Nicotinamide for the treatment of heart failure with preserved ejection fraction. Nicotinamide for the treatment of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats) or cardiometabolic syndrome (in ZSF1 obese rats). Mechanistically, this effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics, as evidenced by cardiac trasncriptome and metabolome analyses. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium ATPase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD+ precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD+ precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans. Overall design: The aim of this study was to investigate the role of NAD+ in diastolic dysfunction and HFpEF. We quantified cardiac NAD+ in clinical and experimental HFpEF and evaluated the association between dietary intake of naturally occurring NAD+ precursors and cardiac mortality in a long-term human cohort. To examine the effect of increasing cellular NAD+ abundance on diastolic dysfunction in vivo, the NAD+ precursor NAM was orally supplemented to ZSF1 obese rats, which model key risk factors for HFpEF, namely hypertension, obesity and metabolic syndrome. We applied a multitude of in vivo and in vitro assays, including invasive hemodynamics, echocardiography, exercise tolerance testing with indirect calorimetry, RNA sequencing, metabolome profiling, and myocardial bioenergetics. For RNA sequencing, 4 myocardial rat samples per group were used, including lean ZSF1 rats as non-failing controls.

射血分数保留型心力衰竭（HFpEF）是一种患病率极高且难以治愈的心脏失代偿亚型，常与舒张功能障碍相关。本研究证实，HFpEF患者的舒张功能障碍与心脏烟酰胺腺嘌呤二核苷酸（NAD+）水平不足存在关联。通过口服补充其前体烟酰胺以提升NAD+水平，可改善衰老（2岁龄C57BL/6J小鼠模型）、高血压（Dahl盐敏感性大鼠模型）或心脏代谢综合征（ZSF1肥胖大鼠模型）诱导的舒张功能障碍。
从机制上看，该作用部分通过减轻全身共病状况、增强心肌生物能功能实现，这一点可通过心脏转录组（transcriptome）与代谢组（metabolome）分析得到验证。同时，烟酰胺可分别通过促进肌联蛋白（titin）的去乙酰化、提升肌浆网钙ATP酶2a（sarcoplasmic reticulum calcium ATPase 2a）的活性，直接改善心肌细胞被动僵硬度与钙依赖性主动舒张功能。
在一项长期人类队列研究中，膳食中天然存在的NAD+前体摄入水平较高，与较低的血压水平及更低的心脏死亡风险相关。综上，本研究结果提示NAD+前体（尤其是烟酰胺）可作为治疗人类舒张功能障碍与HFpEF的潜在治疗药物。
整体研究设计：本研究旨在探究NAD+在舒张功能障碍与HFpEF中的作用。我们定量检测了临床及实验性HFpEF模型中的心脏NAD+水平，并在长期人类队列中评估了天然NAD+前体的膳食摄入与心脏死亡风险之间的关联。为考察体内提升细胞NAD+丰度对舒张功能障碍的改善作用，我们将NAD+前体烟酰胺经口给药给ZSF1肥胖大鼠——该模型可模拟HFpEF的关键危险因素：高血压、肥胖与代谢综合征。本研究采用了多种体内、体外实验手段，包括有创血流动力学检测、超声心动图检查、结合间接量热法的运动耐量试验、RNA测序（RNA sequencing）、代谢组（metabolome）分析及心肌生物能学检测。在RNA测序实验中，每组设置4份大鼠心肌样本，以瘦型ZSF1大鼠作为非心力衰竭对照。