Department of Medicine Division of Cardiology University of Miami Leonard M. Miller School of Medicine Miami FL.
Interdisciplinary Stem Cell Institute University of Miami Leonard M. Miller School of Medicine Miami FL.
J Am Heart Assoc. 2022 Sep 6;11(17):e027216. doi: 10.1161/JAHA.122.027216. Epub 2022 Sep 3.
Background The pathways of diastolic dysfunction and heart failure with preserved ejection fraction driven by lipotoxicity with metabolic syndrome are incompletely understood. Thus, there is an urgent need for animal models that accurately mimic the metabolic and cardiovascular phenotypes of this phenogroup for mechanistic studies. Methods and Results Hyperlipidemia was induced in WT-129 mice by 4 weeks of biweekly poloxamer-407 intraperitoneal injections with or without a single intravenous injection of adeno-associatedvirus 9-cardiac troponin T-low-density lipoprotein receptor (n=31), or single intravenous injection with adeno-associatedvirus 9-cardiac troponin T-low-density lipoprotein receptor alone (n=10). Treatment groups were compared with untreated or placebo controls (n=37). Echocardiography, blood pressure, whole-body plethysmography, ECG telemetry, activity wheel monitoring, and biochemical and histological changes were assessed at 4 to 8 weeks. At 4 weeks, double treatment conferred diastolic dysfunction, preserved ejection fraction, and increased left ventricular wall thickness. Blood pressure and whole-body plethysmography results were normal, but respiration decreased at 8 weeks (<0.01). ECG and activity wheel monitoring, respectively, indicated heart block and decreased exercise activity (<0.001). Double treatment promoted elevated myocardial lipids including total cholesterol, fibrosis, increased wet/dry lung (<0.001) and heart weight/body weight (<0.05). Xanthelasma, ascites, and cardiac ischemia were evident in double and single (p407) groups. Sudden death occurred between 6 and 12 weeks in double and single (p407) treatment groups. Conclusions We present a novel model of heart failure with preserved ejection fraction driven by dyslipidemia where mice acquire diastolic dysfunction, arrhythmia, cardiac hypertrophy, fibrosis, pulmonary congestion, exercise intolerance, and preserved ejection fraction in the absence of obesity, hypertension, kidney disease, or diabetes. The model can be applied to dissect pathways of metabolic syndrome that drive diastolic dysfunction in this lipotoxicity-mediated heart failure with preserved ejection fraction phenogroup mimic.
脂毒性与代谢综合征共同作用导致射血分数保留心力衰竭的舒张功能障碍途径尚不完全清楚。因此，迫切需要能够准确模拟该表型群代谢和心血管表型的动物模型，以进行机制研究。
在 WT-129 小鼠中，通过每两周进行 4 次腹腔内注射聚氧乙烯 407 或单次静脉注射腺相关病毒 9-肌钙蛋白 T-低密度脂蛋白受体（n=31），或单独单次静脉注射腺相关病毒 9-肌钙蛋白 T-低密度脂蛋白受体（n=10）来诱导高血脂症。将治疗组与未治疗或安慰剂对照组（n=37）进行比较。在 4 至 8 周时评估超声心动图、血压、全身 plethysmography、心电图遥测、活动轮监测、生化和组织学变化。在 4 周时，双重治疗导致舒张功能障碍、射血分数保留和左心室壁厚度增加。血压和全身 plethysmography 结果正常，但 8 周时呼吸减少（<0.01）。心电图和活动轮监测分别表明存在心脏传导阻滞和运动活动减少（<0.001）。双重治疗导致心肌脂质升高，包括总胆固醇、纤维化，增加湿/干肺重量（<0.001）和心脏重量/体重（<0.05）。在双重和单（p407）治疗组中可见黄瘤、腹水和心肌缺血。双重和单（p407）治疗组在 6 至 12 周之间发生猝死。
我们提出了一种新的由血脂异常驱动的射血分数保留心力衰竭模型，其中小鼠在没有肥胖、高血压、肾病或糖尿病的情况下，出现舒张功能障碍、心律失常、心脏肥大、纤维化、肺充血、运动不耐受和射血分数保留。该模型可用于剖析导致这种脂毒性介导的射血分数保留心力衰竭表型群模拟舒张功能障碍的代谢综合征途径。
