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Introduction: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder caused by pathogenic variants in the COL3A1 gene, often leading to arterial, intestinal, and uterine rupture. While vascular complications are well-documented, the prevalence and characteristics of cardiac arrhythmias in this population remain underexplored. Aim: To assess the prevalence of arrhythmias and conduction abnormalities in patients with confirmed vEDS. Methods: A retrospective cohort study was conducted across all three Mayo Clinic sites. Patients with vEDS were initially identified using an electronic data extraction tool. Each case was subsequently confirmed through detailed chart review. Additional reviews were performed to assess the prevalence of heart blocks and both atrial and ventricular arrhythmias. Statistical analysis was conducted using SPSS to determine the prevalence of each arrhythmia type. Results: A total of 132 patients with confirmed vEDS were included in the study. The mean age was 45.7 ± 13 years. The cohort was predominantly white (93.7%), with 47 males (35.6%) and 85 females (64.4%). Atrial arrhythmias were identified in 15 patients (11.4%), including atrial fibrillation in 14 (10.6%) and atrial flutter in 8 (6.1%). Supraventricular tachycardia (SVT) was observed in 15 patients (11.4%). Conduction abnormalities included first-degree AV block in 8 (6.1%), second-degree AV block in 3 (2.3%), left bundle branch block in 8 (6.1%), and right bundle branch block in 15 (11.4%) patients. Ventricular arrhythmias were observed in 6 patients (4.5%) with sustained ventricular tachycardia, 6 (4.5%) with non-sustained ventricular tachycardia, and 7 (5.3%) with ventricular fibrillation. Postural orthostatic tachycardia syndrome (POTS) or orthostatic hypotension was documented in 18 patients (13.6%). Conclusion: Although arrhythmias are not the most common manifestation of vEDS, their prevalence in this cohort is notably higher than in the general population and tends to occur at a younger age. These findings support the consideration of routine screening for atrial and ventricular arrhythmias in patients with vEDS as part of their long-term cardiovascular management.

Introduction: Designer receptors exclusively activated by designer drugs (DREADDs) are a robust chemogenetic tool for the interrogation of cellular electrical activity. Particularly, hM4Di activates the Gi signaling pathway, and can induce cellular hyperpolarization, leading to decreased electrical activity. Our aim is to engineer human induced pluripotent stem cell-derived cardiomyocytes (hiSPC-CMs) with controllable electromechanical properties to elucidate the role of transplanted hiPSC-CMs in cardiac regeneration. We hypothesize that activating hM4Di in transgenic hiSPC-CMs will inhibit their electrical activity. Methods: We developed a new hiPSC line expressing DREADD using the PiggyBac system (PB). The PB transposon included the hM4Di gene under the cTnT promoter, with mCherry and puromycin resistance genes as transfection markers ( Fig 1A ). After establishing the line, we differentiated these hiPSCs into DREADD-expressing cardiomyocytes (hiPSC-CM M4Di ). We activated hM4Di using clozapine N-oxide (CNO) and determined the optimal concentration through a concentration swipe. Optical mapping was used to analyze the electrical activity of hiPSC-CM M4Di . Results: After transfection, we observed the expression of mCherry in hiPSCs ( Fig 1B ). Additionally, we confirmed that these cells retained their pluripotency by evaluating the stemness markers Sox2 and Nanog ( Fig 1C ). Then, we performed directed cardiac differentiation. The cells showed spontaneous beating after day 8 of differentiation. We determined that the optimal concentration for hiPSC-CM M4Di inhibition was 200µM CNO, based on concentration swipe. Furthermore, our optical mapping data showed that spontaneous beating rate was decreased 30 minutes after adding CNO and completely stopped at 60 minutes. The spontaneous beating recovered after CNO was removed. CNO did not affect the electrical behavior of wild type cells (Fig 1D) . Conclusions: We developed a transgenic hiPSC line expressing DREADD. The produced hiPSC-CM M4Di responded positively to the CNO ligand, allowing inhibition of their electromechanical activity. This cell line holds potential for investigating the electrophysiology of grafted hiPSC-CMs, and for application as disease model in vitro.

Introduction: Hyperpolarized [1- 13 C] pyruvate magnetic resonance imaging (HP- 13 C MRI) enables real-time, noninvasive assessment of myocardial metabolism. While the technique is increasingly applied in cardiac research, dedicated tools for standardized analysis remain limited. We developed HP- 13 CMRAnalyst , a MATLAB-based application that supports dynamic 13 C data processing through semi-automated segmentation, time-course extraction, and metabolic ratio mapping (Figure 1A). Hypothesis: An integrated platform combining multi-frame 13 C data import, cine co-registration, multi-segment analysis, and voxel-level ratio mapping facilitates reproducible quantification of myocardial metabolism. Methods: HP- 13 CMRAnalyst was implemented in MATLAB App Designer and distributed as an .mlappinstall package. It accepts DICOM or NIfTI dynamic pyruvate, lactate, and bicarbonate images (∼3 s resolution; ≤ 60 s)(Figure 1B). Cine-registered T 1 -weighted images guide AHA 17-segment LV segmentation on short axis (SAX) and long axis (LAX) views (Figure 1C). A time slider displays metabolite overlays. Peak intensities are extracted per segment to compute bicarbonate/lactate and bicarbonate/pyruvate ratios. Pixel-wise ratio maps are exported as CSV, MATLAB struct, and PDF summaries. Results: Eight subjects (n = 4 healthy; n = 4 coronary artery disease [CAD]), each imaged pre- and post-CABG (total n = 12 datasets; age 55 ± 12 years), were processed in < 5 min per dataset on a standard desktop (MATLAB R2024b). Semi-automated versus manual segmentation agreement was high (Dice 0.89–0.93). Inter-observer variability for segmental bicarbonate/(bicarbonate + lactate) ratios were minimal biases < 0.005 and limits of agreement within ± 0.083 across all observer pairs (Figure 1D). Ratio maps qualitatively revealed regional metabolic heterogeneity. Automated reports accurately reflected metadata and segmental summaries. The GUI, logs, and summary files streamline standardized processing. Conclusions: HP- 13 CMRAnalyst delivers a rapid (< 5 min), reproducible framework for dynamic HP- 13 C MRI analysis. By combining semi-automated segmentation and pixel-level ratio mapping with low inter-observer variability, this platform may accelerate adoption of 13 C metabolic imaging in human cardiac research.

Background: Despite obesity being a major cardiovascular risk factor, studies in heart failure populations have reported an inverse association between body mass index and mortality—a phenomenon termed the "obesity paradox." However, the consistency and shape of this relationship across different HF phenotypes and clinical subgroups remain unclear. This meta-analysis aimed to quantify the dose-response relationship between BMI and mortality in HF patients and assess potential variations across subgroups. Hypothesis: Higher BMI is associated with reduced mortality in patients with heart failure, and that this relationship varies across clinical subgroups and U-shaped relationship. Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A search strategy was developed, and studies were extracted from Cochrane and PubMed databases through December 2023. The main outcomes were all-cause mortality, cardiovascular deaths, and heart failure hospitalizations. Data were summarized as hazard ratios with 95% confidence intervals, and a spline model was used to assess non-linear relationships, with 21.7 kg/m2 as the reference point in the dose-response curve. PROSPERO: CRD42023455124 Results: Thirty-three studies (457,124 person-years) showed that each 5 kg/m2 increase in BMI was significantly associated with a 6% reduction in all-cause mortality (HR 0.94; 95% CI 0.92–0.96). Significant reductions were observed in acute decompensated heart failure (7%), HFpEF (9%), HFrEF (8%), diabetes (9%), males (9%), and females (8%). Cardiovascular mortality declined by 5% per 5 kg/m2 increase. Non-linear analysis revealed a significant U-shaped relationship, with lowest all-cause mortality between BMI 21.7 and 39 kg/m2. Subgroup analysis showed significant non-linear all-cause mortality reductions in acute decompensated heart failure (23.5–26 kg/m2), HFpEF (21.7–31 kg/m2), HFrEF (21.7–43 kg/m2), females (24–25.5 kg/m2), diabetes (21.7–36 kg/m2), and non-diabetics (21.7–33 kg/m2). Conclusion: Higher BMI is significantly associated with lower all-cause and cardiovascular mortality in patients with heart failure, supporting the presence of an obesity paradox. This protective effect was consistent across clinical subgroups, including HFpEF, HFrEF, males, females, and individuals with diabetes. The BMI paradox was evident in patients with acute decompensated heart failure, HFpEF, HFrEF, females, and both with and without diabetes.

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

Introduction: Seasonal, geographic, and socioeconomic factors all influence cardiovascular (CV) mortality. Long-term seasonal trends across United States regions remain insufficiently characterized. Research Question: We evaluated longitudinal trends in CV mortality across seasons in the U.S., stratified by geographic region and degree of urbanisation, from 1999 through 2020. Methods: Data on CV mortality (ICD-10: I00-I99) were extracted from the CDC WONDER database and stratified by season (Winter, Spring, Summer, Fall), U.S. Census region (Northeast, Midwest, South, West), and degree of urbanisation (6-level National Center for Health Statistics classification). Age-adjusted mortality rates (AAMRs) were calculated, and Joinpoint regression was used to estimate annual percent change (APC) and average annual percent change (AAPC) with 95% confidence intervals. Results: From 1999 to 2020, 18.8 million CV deaths were recorded (Table 1). Winter accounted for the highest mortality burden across all regions and urban settings but also showed the greatest improvement of the the 20-year study period, with AAPC reductions most pronounced in the Northeast (–2.83%) and Large Central Metro areas (–2.79%; p < 0.000001 for all trends; Figure 1). Summer and Fall, while associated with fewer deaths, showed slower progress, particularly in the Midwest (Fall AAPC: –1.81%; Summer: –1.77%) and rural areas (NonMetro Fall AAPC: –1.56%). Notably, Midwest Fall mortality demonstrated a statistically significant reversal, with an APC increase of +3.87% from 2018 to 2020 (p = 0.02)(Figure 1). Conclusion: CV mortality in the U.S. follows a distinct and evolving seasonal pattern. Although winter remains the deadliest season, it has seen the most substantial mortality reductions, likely tied to improved awareness, continuity of care, and cold-weather adaptations. However, slower progress during summer and fall, particularly in the Midwest and rural areas, reveals growing seasonal and geographic disparities. Most notably, the recent and statistically significant rise in Midwest fall mortality signals an urgent concern. This reversal may reflect emerging climate stressors such as prolonged heat, air pollution, and environmental volatility during transitional months compounded by reduced healthcare access or changing behavioral risk factors. These findings call for year-round, seasonally tailored public health strategies especially for underserved and climate-vulnerable populations.

Background: HIV cardiomyopathy (HIV-CM) is associated with significant morbidity and mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have benefits in heart failure (HF), but their role in the specialized population of HIV-CM is poorly understood. Methods: Patients in the TriNetX Network with HIV-CM and SGLT2i therapy were compared to a propensity matched control group of patients with HIV-CM without SGLT2i use. The primary endpoint was all-cause mortality. Secondary endpoints included all-cause hospitalization, acute heart failure (HF), acute myocardial infarction (MI), stroke, cardiac arrest, new atrial fibrillation, and ventricular tachycardia. Results: In the total of 2,606 included patients, SGLT2i therapy was associated with significant reduction in all-cause mortality (HR 0.475, 95%CI 0.337–0.671) and all-cause hospitalization (HR 0.725, 95%CI 0.646–0.814). No significant differences were observed rates of acute HF (HR 1.111, 95% CI 0.957–1.289), myocardial infarction (HR 0.828, 95% CI 0.555-1.235), stroke (HR 0.995, 95% CI 0.747–1.327), cardiac arrest (HR 0.564, 95% CI 0.308-1.036), atrial fibrillation (HR 0.954, 95% CI 0.798–1.140), or ventricular tachycardia (HR 1.225, 95% CI 0.898–1.672). Conclusions: SGLT2i use was associated with significant reductions in all-cause mortality and hospitalizations in patients with HIV-CM, but not cardiac specific outcomes.

Introduction: Pressure-adjusted heart rate (PAHR) provides an integrated assessment of hemodynamic decompensation in critically ill patients. Research Question: How does PAHR perform in critically ill patients with cardiovascular disease? Aims: We sought to evaluate the prognostic value of PAHR on mortality in patients admitted to the cardiovascular intensive care unit (CICU). Methods: A retrospective cohort of patients admitted to the CICU at a tertiary-care academic institution, between 2007 and 2018, who had a transthoracic echocardiogram (TTE) within one day of admission were evaluated. Heart rate (HR), right atrial pressure (RAP), and mean arterial pressure (MAP), obtained from TTE, were used to calculate PAHR as RAP * HR / MAP. Results: Among 5411 patients included for analysis (median age 70.1 years, 38.6% female, 92.4% White), higher PAHR was associated with greater severity of acute illness, burden of comorbidities, and use of critical care therapies. Median values (25 th percentile, 75 th percentile) for HR were 73.0 (63.0, 87.0) beats per minute (bpm), RAP 10.0 (5.0, 14.0) mm Hg, and MAP 81.3 (72.3, 91.7) mm Hg. Median PAHR was significantly higher among patients who died during hospitalization (14.3 bpm vs 6.8 bpm, p <0.001). In addition, TTE measurements of biventricular function, intracardiac filling pressures, and cardiac output were worse among those with higher PAHR (Table). Adjusted in-hospital mortality increased incrementally with higher PAHR, regardless of admission diagnosis, biventricular function, and critical care therapies (adjusted odds ratio [OR] 1.03 per 1 bpm higher, 95% confidence interval [CI] 1.01-1.05, p = 0.001; adjusted OR per quartile 1.37, 95% CI 1.19-1.59, p <0.001, Figure 1). Similarly, one-year mortality increased incrementally with higher PAHR (adjusted hazard ratio 1.03 per 1 bpm higher, 95% CI 1.02-1.04, p <0.001, Figure 2). When compared to component values, including the modified shock index, which is defined by HR / MAP, PAHR had the highest area under the curve (C-statistic 0.75). Conclusions: PAHR is a readily determinable composite measure of filling pressures and vascular resistance that enhances clinical risk stratification of critically ill patients by TTE. Among a diverse cohort of CICU patients, higher PAHR was associated with greater in-hospital and one-year mortality, regardless of admission diagnosis, biventricular function, or illness severity.

Background: Obicetrapib is a next-generation cholesteryl ester transfer protein (CETP) inhibitor. It has emerged as a promising agent for improving lipid parameters and potentially reducing risk of atherosclerotic cardiovascular disease (ASCVD). Methods: A systematic search of databases, including PubMed, Scopus, Embase, Web of Science, Clinical Trials, and Cochrane Library, was conducted to identify relevant randomized controlled trials (RCTs). Outcomes included the assessment of LDL-C reduction, changes in ApoB, non-HDL-C, HDL-C, triglycerides, Lp(a), MACE, as well as the safety and tolerability profile of Obicetrapib in patients with dyslipidemia or ASCVD. Standardized mean differences (SMD) with 95% confidence intervals (CI) were pooled using random-effects. Results: Seven RCTs encompassing 3483 patients were included. Obicetrapib significantly improved lipid parameters. It reduced LDL-C (MSD: –35.43; 95% CI: –40.14 to –30.17; I2 = 93.26%), non-HDL-C (MSD: –36.42; 95% CI: –42.77 to –30.07; I2 = 99.06%), ApoB (MSD: –23.38; 95% CI: –30.68 to –16.08; I2 = 88.56%), and Lp(a) (MSD: –23.95; 95% CI: –35.26 to –12.63; I2 = 77.14%). Obicetrapib also led to a reduction in TG levels (MSD: –0.12; 95% CI: –0.19 to –0.05; I2 = 0.00%). In contrast, favorable increases were observed in HDL-C (MSD: 77.35; 95% CI: 64.56 to 90.13; I2 = 95.82%) and ApoA1 (MSD: 63.93; 95% CI: 53.65 to 74.21; I2 = 81.89%). Despite high heterogeneity, these results support Obicetrapib’s effectiveness in improving atherogenic lipid markers. Obicetrapib demonstrated a safety profile comparable to placebo. The overall risk of any adverse event was slightly reduced in the Obicetrapib group compared to placebo, but the 95% CI included 1, (RR: 0.96; 95% CI: 0.76 to 1.21; I2 = 66.3%; p = 0.01). Specific adverse events such as diarrhea (OR: 1.56; 95% CI: 0.34 to 7.11; I2 = 5.16%; p = 0.57), headache (OR: 1.17; 95% CI: 0.74 to 1.84; I2 = 0.00%; p = 0.50), and back pain (RR: 0.36; 95% CI: 0.11 to 1.16; I2 = 18.3%; p = 0.26) were also not significantly different between groups. Overall, Obicetrapib appears well-tolerated without increased adverse events. Conclusion: Obicetrapib significantly improved lipid parameters, notably reducing LDL-C, non-HDL-C, ApoB, Lp(a), and triglycerides, while increasing HDL-C and ApoA1, with a favorable and comparable safety profile.

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