Cardiovascular Outcomes Research Articles

Abstract 4116692: Cardiovascular Safety of Fertility Therapy: A Systematic Review and Meta-Analysis

Background and Aims: The increasing use of assisted reproductive technology (ART) has raised concerns regarding its long-term cardiovascular safety due to potential hormonal imbalances and pro-thrombotic states. This study aimed to assess the long-term cardiovascular risk associated with fertility treatments in women. Methods: Following PRISMA guidelines, a systematic review and meta-analysis was conducted via MEDLINE (Pubmed) from inception to January 2024. Randomized, cohort or case-control studies were included if fulfilling the following criteria: the association between fertility therapy and the subsequent cardiovascular outcome was reported and conditioned on confounding factors (at least age); the presence of a control group; minimum one-year follow-up. Effect size (ES) estimates of the association between fertility therapy and subsequent cardiovascular disease were pooled using the DerSimonian and Laird random-effects model. Heterogeneity was assessed with the I 2 index. This study is registered with PROSPERO (CRD42024505605). Results: Of 7,298 articles screened, eleven studies were included, encompassing 606,912 women undergoing ART and 70,562,486 controls. The analysis found no increase in the long-term risk of major adverse cardiovascular events (ES=0.97, 95% CI=0.81-1.16, I 2 =89.55%, p=0.73), coronary heart disease (ES=0.88, 95% CI=0.71-1.10, I 2 =24.36%, p=0.26), stroke (ES=1.20, 95% CI=0.96-1.49, I 2 =48.33%, p=0.11), heart failure (ES=0.74, 95% CI=0.60-0.94, I 2 =0.00%, p=0.01), venous thromboembolism (ES=1.03, 95% CI=0.78-1.34, I 2 =54.41%, p=0.85), hypertension (ES=1.08, 95% CI=0.88-1.326, I 2 =94.63%, p=0.46), or diabetes (ES=1.03, 95% CI=0.86-1.22, I 2 =78.44%, p=0.77). Conclusions: ART does not increase the long-term risk of cardiovascular diseases in women. These results support the cardiovascular safety of fertility treatments, though further research into specific ART techniques and extended follow-up is recommended.

Abstract 4125493: Is There an Obesity Paradox for Cardiovascular Outcomes in Patients Undergoing Transcatheter Edge-to-Edge Repair? A Pilot Meta-Analysis

Background: The impact of body mass index (BMI) on Transcatheter Edge-to-Edge Repair (TEER) outcomes remains uncertain, with studies showing conflicting results. Some suggest an 'obesity paradox' exists, favoring better outcomes for obese patients and worse outcomes for underweight patients, while others report no significant impact of BMI. Methodology: We conducted a systematic literature search using major databases to identify studies investigating the association between baseline BMI status and post-procedural outcomes in patients undergoing TEER. Patients were categorized into four BMI groups: underweight (BMI < 18.5 kg/m 2 ), normal weight (BMI 18.5-24.9 kg/m 2 ), overweight (BMI 25-29.9 kg/m 2 ), and obese (BMI ≥ 30 kg/m 2 ). The endpoints included were the risk of in-hospital mortality, myocardial infarction, and stroke. Data were pooled using Review Manager with a random-effects model. Risk ratios (RRs) with their 95% confidence intervals (CIs) were used as the effect measure. Statistical significance was set at p<0.05. Results: Our study included a total of six observational studies, encompassing 7,627 obese and 74,820 non-obese patients. The outcome of in-hospital mortality revealed no significant difference between the two groups (RR: 0.85; 95% CI: 0.57, 1.27; p=0.43). Subgroup analysis showed a trend towards higher in-hospital mortality risk for underweight patients compared to overweight (RR: 1.48; 95% CI: 1.11, 1.95; p=0.007) and obese patients (RR: 1.40; 95% CI: 1.02, 1.92; p=0.04). The comparison between underweight and normal-weight patients did not reach statistical significance (RR: 1.18; 95% CI: 0.91, 1.55; p=0.22). Additionally, the risk of myocardial infarction (RR: 1.10; 95% CI: 0.77, 1.58; p=0.59) and stroke (RR: 0.43; 95% CI: 0.13, 1.42; p=0.17) did not differ significantly between obese and non-obese patients. Conclusions: Our study found no significant difference in in-hospital mortality between obese and non-obese patients. However, underweight patients had a higher mortality risk compared to both overweight and obese patients. While myocardial infarction rates were similar across all groups, there was a non-significant trend suggesting a potentially lower risk of stroke in obese patients. These findings warrant further prospective studies to provide robust evidence.

Abstract 4135712: Mortality and Cardiovascular Complications Associated with Weight Loss Drugs among Breast Cancer Females Under Cardiotoxic Therapies: A Real-World Populational Study in the United States

Background: Obesity is an adverse prognostic factor for breast cancer (BC). While liraglutide and semaglutide, derived from antidiabetic glucagon-like peptide-1 receptor agonists (GLP1RA), are established weight loss drugs known for their cardiovascular safety in the general obese population, their safety in BC patients undergoing cardiotoxic antineoplastic therapies remains less understood. Objective: To investigate the mortality and cardiovascular outcomes related to GLP1RA used for weight loss among the highly susceptible BC females. Methods: This retrospective cohort study was based on the TrinetX network, comprising real-time health records from over 60 US healthcare organizations. The study population included obese females (≥18 years old) who received at least three prescriptions of either exclusive GLP1RA (liraglutide or semaglutide) or non-GLP1RA weight loss drugs (phentermine, bupropion-naltrexone, orlistat) upon BC diagnosis between 01/01/2015 and 01/01/2022. The index date was the initiation of systemic anti-cancer treatment, including chemotherapy (anthracycline, taxane, or cyclophosphamide), and/or anti-HER2 agents (trastuzumab, pertuzumab, or lapatinib). We used 1:1 propensity score-matching (PSM) to balance demographics, BMI, comorbidities, concurrent medications for cardiovascular diseases and metabolic disorders, BC receptor status and prior treatment, and levels of serum cholesterol (LDL, HDL) and hemoglobin A1c. Cox regression models were applied to compute hazard ratios (HR) and 95% confidence intervals (CIs). Follow-up continued until 05/24/2024, or until adverse cardiovascular events or death occurred. Results: Among 380 PSM-balanced pairs, the GLP1RA group (mean age: 57.6±11) showed significantly lower risks of all-cause mortality (HR 0.593, 95% CI 0.457-0.77), acute heart failure (HR 0.496, 95% CI 0.286-0.859), angina pectoris (HR 0.566, 95% CI 0.343-0.936), and acute stroke (HR 0.661, 95% CI 0.46-0.951) than the non-GLP1RA group (mean age: 57.5±12). Otherwise, no significant difference was shown in acute myocardial infarction (HR 0.787, 95% CI 0.495-1.251), pulmonary hypertension (HR 0.777, 95% CI 0.55-1.099), or arrhythmias (HR 0.829, 95% CI 0.566-1.215). Conclusion: Compared to non-GLP1RA weight loss agents, GLP1RA offers better survival and cardiovascular protection for BC patients undergoing cardiotoxic therapies. Future studies are warranted to validate the safety of these weight loss drugs during the BC treatment continuum.

Abstract 4135984: Comparison of Immediate and Staged Complete Revascularization in STEMI Patients with Multivessel Disease: Meta-Analysis of Randomized Controlled Trial

Background: Patients diagnosed with ST-segment elevation myocardial infarction (STEMI) frequently present with multivessel coronary artery disease (CAD) at the time of primary percutaneous coronary intervention (PCI). The optimal timing of complete revascularization (CR) in these cases remains a subject of ongoing debate. Objective: To assess major cardiovascular outcomes and procedural complications in STEMI patients with multivessel CAD undergoing immediate versus staged CR post index procedure. Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing immediate to staged CR in STEMI and multivessel CAD. Trials were identified via a systematic search of MEDLINE, Embase, and Cochrane Libraries from database inception to March 6, 2024. The data were analyzed using RevMan software. Results: Among five RCTs (n=1,415) the majority of participants were male, the weighted mean follow-up duration across studies was 15.6 months. Immediate versus staged CR showed no significant differences in MACE (13.3% vs 9.8%; RR: 1.07, 95% CI [0.62, 1.83]), all-cause mortality (3% vs 4.55%; RR: 0.70, 95% CI [0.41, 1.21]), or MI (4.5% vs 2.6%; RR: 1.43, 95% CI [0.58, 3.55]). However, the staged group had higher unplanned revascularization incidence (8.6% vs 4.4%; RR: 1.92, 95% CI [1.21, 3.04]). Conclusion: Staged revascularization in STEMI patients with multivessel CAD demonstrates comparable effectiveness to immediate revascularization but leads to a greater number of unplanned revascularization procedures, likely due to delayed intervention. The early implementation of staged PCI during the initial hospitalization phase may provide equivalent efficacy to immediate complete revascularization. Nonetheless, further research is necessary to corroborate these findings.

Abstract 4129965: Efficacy of Sodium Glucose Cotransporter 2 Inhibitors In Patients With Acute Myocardial Infarction: A Meta-Analysis of Randomized Controlled Trials

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with or without type 2 diabetes and heart failure (HF). However, studies have shown conflicting evidence regarding their efficacy in patients following acute myocardial infarction (MI). We conducted a systematic review and meta-analysis to synthesize the available evidence regarding the effectiveness of SGLT2 inhibitors in MI. Methods: A systematic literature search was conducted using PubMed/MEDLINE, the Cochrane Library, and Embase databases to identify randomized controlled trials (RCTs) that compared clinical outcomes of SGLT2 inhibitors with placebo following MI. We conducted the statistical analysis using RevMan, version 5.4, and pooled risk ratios (RRs) along the corresponding 95% confidence interval (CI) for all outcomes. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Results: Five RCTs reporting data for 11,211 patients were included in our study. Our pooled analysis showed that SGLT2 inhibitors significantly reduced the risk of hospitalizations for heart failure (HHF) (RR = 0.76, 95% CI: 0.61-0.88, p = 0.001; high certainty). In terms of absolute effects, this translated to 12 fewer HHF per 1,000 patients who received SGLT2 inhibitors compared with the placebo (absolute risk difference 12 (95% CI 17 to 5) fewer per 1000 patients) in patients with MI. However, the risk of all-cause mortality (RR = 1.05, 95% CI: 0.78-1.41, p = 0.76; high certainty), cardiovascular (CV) mortality (RR = 1.04, 95% CI = 0.84-1.29, p = 0.73; high certainty), and all-cause hospitalizations (RR = 1.06, 95% CI: 0.96-1.17, p = 0.25; high certainty) remained comparable across the two groups. Conclusion: SGLT2 inhibitors reduce HHF without affecting all-cause mortality, CV mortality, and all-cause hospitalizations. However, further evidence is required to reach a definitive conclusion.

Evidence for Aldosterone Antagonism in Heart Failure

Activation of the renin–angiotensin–aldosterone system is the ultimate pathophysiological hallmark in heart failure. Though aldosterone primarily appears to regulate electrolyte homeostasis by acting on distal nephrons in the kidneys, its effects are far-reaching across the cardiovascular system as its receptors are also expressed in vascular smooth muscle cells, endothelial cells, macrophages and cardiomyocytes. Aldosterone excess leads to vascular stiffness, vasoconstriction, endothelial dysfunction, inflammation, oxidative stress, cardiac fibrosis and hypertrophy, atherogenesis and thrombosis. Hence, aldosterone antagonism is an attractive proposition for heart failure management. The first-generation non-selective mineralocorticoid receptor antagonist spironolactone produced a spectacular reduction of cardiovascular outcomes in the seminal RALES study, while the selective second-generation congener eplerenone boasts two positive studies: EPHESUS and EMPHASIS-HF. The TOPCAT trial indicated that a specific subgroup of patients with heart failure with preserved ejection fraction may benefit from targeted therapy of mineralocorticoid receptor antagonists. Newer-generation non-steroidal mineralocorticoid antagonists and aldosterone synthase inhibitors are being evaluated in randomised trials.

Abstract 4136600: Hypertensive disorders of pregnancy and the risk of Dementia, Alzheimer’s disease, and Vascular Dementia. A Systematic review and Meta-analysis of 25,03,538 women participants.

Background: Hypertensive disorders of pregnancy (HDP) are associated with maternal adverse cardiovascular outcomes. However, their association with maternal Dementia and Alzheimer’s disease is not well established with limited and conflicting results to date. Objective: We sought to evaluate the association between HDP and risk of incidence of Dementia, and Alzheimer’s disease. Methods: We performed a systematic review and meta-analysis of available literature that enrolled women with HDP and women without HDP groups. PubMed, Embase and ClinicalTrials.gov were systematically searched from inspection till May 2024 without any language restrictions. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) were pooled using a random-effect model. Results: A total of 8 studies with 2503538 patients (1,51,905 in women with HDP and 23,51,633 in the women without HDP group) were included. Pooled analysis shows that HDP women were having 37% higher risk of dementia (aHR, 1.37(95%CI: 1.27-1.46), P<0.001, I2=0%) when compared with women without HDP. Further pooled analysis showed that women with HDP were having 28% higher risk of Alzheimer’s disease (aHR, 1.28(95%CI: 1.56), P<0.001, I2=53.98%), and 2-fold higher risk of vascular dementia (aHR, 2.49(95%CI: 1.29-3.68), P<0.001, I2=71.51%) when compared with women without HDP. Conclusion: Women with HDP were at higher risk of developing Dementia, and Alzheimer's disease in future.

Abstract 4134345: Diastolic Dysfunction And The Risk Of Stroke And Major Bleeding

Background: Diastolic dysfunction (DD) is associated with adverse cardiovascular outcomes including atrial fibrillation. Whether DD is independently associated with incident ischemic stroke/transient ischemic attack (TIA) and with bleeding events is not well established. Aims: To examine the association of presence and severity of DD with the risk of incident ischemic stroke/TIA and major bleeding. Methods: A total of 219,667 patients who underwent at least one echocardiogram between 2010 and 2022 at a large academic institution and were followed for at least 3 months were included. Patients with prior history of stroke or TIA (n=21,505, 10%) were excluded. Smart key-phrase search was applied to echocardiographic reports to classify patients into 4 groups, based on the most severe DD assessment: Normal (n=113,265), grade I (n=21,981), grade II (n=7,215), and grade III (n=1,627). Patients in whom the presence of DD could not be determined (n=54,074) were excluded. The final study cohort (n=144,088) was followed to the endpoint of hospital admission for ischemic stroke/TIA or for major bleeding. Results: Over a median follow-up of 3.4 years, 3482 (2.4%) patients were hospitalized for stroke/TIA and 6994 (4.9%) for major bleeding. After adjusting for several confounding variables (Table), DD remained a strong predictor of incident stroke/TIA (hazard ratio (HR)=1.34 per grade increase in DD, p<0.001, Figure) and of major bleeding (HR=1.32 per grade increase in DD, p<0.001, Figure). These results were similar in patients with (n=11,508, 8%) or without prior history of atrial fibrillation. Conclusions: Patients with DD have a heightened risk of ischemic cerebrovascular accidents and major bleeding independent of the presence of atrial fibrillation. These risks escalate with the severity of DD. DD should be considered when counseling patients regarding their risk profile and management options.

Abstract 4135465: Efficacy of SGLT-2 inhibitors combined with percutaneous coronary intervention on clinical and echocardiographic parameters in patients with acute myocardial infarction: A systematic review and meta-analysis

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown benefits in improving cardiovascular outcomes in heart failure (HF) patients and may mitigate symptom progression in myocardial infarction (MI). However, their efficacy in acute MI patients undergoing percutaneous coronary intervention (PCI) is unclear. This study aims to evaluate whether SGLT2i combined with PCI improves clinical and echocardiographic outcomes. Methods: A comprehensive search of electronic databases, PubMed, Cochrane Central and SCOPUS was conducted from inception till May 2024. The study was conducted adhering to the PRISMA guidelines. The clinical benefit of PCI plus SGLT2i was assessed through risk reduction of acute kidney injury (AKI), CV death (CVD), hospitalization due to HF (hHF), all-cause mortality (ACM), and revascularization. Echocardiographic outcomes assessed were change in left ventricular ejection fraction (LVEF) and LV end-diastolic volume (LVEDV). Results were presented as risk ratios (RR) along with their 95% CI for dichotomous data while weighted mean difference (WMD) were reported for continuous outcomes. The data was aggregated using a random effects model. Results: Our analysis included eleven records comprising 6,411 participants. The results indicated that PCI plus SGLT2i significantly reduced the risk of AKI (RR: 0.66, 95% CI: [0.52, 0.83], p<0.01) and ACM (RR: 0.54, 95% CI: [0.4, 0.7], p<0.01) compared to PCI alone. However, the reduction in risk for CVD was not statistically significant (RR: 0.56, 95% CI: [0.2, 1.1], p=0.09), as was the case for hHF (RR: 0.65, 95% CI: [0.3, 1], p=0.07). Additionally, there was no significant difference in the risk of revascularization between the two groups (RR: 2.9, 95% CI: [0.62, 14.39], p=0.17). PCI plus SGLT2i was also significantly associated with an increase in LVEF (WMD: 2.73, 95% CI: [1.09, 4.36], p<0.01) and decrease in LVEDV (WMD: -8.0, 95% CI: [-13.17, -2.90], p<0.02). Conclusion: Our study demonstrates that SGLT2i administration in MI patients undergoing PCI leads to improved renal and mortality outcomes, along with enhanced cardiac function. These benefits are hypothesized to result from kidney-mediated natriuretic effects, improved blood flow regulation, reduced endothelial dysfunction, and decreased arterial stiffness, which optimize cardiac function. We recommend future studies with larger sample sizes and longer follow-ups to assess the long-term benefits of SGLT2i combined with PCI.

Abstract 4135968: Radiomic features of skeletal muscle on prostate T1-Weighted MRI associated with MACE outcomes in prostate cancer patients undergoing hormonal therapy

Background: Patients with high-risk prostate cancer (PC) who undergo hormonal therapy(HT) frequently die of major adverse cardiovascular events (MACE). Skeletal muscle on abdominal T1-weighted MRI (T1W) has been shown to be associated with cardiovascular fitness. Aims: To quantify heterogeneity associated with skeletal muscle tissue composition on prostate MRI patients undergoing HT using computationally derived radiomic features and identify their association with MACE. Methods: Cohort of N=58 men diagnosed with PC who underwent a 3 Tesla pre-treatment multi-parametric MRI followed by HT and followed up for MACE events were identified. MACE is defined as a composite of cardiovascular death, atrial fibrillation, myocardial infarction, ischemic stroke, heart failure, coronary artery disease, and peripheral vascular disease. Regions of interest (ROI) of skeletal muscle, including the obturator externus, pectineus, and the adductor group of muscles, were delineated on axial T1W under the guidance of an experienced radiologist. A set of 120 radiomic features, including gray level statistics, co-occurrence, wavelet, and texture energy-based features, were extracted within the ROI which quantifies underlying subvisual texture-based heterogeneity. Radiomics associated with MACE events were identified using the Wilcoxon rank-sum test and univariate Cox-regression (p<0.05). Results: Of the N=58 patients included in this study, 18 experienced MACE. The most common MACE event was AF (8.6%). Median-time-to-MACE event was 7.3 years (6.2-8.2). 3 radiomic features (Table 1) quantifying the heterogeneity of skeletal muscle on prostate T1W were observed to be associated with MACE. Specifically, we observe that first order features have a lower response and wavelet features have a lower response in MACE patients which suggests a higher degree of local deformations and heterogeneity in skeletal tissue compared to non-MACE patients. Conclusions: Results from our study suggest that radiomics quantified texture characteristics of skeletal muscle tissue may indicate cardiovascular fitness, reflecting the likelihood of experiencing MACE following initiation of HT in PC men. Pre-treatment identification of PC patients at high risk of MACE may allow for alternative treatment options improving cardiovascular outcomes. Future studies will involve exploring larger, multi-site cohorts and machine learning modeling to determine cardiovascular risk.

Abstract 4115541: Association of Glucagon-like Peptide 1 Receptor Agonist Use with Incident Atrial Fibrillation

Background: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have shown efficacy for reducing cardiovascular morbidity and mortality in patients with diabetes mellitus (DM), but conflicting evidence exists regarding their impact on cardiac arrhythmias. Whereas some studies suggested a possible association between GLP-1RA use and arrhythmogenesis, other studies suggested decreased association with atrial fibrillation (AF). Overall, large-scale real-world data evaluating risk of AF in association with GLP-1RAs are lacking. Objective: To compare risk of incident AF after initiation of GLP1-RA vs Dipeptidyl peptidase-4 inhibitors (DPP4i), as active comparators, in patients with DM. Methods: This retrospective propensity score-matched cohort study was conducted within the Veterans Health Administration from fiscal years 2006 to 2021. The study included U.S. veterans aged 35 years or older who initiated either GLP1-RA or DPP4i prescriptions. The primary outcome assessed was a composite outcome of atrial fibrillation (AF), defined as a diagnosis of AF/flutter based on administrative codes or undergoing an AF procedure. Results: Out of 116,235 GLP1-RA users and 217,668 DPP4i users, we propensity score-matched 80,948 pairs, on 88 characteristics, including demographics, comorbidities, vital signs, cardiovascular risk score, healthcare utilization, DM control, laboratory investigation, and medications. Composite outcome of AF was similar in GLP-1RA group (4.1%) and DPP4i group (4.3%); odds ratio (OR) 0.96, 95% confidence interval (CI) 0.92-1.01. Secondary analyses stratified by medication use duration showed no significant differences in composite AF risk (P>0.05). Notably, individuals achieving weight loss of 2%, 5%, or 10% of baseline body weight had significantly lower AF incidence, whereas no significant differences were observed in those with no weight loss or weight gain (OR 0.99, 95% CI 0.91-1.07). Conclusions: Use of GLP1-RA in patients with DM was not associated with a decreased risk of AF when compared with the use of DPP4i. In the subgroup analysis, significantly lower AF risk was seen in the GLP-1 RA group who achieved weight loss vs. DPP4i and this highlights weight loss as a potential modifier of cardiovascular outcomes in DM.

Abstract 4124690: Effect of Colchicine on the Perivascular Inflammation Index of Coronary Computerized Tomography Angiogram: COPIX trial

Inflammation is an important pillar of atherogenesis in coronary disease. Studies have documented the prognostic power of measuring the attenuation of coronary perivascular adipose tissue (PVAT) and its good correlation as an early inflammatory biomarker in the atherogenesis process. Colchicine, a medication with well-documented anti-inflammatory action and with an impact on reducing cardiovascular outcomes, may influence reducing FAI (Fat Attenuation index) assessed by coronary tomography angiography. This study aims to evaluate the effect of colchicine in reducing coronary inflammation after 12 months of using the medication. Methods: Single- center, randomized, prospective, open, ongoing study, carried out at the Heart Institute of the University of São Paulo (InCor HCFMUSP). Forty patients with documentation of FAI ≥ 70 HU in the right coronary artery (RCA) and/or left descending artery (LAD) were randomized to receive colchicine 0.5 mg/day for a period of 12 months. The primary outcome was the quantification of FAI in both therapeutic groups (colchicine and control) after a 12-month follow-up. As a secondary outcome, we evaluated the variation in total atheroma volume, calcium score, progression or regression of high plaque findings, variation low attenuation plaque volume and clinical outcomes. Results: Forty patients were included between May 2021 to April 2023, of which 22 were in the Colchicine group and 18 in the Control group. As a primary outcome, no FAI improvement in RCA and LAD was documented after a 12-month follow-up. In the Colchicine group, the mean FAI in initial LAD of −70.37 ± 7.1 HU improved to −72.90 ± 6.2 HU, but without statistical significance (p = 0.82) and Control group −69,13 ± 7,7 HU to −71,73 ± 6,3 HU (p= 0,64). FAI RCA from − 67.69 ± 5.4 HU to −71.23 ± 4.7 HU, without significance (p = 0.10) in Colchicine group and – 65,48 ± 5,5 HU to −69,08 ± 7,8 HU (p = 0,19) in control group. Conclusion: To date, a total of 40 patients have been randomized. In this interim analysis, with 50% of the sample already undergoing control coronary CT angiography, no association was observed with the use of colchicine and improvement in coronary inflammation after 12 months of using the medication.

Abstract 4121215: Efficacy and Safety of Empagliflozin in Patients with Acute Myocardial Infarction: A meta-analysis of randomized controlled trials

Background: Empagliflozin is a sodium glucose co-transporter 2 inhibitor that improves cardiovascular outcomes in patients with type 2 diabetes mellitus, chronic kidney disease and heart failure. Less is known about the efficacy and safety of empagliflozin in patients after acute myocardial infarction. Methods: PubMed, Embase and Cochrane databases were searched for randomized controlled trials (RCTs) that reported the outcomes of interets including all-cause mortality, death from cardiovascular causes, hospitalization due to heart failure etc. Risks ratios (RR) or mean difference (MD) and their 95% confidence intervals (CIs) were computed with the use of random-effect model. Heterogeneity was examined with I 2 statistics. Results: We included 12 RCT articles consisting of 23,178 patients that received empagliflozin after acute myocardial infarction were considered. Empagliflozin was associated with significantly reduced incidence of all-cause mortality (RR 0.72; 95% CI [0.61, 0.85]; P < 0.0001; 5.9% vs 7.4%), death from cardiovascular causes (RR 0.66; 95% CI [0.52, 0.83]; P = 0.0004; 4.0% vs 5.4%), and hospitalization for heart failure (RR 0.66; 95% CI [0.58, 0.76]; P < 0.00001; 3.2% vs 4.7%), acute kidney injury (RR 0.52; 95% CI [0.31, 0.86]; P = 0.01), acute renal failure (RR 0.71; 95% CI [0.55, 0.91]; P = 0.008), adverse events leading to discontinuation (RR 0.89; 95% CI [0.80, 0.99]; P = 0.03), systolic blood pressure (MD -8.59; 95% CI [-13.26, -3.93], P = 0.0003), and thromboembolic events (RR 0.51; 95% CI [0.28, 0.92]; P = 0.03) compared to placebo. However, there was no significant difference between groups with respect to fatal or nonfatal stroke (RR 1.15; 95% CI [0.91, 1.46]; P = 0.23), adverse events leading to lower limb amputation (RR 1.11; 95% CI [0.62, 1.99]; P = 0.73), estimated glomerular filtration rate (MD 0.45; 95% CI [-0.20, 1.10]; P = 0.17), diastolic blood pressure (MD -2.53; 95% CI [-5.40, 0.34]; P = 0.08), body weight (MD -1.04; 95% CI [-4.08, 1.99]; P = 0.50), urinary tract infection (MD 1.04; 95% CI [0.92, 1.17]; P = 0.55), NT- proBNP (MD -115.93; 95% CI [-271.52, 39.66]; P = 0.14), glycated hemoglobin (MD -0.10; 95% CI [-0.41, 0.22]; P = 0.55), and hypoglycemia (RR 0.98; 95% CI [0.89, 1.08]; P = 0.70). Conclusion: Our findings suggest that empagliflozin has superior efficacy and safety compared to placebo for the treatment of patients with acute myocardial infarction with no impact on UTI, eGFR, NT-proBNP, and hypoglycemia.

Abstract 4136930: Plasminogen Activator Urokinase Receptor (PLAUR) Levels are a Predictor of Adverse Cardiovascular Outcomes in the General Population, Independent of High-Sensitive CRP (hs-CRP)

Background: The gene Plasminogen Activator Urokinase Receptor (PLAUR) encodes the urokinase plasminogen activator surface receptor (uPAR), which upon cleavage releases Soluble Urokinase Plasminogen Activator Receptor (suPAR). SuPAR has emerged as a novel biomarker of inflammation and immunity and is associated with adverse cardiovascular events, particularly coronary artery disease (CAD), regardless of hs-CRP levels, a well-established inflammatory biomarker. However, whether the PLAUR gene predicts adverse cardiovascular events remains uncertain. Methods: We investigated the relationship between PLAUR levels, measured via Olink Immunoassay, in 40,790 individuals from the UK Biobank, and the occurrence of adverse cardiovascular events such as myocardial infarction (MI), as well as all-cause and cardiovascular mortality. Our analysis involved the use of Cox and Fine and Gray proportional hazards models, adjusting for age, sex, race, HDL, LDL, triglyceride levels, BMI, prevalence of hypertension (HTN), prevalence of type 2 diabetes (T2D), smoking history, and use of blood pressure and cholesterol medications. Main Outcomes: The primary outcome was a composite outcome of cardiovascular mortality and MI and the secondary outcome was all-cause mortality. Results: The mean (SD) age was 58 (8) years, 45% men and 94% white. During a median follow-up of 14 (interquartile range 12.3 – 15) years, 7.9% of the population had an MI, 2.7% suffered cardiovascular death, 9.5% all-cause mortality. After adjusting for aforementioned demographic and clinical factors, as well as medication usage, each standard deviation increase in PLAUR levels was associated with a heightened risk of incident non-fatal MI and cardiovascular (CV) death, with a hazard ratio (HR) of 2.31 (95% CI 2.00-2.45), and all-cause mortality, with an HR of 3.81 (95% CI 3.48-4.18). Even after further adjustment for hs-CRP levels, PLAUR levels remained predictive of non-fatal MI and CV death (HR 2.03, 95% CI 1.83-2.26) and all-cause mortality (HR 3.43, 95% CI 3.12-3.77). Furthermore, in a fully adjusted Cox regression model, a significant interaction between PLAUR levels and sex (p = 0.0003) was observed in predicting the primary outcome. The interaction was found to have a stronger predictive value in females compared to males. Conclusion: PLAUR levels are a strong predictor of adverse cardiovascular outcomes in the general population, independent of traditional risk factors and inflammation.

Abstract 4138633: Infusion of human apolipoprotein A-I (CSL112) promotes several aspects of reverse cholesterol transport

Background: High-density lipoprotein (HDL)-cholesterol is inversely correlated with cardiovascular risk, but increasing its circulating concentration is insufficient to prevent adverse cardiovascular outcomes. Instead, the emerging paradigm is on increasing the function of HDL and its major protein constituent apolipoprotein A-I (apoA-I), to increase reverse cholesterol transport. Objective: To investigate the effect of apoA-I [human] (CSL112) infusion on HDL protein composition, and provide further insights into the mechanism of action of CSL112 administered post-acute myocardial infarction (AMI). Methods: A mass spectrometry (MS)-based proteomic approach was used to evaluate changes in HDL protein composition in patients (n=50) from the AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) study who received either placebo or CSL112 post AMI. HDL was immuno-isolated from patient plasma using anti-apoA-I antibodies. Cholesterol esterification rate (CER) was measured to determine lecithin-cholesterol acyl transferase (LCAT) activity. Cholesterol efflux capacity (CEC) and hepatocyte uptake were assessed using patient serum in ex vivo cell-based assays. Results: CSL112 induced extensive rearrangement of HDL proteins at 4 hours post-infusion. Levels of apolipoproteins A2, B, C, and E as well as the acute phase proteins serum amyloid A1 and A4 were significantly reduced. By contrast, apoA-I, apoM, and LCAT significantly increased. Elevated apoA-I and LCAT levels on HDL were associated with an increase in CEC, plasma HDL-C levels, and CER in CSL112-treated patients. Furthermore, enhanced CEC strongly correlated with cholesterol uptake by hepatic cells (r=0.95 p<0.001). Conclusion: CSL112 altered HDL composition and increased HDL functionality by promoting multiple steps of the reverse cholesterol transport pathway.

Abstract 4119992: 12-lead electrocardiograms predict adverse cardiovascular outcomes of emergency department patients

Introduction: Chest pain is a common cause for presentation to the emergency department (ED). Identifying patients at increased risk of adverse cardiovascular outcomes may help guide testing. Aims: We sought to determine if deep learning enabled 12-lead electrocardiogram (ECG) analysis may improve prediction of adverse cardiovascular outcomes of ED patients presenting with chest pain compared to conventional approaches. Methods: A pretrained convolutional neural network was applied to derive numerical representations of the index ECG waveforms from patients presenting to the Brigham and Women’s Hospital (BWH) ED with chest pain. We trained a neural network model (‘CP-AI’) to predict 30-day major adverse cardiovascular events (MACE) defined as myocardial infarction (MI), pulmonary embolism (PE), aortic dissection (AD), or mortality using age, sex, cardiac biomarkers (troponin and d-dimer), and the numerical ECG representations as inputs ( Figure 1 ). In a holdout sample of Massachusetts General Hospital (MGH) ED patients, we compared the performance of the CP-AI model to alternative models fit on (1) demographics (‘Age and Sex’) (2) demographics + cardiac biomarkers (‘Biomarker Model’), and (3) demographics + numerical ECG representations (‘ECG Model’). Results: The BWH derivation sample included 18,811 individuals (51% female, mean age 65 ± 16 years). The MGH validation sample included 14,476 individuals (45% female, mean age 65 ± 15 years). The CP-AI model significantly outperformed the comparison models for prediction of 30-day MACE with an area under the receiver operating characteristic curve (AUROC) of 0.82 [95% CI 0.81-0.83] ( Figure 1 ). CP-AI also significantly outperformed the comparison models for classification of the 30-day MACE components including MI (AUROC 0.91 [95% CI 0.90-0.92]), PE (AUROC 0.74 [95% CI 0.72-0.76]), and mortality (AUROC 0.86 [95% CI 0.85-0.87]), but not aortic dissection (0.71 [95% CI 0.68-0.75]). Conclusions: The integration of deep learning ECG analysis with conventional assessment improved prediction of adverse cardiovascular of ED patients presenting with chest pain.

Abstract 4129453: Comparing Cardiovascular Outcomes in Patients with Lyme Disease and Babesiosis: A Retrospective Cohort Study

Intro: In the U.S, Lyme disease and Babesiosis are among the four most common tick-borne illnesses, with an annual average of 36,000 and 2200 cases respectively from 2016-2019. Both have cardiac involvement; 1% of lyme disease cases result in lyme carditis, while babesiosis is associated with arrhythmias and heart failure. Little research has explored the comparative risk of developing cardiac complications between the two. This study investigates cardiovascular complications in cases of Lyme and Babesiosis. Methods: We conducted a retrospective cohort study utilizing data from the TriNetX database and the US Collaborative Network, which together cover 60 healthcare organizations providing real-world electronic health records. We included all individuals diagnosed with either Lyme disease (Cohort A, pre-match n = 317368/post-match n = 4115 ) or babesiosis (Cohort B, pre-match n=4173/post-match n = 4115), identified using ICD-10-CM codes. Patients under 18 years of age, diagnosed with both diseases, or with incomplete follow-up data were excluded. We employed propensity score matching to adjust for age, race, sex, and other clinical parameters to compare the two cohorts equitably. We focused on 4 key outcomes over a 5-year period: arrhythmias, the need for PPM implantation, ACS and HF, utilizing both risk analysis and Kaplan-Meier survival analysis. Results: Interestingly, patients with babesia exhibited a greater likelihood of developing HF (OR: 1.279, 95% CI (1.073,1.524)). The development of arrhythmias between the two groups was not statistically significant with an OR of 1.013 (95% CI (0.837, 1.227)). The need for PPM implantation was not statistically significant between the two groups with an OR of 1.269 (95% CI (0.785, 2.052)). The risk of developing ACS was not statistically significant with an OR of 1.103 (95% CI (0.838, 1.451)) . Conclusion/Discussion: Our findings indicate that patients with babesiosis have a higher likelihood of developing HF compared to those with lyme disease. Surprisingly, there were no significant differences in the rates of arrhythmias or pacemaker implantations between the two cohorts. These results suggest that while overall cardiovascular risks are comparable between the groups, the increased risk of HF in babesiosis needs to be further explored.

Abstract 4126650: Prognostic Value of Femoral-Ankle Pulse Wave Velocity for Cardiovascular Outcomes in Older Adults: The Atherosclerosis Risk in Communities (ARIC) study

Background: Carotid-femoral pulse wave velocity (cfPWV) is a representative measure of central arterial stiffness and an independent predictor of cardiovascular disease (CVD). Femoral-ankle PWV (faPWV) represents peripheral arterial stiffness, but its association with CVD has not been specifically studied. Aim: To compare faPWV and cfPWV regarding their associations with CVD outcomes. Methods: We analyzed 3,402 ARIC participants without prior heart failure (HF), coronary heart disease (CHD), or stroke at visit 5 (2011-13) (mean age 74.8 [SD 4.9] years, 36.1% male, and 78.0% White). faPWV and cfPWV were measured by Omron VP-1000 Plus. The outcomes of interest were composite and individual outcomes of CVD (HF, CHD, and stroke). We ran unadjusted and multivariable Cox proportional hazards models. Results: During a median follow-up of 9.0 years, there were 607 CVD events. Overall, faPWV showed an inverse association with CVD (Table). P-for-trend reached statistical significance in Models 1 and 2 and was borderline significant in Model 3 (p=0.077). In contrast, as anticipated, cfPWV was positively associated with CVD in all Models, although the association was somewhat attenuated in Model 3 (p-for-trend=0.045 and hazard ratio [HR] for top vs. bottom quartile 1.22 [95%CI 0.95-1.56]). Given their opposite patterns, we explored the ratio of cfPWV and faPWV (“cf/fa ratio”) and found that its association with CVD appeared stronger (p-for-trend=0.004 and HR for top vs. bottom quartile 1.37 [1.08-1.74]) than cfPWV. When each CVD subtype was examined separately, HF showed most consistent associations with our stiffness measures, and only the cf/fa ratio remained significant for HF up to Model 3 (p-for-trend=0.010 and HR for top vs. bottom quartile 1.40 [1.03-1.90]). Conclusions: faPWV was inversely associated with CVD, and cf/fa ratio appeared more strongly associated with CVD compared to cfPWV. Our findings indicate distinct prognostic implications of central vs. peripheral arterial stiffness and suggest cf/fa ratio as a new stiffness measure predicting CVD.

Abstract 4113573: Long Noncoding RNAs to Predict COVID-19 Neuro-Cardio-Vascular Outcomes

Introduction/Background: Cardiovascular and neurological diseases develop in a significant proportion of COVID-19 patients. Minimally invasive tools to predict outcome after SARS-CoV-2 infection would enable personalized healthcare, potentially easing the disease burden. We showed that blood levels of the long noncoding RNA lymphoid enhancer-binding factor-1 antisense 1 (LEF1-AS1) predict COVID-19 in-hospital mortality. Hypothesis: LEF1-AS1 is associated with long-term clinical outcomes of COVID-19. Aim: Test the capacity of LEF1-AS1 to predict neuro-cardio-vascular outcomes post-SARS-CoV-2 infection. Methods/Approach: We enrolled 104 primo-infected COVID-19 patients aged 18+ recruited from April to December 2020 in the PrediCOVID national cohort for which 12-month follow-up data were available (Ethics Committee approvals 202003/07 and 202310/02-SU-202003/07). Whole blood samples were collected at baseline and expression levels of LEF1-AS1 were assessed by quantitative PCR. Results/Data: Of the 104 patients, 35 had at least one neurological symptom and one cardiovascular symptom at month 12. Levels of LEF1-AS1 at baseline were lower (p=0.019) in patients who developed neurological and cardiovascular symptoms as compared to patients who did not. Lower LEF1-AS1 was associated with symptoms development with an odds ratio of 0.48 (95% CI 0.28-0.83) from logistic regression model adjusted for age, sex, comorbidities and disease severity at baseline. Addition of LEF1-AS1 to a clinical model including age, sex, comorbidities and baseline severity yielded an incremental predictive value as attested by an increased AUC from 0.79 to 0.83 (likelihood ratio test p=0.005), a net reclassification index of 0.54 (p=0.007) and an integrated discrimination improvement of 0.08 (p=0.009). Conclusion: Blood levels of LEF1-AS1 predict 12-month neurological and cardiovascular outcomes of COVID-19 patients. This needs to be validated in larger populations.

Incidental Coronary Artery Calcification and the Risk of Major Adverse Cardiovascular Outcomes

Incidental Coronary Artery Calcification and the Risk of Major Adverse Cardiovascular Outcomes