Journal of the American College of Cardiology

Background: Despite optimal lipid-lowering and antithrombotic therapy, substantial residual cardiovascular risk persists in established atherosclerotic cardiovascular disease (ASCVD), partly driven by chronic vascular inflammation. Methods: Systematic review and meta-analysis of RCTs comparing colchicine to placebo or no treatment in adults with established ASCVD. Searches on March 21, 2026 (PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP). PROSPERO CRD420261346516. Primary outcome: 4-point MACE (CV death, MI, stroke, urgent revascularization). DerSimonian-Laird random-effects with HKSJ adjustment. Exploratory trial-level meta-regression: time-to-initiation (TTI) and cumulative dose as continuous moderators. Results: DL pooled HR for 4-point MACE: 0.68 (95% CI 0.51-0.89; p=0.0060). HKSJ-adjusted HR: 0.68 (95% CI 0.27-1.70; p=0.3018). Substantial heterogeneity (I2=81.4%; 95% prediction interval 0.29-1.57, crossing 1.0). Exploratory meta-regression: TTI (beta=-0.00187/day, p=0.003) and cumulative dose (beta=-0.00163/mg-day, p=0.0003; k=5, explicitly underpowered). Non-CV mortality: HR 1.07 (0.76-1.50; p=0.694). GI discontinuation: pooled RR 1.95 (1.09-3.48; p=0.024). GRADE certainty: Moderate (4-point MACE). Conclusions: Low-dose colchicine is associated with reduced 4-point MACE in ASCVD (DL HR 0.68; HKSJ HR 0.68). The substantial heterogeneity and wide prediction interval indicate that effect size varies substantially across clinical settings. The divergence between CLEAR SYNERGY (acute; HR 0.99) and sub-acute/chronic trials (HR 0.33-0.77) drives heterogeneity. Meta-regression suggests TTI and cumulative exposure may be key moderators but is underpowered. The non-CV mortality signal is not confirmed. This analysis informs precision anti-inflammatory prescribing in ASCVD.

BackgroundAortic valve replacement (AVR), through transcatheter (TAVR) or surgical (SAVR) means, serves as a pivotal therapeutic approach for severe aortic stenosis (AS). While both modalities show advantages over conservative management, the long-term mortality benefits post-AVR, especially when comparing TAVR with SAVR, remain uncertain. ObjectivesThis study aimed to perform an in-depth meta-analysis of randomized controlled trials (RCT) comparing TAVR versus SAVR, as well as their outcomes against conservative management. MethodsElectronic databases were searched up to December 7, 2023. Individual patient data extracted from Kaplan-Meier plots, underwent pooling and modeling with stratification by surgical risk. The primary endpoint was all-cause mortality at 5 years. ResultsThe study included eleven RCTs and twelve non-RCTs, encompassing 4215 patients undergoing TAVR, 4017 undergoing SAVR and comparing 11,285 AVR patients with 23,358 receiving conservative management. TAVR exhibited significantly lower all-cause mortality at 6 months (HR 0.62, 95% CI: 0.52-0.74) compared to SAVR, with no significant difference beyond 6 months (HR 1.08, 95% CI: 0.98-1.19). Additionally, over a 5-year period, there were no significant disparities in cardiovascular mortality (HR 0.98, 95% CI: 0.83-1.16) or stroke (HR 1.02, 95% CI: 0.75-1.38) between TAVR and SAVR, while TAVR exhibited a notable advantage with a markedly reduced risk of cardiovascular mortality in the initial 6 months (HR 0.64, 95% CI: 0.46-0.87) and stroke within the first month post-procedure (HR 0.31, 95% CI: 0.19-0.51). Furthermore, the mean aortic valve area and pressure gradient remained comparable between TAVR and SAVR, exhibiting stability throughout the 5-year follow-up period. AVR markedly reduced all-cause mortality compared to medical therapy (P < 0.001), with 5-year crude mortality rates of 31.6% versus 49.3%, and a difference in restricted mean survival time of 8.9 months. Similar outcomes were observed across high, intermediate, and low surgical risk categories. ConclusionsWhile TAVR demonstrated early mortality reduction compared to SAVR, no distinctions emerged in the overall 5-year follow-up, regardless of surgical risk. AVR notably improved survival over conservative therapy. This study advocates for the preference of TAVR or SAVR in severe AS patients when feasible.

BackgroundAbdominal aortic aneurysm (AAA) represents a significant cause of mortality, yet no medical therapies have proven efficacious. The aim of the current study was to leverage human genetic evidence to inform clinical development of interleukin-6 (IL6) signaling inhibition for treatment of AAA. MethodsWe focused on rs2228145, a missense variant in the IL6R gene region whose associations are expressed per additional copy of the C allele, corresponding to the genetically-predicted effect of IL6 signaling inhibition. We consider genetic associations with AAA risk in the AAAgen consortium (39,221 cases, 1,086,107 controls) and UK Biobank (2215 cases, 365,428 controls). To validate against known effects of IL6 signaling inhibition, we present associations with rheumatoid arthritis, polymyalgia rheumatica, and severe COVID-19. To explore mechanism specificity, we present associations with thoracic aortic aneurysm, intracranial aneurysm, and coronary artery disease. We further evaluated associations with measures of the abdominal aorta in UK Biobank, and explored genetic associations in clinically-relevant subgroups of the population. ResultsWe observed strong genetic associations with AAA risk in the AAAgen consortium and in UK Biobank: odds ratio (OR) 0.91 (95% confidence interval [CI]: 0.90 to 0.92, p = 4x10-30) and OR 0.90 (95% CI: 0.84, 0.96, p=0.0007), respectively. The association with AAA risk in UK Biobank was linear in the number of minor alleles: OR 0.91 (95% CI: 0.83, 1.00) in heterozygotes and OR 0.80 (95% CI: 0.71, 0.92) in minor homozygotes. The association was similar for fatal AAA, but with greater uncertainty due to the lower number of events. The association with AAA was of greater magnitude than associations with coronary artery disease and even rheumatologic disorders for which IL6 inhibitors have been approved. No strong associations were observed with thoracic aortic aneurysm, intracranial aneurysm, or abdominal aorta diameter in the general population without AAA. Associations attenuated towards the null in populations with concomitant inflammatory or connective tissue disease. ConclusionsThis drug target Mendelian randomization study supports that IL6 signaling inhibition will be efficacious for treating AAA, but not other types of aneurysmal disease. These findings serve to help inform clinical development of IL6 signaling inhibition for AAA treatment.

BackgroundLeft atrial appendage closure (LAAC) and direct oral anticoagulants (DOACs) have emerged as alternatives to warfarin for stroke prevention in atrial fibrillation (AF). However, recent trials have shown variable results igniting the debate on this topic. MethodsWe performed a systematic review and network meta-analysis (NMA) of RCTs comparing LAAC, DOACs, and warfarin in patients with AF. The primary efficacy outcome was ischemic stroke or systemic embolism (IS/SE) and the primary bleeding outcome was hemorrhagic stroke (HS). Secondary outcomes included net adverse clinical events (NACE) and major or clinically relevant bleeding (MCRB). Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using a random-effects model. ResultsTen RCTs (LAAC: 6 trials; DOAC: 8 trials; warfarin: 6 trials) enrolling 78,594 patients fulfilled the inclusion criteria. There were no significant differences for the primary efficacy outcome of IS/SE among the 3 strategies. However, when compared with warfarin, both DOACs (OR 0{middle dot}43, 95% CI 0{middle dot}34-0{middle dot}54) and LAAC (OR 0{middle dot}34, 95% CI 0{middle dot}18-0{middle dot}63) reduced the primary safety outcome of HS, with no significant difference between them (OR 0{middle dot}79, 95% CI 0{middle dot}44-1{middle dot}3). For NACE, both DOACs (OR 0{middle dot}87, 95% CI 0{middle dot}83-0{middle dot}91) and LAAC (OR 0{middle dot}85, 95% CI 0{middle dot}73-0{middle dot}99) were superior to warfarin, with similar performance between them (OR 0{middle dot}98, 95% CI 0{middle dot}84-1{middle dot}13). For MCRB, DOACs were superior to warfarin (OR 0{middle dot}79, 95% CI 0{middle dot}63-0{middle dot}99), while LAAC showed a non-significant trend towards benefit. ConclusionIn this meta-analysis of RCTs with data from over 78,000 patients, LAAC and DOACs significantly reduced NACE driven by lower hemorrhagic stroke and provided equivalent IS/SE protection compared with warfarin, making LAAC a potential viable alternative to oral anticoagulation in appropriately selected AF patients. FundingNone.

Background Non-vitamin K antagonist oral anticoagulants (NOACs) are the guideline-recommended standard for stroke prevention in atrial fibrillation (AF), yet bleeding risks limit real-world adherence. Percutaneous left atrial appendage closure (LAAC) offers a mechanical alternative without definitive comparative synthesis. Objectives To evaluate percutaneous LAAC versus NOAC therapy by synthesizing all contemporary NOAC-era randomized controlled trials (RCTs). Methods Five databases and registries (PubMed, MEDLINE, Embase, Cochrane CENTRAL, ClinicalTrials.gov) were searched from inception to 8 May 2026 for RCTs comparing percutaneous LAAC against NOACs in adults with non-valvular AF. Risk of bias was assessed using Cochrane RoB 2. Ischemic stroke was pooled using a random-effects DerSimonian-Laird model; primary efficacy composite and non-procedural bleeding were evaluated via pre-specified narrative synthesis. Results Four RCTs (CHAMPION-AF, OPTION, PRAGUE-17, CLOSURE-AF) comprising 5,890 patients were included. LAAC achieved noninferiority for the primary efficacy composite in three trials and demonstrated a statistically significant 45-56% reduction in non-procedural bleeding across the three moderate-risk trials. CLOSURE-AF did not meet noninferiority but retained a directionally consistent bleeding reduction. Pooled ischemic stroke analysis (HR 1.31; 95% CI 0.96-1.80; I^2=0%) showed no statistically significant increase in stroke risk, though a consistent directional trend toward more ischemic events was observed. Conclusions LAAC significantly reduces non-procedural bleeding in moderate-risk AF patients, though this benefit attenuates in very high-risk populations. A consistent, statistically nonsignificant ischemic stroke trend and population-dependent efficacy establish LAAC as a shared decision-making alternative to NOACs rather than a universal replacement, pending 5-year CHAMPION-AF data.

BackgroundSodium-glucose co-transporter 2 (SGLT2) inhibitors have emerged as a cornerstone of heart failure (HF) therapy, yet the totality of randomized evidence -- including smaller trials -- has not been comprehensively synthesized. We aimed to evaluate the efficacy and safety of SGLT2 inhibitors across the full spectrum of HF. MethodsWe searched PubMed, Cochrane CENTRAL, ClinicalTrials.gov, and WHO ICTRP from inception to March 2026 for randomized controlled trials comparing any SGLT2 inhibitor with placebo or standard care in adults with HF. Primary outcomes were all-cause mortality (ACM) and HF hospitalization (HFH). We used random-effects models with Mantel-Haenszel risk ratios and Hartung-Knapp-Sidik-Jonkman confidence intervals. Certainty of evidence was assessed using GRADE. The protocol was registered prospectively (PROSPERO CRD420251167908). ResultsOf 6,239 records identified, 114 studies met inclusion criteria and 59 RCTs (29,692 participants) were included in quantitative synthesis. SGLT2 inhibitors significantly reduced ACM (RR 0.90 [0.83, 0.98], p = 0.016; 26 trials; I2 = 0%; low certainty) and HFH (RR 0.74 [0.69, 0.79], p < 0.001; 15 trials; I2 = 0%; moderate certainty). The composite of CVD and HFH was reduced (RR 0.80 [0.75, 0.85], p < 0.001; high certainty). Genital infections were significantly increased (RR 3.75 [1.72, 8.19], p = 0.007). Results were robust across 12 sensitivity analyses and 4 alternative statistical models. ConclusionsSGLT2 inhibitors reduce all-cause mortality, HF hospitalization, cardiovascular death, and serious adverse events in adults with HF, with an acceptable safety profile apart from increased genital infections. These findings support the use of SGLT2 inhibitors as a foundational therapy across the HF spectrum.

Bicuspid aortic valve (BAV) is the most common congenital heart malformation and predisposes to thoracic aortic aneurysms. The Montalcino Aortic Consortium (MAC) registry collects genetic and phenotypic data on individuals with heritable thoracic aortic disease genes (HTAD PVs) that primarily regulate smooth muscle cell contraction or TGF-{beta} signaling (TGF-{beta} PVs, termed Loeys-Dietz Syndrome (LDS)). We evaluated associations between BAV, HTAD PVs and aortic outcomes in the MAC cohort. BAV was present in 48 (6%) of 816 MAC participants (age 38 [IQR 20-52] years, 51% female) and was not significantly increased in males or in the entire TGF-{beta} PV group (417 with TGF-{beta} PVs, p=0.14) but was enriched in participants with TGFBR1 or TGFBR2 PVs (16/168, 10% vs. 32/648, 5%, PR 1.93 [1.08, 3.43], p<0.05). BAV was associated with aortic regurgitation (AR, 17/46, 37% vs. 84/752, 11%, PR 3.3 [2.2-5.1], P<0.001), younger age at first aortic event (24 vs. 40 years, p<0.001), primarily reflecting increased proximal aortic repair (27/48, 56% vs. 227/768, 30%, PR 1.90 [1.45, 2.50], P<0.0001), but not aortic dissection (6/48, 13% vs. 134/768, 18%, P>0.5). Sinus of Valsalva dilation (Z>3, 25/48, 52% vs. 128/768, 17%, P<0.0001) and ascending aorta dilation (Z>3, 12/48, 25% vs. 26/768, 3%, P<0.0001) were more common in participants with BAV. Participants with both TGF-{beta} PV and BAV more frequently had aortic valve surgery (17/30, 57% vs. 110/387, 28%, PR 1.99 [1.40-2.83], p<0.01) and sinus of Valsalva dilation (20/29, 69% vs. 91/258, 35% PR 1.96 [1.40-2.63], p<0.001), but not ascending dilation, than participants with TGF-{beta} PV who did not have BAV. BAV is enriched in individuals with HTAD PV, most prominently in the subgroup with LDS TGFBR1 and TGFBR2, and is associated with accelerated aortic valve and aortic diseasebut does not confer an increased risk for aortic dissection. These observations highlight the potential benefits of genetic testing for BAV patients who have a family history of HTAD, a sinus of Valsalva aneurysm, or clinical features suggestive of LDS.

ImportanceGlucagon-like peptide-1 (GLP-1) agonists have been proven beneficial in reducing risk of and injury associated with several cardiovascular diseases. The efficacy in cardiopulmonary bypass (CPB)-assisted cardiac surgery is unknown. ObjectiveThis trial aimed to investigate the efficacy of an infusion of the GLP-1 antagonist Exenatide during and after open heart surgery in reducing risk of death and major organ failure. DesignRandomized, double-blinded, 2-by-2 factorial design, clinical trial, also including liberal (FiO2 of 100%) or restrictive (FiO2 of 50%) oxygenation during and after bypass. The present paper presents the results of the Exenatide intervention. SettingSingle site, tertiary heart center. ParticipantsAdult patients undergoing elective cardiopulmonary bypass-assisted coronary artery bypass grafting and/or aortic valve replacement. InterventionInfusion of 17.4 {micro}g og Exenatide or placebo during cardiopulmonary bypass and the first hour after weaning thereof Main outcomesThe main outcome was time to a composite endpoint consisting of death, stroke, renal failure requiring dialysis, or new/worsening heart failure during follow-up. Secondary endpoints included occurrence of prespecified adverse events. ResultsA total of 1389 patients were included in the analyses. Within a follow-up period of median of 5.9 years (min - max; 2.5 - 8.3 years), 170 patients (24%) in the Exenatide group and 165 patients (24%) experienced a primary endpoint. We found no difference in time to first event between patients randomized to FiO2 50% versus FiO2 100% (HR 1.0 [95%CI 0.83 - 1.3], p = 0.80). We found no significant difference in rates of adverse events between the two groups. Conclusions and RelevanceExenatide during cardiopulmonary bypass and weaning thereof did not significantly reduce the incidence of death, stroke, renal failure, or new/worsening heart failure in patients undergoing coronary artery bypass grafting and/or aortic valve replacement. Trial registrationO_LIDanish Medicines Agency: Protocol no. HJE-PHARMA-001, EudraCT no. 2015-003050-41, 2nd of October 2015 C_LIO_LILocal Ethics Committee "Videnskabsetisk komite C, Region Hovedstaden": No. H-15010562 C_LI www.clinicaltrials.gov: ID no. NCT0267393 Key PointsO_ST_ABSQuestionC_ST_ABSIs a single dose of Exenatide effectively reducing risk of death or major organ injury in patients undergoing cardiopulmonary bypass (CPB)-assisted cardiac surgery? Findings1400 patients undergoing coronary artery bypass grafting and/or aortic valve replacement were randomized to 17,4 {micro}g of Exenatide or placebo during CPB and the first hour after weaning. The hazard ratio (95%CI) for time to the first occurring composite endpoint consisting of death, stroke, renal failure requiring dialysis, and new/worsening heart failure was 1.0 (0.83 - 1.3). MeaningExenatide infusion during CPB-assisted cardiac surgery does not improve outcomes.

Background: In severe aortic stenosis patients undergoing TAVR, whether coexisting coronary disease prompts revascularization and its optimal timing remain unclear. Aim: To evaluate the efficacy and safety of PCI before TAVR compared to deferred PCI in patients with severe aortic stenosis and concomitant coronary artery disease. Methods: We performed a meta-analysis of RCTs. PubMed, Embase, Scopus, CENTRAL, and Web of Science were searched for RCTs comparing PCI before TAVR versus no PCI. HRs with 95% CIs were pooled using random-effects models. Results: Three RCTs (ACTIVATION, NOTION 3, PRO-TAVI) enrolling 1,156 patients (579 PCI, 577 no PCI) were included. Routine PCI before TAVR did not reduce all-cause mortality (HR 0.88, 95% CI 0.67 to 1.17; p=0.38) or cardiovascular death (HR 0.77, 95% CI 0.49 to 1.19; p=0.23). PCI significantly reduced any revascularization (HR 0.24, 95% CI 0.06 to 0.86; p=0.029), and urgent revascularization (HR 0.33, 95% CI 0.12 to 0.87; p=0.025). MI was not significantly reduced with PCI (HR 0.84, 95% CI 0.44 to 1.59; p = 0.59). Stroke showed a borderline trend favoring PCI (HR 0.69, 95% CI 0.46 to 1.04; p=0.073). PCI significantly increased any bleeding (HR 1.96, 95% CI 1.28 to 3.0; p=0.002) and major bleeding (HR 1.88, 95% CI 1.07 to 3.31, p=0.027). Neither AKI nor rehospitalization differed significantly between groups. Leave-one-out sensitivity analyses confirmed the stability of mortality, stroke, and bleeding estimates. Conclusions: Routine PCI before TAVR does not reduce mortality. It lowers urgent revascularization and trends toward less stroke but nearly doubles bleeding. Findings support selective, individualized PCI rather than routine revascularization before TAVR.

BackgroundVaricose veins represent a common cause of cardiovascular morbidity, with limited available medical therapies. Although varicose veins are heritable and epidemiologic studies have identified several candidate varicose veins risk factors, the molecular and genetic basis remains uncertain. Here, we analyzed the contribution of common genetic variants to varicose veins using data from the VA Million Veteran Program and other large multi-ancestry biobanks. Among 49,765 individuals with varicose veins and 1,334,301 disease-free controls, we identified 139 risk loci. We identified genetic overlap between varicose veins, other vascular diseases, and dozens of anthropometric factors. Using Mendelian randomization, we prioritized novel therapeutic targets via integration of proteomic and transcriptomic data. Finally, topological enrichment analyses confirmed the biologic roles of endothelial shear flow disruption, inflammation, vascular remodeling, and angiogenesis. These findings may facilitate future efforts to develop non-surgical therapies for varicose veins.

BackgroundCardiovascular and cerebrovascular risks of SARS-CoV-2 infection and mRNA vaccination remain incompletely defined and lacking comparative outcomes such as sex-specific vulnerabilities. MethodsUsing the TriNetX Research Network (December 2020-December 2024), we identified four mutually exclusive cohorts: uninfected/unvaccinated (naive), infected/unvaccinated, vaccinated-only, and infected/vaccinated (hybrid immunity). We compared 50 prespecified cardiovascular, cerebrovascular, and mortality outcomes across four pairwise cohort comparisons, with analyses stratified by sex and time of event windows (0-3, 3- 6, 6-9, and >9months). Different vaccine dosing strategies were analyzed. ResultsAmong 30.3 million individuals, infection was associated with a 4.5-fold increased mortality in males and 4.0-fold in females (p<0.001) as well as marked increases in myocarditis, myocardial infarction, and pulmonary embolism. Inflammatory cardiac complications occurred four times more often after infection than vaccination. Vaccination alone conferred a 76% reduction in major adverse cardiovascular events (MACE) in males and 69% in females, with no detectable cardiovascular toxicity. Post-infection vaccination provided an additional 36-38% MACE reduction, though males with hybrid immunity had a late increased risk of pericarditis. Completing the two-dose vaccine series maximally reduced mortality (by 77%) and myocarditis (by 62%) versus single dosing; further doses gave minimal additional benefit but sustained the benefit of the primary vaccination series. Females had higher infection-linked myocarditis risk despite lower mortality. ConclusionsSARS-CoV-2 infection confers substantially greater and sustained cardiovascular and cerebrovascular risk than mRNA vaccination, confirming a highly favorable benefit-risk profile for vaccination. These findings support extended cardiovascular surveillance after infection and targeted, risk-based vaccination strategies.

BackgroundIron deficiency affects nearly half of patients with heart failure with reduced ejection fraction and is associated with impaired functional capacity, recurrent hospitalizations, and increased mortality. Intravenous iron therapy improves exercise tolerance, but the comparative effectiveness of different formulations remains uncertain. ObjectivesTo compare the efficacy of ferric carboxymaltose, ferric derisomaltose, and iron sucrose in patients with heart failure with reduced ejection fraction and iron deficiency using a network meta-analysis. MethodsWe systematically searched PubMed, the Cochrane Central Register of Controlled Trials, and Web of Science through August 2025 for randomized controlled trials of intravenous ferric carboxymaltose, ferric derisomaltose, or iron sucrose versus placebo. Fifteen randomized controlled trials published between 2007 and 2025 enrolling 7,761 patients were included. The primary outcomes were hospitalization for heart failure, all-cause mortality, and cardiovascular mortality. Secondary outcomes included change in six-minute walk distance, serum ferritin, and transferrin saturation. A frequentist random-effects network meta-analysis was performed, and treatment rankings were assessed using surface under the cumulative ranking curve probabilities. ResultsTwelve trials reported hospitalization for heart failure, showing significant reduction with ferric carboxymaltose (risk ratio 0.80, 95% confidence interval 0.69-0.92) and nonsignificant trends with ferric derisomaltose (0.80, 0.61-1.04) and iron sucrose (0.41, 0.15-1.07). No formulation reduced all-cause or cardiovascular mortality. Functional capacity improved with all formulations (mean difference +21.1 to +54.0 meters versus placebo), though heterogeneity was high. Ferritin and transferrin saturation increased significantly across all formulations, with the largest ferritin gain from ferric derisomaltose (+329 {micro}g/L) and the most consistent transferrin saturation improvement from ferric carboxymaltose (+7.1%). ConclusionsIn patients with heart failure with reduced ejection fraction and iron deficiency, intravenous iron therapy--particularly ferric carboxymaltose--reduces hospitalization for heart failure, improves functional capacity, and corrects iron indices. Mortality benefits remain uncertain. These findings support guideline-endorsed use of intravenous iron, with ferric carboxymaltose as the best-studied option, while further outcome data for ferric derisomaltose and iron sucrose are needed.

BackgroundMigraine is a prevalent neurological condition associated with increased cardiovascular risk; however, the pathophysiologic mechanisms underlying this association remains poorly understood, and the long-term cardiovascular effects of migraine preventive medications have yet to be determined. MethodsWe emulated two separate two-arm target trials comparing patients who initiated lisinopril/candesartan or anti-calcitonin gene-related peptide (aCGRP) treatments versus those receiving topiramate for migraine prevention within the U.S. Department of Veterans Affairs between June 1, 2018 and September 30, 2024. The outcome was major adverse cardiovascular event (MACE) including myocardial infarction (MI), ischemic stroke, intracerebral and subarachnoid hemorrhage (ICH/SAH) and all-cause mortality. Five-year cumulative incidences, risk differences, risk ratios and overall hazard ratios (HRs) were estimated. ResultsAmong 48,610 patients initiating lisinopril/candesartan (mean [SD] age, 52.3 [12.3] years; 18.9% women) and 25,635 initiating aCGRP treatment (mean [SD] age, 47.2 [12.2] years; 39.4% women), lisinopril/candesartan was associated with a higher risk of MACE (HR 1.21; 95%CI, 1.10-1.34), particularly MI (HR 1.28; 95%CI, 1.03-1.59). The MI risk was greater in patients without documented cardiovascular indications (HR 2.75; 95%CI, 2.01-3.77), patients aged <40 years (HR 3.18; 95%CI, 1.63-6.20), or with baseline systolic blood pressure <130 mm Hg (HR 1.86; 95%CI, 1.44-2.39). aCGRP use was associated with a reduced risk of MI (HR 0.80; 95% CI, 0.62-1.02) and was not associated with ischemic stroke (HR 1.11; 95% CI, 0.84-1.49) or ICH/SAH (HR 0.95; 95% CI, 0.65-1.38). ConclusionsIn this retrospective cohort study, lisinopril/candesartan may increase cardiovascular risk among migraine patients, particularly those at low risk of atherosclerosis, while aCGRP treatment appears safe and potentially protective against MI. These findings suggest a role for neurogenic inflammation-mediated by CGRP and substance P-in migraine-associated, non-atherosclerotic cardiovascular risk. Future research is warranted.

We performed a systematic review and meta-analysis of randomized controlled trials evaluating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus placebo in adults with heart failure (HF), searching PubMed, Cochrane CENTRAL, and ClinicalTrials.gov through February 2026. The primary outcome was the composite of cardiovascular death and first HF hospitalization. Random-effects meta-analysis used restricted maximum likelihood estimation with Hartung-Knapp-Sidik-Jonkman adjustment. We included 14 studies (6 dedicated HF trials and 8 cardiovascular outcomes trial HF subgroup analyses) encompassing 18,558 patients, of whom 2,499 were randomized in dedicated HF trials. The primary composite did not reach statistical significance (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.73-1.01; P=0.067; I2=47%). GLP-1 RAs significantly reduced all-cause mortality (HR 0.87, 95% CI 0.81-0.93; P<0.001; I2=0%), major adverse cardiovascular events (HR 0.83, 95% CI 0.73-0.95; P=0.019), and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (+7.4 points, 95% CI 6.3-8.5) and 6-minute walk distance (+17.6 m, 95% CI 13.4-21.7). Excluding the FIGHT trial (acute HFrEF) yielded a significant primary composite (HR 0.83, P=0.011). The mortality signal was driven primarily by CVOT subgroups; the largest dedicated HFpEF trial (SUMMIT) showed numerically higher mortality (HR 1.25). The strongest evidence supports GLP-1 RAs in HFpEF with obesity. HighlightsO_LIPrimary composite of CV death + HHF was not significant (HR 0.86, P=0.067) C_LIO_LIGLP-1 RAs reduced all-cause mortality (HR 0.87) with no heterogeneity C_LIO_LIKCCQ-CSS improved by 7.4 points and 6MWD by 17.6 m in HFpEF trials C_LIO_LIMortality benefit driven by CVOT subgroups, not dedicated HF trials C_LIO_LIStrongest evidence supports GLP-1 RAs in HFpEF with obesity C_LI

BackgroundPulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are disorders of the pulmonary vasculature that cause right ventricular dysfunction. Systemic consequences of right ventricular dysfunction include damage to other solid organs, such as the liver. However, the profiles and consequences of hepatic injury due to PAH and CTEPH have not been well-studied. MethodsWe aimed to identify underlying patterns of liver injury in a cohort of PAH and CTEPH patients enrolled in 15 randomized clinical trials conducted between 1998 and 2012. We used unsupervised machine learning to identify liver injury clusters in 13 trials and validated the findings in two additional trials. We then determined whether these liver injury clusters were associated with clinical outcomes or treatment effect heterogeneity. ResultsOur training dataset included 4,219 patients and our validation dataset included 1,756 patients with complete liver laboratory panels (serum total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin). Using k-means clustering paired with factor analysis, we identified four unique liver phenotypes (no liver injury, hepatocellular injury, cholestatic injury, and combined injury patterns). Patients in the cholestatic injury liver cluster had the shortest time to clinical worsening and highest chance of worsening World Health Organization functional class. Randomization to the experimental arm was associated with a transition to healthier liver clusters compared to randomization to the control arm. The cholestatic injury group experienced the greatest placebo-corrected treatment benefit in terms of six-minute walk distance. ConclusionsLiver injury patterns were associated with adverse outcomes in patients with PAH and CTEPH. Randomization to active treatment of pulmonary hypertension in these clinical trials had beneficial effects on liver health compared to placebo. The independent role of liver disease (often subclinical) in determining outcomes warrants prospective studies of the clinical utility of liver phenotyping for PAH prognosis and contribution to clinical disease.

BackgroundPulmonary embolism (PE) is frequently suspected in patients with cancer due to non-specific symptoms suggestive of PE and their inherent risk of venous thromboembolism (VTE). Commonly used clinical decision rules (CDRs) and D-dimer testing may be less reliable in this specific population. Due to the lack of guideline recommendations on the optimal diagnostic approach and the perceived futility of D-dimer in patients with cancer, clinicians often use computed tomography pulmonary angiography (CTPA) as a sole diagnostic test. This practice exposes patients to potentially unnecessary radiation and harm, and contributes to a significant burden on healthcare systems through inefficient resource allocation. The YEARS algorithm is an easy-to-use CDR that has been shown to safely exclude PE without the need for CTPA in a diverse population of patients with suspected PE. ObjectiveTo compare the safety and efficiency of the YEARS algorithm to the safety and efficiency of CTPA only in the diagnostic management of acute PE in cancer patients. Design and interventionsThe Hydra study (ClinicalTrials.gov NCT04657120) is an investigator-initiated, multicentre, multinational open-label, randomised, non-inferiority trial with blinded adjudication of outcome events, comparing the YEARS algorithm with CTPA only in the diagnostic work-up of cancer patients with clinically suspected acute PE. Participants are randomised in a 1:1 ratio to each diagnostic strategy via a web-based system. The trial anticipates to include 1566 patients. ParticipantsConsecutive patients with active cancer who are hospitalized or present to the emergency department, outpatient clinic, or thrombosis clinic with clinically suspected PE and who are not receiving therapeutic anticoagulation or have an indication for anticoagulation therapy other than PE. Study outcomesThe primary safety outcome is the proportion of symptomatic and objectively proven fatal or non-fatal VTE (i.e., PE or deep vein thrombosis in the upper or lower extremities) or death with undetermined cause where acute PE could not be ruled out as contributing factor during three months follow-up in patients in whom PE was ruled out at initial testing. The primary efficiency outcome is the proportion of negative CTPA scans for PE, relative to the total number of CTPA scans performed at initial testing. ImplicationThis trial will provide pivotal data on the optimal diagnostic approach for suspected acute PE in patients with cancer. Strengths and limitations of this studyO_LIThe Hydra study is the first prospective, randomised trial comparing the safety and efficiency of the YEARS algorithm with CTPA only for suspected acute PE in patients with active cancer. C_LIO_LIThe enrolment of a large number of patients from multiple teaching and general hospitals across various clinical settings and countries enhances the generalisability of this study. C_LIO_LIThe randomised design and the vulnerable study population may render the study challenging. C_LI

We used expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) to conduct genome-wide Mendelian randomization (MR) using 27,799 cases of heart failure (HF) with reduced ejection fraction (HFrEF), 27,579 cases of HF with preserved ejection fraction (HFpEF), and 367,267 control individuals from the Million Veteran Program (MVP). We identified 70 HFrEF and 10 HFpEF gene-hits, of which 58 are novel. In 14 known loci for unclassified HF, we identified HFrEF as the subtype responsible for the signal. HFrEF hits ZBTB17, MTSS1, PDLIM5, and MLIP and novel HFpEF hits NFATC2IP, and PABPC4 showed robustness to MR assumptions, support from orthogonal sources, compelling evidence on mechanism of action needed for therapeutic efficacy, and no evidence of an unacceptable safety profile. We strengthen the value of pathways such as ubiquitin-proteasome system, small ubiquitin-related modifier pathway, inflammation, and mitochondrial metabolism as potential therapeutic targets for HF management. We identified IL6R, ADM, and EDNRA as suggestive hits for HFrEF and LPA for HFrEF and HFpEF, which enhances the odds of success for existing cardiovascular investigational drugs targeting. These findings confirm the unique value of human genetic studies in HFrEF and HFpEF for discovery of novel targets and generation of therapeutic target profiles needed to initiate new validation programs in HFrEF and HFpEF preclinical models.

BackgroundThe left ventricular outflow tract (LVOT) and ascending aorta are spatially complex, with distinct pathologies and embryologic origins. Prior work examined genetics of thoracic aortic diameter in a single plane. We sought to elucidate the genetic basis for the diameter of the LVOT, the aortic root, and the ascending aorta. MethodsWe used deep learning to analyze 2.3 million cardiac magnetic resonance images from 43,317 UK Biobank participants. We computed the diameters of the LVOT, the aortic root, and at six locations in the ascending aorta. For each diameter, we conducted a genome-wide association study and generated a polygenic score. Finally, we investigated associations between these polygenic scores and disease incidence. Results79 loci were significantly associated with at least one diameter. Of these, 35 were novel, and a majority were associated with one or two diameters. A polygenic score of aortic diameter approximately 13mm from the sinotubular junction most strongly predicted thoracic aortic aneurysm in UK Biobank participants (n=427,016; HR=1.42 per standard deviation; CI=1.34-1.50, P=6.67x10-21). A polygenic score predicting a smaller aortic root was predictive of aortic stenosis (n=426,502; HR=1.08 per standard deviation; CI=1.03-1.12, P=5x10-6). ConclusionsWe detected distinct common genetic loci underpinning the diameters of the LVOT, the aortic root, and at several segments in the ascending aorta. We spatially defined a region of aorta whose genetics may be most relevant to predicting thoracic aortic aneurysm. We further described a genetic signature that may predispose to aortic stenosis. Understanding the genetic contributions to the diameter of the proximal aorta may enable identification of individuals at risk for life-threatening aortic disease and facilitate prioritization of therapeutic targets.

BackgroundHeart failure (HF) following an acute myocardial infarction (post-MI HF) has been studied as an additional sub-type of HF to broaden the indications for HF drugs. Post-MI HF and HFrEF are pathophysiologically similar and share pharmacotherapies. In this meta-analysis, we examined the concordance between all-cause mortality data for drugs indicated for HFrEF and post-MI HF. We used our analysis to calculate the projected all-cause mortality hazard ratios (HRs) for the pending dapagliflozin (DAPA-MI) and empagliflozin (EMPACT-MI) post-MI HF trials. MethodsUsing CenterWatch and UpToDate, we identified all FDA-approved drugs for NYHA Class II to IV HFrEF. We searched each of these drugs on FDALabel and ClinicalTrials.gov to identify their registration trials measuring all-cause mortality for HFrEF and, if available, in the post-MI setting--including trials where participants displayed a left ventricular ejection fraction of <40% ("post-MI HF"). For each of the included studies, we extracted the all-cause mortality HRs, their 95% confidence intervals, and the control-group used. For all drugs studied in both indications, we plotted the all-cause mortality HRs for HFrEF against those for post-MI (HF) and calculated the linear regressions. ResultsThis meta-regression pooled data from 29 completed trials underlying 20 drugs. Two pending trials were also analyzed. Nine drugs (metoprolol, carvedilol, spironolactone, eplerenone, sacubitril-valsartan, lisinopril, enalapril, valsartan, losartan) had all-cause mortality data in both HFrEF and post-MI generally, with a linear coefficient of determination of 0.93. Five of these drugs (carvedilol, eplerenone, sacubitril-valsartan, valsartan, losartan) were studied in both HFrEF and non-acute post-MI HF, displaying a linear coefficient of determination of 0.99. Using our model, we predict the all-cause mortality HRs that will be observed in the EMPACT-MI and DAPA-MI trials will be 0.85 and 0.89, respectively. ConclusionsIn this meta-regression of registration trials for drugs studied in both HFrEF and post-MI (HF), all-cause mortality effects were highly concordant. We also find asymmetries in the assessment of HF drug indications, whereby drugs are seldom assessed for an all-cause mortality benefit in both HFrEF and in post-MI HF. Future studies may use these results to guide future HF RCT development.

ImportanceObesity and autoimmune diseases (AID) are each associated with elevated risk of cardiovascular and thromboembolic events due to chronic systemic inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated cardiovascular and metabolic benefits in patients with type 2 diabetes and obesity, but their effects in patients with obesity and comorbid AID remain uncertain. ObjectiveTo evaluate the association between GLP-1RA use and the risk of major adverse cardiovascular and thromboembolic events among adults with obesity and AID eligible for anti-obesity medication (AOM) therapy. DesignThis retrospective cohort study emulated a target trial using 2014-2024 electronic health record data from the OneFlorida+ network, which includes 21 million individuals across Florida, Georgia, and Alabama. Adults with obesity and AID who met AOM eligibility criteria were included. Propensity score matching (1:1) was applied using a time-dependent framework to balance baseline covariates between GLP-1RA users and non-users. ParticipantsAID Adults ([&ge;]18 years) who were eligible for AOM treatment. ExposureGLP-1RA use versus non-use. Main Outcomes and MeasuresThe primary outcomes were myocardial infarction, stroke or transient ischemic attack (TIA), pulmonary embolism (PE), venous thromboembolism (VTE), and coronary revascularization. Secondary outcomes included hospitalization, emergency department (ED) visits, and all-cause mortality. ResultsThe matched cohort included 13,204 GLP-1RA users and 13,204 non-users (mean age, 54.7 {+/-} 14.5 years; 73.4% female; mean BMI, 37 kg/m{superscript 2}). Compared with non-users, GLP-1RA users had lower incidence rates (per 1000 person-years) of PE (6.4 vs 9.5), VTE (16.6 vs 20.4), and mortality (9.5 vs 16.9). GLP-1RA use was associated with lower hazard of stroke/TIA (HR, 0.87 [95% CI, 0.76-0.99]; P = .039), PE (HR, 0.69 [95% CI, 0.56-0.86]; P = .001), VTE (HR, 0.83 [95% CI, 0.72-0.95]; P = .007), ED visits (HR, 0.79 [95% CI, 0.75-0.83]; P = .000), and mortality (HR, 0.56 [95% CI, 0.47-0.66]; P = .000). Conclusions and RelevanceAmong adults with obesity and AID, GLP-1RA use was associated with reduced thromboembolic events, lower emergency department utilization, and decreased mortality. These findings suggest potential cardiovascular and survival benefits of GLP-1RAs in a high-risk, understudied population. Key PointsO_ST_ABSQuestionC_ST_ABSIs the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) associated with cardiovascular and thromboembolic outcomes among adults with obesity and autoimmune disease (AID)? FindingsIn this target trial emulation using 2014-2024 electronic health record data from the OneFlorida+ network, 13,204 GLP-1RA users were compared with 13,204 matched non-users. GLP-1RA use was associated with significantly lower risks of pulmonary embolism, venous thromboembolism, emergency department visits, and all-cause mortality, with marginal associations for stroke or transient ischemic attack. MeaningAmong adults with obesity and AID, GLP-1RA therapy may confer thromboembolic and survival benefits without increasing cardiovascular risk.