BACKGROUND Heart failure with preserved ejection fraction (HFpEF) is an emerging major unmet need and one of the most significant clinic challenges in cardiology. The pathogenesis of HFpEF is associated with multiple risk factors. Hypertension and metabolic disorders associated with obesity are the 2 most prominent comorbidities observed in patients with HFpEF. Although hypertension-induced mechanical overload has long been recognized as a potent contributor to heart failure with reduced ejection fraction, the synergistic interaction between mechanical overload and metabolic disorders in the pathogenesis of HFpEF remains poorly characterized. METHOD We investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction in lean C57Bl/6J or obese/diabetic B6.Cg-Lepob/J (ob/ob) mice, followed by single-nuclei RNA-seq and targeted manipulation of a top-ranked signaling pathway differentially affected in the 2 experimental cohorts. RESULTS In contrast to the post-transverse aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-transverse aortic constriction ob/ob mice showed no significant changes in ejection fraction but developed characteristic pathological features of HFpEF, including diastolic dysfunction, worsened cardiac hypertrophy, and pathological remodeling, along with further deterioration of exercise intolerance. Single-nuclei RNA-seq analysis revealed significant transcriptome reprogramming in the cardiomyocytes stressed by both pressure overload and obesity/diabetes, markedly distinct from the cardiomyocytes singularly stressed by pressure overload or obesity/diabetes. Furthermore, glucagon signaling was identified as the top-ranked signaling pathway affected in the cardiomyocytes associated with HFpEF. Treatment with a glucagon receptor antagonist significantly ameliorated the progression of HFpEF-related pathological features in 2 independent preclinical models. Importantly, cardiomyocyte-specific genetic deletion of the glucagon receptor also significantly improved cardiac function in response to pressure overload and metabolic stress. CONCLUSIONS These findings identify glucagon receptor signaling in cardiomyocytes as a critical determinant of HFpEF progression and provide proof-of-concept support for glucagon receptor antagonism as a potential therapy for the disease.

中文翻译：

---

胰高血糖素受体拮抗剂治疗射血分数保留的心力衰竭。


背景 射血分数保留的心力衰竭 （HFpEF） 是一个新兴的未满足的主要需求，也是心脏病学领域最重要的临床挑战之一。HFpEF 的发病机制与多种危险因素有关。高血压和与肥胖相关的代谢紊乱是在 HFpEF 患者中观察到的 2 种最突出的合并症。尽管高血压诱导的机械超负荷长期以来一直被认为是导致射血分数降低的心力衰竭的有效因素，但机械超负荷与 HFpEF 发病机制中代谢紊乱之间的协同相互作用仍然不清楚。方法 我们通过在瘦 C57Bl/6J 或肥胖/糖尿病 B6 中应用横主动脉收缩来研究心脏并发机械和代谢应激的功能结果和潜在机制。Cg-Lepob/J （ob/ob） 小鼠，然后是单核 RNA-seq 和靶向操作在 2 个实验队列中受到差异影响的排名靠前的信号通路。结果 与横主动脉缩窄后 C57Bl/6J 瘦小鼠出现心力衰竭病理特征伴射血分数随时间降低相比，横主动脉缩窄后 ob/ob 小鼠射血分数无显著变化，但出现 HFpEF 的特征性病理特征，包括舒张功能障碍、心脏肥大恶化和病理重塑，以及运动不耐受的进一步恶化。 单核 RNA-seq 分析显示，受压力超负荷和肥胖/糖尿病压力的心肌细胞中存在显着的转录组重编程，与受压力超负荷或肥胖/糖尿病单独压力的心肌细胞明显不同。 此外，胰高血糖素信号转导被确定为与 HFpEF 相关的心肌细胞中受影响的排名第一的信号通路。在 2 个独立的临床前模型中，胰高血糖素受体拮抗剂治疗显着改善了 HFpEF 相关病理特征的进展。重要的是，胰高血糖素受体的心肌细胞特异性基因缺失也显著改善了响应压力超负荷和代谢应激的心脏功能。结论 这些发现确定心肌细胞中的胰高血糖素受体信号转导是 HFpEF 进展的关键决定因素，并为胰高血糖素受体拮抗作用作为该疾病的潜在疗法提供了概念验证支持。