Does pulsed field ablation (PFA) for pulmonary vein isolation affect structures beyond the pulmonary veins? Host Mitsuaki Sawano, MD, welcomes Yosuke Nakatani, MD (Gunma University) to discuss his recent JACC: Clinical Electrophysiology study examining the effects of PFA on the vein of Marshall (VoM). In this prospective study of 72 patients undergoing PFA using three different systems, a microelectrode catheter was positioned within the VoM to continuously record electrograms during ablation. PFA acutely altered VoM electrograms in 44% of patients, including complete elimination in 22%, but persistent VoM modification remained in only 14% by the end of the procedure. Importantly, the effect was strongly related to the distance between the PFA electrode and the VoM, suggesting that catheter geometry and proximity may matter more than energy strength alone. We discuss what these findings reveal about the unintended collateral effects of PFA, why most acute VoM effects rapidly recover, whether PFA could ever replace ethanol infusion for VoM ablation, and how a research idea conceived during Dr. Nakatani's fellowship in Bordeaux ultimately became a first-in-human mechanistic study in Japan.

Which of the thousands of biomarkers associated with cardiovascular disease could actually become a useful drug target? Host Mitsuaki Sawano, MD, and co-host Nobuhiro Ikemura, MD, welcome Satoshi Yoshiji, MD, PhD (McGill University) to discuss a recent JACC study tackling this question in ischemic heart disease. Starting with 9,520 circulating proteins, the investigators used human genetics to move beyond association toward stronger evidence for causality, combining Mendelian randomization, genetic colocalization, multiple proteomic platforms, and cross-ancestry validation to narrow thousands of signals to a small group of potential therapeutic targets. We break down what these methods actually mean for clinicians: what cis-pQTLs tell us, why MR alone is not enough, what colocalization adds, and why validation across platforms and populations matters. The episode explores how this emerging approach could help determine which biological targets are worth pursuing in drug development and ultimately testing in clinical trials.

Hosts Mitsuaki Sawano, MD, Satoshi Shoji, MD, and Kentaro Ejiri, MD, welcome Yoshito Kadoya, MD, PhD (University of British Columbia / St. Paul's Hospital) to discuss his JACC: Cardiovascular Imaging study, "PET-Based Coronary Microvascular Dysfunction Phenotypes and Outcomes in Patients With Normal Myocardial Perfusion." Among 3,317 patients with normal relative perfusion on cardiac PET, the study examined four phenotypes defined by myocardial flow reserve and stress myocardial blood flow. Both classical CMD and endogen CMD were associated with higher long-term cardiovascular risk, suggesting that reduced MFR may remain clinically meaningful even when stress myocardial blood flow is preserved. The episode explores how PET can phenotype coronary microvascular dysfunction, differences between invasive and noninvasive approaches to CMD, and Dr. Kadoya's cardiac imaging training and career in Canada.