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.

Host Mitsuaki Sawano, MD, welcomes Shuhei Nomura, PhD (Tohoku University), Lisa Yamasaki, MD (Harvard T.H. Chan School of Public Health), and Haruka Sakamoto, MD, PhD (St. Luke's International Hospital) to discuss two policy reviews published in The Lancet Regional Health – Western Pacific. Fifteen years after the 2011 Lancet Japan Series, Japan faces population aging, rising long-term care needs, workforce shortages, financial pressures, and a rapidly changing global health environment. The episode explores how Japan can shift from hospital-centered care toward prevention and community-based care while also rethinking its role in global health. The guests discuss why domestic reform and international collaboration must increasingly move together, and what Japan can learn from its neighbors as it prepares for 2040.

Hosts Mitsuaki Sawano, MD, and Hiroyuki Sato, MD, welcome Kazutaka Nakasone, MD (Kobe University) to discuss his JACC: Clinical Electrophysiology study on atrial tachycardia (AT) after pulsed field ablation (PFA) for atrial fibrillation. In a 5-center European registry of 4,144 patients, 76 (1.8%) underwent repeat ablation for AT. Most ATs were left atrial macroreentrant tachycardias, with approximately 86% involving dual-loop circuits. The episode explores why comprehensive left atrial mapping may be key to selecting the optimal ablation line, the impact of PVI versus posterior wall isolation, and the potential role of 3D mapping. Dr. Nakasone also shares how the study grew from his fellowship in Brussels and his experience training in Belgium.

Hosts Mitsuaki Sawano, MD, and Satoshi Shoji, MD, welcome Misato Chimura, MD, PhD (University of Glasgow) to discuss her ESC SimPub paper in JACC, "Low-normal hemoglobin concentrations and clinical outcomes in heart failure." Using individual participant-level data from 11 randomized trials including 42,213 patients across the full LVEF spectrum, the study examined the continuous relationship between hemoglobin and clinical outcomes. Risk was lowest around 14 g/dL in women and 15 g/dL in men, while even patients just above the WHO anemia threshold had higher event rates. The episode explores why "normal" may not always mean low risk in heart failure, the role of iron deficiency, how these findings should and should not influence clinical practice, and the research environment behind the study at the University of Glasgow.

Hosts Mitsuaki Sawano, MD, and Shun Kohsaka, MD, welcome Kazuma Ohyama, MD, PhD (Tohoku University) to discuss the BRIDGE trial, Protocol-Based Implementation of Early Intensive Lipid Management After Acute Coronary Syndrome. In this 10-center cluster-randomized trial, hospitals were assigned to either protocol-based or standard lipid management after emergency PCI for ACS. Rather than simply reminding clinicians to intensify therapy, the intervention specified what treatment to initiate, when to reassess LDL-C, when to escalate therapy, and who was responsible for each step. At 6 months, LDL-C <70 mg/dL was achieved in 86.4% of patients in the protocol-based group versus 73.7% with standard care, while LDL-C <55 mg/dL was achieved in 60.8% versus 34.5%. The episode explores why implementation gaps persist despite strong evidence for statins, ezetimibe, and PCSK9 inhibitors, how cluster randomization helps evaluate system-level interventions, the practical role of CRC support and standardized care pathways, and how Japan-specific statin dosing should be considered when interpreting the results. Dr. Ohyama also shares the intense SimPub process surrounding ESC 2026, including multiple major revisions within days, and why the key message of BRIDGE is not simply that stronger drugs lower LDL-C, but that a simple, clearly assigned protocol can help translate established evidence into actual clinical practice.

Hosts Mitsuaki Sawano, MD, Takeshi Kitai, MD, PhD, Kentaro Ejiri, MD, PhD, and Satoshi Shoji, MD, PhD, highlight three JACC papers presented at ESC 2026 and simultaneously published with the meeting. Dr. Kitai discusses new HELIOS-B insights on whether the benefits of vutrisiran in transthyretin amyloidosis with cardiomyopathy are maintained among patients already receiving tafamidis. Dr. Ejiri reviews a nationwide Swedish study of nearly 500,000 heart failure hospitalizations examining how cold spells, heat waves, and non-optimal temperatures influence short-term HF risk, including the different timing of risk after rising versus falling temperatures. Dr. Shoji explores how lepodisiran, an extended-duration siRNA targeting lipoprotein(a), markedly reduces oxidized phospholipids carried by Lp(a), providing further insight into the mechanisms linking Lp(a) with cardiovascular risk. The team discusses what these findings add to current evidence, how they may translate to clinical practice in Japan, and the key questions that remain.

Hosts Mitsuaki Sawano, MD, Shun Kohsaka, MD, Nobuhiro Ikemura, MD, and Satoshi Shoji, MD, welcome Yohei Sotomi, MD, PhD (The University of Osaka), and Ken Kozuma, MD, PhD (Teikyo University) for a special episode made possible through the JACC–Lancet partnership to discuss the OPTIMA-AF trial, published in The Lancet. In this investigator-initiated, multicenter randomized trial of 1,079 patients with atrial fibrillation undergoing PCI, 1 month of DOAC plus a P2Y12 inhibitor followed by DOAC monotherapy was compared with 12 months of dual antithrombotic therapy. The 1-month strategy met the prespecified noninferiority criterion for death or thromboembolic events and reduced major or clinically relevant non-major bleeding from 8.8% to 4.5%. The episode explores whether antithrombotic therapy after PCI can safely be shortened, how intracoronary imaging and contemporary PCI may influence this balance, and how the findings should be interpreted in clinical practice. Drs. Sotomi and Kozuma also take us behind the scenes of OPTIMA-AF, from an ambitious idea born through a research competition among Osaka University-affiliated hospitals, through COVID-related enrollment challenges and a prolonged recruitment period, to an initial rejection, appeal, extensive revision, and eventual publication in The Lancet.