Hosts Mitsuaki Sawano, MD, Kentaro Ejiri, MD, and Satoshi Shoji, MD, welcome Dr. Shunsuke Inoue of The University of Tokyo to discuss clonal hematopoiesis of indeterminate potential (CHIP) and its cardiovascular implications. Dr. Inoue provides expert commentary on two recent JACC publications: a Women’s Health Initiative analysis linking CHIP mutations such as TET2, ASXL1, and JAK2 with distinct cardiovascular outcomes in older women, and an exploratory substudy of the LoDoCo2 trial examining whether low-dose colchicine modifies CHIP clone dynamics. Together, these studies highlight the complexity of CHIP as both a biomarker and a potential therapeutic target, raising new questions about how age, mutation subtype, and anti-inflammatory strategies intersect in cardiovascular risk.

Hosts Mitsuaki Sawano, MD, and colleagues welcome Dr. Jun Yasuhara (Center for Cardiovascular Research and Heart Center, Nationwide Children’s Hospital) and Dr. Toshiomi Katsuki (Saitama City Hospital) for a Basic to Translational Science special. Dr. Jun Yasuhara presents his mouse model study on congenital aortic valve disease, showing how disruption of NOTCH1 and GATA5 produces a highly penetrant, clinically relevant bicuspid aortic valve and progressive aortic stenosis phenotype. Dr. Toshiomi Katsuki highlights his work on Scarb1 in endothelial cells, revealing how this receptor mediates maladaptive crosstalk with fibroblasts under pressure overload. Using single-cell RNA sequencing and spatial transcriptomics, his team mapped pathogenic signaling networks and demonstrated that knocking out Scarb1 or pharmacologically inhibiting it attenuates heart failure progression, positioning endothelial cells as a novel therapeutic target.

Hosts Mitsuaki Sawano, MD, Kentaro Ejiri, MD, and Satoshi Shoji, MD, welcome Dr. Shunsuke Uetake of Nippon Medical School Chiba Hokusoh Hospital to discuss the clinical presentation and long-term outcomes of late-onset symptomatic arrhythmogenic right ventricular cardiomyopathy (ARVC), based on a retrospective cohort study recently published in JACC: Clinical Electrophysiology. Dr. Uetake reviews findings from 76 probands with definite ARVC by 2010 Task Force criteria who presented with symptomatic ventricular arrhythmias between 2004 and 2024. Patients were divided into early-onset (≤40 years) and late-onset (>40 years) groups. Compared with early-onset disease, late-onset ARVC was associated with less severe initial presentation (palpitations more common, fewer syncope or cardiac arrest cases), slower ventricular tachycardia cycle length, and fewer arrhythmic events and heart failure progression during long-term follow-up, despite similar structural substrate on electroanatomical mapping. These results highlight that age of onset, even within the same genetic background, may shape the arrhythmic burden and clinical trajectory of ARVC, raising new questions about risk stratification and management in this rare but high-stakes cardiomyopathy.

Mitsuaki Sawano, MD, with Nobuhiro Ikemura, MD highlight two JACC papers simultaneously published at ESC 2025. “Comparison of Extended Cryoballoon Ablation, Standard Cryoballoon Ablation, and Radiofrequency Catheter Ablation in Patients with Persistent AF (EXCAPE-AF Trial)” – In persistent AF, extended CB with posterior wall isolation offered no benefit over standard CB or RF, underscoring PVI as central. 2nd paper titled “Impact of Obicetrapib on Major Adverse Cardiovascular Events in High-Risk Patients: A Pooled Analysis” – This next-gen CETP inhibitor produced robust lipid lowering and a signal for coronary event reduction, reviving interest after prior CETP concerns.

Hosts Mitsuaki Sawano, MD, Shun Kohsaka, MD, and Satoshi Shoji, MD, highlight two JACC papers simultaneously published at ESC 2025. Computed Tomography Angiography or Standard of Care after Left Main PCI? The PULSE Trial tested routine CCTA follow-up versus symptom- or ischemia-driven management after LM PCI. While the primary composite outcome showed no difference, CCTA reduced spontaneous MI but increased imaging-driven revascularization. The Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction: A Novel Framework to Explain Pathogenesis and Guide Treatment by Dr. Milton Packer proposes that HFpEF is driven by visceral adiposity–mediated adipokine imbalance, leading to systemic inflammation, hypertrophy, and fibrosis, offering a unifying framework for pathogenesis and therapeutic strategies.

Hosts Mitsuaki Sawano, MD, Shun Kohsaka, MD, and Satoshi Shoji, MD, highlight two JACC papers simultaneously published at ESC 2025. Twice-A-Day Clopidogrel vs Ticagrelor to Reduce Short-Term MACE after Primary PCI: The TADCLOT Trial tested whether ticagrelor is superior to high-dose clopidogrel in reducing 30-day MACE after primary PCI for STEMI. While no difference was observed at 30 days, ticagrelor showed a signal for early ischemic protection at 7 and 14 days without excess bleeding. Personalized or Standard Duration of Dual Antiplatelet Therapy after PCI: The PARTHENOPE Trial compared risk score–guided DAPT durations (3, 6, or 24 months) against the standard 12-month strategy in over 2,000 PCI patients. Personalized therapy reduced NACE at 24 months, driven by fewer ischemic events, with no excess in bleeding.

Hosts Mitsuaki Sawano, MD, and Kentaro Ejiri, MD, highlight two JACC papers simultaneously published at ESC 2025. Prediction of Aortic Stenosis Progression Using Artificial Intelligence: A Machine Learning Model reports an interpretable algorithm using echo parameters alone to forecast AS progression within 5 years. Mechanistic Basis for Differential Effects of Interatrial Shunt Treatment in HFrEF vs HFpEF: The RELIEVE-HF Trial examines structural and hemodynamic differences explaining why shunt therapy reduced LV volumes in HFrEF but increased PASP and RA area in HFpEF.

Hosts Mitsuaki Sawano, MD, Shun Kohsaka, MD, Nobuhiro Ikemura, MD, and Satoshi Shoji, MD, welcome Dr. Hidenori Yaku to discuss orthostatic pulse pressure (OPP) as a marker of preload insufficiency in HFpEF, based on a prespecified analysis from the PRESERVED-HF trial. Dr. Yaku reviews findings from 324 patients with HFpEF randomized to dapagliflozin or placebo. Across groups with high, intermediate, or low OPP, dapagliflozin improved health status as measured by the Kansas City Cardiomyopathy Questionnaire and increased six-minute walk distance, with no significant interaction by OPP level. However, fluid depletion–related adverse events, although infrequent overall, were observed more often in patients with the lowest OPP. These results suggest that simple measurement of OPP may help identify patients at higher risk for volume depletion events, while the symptomatic and functional benefits of SGLT2 inhibition are preserved across the spectrum of OPP.