Takumi Inoue

Aims: B-type natriuretic peptide (BNP) levels of 35–100 pg/mL, common in preclinical heart failure (HF), are associated with heterogeneous prognosis and are influenced by age and renal function. We aimed to characterize risk heterogeneity in preclinical HF patients with BNP levels of 35–100 pg/mL and to develop a practical risk stratification model. Methods and results: Data from the Chronic Heart Failure Registry and Analysis in the Tohoku District-2 (CHART-2) Study, a prospective multicentre cohort with long-term follow-up, were analysed. Among patients with Stage B HF (n = 4074; age 67.6 ± 12.0 years), the predictability of BNP for 10-year HF-related events was evaluated across strata of age and estimated glomerular filtration rate (eGFR). In patients with BNP levels of 35–100 pg/mL, a composite risk score—the Pre-Heart Failure Assessment and Screening Evaluation (PHASE) Index—was developed using classification and regression tree analysis and multivariable Cox proportional hazards modelling. BNP discrimination varied significantly by age and eGFR (P < 0.05), indicating that a single BNP threshold is insufficient for risk stratification in preclinical HF. The PHASE Index, incorporating age, BNP, eGFR, left ventricular ejection fraction, body mass index, and hypertension, stratified patients with BNP levels of 35–100 pg/mL into four categories and demonstrated superior discrimination compared with BNP alone (c-index 0.723 vs. 0.587, P < 0.05). Conclusion: Patients with preclinical HF and BNP levels of 35–100 pg/mL exhibit substantial risk heterogeneity. The PHASE Index improves identification of high-risk individuals and provides a pragmatic tool for risk stratification beyond the conventional BNP threshold.

BACKGROUND: Pulmonary hypertension (PH) due to left heart disease (group 2 PH) is associated with a worse prognosis than isolated heart failure. Both pulmonary arterial hypertension (group 1 PH) and group 2 PH are involved in pulmonary artery (PA) remodeling, which is potentially driven by shared molecular mechanisms. The aim of this study was to investigate the underlying processes contributing to PA remodeling in group 2 PH. METHODS: To mimic the response to a left-sided pressure load, pulmonary arterial smooth muscle cells (PASMCs) were subjected to mechanical stretch. RNA sequencing of PAs from patients with group 2 PH was performed using the Gene Expression Omnibus database. Mice with transverse aortic constriction and spontaneously hypertensive rats were used as group 2 PH models, and they were treated with adeno-associated virus via intratracheal instillation. RESULTS: RNA sequencing of PASMCs after the stretch stress identified 1585 genes specifically upregulated in PASMCs from patients with group 1 PH. Further PA and plasma analyses from patients with group 2 PH, integrated with group 1 PH findings, identified enhancement of TGF-β (transforming growth factor-beta) signaling by the INHBA (inhibin subunit beta A) as a key feature. Metabolomics revealed that stretch-induced mitochondrial dysfunction in PASMCs caused lactic acidosis via enhancement of PDK1 (pyruvate dehydrogenase kinase 1) and c-MYC, leading to increased INHBA expression. Mice with transverse aortic constriction exhibited increased INHBA expression, decreased PDH (pyruvate dehydrogenase) expression, and acidic alterations in PAs. Targeted silencing of INHBA or PDK1 using adeno-associated virus in mice with transverse aortic constriction attenuated PA remodeling, improved right ventricular function, and reduced PH. CONCLUSIONS: Integrated RNA sequencing and metabolomics with stretched PASMCs and animal models identified mitochondrial dysfunction and subsequent acidic alterations as stimulators of increased INHBA expression and TGF-β signaling. These mechanisms contributed to PA remodeling in group 2 PH and provided potential therapeutic strategies.