Small Molecule PCSK9 Inhibitor for Hypercholesterolemia | JACC | ACC.25

JACC Associate Editor Khurram Nasir, MBBS, FACC, speaks with author Michael J. Koren, MD, FACC, on his Featured Clinical Research study published in JACC and presented at ACC.25. This randomized, multicenter, double-blind, placebo-controlled, dose-ranging phase 2 study assessed efficacy, safety, and tolerability of AZD0780, a small molecule PCSK9 inhibitor. The study randomized 428 patients (426 started treatment) with hypercholesterolemia on standard-of-care statin therapy to daily oral administrations of AZD0780 1, 3, 10 or 30 mg, or matching placebo for 12 weeks. AZD0780 significantly reduced LDL-C levels versus placebo at all doses (from 35.3% to 50.7%) and demonstrated a safety and tolerability profile similar to placebo. These findings support further development of AZD0780 as part of a simple, oral regimen for lowering LDL-C beyond that achieved with statin therapy.

This interview with JACC: Associate Editor Neha J. Pagidipati, MD, FACC, and author Kausik Ray, MD, FACC, reviews Dr. Ray’s phase one study on solbinsiran, an siRNA therapy targeting ANGPTL3 to reduce triglycerides and cardiovascular risk. Dr. Ray explains the study's findings, including significant reductions in triglycerides, ApoB, and LDL, with a favorable safety profile. The conversation also touches on the broader landscape of ANGPTL3 inhibitors, the implications of HDL reduction, and the anticipation of phase two results to be presented at ACC 2025.

Join here for an insightful discussion with Federico Pappalardo, MD and Sanket Dhruva, MD, FACC on the groundbreaking ALT-SHOCK 2 RCT, the largest randomized trial on intra-aortic balloon pump therapy in heart failure cardiogenic shock. Learn about the trial's key findings, implications for clinical practice, and the future of mechanical circulatory support in this critically ill patient population.

Join JACC Associate Editor Khurram Nasir, MBBS, FACC, and author Rohan Khera, MD, FACC, as they discuss the latest study on tirzepatide presented at ACC.25 and published in JACC. Tirzepatide, a dual GIP/GLP-1 receptor agonist, exerts pleiotropic effects on cardiometabolic health. This study evaluated its efficacy in improving cardiometabolic outcomes in individuals with T2D. An individual participant data meta-analysis was conducted, pooling data from seven Phase 3 RCTs comparing tirzepatide with placebo or standard antihyperglycemic agents. The study outcomes included cardiometabolic components of metabolic syndrome (MetS), elevated BMI, and MetS. Tirzepatide significantly reduced the odds of these abnormalities and effectively resolved MetS, with superior efficacy observed in younger individuals and those not on baseline SGLT2is. These findings support the potential of tirzepatide to improve cardiometabolic health in T2D.

This discussion between JACC: Clinical Electrophysiology Associate Editor Sumeet Chugh, MD, FACC and author Jonathan Drezner discuss this research study presented at ACC.25 and published in JACC. In the observational study, they identified cases of sudden cardiac arrest (SCA) among young competitive athletes >/=11 years old from 7/1/2014-7/30/2023. During the 9-year study period, overall survival after SCA (49%,range 30-66%) and survival after exertional SCA (57%,range 38-72%) increased. Black race (RR=0.63,95% CI 0.53-0.76), Other race (RR=0.69,95% CI 0.50-0.94), and non-exertional SCA (RR=0.43,95% CI 0.32-0.59) were associated with lower survival from SCA adjusting for level of competition and sex. While survival from SCA among young competitive athletes in the United States has improved in the last decade, important racial disparities in outcomes were observed warranting additional research and prevention strategies.

Makoto Mori, MD, JACC: Associate Editor, is joined by author John K. Forrest, MD, FACC, discussing this study from Forrest et al presented at ACC.25 and published in JACC. Patients with severe aortic stenosis who were treated with either a supraannular self-expanding TAVR or surgery showed comparable rates of all-cause mortality and disabling stroke at 5 years, strengthening TAVR as a safe, effective, and durable alternative to surgery for patients, regardless of their surgical risk.

Hosts Mitsuaki Sawano, MD, and Regional Associate Editor Nobuhiro Ikemura, MD, welcome Takashi Ikenouchi, MD, a physician scientist at the Cedars-Sinai Medical Center, Smidt Heart Institute, to discuss the headline-grabbing “Gold Card” sale and a novel approach to atrial fibrillation: an embryological classification of arrhythmogenic triggers. While pulmonary vein isolation (PVI) remains the cornerstone of AF ablation, up to 30% of triggers originate outside the pulmonary veins, contributing to recurrence and suboptimal outcomes. As PVI outcomes begin to plateau, this embryology-informed framework—categorizing triggers into common pulmonary vein, sinus venosus, and primitive atrium origins—offers a path toward more personalized and precise AF therapies.

In this episode, Dr. Valentin Fuster presents key findings from the April 8, 2025 issue of the Journal of the American College of Cardiology, covering three groundbreaking studies. Topics include the newly defined threshold for mild aortic stenosis using MRI, the relationship between heat wave exposure and cardiac mortality, and the long-term outcomes of aortic valve performance in patients undergoing TAVR versus surgery.

In this podcast, Dr. Valentin Fuster discusses a groundbreaking study on mild aortic stenosis, which redefines its diagnostic threshold using deep learning and velocity-encoded MRI. The findings suggest that even mild cases, previously considered benign, are linked to increased cardiovascular risks, highlighting the potential for early intervention and the critical role of AI in advancing cardiovascular research.

In this podcast, Dr. Valentin Fuster discusses a groundbreaking study examining the non-linear relationship between cardiac mortality and heat waves, focusing on how excess temperature during these events can impact heart disease death rates. The study reveals that compound heat waves, involving both day and night temperatures, significantly increase mortality risks, emphasizing the need for more precise heat wave definitions and health measures to protect vulnerable populations in a warming climate.