 50 top-cited cardiology and cardiovascular disease journals identified were based in HICs. A total of 1,762 editors were included. Most editorial positions were held by men (67%), with women accounting for 28%. One editor was identified as non-binary, and the gender of 91 editors (5%) could not be determined based on publicly available information (Table 1). Pronouns were identifiable for all EIC (n=52), out of which 87% were men (n=45) and 13% were women (n=7). Ninety-five percent of editors were affiliated with institutions based in HIC, while only 5% were based in UMIC (n=71), LMIC (n=16), or LIC (n=5). The most represented countries were the US (41%), Italy (8%), and the UK (7%) (Figure 2). All EICs (100%) were affiliated with institutions based in HICs, mainly the US (52%) and the UK (10%) (Figure 3). Conclusion: Editors of top-cited cardiology journals are predominantly men affiliated with HICs. Diverse editorial leadership in academic cardiology journals is needed to reflect global perspectives in research.
Abstract 4368666: Prognosis of right bundle branch block in heart failure patients: a reconstructed time-to-event meta-analysis
Almaadawy, Omar , Mostafa, Naydeen , Hamed, Belal, Abdelsattar, Nada K. , Sarhan, Menna , Soliman, Esraa , Mohyeldin, Eman, Zreigh, Sofian , Rustm, Mohamad, HASSAN, ABDULAHI, Elbenawi, Hossam , Georges, Claudia, Ahmed, Mustafa M. , Mansour, Ahmed , Hamed, Belal, Taha, Taha E. , Rustm, Mohamad , HASSAN, ABDULAHI, Mansour, Ahmed

Circulation | November 3, 2025 | Volume: 152 | Issue: Suppl_3 | Pages: No page available

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Background: The growing epidemiologic burden of heart failure (HF) poses a significant public health challenge. The development of conduction abnormalities influences HF outcomes, with left bundle branch block (LBBB) established as an independent mortality predictor. However, the impact of right bundle branch block (RBBB) on HF mortality is still controversial. The aim of this study is to compare survival in HF patients with and without RBBB. Methods: A comprehensive search was conducted on PubMed, Scopus, Web of Science, and Cochrane Library from inception to 12 October 2024. Raw data coordinates were extracted from Kaplan–Meier curves and merged into one dataset to reconstruct individual patient data. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated using the Cox regression model. Dichotomous outcomes were pooled as risk ratios (RR) with 95% confidence interval (CI) using a random-effects model. Results: 13 studies incorporating 25714 HF patients were included in our analysis. Patients with RBBB had a significantly lower median survival of 41.0 months (95% CI: 39.0 – 44.8) compared to 51.2 months (95% CI: 49.2 – 52.8) in patients without RBBB. Survival at 1,3, and 5 years in RBBB patients was 74.2%, 54.0%, and 39.4%, respectively, compared to 77.2%, 58.1%, and 45.4% in patients without RBBB. The HR for mortality was 0.87 (95% CI: 0.83 – 0.91, p < 0.001), indicating a 13% lower risk of death in patients without RBBB compared to those with RBBB. There was no significant difference in cardiovascular mortality between groups (RR: 1.34; 95% CI: 0.88 – 2.05; p = 0.17). Conclusion: RBBB was associated with an increased risk of mortality in HF patients. These findings support the use of RBBB as a potential marker for risk stratification in HF. Further research with stricter inclusion criteria is warranted to better understand how the observed association is influenced by preserved versus reduced ejection fraction.
Abstract 4368652: Real-World Risk Reduction of Cardiometabolic Comorbidities and Improvement of Biomarkers among Patients with Overweight or Obesity Treated with Semaglutide 2.4 mg
Ruseva, Aleksandrina , Bassan, Matthew, Du, Ella X. , Fabricatore, Anthony N. , Hartaigh, Bríain ó, Michalak, Wojciech , Ramasubramanian, Ramya, Shen, Pangsibo, Song, Jinlin , Zhao, Zhenxiang , Lopez‐Jimenez, Francisco, Bassan, Matthew, López-Jiménez, Francisco

Circulation | November 3, 2025 | Volume: 152 | Issue: Suppl_3 | Pages: No page available

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Introduction: Semaglutide 2.4 mg has been shown to reduce the risk and severity of cardiometabolic comorbidities (CMCs) and to improve cardiometabolic biomarkers in patients with overweight or obesity in clinical trials. However, real-world evidence in these areas is limited. Research Question: This study compared the incidence rates of CMCs and 12-month changes in biomarkers between adults with overweight/obesity with and without once-weekly subcutaneous semaglutide 2.4 mg use. Methods: A retrospective cohort study using a large U.S. claims database linked with clinical data evaluated patients with semaglutide 2.4 mg use for ≥12 months (June 2021–June 2023) and those without. For each CMC, including hypertension, T2D, dyslipidemia, HF, prediabetes, ASCVD, and CVD, patients were excluded from analysis of each individual CMC if they had claims indicating the corresponding CMC during the 12-month baseline. For each biomarker, patients were required to have the corresponding biomarker measurements at both baseline and 12-month follow-up. For each CMC and biomarker, propensity score weighting was used to balance patient characteristics between semaglutide 2.4 mg users and non-users. Time to CMCs were compared using weighted Cox proportional hazards models and biomarker changes were compared using weighted linear regression. Results: Sample sizes ranged from 14,067 to 25,490 in semaglutide 2.4 mg users and 4,271,926 to 8,578,948 in non-users across CMCs. After balancing, baseline characteristics were similar between users and non-users. Mean age ranged from 44.4 to 47.2 years among users and 44.4 to 47.4 years among non-users; 77%–83% of users and 75%–82% of non-users were women. Compared to non-users, semaglutide 2.4 mg users had significantly lower risk of incident hypertension (Hazard ratio [HR]: 0.62, 95% confidence intervals [CI]: 0.57; 0.68), T2D (HR: 0.45, 95% CI: 0.39; 0.51), HF (HR: 0.48, 95% CI: 0.38; 0.61), prediabetes (HR: 0.75, 95% CI: 0.70; 0.80), ASCVD (HR: 0.65, 95% CI: 0.58; 0.72), and CVD (HR: 0.69, 95% CI: 0.64; 0.75) (all p<0.001). The risk of dyslipidemia was similar between users and non-users (HR: 1.05, 95% CI: 1.00; 1.11, p=0.05). Semaglutide 2.4 mg use was also associated with significant improvements in cardiometabolic biomarkers specified in Table 1 and slower decline in eGFR. Conclusion: In adults with overweight/obesity, semaglutide 2.4 mg was associated with lower risk of specified CMCs and greater improvements in cardiometabolic biomarkers.
Abstract 4369909: Association of right ventricular size and function parameters in Hodgkin and Non-Hodgkin Lymphoma with obesity and cardiovascular risk factors: What matters the most?
Pallares, Eduardo Villa, Muslera, Eduardo Brenner, Nuques, Maria Jose Perez, ARDILA, MARIA F. GOMEZ, Garcia, Eduardo Tellez, Villarraga, Hector, Pallares, Eduardo Villa, Muslera, Eduardo Brenner, Nuques, Maria Jose Perez, ARDILA, MARIA F. GOMEZ, Garcia, Eduardo Tellez, Villarraga, Hector

Circulation | November 3, 2025 | Volume: 152 | Issue: Suppl_3 | Pages: No page available

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Introduction: Anthracycline-induced left ventricular dysfunction is well documented in lymphoma patients. However, the impact of cardiovascular risk factors (CVRF) and obesity on the right ventricle (RV) remains poorly characterized. Hypothesis: How does baseline CVRF burden—including obesity—affect RV structure and function over time in lymphoma patients treated with doxorubicin-based chemotherapy? Methods: A prospective cohort of patients with Hodgkin or non-Hodgkin lymphoma treated with doxorubicin-based chemotherapy at Mayo Clinic between March 1, 2013, and December 31, 2024, underwent echocardiography prior to chemotherapy initiation (T0), at 3–6 months (T1) and 6-18 months (T2) after treatment completion. A dedicated RV 4-Chamber view was used for all measurements. Patients were stratified into five groups: BMI>30, BMI>35, no CVRF, 1 CVRF (hypertension, diabetes, dyslipidemia, or smoking status), and ≥2 CVRF. RV parameters included end-diastolic/systolic area, FAC, TAPSE, S′ velocity, TRV, RVSP, and RV free wall strain. Group and time differences were analyzed using the Kruskal–Walli’s test due to non-normal distribution. Results: Among of 356 lymphoma patients (mean age 59.2 years, IQR:46-69) predominantly male (63.7%), 39.3% met criteria for obesity. At T0, patients with BMI >35 had greater RV end-diastolic (20.4 ± 4.4 vs. 18.7 ± 3.5 mm; p=0.009) and end-systolic diameters (11.0 ± 2.1 vs. 9.9 ± 2.6 mm; p=0.024), higher TRV (2.5 ± 0.4 vs. 2.2 ± 0.3 m/s; p<0.001) vs. no CVRFs. TAPSE was reduced vs. >2 CVRF group (23.7 ± 4.2 vs. 22.1 ± 4.8 mm; p=0.032). At T1, BMI >35 patients showed increased RV end-diastolic (22.3 ± 3.6 mm; p<0.001) and end-systolic areas (12.8 ± 2.9 mm; p<0.001), and worsened RVFWS (−24.0 ± 4.7% vs. −26.1 ± 2.98%; p=0.001) vs. no CVRF. RVSP was higher in those with >2 CVRFs (32.3 ± 5.4 mmHg; p=0.001). At T2, RVFWS was reduced in obese patients (−22.9 ± 3.5% vs. −27.1 ± 4.0%; p<0.001). RVSP stayed elevated in BMI >35 (33.0 mmHg) and >2 CVRFs (30.7 mmHg) vs. no CVRFs (23.7 mmHg; p<0.001). FAC and S′ did not differ significantly. Conclusion: In lymphoma patients treated with anthracyclines, isolated obesity was associated with the most pronounced RV changes—greater than those seen in non-obese patients with other CVRFs. These early and persistent alterations underscore the need for dedicated cardio-oncology care regardless of additional risk factors.
Abstract 4365569: GLP-1 Receptor Agonists and Cardiovascular Outcomes in Patients with Type 2 Diabetes Undergoing TAVI: A Real-World Cohort Study
Pham, Hoang Nhat, Ibrahim, Ramzi, Abdelnabi, Mahmoud, Mahmoud, Ahmed, Shaik, Abdullah, Kamel, Ibrahim, Allam, Mohamed, Habib, Eiad, Bcharah, George, Farina, Juan, Lee, Justin, Ayoub, Chadi, Singh, Amitoj, Chahal, Anwar, Sorajja, Dan, Lee, Kwan, Arsanjani, Reza, Pham, Hoang Nhat, Ibrahim, Ramzi, Abdelnabi, Mahmoud, Mahmoud, Ahmed, Shaik, Abdullah, Kamel, Ibrahim, Allam, Mohamed, Habib, Eiad, Bcharah, George, Farina, Juan, Lee, Justin, Ayoub, Chadi, Singh, Amitoj, Chahal, Anwar, Sorajja, Dan, Lee, Kwan, Arsanjani, Reza

Circulation | November 3, 2025 | Volume: 152 | Issue: Suppl_3 | Pages: No page available

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Introduction: In patients with type 2 diabetes (T2D) at high cardiovascular risk, glucagon-like peptide-1 receptor agonists (GLP1-RAs) have been shown to reduce major adverse cardiovascular events. However, patients with valvular heart disease, including those undergoing transcatheter aortic-valve implantation (TAVI), have been largely excluded from randomized trials. Hypothesis: We investigated whether GLP1-RA use is associated with improved one-year cardiovascular outcomes in patients with T2D undergoing TAVI. Methods: We conducted a retrospective cohort study using the TriNetX network. Adults (≥18 years) with T2D who underwent TAVI between 2015 and 2023 were included and stratified based on GLP1-RA initiation within 14 days post-TAVI. Baseline characteristics, comorbidities, medications, and laboratory data were balanced using 1:1 propensity score matching (PSM). The primary outcome was a composite of all-cause mortality or hospitalization at 1 year. Secondary outcomes included acute heart failure (HF) exacerbation, acute myocardial infarction (AMI), cardiac arrest, and ischemic stroke. Outcomes were assessed from 1 month to 1 year after TAVI. Survival probabilities were estimated using Kaplan-Meier analysis, and hazard ratios (HRs) were calculated with Cox proportional hazards models. Results: Among 20,454 patients with T2D undergoing TAVI from 2015-2023, 937 received GLP1-RAs. After PSM, 930 patients were included in each cohort, with a mean age of 73 years and 37% female. The mean follow-up duration was 342 days for GLP1-RA users and 325 days for non-users. GLP1-RA cohort exhibited a higher 1-year survival probability (93.8%) compared to non-users (89.5%) (HR 0.573 [95% CI, 0.410-0.801]; p=0.001). GLP1-RA use was also associated lower rates of all-cause hospitalization (HR 0.762 [95% CI, 0.652-0.891]; p=0.001), acute HF exacerbation (HR 0.687 [95% CI, 0.566-0.834]; p<0.001), and cardiac arrest (HR 0.452 [95% CI, 0.213-0.960]; p=0.034). No differences were observed in AMI (HR 1.033 [95% CI, 0.750-1.423]; p=0.844), or ischemic stroke (HR 0.875 [95% CI, 0.659-1.162]; p=0.356). Conclusions: In patients with T2D undergoing TAVI, GLP1-RA use is associated with significant survival benefits and improved cardiovascular outcomes, including reductions in acute HF exacerbation, all-cause hospitalization, and cardiac arrest. These findings highlight the need for prospective clinical trials to confirm these results.
Abstract 4365545: Outcomes of Heart Failure in Muscular Dystrophies in Adults: A Nationwide Analysis in the United States
Jabbar, Ali Bin Abdul, Al-Salahat, Ali, Dilsaver, Danielle B., Ismayl, Mahmoud, Goldsweig, Andrew, Aboeata, Ahmed, Jabbar, Ali Bin Abdul, Al-Salahat, Ali, Dilsaver, Danielle B., Ismayl, Mahmoud, Goldsweig, Andrew, Aboeata, Ahmed

Circulation | November 3, 2025 | Volume: 152 | Issue: Suppl_3 | Pages: No page available

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Background: Muscular dystrophies (MDs) may cause heart failure (HF), but outcomes specific to MD-related HF are not well characterized. Research Question: Do the outcomes of HF hospitalizations differ between patients with underlying MDs (MD-HF) vs. patients without MDs (non-MD-HF) in the United States? Methods: Discharge data from HF hospitalizations were abstracted from the Nationwide Readmissions Database (2016-2022) and stratified by the presence or absence of MD (MD-HF vs. non-MD-HF). Logistic regression and lognormal models were estimated to assess differences in inpatient mortality, length of stay (LOS), total costs, complications, and 30-day and 90-day all-cause readmissions. Propensity-score matching (PSM) was used to control baseline differences between the MD-HF and non-MD-HF cohorts. Odds ratios (OR) with associated 95% Confidence intervals (CI) and p-values were reported. Analyses were conducted via SAS v. 9.4, with statistical significance indicated by two-tailed p<.05. Results: 8,466,806 HF hospitalizations were included in the analysis, of which 3688 (0.04%) involved patients with MD. MD-HF hospitalizations involved younger patients (mean age 55.3 vs. 71.3 years, p<0.001) with higher rates of HF with reduced ejection fraction (HFrEF) compared to non-MD-HF hospitalizations (48.1% vs. 34.9%, p<0.001). Compared to non-MD-HF hospitalizations (2.01%), MD-HF hospitalizations (5.82%) were associated with significantly higher odds of inpatient mortality (OR 3.01, 95% CI: 2.03, 4.45); higher complications rate (OR 2.11, 95% CI, 1.77, 2.52) including cardiogenic shock (OR 2.61, 95% CI, 1.90, 3.59), cardiac arrest (OR 2.27, 95% CI, 1.17, 4.41), use of mechanical ventilation (OR 2.23, 95% CI, 1.82, 2.73); higher palliative care consultation (OR 4.52, 95% CI, 3.21, 6.36); as well as more extended hospital LOS (OR 1.18, 95% CI, 1.09, 1.29), higher total costs (OR 1.32, 95% CI, 1.24, 1.41), and higher odds of discharge to rehab facility (OR 2.46, 95% CI, 1.99, 3.03) and home healthcare (OR 1.85, 95% CI, 1.55, 2.21) (all p<0.001). MD was not associated with a significant difference in 30-day (OR 0.94, 95% CI, 0.78, 1.12) and 90-day (OR 0.98, 95% CI, 0.82, 1.17) all-cause readmission rates. Conclusion: MD-HF hospitalizations were associated with higher inpatient mortality, complication rates, resource utilization, discharge to rehab facility and home healthcare, and no difference in readmission rates compared to non-MD-HF hospitalizations.
Abstract 4365531: Acoramidis Effect on All-Cause Mortality in Patients with p.V142I (V122I) Variant ATTR-CM: Findings From the ATTRibute-CM Study
Alexander, Kevin, Sarswat, Nitasha, Davis, Margot, Cuddy, Sarah, Kittleson, Michelle, Shah, Keyur, Griffin, Jan, Ruberg, Frederick, Khouri, Michel, Bhatt, Kunal, Judge, Daniel, Grodin, Justin, Akinboboye, Olakunle, Chen, Chris, Tamby, Jean-Francois, Castano, Adam, Fox, Jonathan, Fontana, Marianna, Gillmore, Julian, Grogan, Martha, Solomon, Scott, Gillmore, Julian D , Alexander, Kevin, Sarswat, Nitasha, Davis, Margot, Cuddy, Sarah, Kittleson, Michelle, Shah, Keyur, Griffin, Jan, Ruberg, Frederick, Khouri, Michel, Bhatt, Kunal, Judge, Daniel P. , Grodin, Justin, Akinboboye, Olakunle, Chen, Chris, Tamby, Jean-Francois, Castano, Adam, Fox, Jonathan, Fontana, Marianna, Gillmore, Julian D. , Grogan, Martha, Solomon, Scott

Circulation | November 3, 2025 | Volume: 152 | Issue: Suppl_3 | Pages: No page available

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Introduction: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) arises from amyloidogenic aggregates of destabilized TTR protein in variant (ATTRv-CM) or acquired wild-type TTR (ATTRwt-CM). The p.V142I (V122I) variant is the most common pathogenic TTR allele in the USA and has higher mortality vs wild type. Acoramidis, an oral TTR stabilizer achieving ≥90% stabilization, is approved in USA, UK, Europe, and Japan for treating ATTR-CM in adults. In ATTRibute-CM (NCT03860935), acoramidis showed a reduction in all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) vs placebo (PBO), with consistent benefit in ATTRwt-CM and ATTRv-CM (all variants). We report clinical outcomes in participants with p.V142I ATTRv-CM. Research Question: What was the efficacy of acoramidis for clinical outcomes (ACM, CVH) in participants with p.V142I ATTRv-CM in ATTRibute-CM? Methods: In ATTRibute-CM, 632 participants were randomized 2:1 to receive acoramidis HCl 800 mg or PBO twice daily for 30 months. All participants enrolled in open-label extension (OLE) received acoramidis only. Exploratory post hoc analyses were done in the p.V142I ATTRv-CM subgroup. Time-to-event analyses used a stratified Cox proportional hazards model using treatment group as an explanatory factor and baseline 6MWD as a covariate, stratified by randomization factors: serum NT-proBNP and eGFR. ACM was analyzed at Month 42 (ATTRibute-CM 30 months + 12 months OLE). Results: Of the 59 patients with ATTRv-CM reported at randomization, 35 (59.3%) had p.V142I (23 acoramidis, 12 PBO) with comparable baseline characteristics; 4 were homozygous for p.V142I (1 acoramidis, 3 PBO). Through Month 30, ACM/first CVH occurred in 43.5% (10/23) of acoramidis vs 83.3% (10/12) in PBO (HR 0.311; 95% CI 0.120–0.805; Figure 1 ). Through Month 42, ACM occurred in 26.1% (6/23) of continuous acoramidis vs 66.7% (8/12) in PBO to acoramidis (HR 0.307; 95% CI 0.097–0.973; Figure 2 ). Conclusions: In participants with p.V142I ATTRv-CM, acoramidis use was associated with 69% risk reduction in ACM/first CVH through Month 30 and ACM through Month 42 vs PBO. This is the first report of clinical benefit of this magnitude observed in this high-risk population. These findings have biologic plausibility and may reflect the near-complete stabilization observed experimentally with acoramidis in p.V142I ATTR fibrils. These observations require confirmation in larger cohort studies.
Abstract 4364249: Mitral Valve Prolapse and Ventricular Arrhythmia Risk in TTN -Mediated Cardiomyopathy
Coderre, Roxanne, Castrichini, Matteo, Garmany, Ramin, Neves, Raquel, Bos, Johan, Ackerman, Michael, Giudicessi, John, Coderre, Roxanne, Castrichini, Matteo, Garmany, Ramin, Neves, Raquel, Bos, Johan, Ackerman, Michael, Giudicessi, John

Circulation | November 3, 2025 | Volume: 152 | Issue: Suppl_3 | Pages: No page available

10.1161/circ.152.suppl_3.4364249 Get It

Introduction: Titin truncating variants (TTNtv) are a common cause of dilated (DCM) and non-dilated left ventricular cardiomyopathy (NDLVC). Mitral valve prolapse (MVP) occurs commonly in the general population and is characterized by myxomatous structural changes of the mitral valve apparatus. Both TTNtv-mediated DCMs and MVP have been associated independently with an increased risk of ventricular arrhythmias (VA) and sudden cardiac arrest/death (SCA/SCD). However, it remains unclear whether TTNtv-positive patients with co-existing MVP are at increased risk for major VA (MVA) events. Therefore, we sought to compare the prevalence of MVA events between TTNtv-positive patients with or without MVP in a large single-center cohort of genetic cardiomyopathy patients. Methods: Retrospective review of 1,230 ACM/DCM patients was used to identify those with a pathogenic/likely pathogenic (P/LP) TTNtv. Independent review of available imaging data was subsequently used to identify TTNtv-positive patients with co-existing MVP. The prevalence of non-SCA MVA and SCA/SCD was then compared between TTNtv-positive patients with and without MVP. Results: Overall, 253/1,230 (21%) of ACM/DCM patients were P/LP TTNtv-positive (43% female; mean age 44±17 years, mean LVEF 39±17%). Amongst these 253 TTNtv-positive patients, 15 (5.9%) had co-existing MVP (33% female, mean age 49±12 years, mean LVEF 48±12%). Collectively, TTNtv-positive patients with MVP were more likely to experience a MVA event than those without MVP [6/15 (40%) vs 41/238 (17%); p=0.03]. This included a higher risk of appropriate VT/VF-terminating ICD shocks [4/15 (27%) vs. 17/238 (7.1%); p=0.03] and SCA [3/15 (20%) vs 12/238 (5%); p=0.05]. However, despite the increased arrhythmic risk observed in TTNtv-positive patients with MVP, no deaths occurred in this subgroup and the overall cardiac mortality rate across the entire TTNtv-positive cohort was low [6/253 (2.4%)]. Conclusion: TTNtv-positive patients with concomitant MVP are at increased risk for MVA events, including SCA. Future studies are needed to i) better define the prognostic utility of MVP in the risk-stratification of TTN-NDLVC/DCM and other genetic cardiomyopathies and ii) determine whether some patients diagnosed with arrhythmogenic MVP syndrome may have TTNtv-mediated NDLVC exacerbated in a focal manner by the increased mechanical strain generated by the presence of the common and likely genetically unrelated myxomatous MVP.