今井 靖

BACKGROUND: Coronary artery disease (CAD) and aortic valve stenosis (AS) often coexist, with AS exacerbating myocardial ischemia and affecting prognosis. AIMS: To investigate the prognostic impact of AS stratified by peak aortic jet velocity (AV-Vel) in patients undergoing PCI. METHODS AND RESULTS: We conducted retrospective multicenter observational study involving patients who underwent percutaneous coronary intervention (PCI) between April 2013 and March 2019. The patients were divided into non-AS group and AS group. The AS group was further categorized: 2.6 ≤ AV-Vel < 3.0 m/s, mild AS; 3.0 ≤ AV-Vel < 4.0 m/s, moderate AS; and AV-Vel ≥ 4.0 m/s, severe AS. The primary outcome was all-cause mortality, and the secondary outcome was major adverse cardiovascular events (MACE), defined as a composite of all-cause mortality, myocardial infarction, or stroke. Multivariable Cox proportional hazards analysis was performed over 5-year observation period, with landmark analyses conducted at 30 days after PCI and from day 31 after PCI to 5 years. In total, 9,690 patients were analyzed (AS group, n = 361). Over a median follow-up of 2.57 (IQR: 0.89-4.24) years, AS group exhibited higher rates of mortality (HR: 3.06; 95% CI: 2.41-3.90; p < 0.001) and MACE (HR: 2.45; 95%CI: 1.97-3.04; p < 0.001) compared with non-AS group. Subgroup analysis revealed that patients with moderate and severe AS had worse short-term mortality and MACE within 30 days after PCI than the non-AS group, while patients with mild to severe AS showed significantly worse long-term outcomes than the non-AS group. CONCLUSIONS: AV-Vel is independently associated with both short- and long-term outcomes in patients undergoing PCI.

Early-stage diagnosis of paroxysmal atrial fibrillation (PAF) is challenging owing to its asymptomatic nature. However, the genetic factors underlying PAF and predictive utility of polygenic risk scores (PRSs) for PAF in Asian populations remain elusive. We aimed to explore the PAF-associated genetic variants in a Japanese cohort and evaluate the predictive performance of PAF-specific PRSs. This study included 2,604 participants. Following exclusion, quality control, and genotype imputation, a genome-wide association study (GWAS) was conducted. The predictive performance of 30 sets of PRS models constructed across various thresholds was evaluated using three machine learning methods. Model performance was assessed using area under the curve (AUC) and SHapley Additive exPlanations (SHAP). The GWAS using 1,038 PAF cases and 744 controls identified 82 genome-wide significant variants ( P  &lt; 5 × 10 ⁻⁸ ), all on chromosome 4q25. Of these, 80 variants clustered upstream of PITX2 , and two were located in LINC01438 . Fine mapping identified two independent intergenic signals, with rs2200732 as the lead single-nucleotide polymorphism. The best PRS-only model achieved an AUC of &gt;0.70, which was improved up to 0.737 in additive models incorporating both PRS and clinical variables. SHAP analysis consistently ranked PRS as the most influential predictor among the clinical variables included in this study. These results suggest that genetic risk, particularly at the established 4q25/ PITX2 locus, contributes substantially to PAF susceptibility in this Japanese cohort and that PRS may improve early risk stratification when integrated with clinical risk factors.

OBJECTIVES: The association between blood pressure (BP) and the mortality risk may vary depending on the comorbidities. This study was conducted to investigate the subgroup-specific correlation between systolic BP (SBP) and mortality in patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). METHODS: The Clinical Deep Data Accumulation System for PCI (CLIDAS-PCI), a nation-wide multicenter database with seven tertiary medical hospitals in Japan, retrospectively collected data on patients undergoing PCI for acute coronary syndrome or stable coronary artery disease. Cubic spline curves modeled the relationship between SBP and all-cause death in the entire cohort and subgroups stratified by age, sex, diabetes, left ventricular (LV) hypertrophy, renal function and LV systolic function. We assessed the SBP, which minimizes mortality risk. RESULTS: A total of 8384 patients [71 [IQR 64, 78] years, 6494 (77%) male] with SBP at hospital discharge were analyzed. During 2.7 years of median follow-up, 695 deaths occurred. In the overall population, spline analysis demonstrated a nadir range of mortality risk around an SBP of 110-130 mmHg. Subgroup analyses revealed that elderly (age ≥ 80 years), those with renal dysfunction, and those with preserved LV systolic function had higher SBP levels associated with lowest risk. Conversely, patients <80 years, those with better renal function, and those with LV systolic dysfunction exhibited lower SBP levels at lowest risk. CONCLUSION: This study demonstrated differential association between SBP and mortality risk in various subgroups, highlighting the need for personalized BP management in multimorbid patients with coronary artery disease.

AIMS: Hypoxia-inducible factor (HIF) signalling influences cardiomyocyte differentiation, maturation, and metabolic adaptation under pathological conditions. HIF-Prolyl hydroxylase domain (HIF-PH) inhibitors, which target this pathway, have been introduced for the treatment of renal anaemia. Their precise effect or safety on cardiac function remains unclear because their pharmacokinetics and distribution are not well-understood. This study aimed to examine HIF signalling activation in adult cardiomyocytes (CMs). METHODS AND RESULTS: We used tamoxifen (TAM)-inducible, CM-specific von Hippel-Lindau (VHL) knockout (VHL-MCM) mice to activate CM HIF signalling. Then we subjected the mice to normal ageing or high-fat diet (HFD) and L-NAME feeding, a murine model of heart failure with preserved ejection fraction (HFpEF). In normal ageing group, there was no difference in the echocardiographic parameters or tissue fibrosis between VHL-MCM and control mice. VHL-MCM mice exhibited significantly increased capillary density and higher expression levels of HIF-target genes (P = 0.0248, two-way ANOVA). Under HFD + L-NAME treatment, VHL-MCM mice showed transient but significantly preserved global longitudinal strain (GLS) at 12 weeks post-TAM injection compared to controls (P = 0.0284, two-way ANOVA). Sirius red staining indicated a trend towards reduced whole-heart and interstitial fibrosis with significant increase in capillary density in VHL-MCM mice. CONCLUSION: Sustained HIF signalling activation in adult CM does not impair the cardiac structure and function in normal ageing process and shows transient yet beneficial effect in murine HFpEF model.