Pepin Mark E, Konrad Philipp J M, Nazir Sumra, Bazgir Farhad, Maack Christoph, Nickel Alexander, Gorman Joshua M, Hohl Mathias, Schreiter Friederike, Dewenter Matthias, de Britto Chaves Filho Adriano, Schulze Almut, Karlstaedt Anja, Frey Norbert, Seidman Christine E, Seidman Jonathan G, Backs Johannes
Medical Faculty Heidelberg, Institute of Experimental Cardiology (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.), Heidelberg University, Germany.
Department of Internal Medicine VIII (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.), Heidelberg University Hospital, Germany.
Circ Res. 2025 Jun 6;136(12):1564-1578. doi: 10.1161/CIRCRESAHA.125.326154. Epub 2025 May 9.
Clinical management of heart failure with preserved ejection fraction (HFpEF) is hindered by a lack of disease-modifying therapies capable of altering its distinct pathophysiology. Despite the widespread implementation of a 2-hit model of cardiometabolic HFpEF to inform precision therapy, which utilizes HFD+L-NAME (ad libitum high-fat diet and 0.5% N[ω]-nitro-L-arginine methyl ester), we observe that C57BL6/J mice exhibit less cardiac diastolic dysfunction in response to HFD+L-NAME.
Genetic strain-specific single-nucleus transcriptomic analysis identified disease-relevant genes that enrich oxidative metabolic pathways within cardiomyocytes. Because C57BL/6J mice are known to harbor a loss-of-function mutation affecting the inner mitochondrial membrane protein (nicotinamide nucleotide transhydrogenase), we established an isogenic model of loss-of-function to determine whether intact NNT is necessary for the pathological cardiac manifestations of HFD+L-NAME. Twelve-week-old mice cross-bred to isolate wild-type () or loss-of-function () in the C57BL/6N background were challenged with HFD+L-NAME for 9 weeks (N=6-10).
mice exhibited impaired ventricular diastolic relaxation and pathological remodeling, as assessed via noninvasive echocardiographic quantification of early diastolic pulse-wave velocity (E) to mitral annular velocity (e') ratio (E/e') (42.8 versus 21.5, =1.2×10), E/A (early-to-late mitral inflow velocity ratio) (2.3 versus 1.4, =4.1×10), diastolic stiffness (0.09 versus 0.04 mm Hg/μL, =5.1×10), and myocardial fibrosis (=2.3×10). Liquid chromatography and mass spectroscopy exposed a 40.0% reduction in NAD (=8.4×10) and a 38.8% reduction in the ratio of reduced-to-oxidized glutathione (GSH: GSSG, =2.6×10) among mice after HFD+L-NAME feeding. Using single-nucleus ligand-receptor analysis, we implicate Fgf1 (fibroblast growth factor 1) as a putative NNT-dependent mediator of cardiomyocyte-to-fibroblast signaling in myocardial fibrosis.
Together, these findings underscore the pivotal role of mitochondrial dysfunction in HFpEF pathogenesis, implicating both NNT and Fgf1 as novel therapeutic targets.
射血分数保留的心力衰竭（HFpEF）的临床管理因缺乏能够改变其独特病理生理学的疾病修饰疗法而受到阻碍。尽管广泛采用了一种用于指导精准治疗的心脏代谢性HFpEF双打击模型，即利用高脂饮食（HFD）+左旋精氨酸甲酯（L-NAME），但我们观察到C57BL6/J小鼠对HFD+L-NAME的心脏舒张功能障碍反应较小。
基因品系特异性单核转录组分析确定了在心肌细胞内丰富氧化代谢途径的疾病相关基因。由于已知C57BL/6J小鼠存在影响线粒体内膜蛋白（烟酰胺核苷酸转氢酶）的功能丧失突变，我们建立了功能丧失的同基因模型，以确定完整的NNT对于HFD+L-NAME的病理性心脏表现是否必要。将12周龄在C57BL/6N背景下杂交以分离野生型（ ）或功能丧失型（ ）的小鼠用HFD+L-NAME攻击9周（N = 6 - 10）。
通过无创超声心动图对舒张早期脉搏波速度（E）与二尖瓣环速度（e'）之比（E/e'）（42.8对21.5， = 1.2×10）、E/A（二尖瓣流入早期与晚期速度比）（2.3对1.4， = 4.1×10）、舒张硬度（0.09对0.04 mmHg/μL， = 5.1×10）和心肌纤维化（ = 2.3×10）进行量化评估，发现 小鼠出现心室舒张松弛受损和病理性重塑。液相色谱和质谱分析显示，在给予HFD+L-NAME后， 小鼠体内的烟酰胺腺嘌呤二核苷酸（NAD）降低了40.0%（ = 8.4×10），还原型谷胱甘肽与氧化型谷胱甘肽的比率（GSH:GSSG）降低了38.8%（ = 2.6×10）。使用单核配体-受体分析，我们认为成纤维细胞生长因子1（Fgf1）是心肌纤维化中心肌细胞与成纤维细胞信号传导的一种假定的NNT依赖性介质。
总之，这些发现强调了线粒体功能障碍在HFpEF发病机制中的关键作用，表明NNT和Fgf1均为新的治疗靶点。
