Williams Monique, Kamiar Ali, Condor Capcha Jose Manuel, Rasmussen Monica Anne, Alitter Qusai, Kanashiro Takeuchi Rosemeire, Mitsuru Takeuchi Lauro, Hare Joshua M, Shehadeh Lina A
Department of Medicine, Division of Cardiology, University of Miami Leonard M. Miller School of Medicine; Interdisciplinary Stem Cell Institute, University of Miami Leonard M. Miller School of Medicine.
Interdisciplinary Stem Cell Institute, University of Miami Leonard M. Miller School of Medicine; Department of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine.
J Vis Exp. 2024 Mar 29(205). doi: 10.3791/66442.
The pathophysiology of heart failure with preserved ejection fraction (HFpEF) driven by lipotoxicity is incompletely understood. Given the urgent need for animal models that accurately mimic cardio-metabolic HFpEF, a hyperlipidemia-induced murine model was developed by reverse engineering phenotypes seen in HFpEF patients. This model aimed to investigate HFpEF, focusing on the interplay between lipotoxicity and metabolic syndrome. Hyperlipidemia was induced in wild-type (WT) mice on a 129J strain background through bi-weekly intraperitoneal injections of poloxamer-407 (P-407), a block co-polymer that blocks lipoprotein lipase, combined with a single intravenous injection of adeno-associated virus 9-cardiac troponin T-low-density lipoprotein receptor (AAV9-cTnT-LDLR). Extensive assessments were conducted between 4 and 8 weeks post-treatment, including echocardiography, blood pressure recording, whole-body plethysmography, echocardiography (ECG) telemetry, activity wheel monitoring (AWM), and biochemical and histological analyses. The LDLR/P-407 mice exhibited distinctive features at four weeks, including diastolic dysfunction, preserved ejection fraction, and increased left ventricular wall thickness. Notably, blood pressure and renal function remained within normal ranges. Additionally, ECG and AWM revealed heart blocks and reduced activity, respectively. Diastolic function deteriorated at eight weeks, accompanied by a significant decline in respiratory rates. Further investigation into the double treatment model revealed elevated fibrosis, wet/dry lung ratios, and heart weight/body weight ratios. The LDLR/P-407 mice exhibited xanthelasmas, ascites, and cardiac ischemia. Interestingly, sudden deaths occurred between 6 and 12 weeks post-treatment. The murine HFpEF model offers a valuable and promising experimental resource for elucidating the intricacies of metabolic syndrome contributing to diastolic dysfunction within the context of lipotoxicity-mediated HFpEF.
由脂毒性驱动的射血分数保留的心力衰竭（HFpEF）的病理生理学尚未完全明确。鉴于迫切需要能够准确模拟心脏代谢性HFpEF的动物模型，通过逆向工程HFpEF患者中观察到的表型，开发了一种高脂血症诱导的小鼠模型。该模型旨在研究HFpEF，重点关注脂毒性与代谢综合征之间的相互作用。通过每两周腹腔注射泊洛沙姆-407（P-407，一种阻断脂蛋白脂肪酶的嵌段共聚物），并结合单次静脉注射腺相关病毒9-心肌肌钙蛋白T-低密度脂蛋白受体（AAV9-cTnT-LDLR），在129J品系背景的野生型（WT）小鼠中诱导高脂血症。在治疗后4至8周进行了广泛评估，包括超声心动图、血压记录、全身体积描记法、超声心动图（ECG）遥测、活动轮监测（AWM）以及生化和组织学分析。LDLR/P-407小鼠在四周时表现出独特特征，包括舒张功能障碍、射血分数保留以及左心室壁厚度增加。值得注意的是，血压和肾功能仍在正常范围内。此外，ECG和AWM分别显示出心脏传导阻滞和活动减少。八周时舒张功能恶化，同时呼吸频率显著下降。对双重治疗模型的进一步研究显示纤维化、肺湿/干比以及心脏重量/体重比升高。LDLR/P-407小鼠出现睑黄瘤、腹水和心脏缺血。有趣的是，治疗后6至12周之间发生了猝死。该小鼠HFpEF模型为阐明在脂毒性介导的HFpEF背景下导致舒张功能障碍的代谢综合征的复杂性提供了宝贵且有前景的实验资源。
