Pathogenic Cardiomyopathy-Associated Gene Variants and Prognosis in Atrial Fibrillation: Results in 18,000 Clinical Trial Participants.

Background: Genetic variants in cardiomyopathy genes are associated with risk of atrial fibrillation (AF), although data on clinical outcomes for AF patients with such variants remain sparse.

Objectives: We aimed to study the prognostic implication of rare cardiomyopathy-associated pathogenic variants (CMP-PLP) in AF patients from large, well-phenotyped clinical trials.

Methods: CMP-PLP carriers were identified using exome sequencing in 5 multinational trials from the Thrombolysis in Myocardial Infarction study group (ENGAGE AF, FOURIER, SAVOR, PEGASUS, and DECLARE), with replication in the EAST-AFNET-4 trial.

Dapagliflozin in Patients Hospitalized for Heart Failure: Primary Results of the DAPA ACT HF-TIMI 68 Randomized Clinical Trial and Meta-Analysis of Sodium-Glucose Cotransporter-2 Inhibitors in Patients Hospitalized for Heart Failure.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk of cardiovascular death or worsening heart failure (HF) in outpatients with HF. Data are limited regarding initiation in patients hospitalized for HF.

Methods: We conducted a randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of in-hospital initiation of dapagliflozin (10 mg daily) in patients hospitalized for HF.

A Polygenic Risk Score to Predict Incident Heart Failure Across the Spectrum of Cardiovascular Risk.

Background: The clinical utility of a heart failure (HF) polygenic risk score (PRS) is uncertain.

Objectives: The purpose of this study was to investigate the ability of an HF PRS to predict new-onset HF in individuals across the spectrum of cardiovascular risk.

Methods: An HF PRS (>1 million single nucleotide variations) was used to stratify individuals from 7 clinical studies to low (quintile [Q] 1), intermediate (Q2-Q4), or high (Q5) genetic risk.

Long-Acting Factor XI Inhibition and Periprocedural Bleeding: An Analysis From AZALEA-TIMI 71.

Background: In AZALEA-TIMI 71 (A Multicenter, Randomized, Active-Controlled Study to Evaluate the Safety and Tolerability of Two Blinded Doses of Abelacimab Compared with Open-Label Rivaroxaban in Patients with Atrial Fibrillation-Thrombolysis In Myocardial Infarction 71), abelacimab, a novel factor XI inhibitor, significantly reduced the rate of major or clinically relevant nonmajor (CRNM) bleeding compared with rivaroxaban in patients with atrial fibrillation (AF). Abelacimab is long-acting with a half-life of ∼28 days.

Objectives: The purpose of this study was to examine periprocedural bleeding among patients undergoing invasive procedures in the context of long-acting factor XI inhibition with abelacimab.

Risks for sudden cardiac and undetermined cause of death among people with HIV in the REPRIEVE primary cardiovascular prevention trial.

Objective: People with HIV (PWH) are at increased risk of sudden cardiac death (SCD) but the mechanisms are unclear limiting prevention efforts. We leveraged the global REPRIEVE trial with carefully adjudicated atherosclerotic cardiovascular disease (ASCVD) outcomes to determine cardiac, behavioral, and HIV-specific risks associated with SCD and assess potential similarities to undetermined deaths (UDD).

Design/methods: REPRIEVE included 7769 PWH with low-to-moderate traditional ASCVD risk without known ASCVD randomized to pitavastatin vs.

Rationale and Design of the Dapagliflozin Effect on Cardiovascular Events in Acute Heart Failure (DAPA ACT HF)-TIMI 68 Trial.

Although sodium-glucose cotransporter 2 inhibitors reduce the risk of cardiovascular death or worsening heart failure (HF) in patients with chronic HF, there are limited data on initiation in hospitalized patients with HF. DAPA ACT HF-TIMI 68 (Dapagliflozin and Effect on Cardiovascular Events in Acute Heart Failure - Thrombolysis in Myocardial Infarction 68) is an international, randomized, double-blind trial evaluating the initiation of dapagliflozin (10 mg daily) vs placebo in 2,401 patients hospitalized for acute HF. Patients were enrolled irrespective of left ventricular ejection fraction, type 2 diabetes status, or chronicity of HF (de novo and worsening chronic HF).

Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities.

Genomics can provide insight into the etiology of type 2 diabetes and its comorbidities, but assigning functionality to non-coding variants remains challenging. Polygenic scores, which aggregate variant effects, can uncover mechanisms when paired with molecular data. Here, we test polygenic scores for type 2 diabetes and cardiometabolic comorbidities for associations with 2,922 circulating proteins in the UK Biobank.

Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation.

Background: Abelacimab is a fully human monoclonal antibody that binds to the inactive form of factor XI and blocks its activation. The safety of abelacimab as compared with a direct oral anticoagulant in patients with atrial fibrillation is unknown.

Methods: Patients with atrial fibrillation and a moderate-to-high risk of stroke were randomly assigned, in a 1:1:1 ratio, to receive subcutaneous injection of abelacimab (150 mg or 90 mg once monthly) administered in a blinded fashion or oral rivaroxaban (20 mg once daily) administered in an open-label fashion.

Type 2 diabetes genetic risk and incident diabetes across diabetes risk enhancers.

Aims: To evaluate the predictive value of a contemporary type 2 diabetes (T2D) polygenic score (PGS) in detecting incident diabetes across a range of diabetes risk factors.

Materials And Methods: We analysed participants in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial (ClinicalTrials.gov, number NCT0176463), which compared the efficacy of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab versus placebo in lowering cardiovascular outcomes in participants with stable atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg/dL (1.

Cardiovascular and renal benefits of sodium-glucose cotransporter-2 inhibitors: pathophysiologic mechanisms and clinical evidence.

Large-scale clinical outcome trials have demonstrated significant reductions in cardiovascular (CV) and renal outcomes with sodium-glucose cotransporter-2 inhibitors (SGLT2i). These benefits are sustained in patients with a range of left ventricular ejection fractions (LVEF), irrespective of diabetes status, and in a variety of clinical settings, prompting incorporation into clinical practice guidelines for patients with chronic kidney disease (CKD), heart failure (HF), and atherosclerotic cardiovascular disease (ASCVD). The clinical benefits are mediated by an interplay of cardio-metabolic-renal mechanisms, and they have a favorable safety profile.

Reductions in remnant cholesterol and VLDL cholesterol through inhibition of ANGPTL3 protein synthesis: an analysis from the TRANSLATE-TIMI 70 trial.

Aims: Remnant cholesterol and very low-density lipoprotein cholesterol (VLDL-C) are increasingly recognized risk factors for atherosclerotic disease with few therapeutic options. Angiopoietin-like 3 (ANGPTL3), a key protein in the metabolism of triglyceride-rich lipoproteins, is a promising target.

Methods And Results: TRANSLATE-TIMI 70 was a double-blind, placebo-controlled randomized trial testing seven dose regimens of vupanorsen, an antisense oligonucleotide against ANGPTL3, in adults with non-HDL-C ≥ 100 mg/dL and triglycerides 150-500 mg/dL.

Hepatic fat changes with antisense oligonucleotide therapy targeting ANGPTL3.

Background: Angiopoietin-like protein 3 (ANGPTL3) is a novel therapeutic target for hyperlipidemia. Vupanorsen, an antisense oligonucleotide targeting ANGPTL3, reduced triglycerides up to 57% in a phase 2b trial, but caused dose-dependent increases in hepatic fat fraction (HFF).

Objective: To determine the degree of HFF progression with escalating doses of vupanorsen, differential HFF increases in key patient subgroups, and the correlation between changes in HFF and liver enzymes.

Pitavastatin to Prevent Cardiovascular Disease in HIV Infection.

Background: The risk of cardiovascular disease is increased among persons with human immunodeficiency virus (HIV) infection, so data regarding primary prevention strategies in this population are needed.

Methods: In this phase 3 trial, we randomly assigned 7769 participants with HIV infection with a low-to-moderate risk of cardiovascular disease who were receiving antiretroviral therapy to receive daily pitavastatin calcium (at a dose of 4 mg) or placebo. The primary outcome was the occurrence of a major adverse cardiovascular event, which was defined as a composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral arterial ischemia, revascularization, or death from an undetermined cause.