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Abstract Background Sodium-glucose co-transporter inhibitors (SGLT2i) have been associated with improved outcomes in heart failure patients, reducing hospitalizations and mortality. However, patients with cardiac amyloidosis were largely excluded from major trials. Therefore, we conducted a meta-analysis to evaluate the potential benefits of SGLT2i in this population. Purpose To assess the potential benefits of SGLT2i in patients with cardiac amyloidosis. Methods We searched PubMed and Embase for studies comparing SGLT2i use with placebo in patients with cardiac amyloidosis. The primary outcomes analyzed were: (1) all-cause mortality, (2) cardiovascular mortality, (3) hospitalizations, and (4) NT-proBNP levels. A random-effects model was used to calculate the pooled risk ratio (RR) or mean difference (MD) with a 95% confidence interval (CI). Heterogeneity was assessed using Cochran’s Q test and I² statistics. Results We included five observational studies comprising 5,101 patients, of whom 2,528 were receiving SGLT2i. The mean follow-up period ranged from 3 months to 8.7 years. All-cause mortality was significantly lower in the SGLT2i group compared to controls (Figure 1a: RR 0.37; 95% CI 0.28–0.49; p < 0.00001; I² = 12%). Cardiovascular mortality was also significantly reduced in the SGLT2i group (Figure 1b: RR 0.30; 95% CI 0.16–0.55; p < 0.00001; I² = 25%). NT-proBNP levels were significantly lower in the SGLT2i group (Figure 2a: MD -299.66; 95% CI -493.24 to -106.08; p = 0.002; I² = 0%). There was no significant difference in hospitalization rates between groups (Figure 2b: RR 0.75; 95% CI 0.17–3.38; p = 0.70; I² = 94%). Conclusion These findings suggest that SGLT2i use in cardiac amyloidosis is associated with significant reductions in all-cause mortality, cardiovascular mortality, and NT-proBNP levels. However, no significant impact on hospitalization rates was observed. Further randomized controlled trials are warranted to confirm these results

Abstract Background Artificial intelligence enhanced electrocardiograms (AI-ECG) have matured over the past 10 years. More recently, the AI-ECG estimate of biological sex has shown potential as a novel tool for cardiovascular risk stratification among women. Cardiovascular disease is a leading cause of pregnancy-related mortality; however, there have been limited approaches for estimating the physiological demands of pregnancy and its impact of maternal cardiovascular outcomes. Purpose To estimate pregnancy-related changes on AI-ECG-based sex and age estimation in a prospective cohort of otherwise healthy, complication free pregnant women. Methods This secondary analysis of the SPEC-AI Nigeria Clinical Trial identified pregnant women without any pregnancy-related complications (at baseline or during follow-up) who had at least two 12 lead ECGs recorded during the study. The ECGs were analyzed with previously-developed algorithms to predict age and biological sex. To address bias in the AI-ECG age estimate, a reference cohort of 25,144 healthy patients was analyzed using quantile regression to estimate the 75th percentile of the reference distribution as a function of age. The estimate of biological sex was used to determine a sex discordance score with a discordance of 0.2 considered clinically relevant. To simplify the trends in the data, the ECGs were categorized as during pregnancy (<=28 days prior to birth), peripartum (+/- 28 days of birth), and postpartum (28+ days after birth), and mixed effects models with a random intercept were used for analysis. Results A total of 207 females with a median age of 31 years (IQR 28 to 36 years) and normal blood pressures (systolic: 110 (IQR 10 to 120); diastolic: 70 (IQR 60-77); mmHg) were included from 5 clinical sites in Nigeria. The majority (73%, 150/207) of participants were in their second trimester at time of enrollment and the median number of ECGs per participant was 3 (max 7). The sex discordance score was elevated in 38% of the women at baseline and this percentage fell to 23% postpartum; which resulted in a decrease in the mean discordance score of 0.03 (95% CI: -0.06 to 0.0; p=0.028). Conversely, the percentage of patients with elevated age prediction increased from 35% to 41% over the course of pregnancy. This resulted in an increase in the bias-corrected AI-ECG age of 3.0 years (95% CI: 1.5 to 4.6 years; p<0.001). Conclusion This study demonstrates the preliminary utility of serial AI-ECG based assessment as a marker for the biological effects of pregnancy. The increase in sex discordance score during pregnancy may be related to changes in cardiac structure, such as increased ventricular mass and chamber dilation which often reverses postpartum. However, the impact on age estimation appeared to persist in the early postpartum period. Further study is warranted to associate any changes observed with long term maternal or fetal outcomes.Figure

Abstract Background Glycosylation, a key post-translational modification, plays a crucial role in biological pathways related to atherosclerosis. Purpose To investigate whether specific immunoglobulin G (IgG) N-glycosylation patterns are associated with premature myocardial infarction (MI) and to evaluate whether a glycan-based score improves case identification beyond traditional cardiovascular risk factors. Methods We measured 27 IgG N-glycans using capillary gel electrophoresis in 377 cases of premature first MI (men ≤55 years; women ≤65 years) and 377 controls matched for age (±5 years), sex, and nationality from the Gulf PREVENT study, a case-control study investigating risk factors for premature MI in the United Arab Emirates. We performed conditional logistic regression to evaluate associations between IgG N-glycans and premature MI, adjusting for age, body mass index, LDL-C, HDL-C, hs-CRP, hypertension, diabetes, and smoking. Using LASSO regression, we derived a novel IgG glycan score as a linear combination of selected glycans associated with premature MI. We evaluated model performance using likelihood ratio tests and the area under the curve (AUC) adapted for the case-control design, using 10-fold cross-validation. Results After adjusting for cardiovascular risk factors, glycan peaks (P) 4, 13, 23, and 27 were positively associated with premature MI (false discovery rate [FDR]<0.05). Bisecting N-acetylglucosamine (GlcNAc) was the consistent glycosylation pattern among these four glycans. In contrast, P 22, a core-fucosylated and monogalactosylated glycan, had inverse association (FDR=0.02) with premature MI. An IgG glycan score, composed of Ps 2, 4, 8, 17, 20, and 24, was associated with twofold increase in premature MI risk per standard deviation increment (aOR,1.98 [95%CI,1.56–2.52]; P<0.001) after adjusting for cardiovascular risk factors. Further, the IgG glycan score significantly improved model fit and performance, as indicated by a significant improvement in the likelihood ratio test and AUC (P<0.001). Conclusion We identified novel IgG N-glycosylation patterns that were associated with premature MI independent of cardiovascular risk factors. Glycans enriched with bisecting GlcNAc had increased risk, while core fucosylation and monogalactosylation had decreased risk. A novel IgG glycan score had 2-fold increased risk of premature MI independent of other risk factors and improved model performance. These findings highlight the potential of IgG N-glycans as biomarkers and therapeutic targets for premature MI.

Abstract Background The impact of treatment for tricuspid regurgitation (TR) across different levels of left ventricular ejection fraction (LVEF) remains uncertain. Purpose This study aimed to compare the outcomes of surgical and transcatheter tricuspid valve interventions (TTVI) to conservative (medical) management across all LVEF categories. Methods Patients with severe isolated TR from the TRIGISTRY, a multicenter international registry, were categorized based on LVEF (preserved EF-pEF:≥50%, mildly reduced EF-mrEF:41–49%, and reduced EF-rEF:≤40%). We assessed the impact of treatment modality and procedural success, defined as residual TR ≤mild-to-moderate, on two-year survival within each LVEF category. Results Among 2,384 patients, 1,383 had pEF, 400 had mrEF, and 601 had rEF. Compared to conservative management, surgery (P<0.0005) and TTVI (P<0.0001) were associated with a survival benefit in patients with pEF. No significant survival advantage was observed in patients with mrEF (P=0.28 for both), nor in those with rEF (P=0.76 and P=0.22 respectively). Similar results were obtained when surgical and transcatheter interventions were grouped together (P<0.0001, P=0.17 and P=0.29 in patients with pEF, mrEF and rEF respectively). Patients with significant residual TR after TTVI exhibited a trend toward worse survival compared to those managed conservatively across all LVEF categories (P=0.47, P=0.33, and P=0.008 respectively)(Figure 1). Conclusion Tricuspid valve intervention, whether surgical or transcatheter-based, was associated with improved survival in patients with preserved LVEF but not in those with mildly reduced or reduced LVEF. Residual TR remained a significant prognostic factor across the entire LVEF spectrum. These findings highlight the need for careful patient selection when considering tricuspid interventions in individuals with reduced LVEF.Figure 1

Background Breast arterial calcifications (BAC) are commonly observed as an incidental finding on screening mammography and have been linked to cardiovascular disease. Whether BAC is independently associated with stroke risk remains uncertain. Methods We conducted a systematic review and meta-analysis in accordance with PRISMA 2020 guidelines. PubMed, Embase, and Scopus were searched from inception to May 2024 for cohort studies evaluating the association between BAC and stroke. Eligible studies included women undergoing mammography with documented BAC status and subsequent stroke outcomes. Data on patient characteristics and vascular risk factors were extracted. Study quality was appraised using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. Random-effects meta-analyses with restricted maximum likelihood (REML) estimation were performed to pool risk ratios (RRs) and mean differences (MDs). Heterogeneity was assessed with the I 2 statistic, and publication bias with Egger’s test. Results Ten cohort studies including 52,413 women were analyzed. The presence of BAC was associated with more than a twofold increased risk of stroke (RR 2.09, 95% CI 1.58–2.75; I 2 = 64.4%). This association persisted after adjustment for age, diabetes, hyperlipidemia, and menopausal status. Compared with BAC-negative women, those with BAC were significantly older (MD 7.07 years, 95% CI 5.44–8.70) and more frequently hypertensive (RR 1.48, 95% CI 1.23–1.78), diabetic (RR 1.67, 95% CI 1.38–2.02), hyperlipidemic (RR 1.27, 95% CI 1.07–1.51), and postmenopausal (RR 1.26, 95% CI 1.00–1.59). Interestingly, BAC was less common among smokers (RR 0.62, 95% CI 0.45–0.86). Egger’s test showed no evidence of publication bias ( p = 0.143). Conclusion BAC detected on screening mammography is independently associated with an increased risk of stroke, even after accounting for traditional risk factors. These findings support BAC as a promising, underutilized imaging biomarker of cerebrovascular risk in women and highlight the need for standardized reporting and prospective validation.

Abstract Background Cardiovascular disease (CVD) is the leading cause of death globally for both men and women, yet women remain historically underrepresented in cardiovascular clinical trials (CV trials), despite facing a disproportionately high burden of morbidity and mortality in many forms of CVD. Purpose We aim to determine the representation of women across a broad range of CV trials. Methods The participation of women in CV trials registered on ClinicalTrials.gov from 2017 to 2023 was systematically determined through the extraction of publicly available information. Data was extracted to identify the country of study, disease type, trial size, clinical intervention and age of the participants. We calculated the proportion of women and the ratio of number of females to male participants (F:M ratio) for each trial. The female participation to prevalence ratio (PPR) was estimated for each trial based on the relative prevalence of the disease by sex in the specified region. Results We identified 1,079 registered CV trials, which included 1,396,104 participants, of whom 571,641 (41.0%) were women. The median F:M ratio was significantly lower for studies on arrhythmia (0.5), coronary heart disease (CHD) (0.39), acute coronary syndrome (ACS) (0.32) and heart failure (HF) (0.51), but was higher for obesity (1.44) and pulmonary hypertension (PH) (2.86) CV trials. F:M ratio was higher for trials on lifestyle intervention (1.51) than for drug trials. PPRs were low for clinical trials on CHD (0.66), ACS (0.79), and stroke (0.74). There was a trend to increasing PPR from 2017 to 2023, p=0.056. Conclusion Representation of women in CV trials varies by disease state, region, intervention, and sponsor type. Better understanding of reasons for these differences may enable more tailored interventions to improve representation of women globally and across therapeutic areas.Figure 1 Figure 2

Abstract Background Obesity is a major public health concern and a leading contributor to premature mortality worldwide. While body mass index (BMI) has long been the standard measure for assessing obesity-related health risks, it fails to distinguish between fat and lean mass or capture the distribution of adiposity—key determinants of metabolic and cardiovascular (CV) health. The Body Roundness Index (BRI), a novel anthropometric measure incorporating waist circumference and height, offers a more precise assessment of body fat distribution and its associated health risks. Although prior studies have linked BRI to all-cause and CV mortality in general populations, its predictive value for premature mortality and potential disparities remain unexplored. Purpose To investigate the association between BRI and premature all-cause (primary outcome) and cardiovascular-specific mortality (secondary outcome) in U.S. adults younger than 65 years. Additionally, we examine whether these associations vary across sociodemographic subgroups. Methods We conducted a nationally representative cohort study using the National Health and Nutrition Examination Survey (NHANES) data (1999–2018) linked to mortality records through December 31, 2019. Adults younger than 65 years were included, excluding those with CV disease or missing covariates. BRI, derived from waist circumference and height, was categorized into quintiles (Q3 as reference). Premature mortality was defined as deaths before age 65. Multivariable Cox proportional hazards models, accounting for NHANES’ complex survey design, were used to assess associations and ensure nationally representative estimates. Nonlinear relationships were examined using restricted cubic splines. Results Among 29,016 (weighted N=1,349,437,788) adults (mean age 42 years; 50% female), 751 premature deaths occurred over a median follow-up of 10 yrs, including 163 attributed to CV causes. In fully adjusted models*, participants in the highest BRI quintile (Q5 vs. Q3) had a 47% higher risk of premature all-cause mortality (HR 1.47; 95% CI, 1.12–1.93; p=0.006) and a 96% higher risk of premature cardiovascular mortality (HR 1.96; 95% CI, 1.12–3.41; p=0.02; Fig.1). Subgroup analyses indicated that the association between high BRI and premature mortality was most pronounced among middle-aged adults (45-64 years: HR 1.80; p-interaction=0.004), males (HR 1.66; p=0.006), and Hispanics (HR 2.17; p=0.007). Similar patterns were observed for premature cardiovascular mortality (Fig.2). Conclusions High BRI is independently associated with increased risks of premature all-cause and cardiovascular mortality, with the strongest effects observed in middle-aged adults. These findings highlight the potential of BRI in risk stratification and underscore the need for targeted interventions to address disparities in premature mortality. Integrating BRI into preventive cardiology and public health strategies may help reduce early mortality.Figure 1 Figure 2

Abstract Background The functional significance of the left ventricular (LV) hypercontractile phenotype (HP) in hypertrophic cardiomyopathy (HCM) remains unclear. Purpose To assess the systemic and coronary hemodynamic correlates of HP in HCM. Methods We enrolled 1533 HCM patients (age 51 ± 15 years, 965 males, 63%) with ejection fraction (EF) ≥50%, referred for rest transthoracic echocardiography (TTE) in 27 laboratories from 13 countries. Two-dimensional volumetric TTE assessment included LV outflow tract gradient (LVOTG), end-diastolic volume (EDV), end-systolic volume (ESV), EF, and LV force (systolic blood pressure + LVOTG/ESV, mmHg/mL). Coronary flow velocity in the mid-distal left anterior descending (LAD) coronary artery was assessed in 325 patients. HP was defined as the highest quartile of the force (> 7.32 mmHg/ml). Results Force was moderately related to EF (r = 0.48, p < 0.0001) and weakly to LVOTG (r = 0.36, p < 0.0001). Compared to non-HP patients, HP showed higher heart rate (72 ± 14 vs 67 ± 14 beats per minute, p <0.0001), lower stroke volume (50 ± 22 vs 67 ± 22 ml, p < 0.0001), larger left atrial volume index (44 ± 16 vs 40 ± 16 ml/m2, p = 0.011) and higher coronary flow velocity in the LAD (n = 325, 41 ± 12 vs 37 ± 14 cm/s, p = 0.021), see Figure. Abnormal B-lines (≥ 2) were present in 11 of the 39 HP compared to 39 of the 271 non-HP patients (28% vs 14 %, p = 0.05). E/e’ ratio was higher in HP (n = 59) vs. non-HP (n = 571) patients (11 ± 5.4 vs 9.6 ± 4.2, p = 0.018). Conclusion In patients with HCM, preserved EF, and no history of coronary artery disease, HP identified by resting TTE with supernormal LV force was associated with an unfavorable systemic hemodynamic and coronary flow profile. Compared to non-HP HCM patients, the HP was characterized by reduced stroke volume, impaired diastolic function, and increased resting coronary flow velocity. HP may reflect inefficient myocardial mechanics, with disproportionate energy expenditure mirrored by higher resting coronary flow despite reduced stroke volume generation, ultimately contributing to adverse remodeling and worse prognosisNon-HP vs HP LAVI and coronary LAD flow

Abstract Background The tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (SPAP) ratio (TAPSE/SPAP) is touted as a measure of right ventricular (RV) to pulmonary artery (PA) coupling, but its intrinsic, independent and incremental impact on outcome remains uncertain, particularly across the quantified severity spectrum of tricuspid regurgitation (TR). Methods We enrolled a prospective repository of patients with native TR, in whom TR quantitation using proximal-isovelocity-surface-area (PISA), SPAP and TAPSE, were all prospectively measured between 09/2003 and 04/2023. We included only patients with functional TR, without congenital or organic heart disease and without indwelling catheter/lead. The primary outcome was mortality under medical management. Results A total of 3,436 patients (median age 77 years, 57.6% female, median effective-regurgitant-orifice-area 39 mm2) were included. The median TAPSE/SPAP ratio was 0.36 (interquartile-range 0.26-0.51). Over a mean follow-up period of 2.4±2.8 years, 854 (24.9%) patients died. Spline regression, adjusted for age, sex, left ventricular ejection fraction, EROA, comorbidity index, and heart failure severity (TriScore), demonstrated that a TAPSE/SPAP remain linked to mortality, with ratio below 0.4 significantly associated with excess mortality risk (Figure). Multivariable models confirmed that higher TAPSE/SPAP ratio remained independently inversely associated with mortality (adjusted-hazard-ratio 0.76 [0.72-0.80] per 0.1 increment, p<0.001). Furthermore TAPSE/SPAP ratio provided incremental and independent prognostic value above and beyond the individual values of TAPSE or SPAP (p<0.001) and threshold for excess mortality remained consistently at 0.4, irrespective of quantified TR severity. Conclusion The TAPSE/SPAP ratio measured prospectively in routine clinical practice, is a strong and independent prognostic indicator in patients with functional TR, that adds to the prognostic value of its components. A TAPSE/SPAP ratio below 0.4 consistently identifies a subgroup at high-risk of mortality under medical management. These data suggest that therapeutic interventions that may impact positively the TAPSE/SPAP ratio should be tested in patients with functional TR.Mortality risk across TAPSE/SPAP ratio