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Background: Effective risk factor modification, including management of obesity and diabetes mellitus (DM), is essential to mitigating cardiovascular complications after hematopoietic stem cell transplantation (HSCT). Given the growing use of GLP-1 receptor agonists (GLP-1 RAs), large-scale studies are needed to assess their cardiovascular impact in patients undergoing HSCT. Methods: Using the TriNetX network, we identified patients who underwent HSCT and had DM or obesity. Patients were categorized into two cohorts: those who received GLP-1 RAs and those who did not. Outcomes, including all-cause mortality, all-cause hospitalization, acute myocardial infarction (AMI), atrial fibrillation (AF), cerebrovascular accident (CVA), and heart failure (HF) exacerbation, were assessed at 1 year, 3 years, and 5 years follow-up. Cohorts were propensity score-matched based on medical comorbidities, transplant diagnoses, and conditioning regimens. Results: Of the initial 17,475 patients with HSCT and DM/obesity, 876 (5.0%, 46.0% females, mean age 58.4 +/- 11.3 years old) received GLP-1 RA and 16,599 (95.0%, 40.8% females, mean age 55.6 +/- 14.3 years old) did not. After propensity score matching, 873 patients were divided equally into each cohort (Table). GLP-1 RA was associated with lower odds of all-cause mortality (1-year: odds ratio [OR]: 0.53; 95% confidence interval [CI]: 0.38–0.76; p<0.01; 3-year: OR: 0.52; CI: 0.40–0.69; p<0.01; 5-year: OR: 0.44; CI: 0.33–0.58; p<0.01), all-cause hospitalization (1-year: OR: 0.74; CI: 0.61–0.89; p<0.01; 3-year: OR: 0.66; CI: 0.55–0.79; p<0.01; 5-year: OR: 0.72; CI: 0.59–0.87; p<0.01), and HF exacerbation (1-year: OR: 0.65; CI: 0.44–0.96; p=0.03; 3-year: OR: 0.59; CI: 0.43–0.81; p<0.01; 5-year: OR: 0.53; CI: 0.38–0.74; p<0.01), compared to the non–GLP-1 RA group. At 5-year follow-up, GLP-1 RA use was also associated with lower odds of AF (OR: 0.71; CI: 0.53–0.94; p=0.02). No significant differences were noted in AMI or CVA at 1-, 3-, and 5-years of follow-up. Conclusion: After propensity score-matching in this retrospective cohort study, GLP-1 RA use was associated with significantly lower odds of all-cause mortality, all-cause hospitalization, and heart failure exacerbation at 1-, 3-, and 5-year of follow-up in patients with DM/obesity who underwent HSCT. At 5 years, use of GLP-1 RA was associated with lower odds of AF.

Background: Older adults with severe aortic stenosis (AS) are at high risk of mortality unless treated by aortic valve replacement (AVR). The Society of Thoracic Surgery (STS) score is primarily used clinically to determine mortality risk from surgical AVR. Due to geriatric comorbidities unique to older adults, traditional methods of risk stratification with STS may have significant shortcomings. Administratively derived risk scores that have prognostic significance in the geriatric population may prove valuable. Methods: We reviewed patients at our hospital system with AS undergoing AVR (surgical and transcatheter) and administratively derived an Elder Risk Assessment (ERA) score from the health record. The ERA score is a composite of age, marital status, number of hospitalized days in previous 2 years, and comorbidities (diabetes, coronary artery disease (CAD), heart failure, stroke, pulmonary disease, cancer, and dementia). Kaplan-Meier method was used to estimate survival by ERA score tertile. Cox regression was used to determine association between ERA and survival after accounting for STS predicted risk. Results: There were a total of 228 patients that underwent AVR (TAVR: 59 (26.1 %); SAVR 167 (73.9%) and had ERA scores derived. The average age was 79.6 (SD 7.6) years) and there were 93 (40.8%) women. Patients were stratified by ERA score tertiles: low (≤6), mid (6-13), or high (≥14). Over a mean follow up of 5.8 (SD 3.1) years, lower ERA scores were associated with better long-term survival (p<0.001). After accounting for age, sex, and STS score, mid ERA (HR 1.61; 95% CI 1.00-2.59; p<0.001) and high (HR 2.90; 95% CI 1.79-4.69; p<0.001) were associated with mortality (reference: low ERA). For every 10-point increase in the ERA, there was a 2-fold increase in adjusted mortality risk (HR 2.14; 95% CI 1.58-2.90; p<0.001). Conclusions: Older adults undergoing AVR for severe AS have specific geriatric comorbidities that may be better characterized using the ERA score. This administratively derived score was independently associated with survival after accounting for the widely used STS risk score.

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.

Environmental degradation due to industrial groundwater contamination is an emerging cardiovascular disease (CVD) risk factor. Our study examines the elevated CVD prevalence, including heart failure (HF) risk factors, in rural Punjab, India, near which a private distillery was linked to long-term groundwater contamination and environmental degradation. Our team primarily focused on CVD prevalence and its associations with environmental toxins. We also explored the role of socio-economic disparities on health outcomes. A cross-sectional study of 4,885 residents in three villages adjacent to the distillery (Mahianwala Kala, Ratol Rohi, Mansoorwaal Kalan) was conducted from October 2022 to August 2023. Health camps with follow-up door-to-door surveys by trained medical personnel collected medical histories, environmental exposure details, and socio-demographic data. Key outcomes included both communicable and non-communicable diseases, such as hypertension, ischemic heart disease, heart failure, and cancer. Logistic regression assessed associations between CVD prevalence, socio-economic status, and pollution exposure, with groundwater testing for heavy metals and chemical oxygen demand (COD). The cohort demonstrated a high CVD burden, with 39% having hypertension (exceeding national averages by more than 50%), 34% having diagnosed CVD, and 21.3% of households reporting an immediate family history of myocardial infarction. Adjusted models highlighted elevated odds of heart disease (OR 1.42; 95% CI 1.31–1.51) and stroke (OR 1.29; 95% CI 1.16–1.38), with higher clustering in low-income families. Concurrent systemic toxicity was also evident, as 60.5% reported dermatological conditions, 10.5% familial cancer, 20.8% with no history of smoking cited COPD-related dyspnea. We also observed elevated miscarriage rates and developmental disabilities in the studied population. Groundwater analysis confirmed contamination with cyanide (0.3 mg/L), lead (0.16 mg/L), and COD (320 mg/L), correlating with self-reported water discoloration and irregularities in taste. Families with polluted water access had a 1.5-fold increased CVD risk. Industrial contamination was linked to higher cardiovascular morbidity and multi-organ health effects in our study's cohort in rural India. The link was exacerbated by socio-economic inequities. These findings highlight the role of environmental degradation in rise in CVD, particularly in low-resource settings.

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: Leadless pacemaker has emerged as a promising alternative to traditional transvenous pacemaker (PM) among elderly patients who are at high risk of complications. Objective: This study aims to assess and compare 5-year clinical outcomes of leadless PM versus transvenous single-chamber PM in elderly patients using a multi-national dataset. Methods: Using the TriNetX Analytics Research Network, we included patients aged ≥65 years who underwent leadless versus transvenous single-chamber PM implantation between 1/1/2014 and 1/1/2020. Propensity score matching (PSM) was performed by using patient’s demographic, LVEF, cardiac comorbidities, and medications. The study outcomes included all-cause mortality and adverse cardiovascular events over a 5-year follow-up period. Results: After PSM, 7,501 patients in each group were analyzed. Leadless PM was associated with a significantly lower odds of 5-year all-cause mortality (odds ratio [OR]: 0.534; 95% confidence interval [CI]: 0.497-0.575), heart failure exacerbation (OR: 0.779, 95% CI: 0.721-0.841), major bleeding (OR: 0.666, 95% CI: 0.604-0.734), cardiac arrest (OR: 0.747, 95% CI: 0.646-0.864) and stroke (OR: 0.825, 95% CI: 0.750-0.908) compared to transvenous single-chamber PM. No significant difference was observed between the two groups in all-cause hospitalization (OR: 1.006, 95%CI: 0.938-1.079), cardiac thrombus (OR: 1.077, 95%CI: 0.791-1.465) or venous thromboembolism (OR: 1.028, 95%CI: 0.916-1.153). Conclusion: Leadless PM was associated with significantly improved mortality and cardiovascular outcomes compared to transvenous single-chamber PM in elderly patients. These findings support the strong consideration of leadless pacing as a strategy to reduce mortality and improve clinical outcomes in this high-risk population.

Background: The comparable long-term benefits of coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) in patients with multivessel disease remains limited in underrepresented populations, particularly in patients with multivessel coronary artery disease and heart failure with severely reduced left ventricular ejection fraction (LVEF <35%). Research Question: Among patients with HF and LVEF < 35% which revascularization strategy (CABG or PCI) provides superior long-term clinical outcomes? Methods: We conducted a systematic review and meta-analysis of observational studies involving patients with ischemic heart disease (IHD), HF and LVEF < 35% undergoing PCI or CABG with a minimum follow-up duration of five years. PubMed, Embase, and Cochrane databases were searched for studies published up to April 15, 2025. We computed hazard ratios (HR) from propensity score matched results. We used Cochrane Review Manager version 9.2.1 for statistical analysis. The primary endpoints of interest included all-cause mortality at 5 to 10 years, repeat revascularization, and all-cause mortality at 10 or more years. Results: We included 8 studies with 12,697 patients (6,187 PCI vs 6,510 CABG). Median follow-up duration ranged from 3.8 to 5.2 years, with the longest reported follow-up up to 13 years. The cumulative, propensity adjusted, incidence of all-cause mortality was significantly lower in the CABG group compared to PCI in 5 to 10 years of follow-up (HR 0.61; 95% CI 0.54-0.69; p<0.001) and ≥ 10 years (HR 0.63; 95% CI 0.53-0.74; p<0.001). Additionally, CABG was associated with a reduced need for repeat revascularization in the 5 to 10 year time frame, with a HR of 0.42 (95% CI 0.22-0.81; p=0.01). Conclusion: In this systematic review and meta-analysis of patients with IHD and an ejection fraction ≤ 35% undergoing revascularization, CABG was associated with a reduction in all-cause mortality at ≥ 5 and ≥ 10 years of follow-up, as compared to PCI.

Introduction: Corticosteroid therapy has been demonstrated to improve prognosis and reduce mortality in patients with severe Coronavirus Disease 2019 (COVID-19) infection by attenuating the exaggerated inflammatory response that emerges in the late phase of infection. However, its impact on patients with pre-existing cardiovascular disease, who are at higher risk of complications, has not been specifically studied. The aim of this study is to evaluate the effect of corticosteroid therapy on mortality and long-term COVID-19 symptoms in this high-risk population. Methods: We analyzed the prospective registry HOPE-2. Patients with previous cardiovascular disease were selected, and 18-month all-cause death was defined as the primary endpoint. Long-term COVID-19 symptoms were considered as secondary endpoints. A total of 1188 patients with previous heart disease were included, of which 453 received corticosteroid treatment. Propensity score matching analysis in a 1:1 fashion was performed based on baseline variables that exhibited a p-value < 0.05 in the univariant analysis and outcome variables that defined corticosteroid use, with a final matched population of 796 patients. Results: In patients with pre-existing heart disease, corticosteroid treatment was not associated with differences in 18-month all-cause mortality (p = 0.52). However, a shorter duration of hospitalization (median: 8 days [IQR: 4–14] and 11 days [IQR: 7–18]; p < 0.001) was observed in patients who received corticosteroids. No significant differences in long-term COVID-19 symptoms were observed between the two groups. Conclusions: In patients with pre-existing heart disease, the absence of a clear harmful effect suggests that the positive effects of corticosteroids may be offset by their potential adverse effects which could contribute to the persistence of long COVID symptoms. This finding may reflect a differential response to corticosteroids in this high-risk subgroup, highlighting the need for further studies to clarify the role of this therapy in such patients.

With rapid industrial expansion, air pollution’s adverse neurological effects have gained increasing attention. Children face a greater risk of neurological damage because of their higher breathing rates, developing brains, and limited ability to detoxify harmful substances. Fine particulate matter has been identified as a primary neurotoxic contributor affecting developing brains. Strong evidence connects environmental pollutant exposure to the prevalence of Autism Spectrum Disorder (ASD), a neurodevelopmental condition marked by lasting difficulties with social communication and interaction. This study explores the association between long-term PM2.5 exposure and ASD symptom exacerbation, investigating underlying mechanisms. We hypothesize that long-term PM2.5 exposure exacerbates ASD symptoms through neuroinflammatory activation, leading to neuronal damage and impaired synaptic plasticity. Our investigation employs three complementary approaches: First, integrated analysis combining Global Burden of Disease data with Mendelian randomization demonstrates a significant association between PM2.5 exposure and increased ASD severity risk. Second, utilizing the China High-Resolution Air Pollution Database in conjunction with cohort studies, we provide evidence that ambient air pollution substantially influences autism severity, with PM2.5 identified as the predominant environmental determinant. Third, through network toxicology, single-cell transcriptomics, and animal experimentation, we demonstrate that chronic PM2.5 exposure exacerbates valproic acid-induced autism-like behaviors in murine models, identifying CTNNB1, PTEN, CCR2, AKT1, and mTOR as potential core mediating genes. Importantly, these findings represent preliminary results. Several potential confounding factors such as co-exposure to other pollutants and socioeconomic variables have not been fully addressed. While our multi-modal approach provides converging lines of evidence, further validation in larger, more diverse populations with refined control of confounders will be essential to establish causality and elucidate mechanisms. Nonetheless, these early insights advance our understanding of PM2.5-induced neurotoxicity in the context of ASD and offer timely, albeit preliminary, evidence to inform public health policy.

Treatment-induced ovarian function loss is a significant concern for many young patients with breast cancer. Accurately predicting this risk is crucial for counselling young patients and informing their fertility-related decision-making. However, current risk prediction models for treatment-related ovarian function loss have limitations. To provide a broader representation of patient cohorts and improve feature selection, we combined retrospective data from six datasets within the FoRECAsT (Infertility after Cancer Predictor) databank, including 2679 pre-menopausal women diagnosed with breast cancer. This combined dataset presented notable missingness, prompting us to employ cross imputation using the k-nearest neighbours (KNN) machine learning (ML) algorithm. Employing Lasso regression, we developed an ML model to forecast the risk of treatment-related amenorrhea as a surrogate marker of ovarian function loss at 12 months after starting chemotherapy. Our model identified 20 variables significantly associated with risk of developing amenorrhea. Internal validation resulted in an area under the receiver operating characteristic curve (AUC) of 0.820 (95% CI: 0.817–0.823), while external validation with another dataset demonstrated an AUC of 0.743 (95% CI: 0.666–0.818). A cutoff of 0.20 was chosen to achieve higher sensitivity in validation, as false negatives—patients incorrectly classified as likely to regain menses—could miss timely opportunities for fertility preservation if desired. At this threshold, internal validation yielded sensitivity and precision rates of 91.3% and 61.7%, respectively, while external validation showed 92.9% and 60.0%. Leveraging ML methodologies, we not only devised a model for personalised risk prediction of amenorrhea, demonstrating substantial enhancements over existing models but also showcased a robust framework for maximally harnessing available data sources.