Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Department of Pharmacology and Toxicology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Kingdom of Saudi Arabia.
Sci Rep. 2020 Jun 16;10(1):9746. doi: 10.1038/s41598-020-65943-9.
The molecular cause(s) for early onset heart failure in people living with HIV-1 infection (PLWH) remains poorly defined. Herein, longitudinal echocardiography was used to assess whether NOD.Cg-Prkdc Il2rgt/SzJ mice reconstituted with human hematopoietic stem cells (Hu-NSG mice) and infected with HIV-1 can recapitulate the salient features of this progressive human disease. Four weeks post infection, Hu-NSG mice of both sexes developed left ventricular (LV) diastolic dysfunction (DD), with 25% exhibiting grade III/IV restrictive DD with mitral regurgitation. Increases in global longitudinal and circumferential strains and declines in LV ejection fraction and fractional shortening were observed eight weeks post infection. After twelve weeks of infection, 33% of Hu-NSG mice exhibited LV dyskinesia and dyssynchrony. Histopathological analyses of hearts seventeen weeks post infection revealed coronary microvascular leakage, fibrosis and immune cell infiltration into the myocardium. These data show for the first time that HIV-1-infected Hu-NSG mice can recapitulate key left ventricular cardiac deficits and pathophysiological changes reported in humans with progressive HIV-1 infection. The results also suggest that HIV-1 infected Hu-NSG mice may be a useful model to screen for pharmacological agents to blunt LV dysfunction and associated pathophysiologic causes reported in PLWH.
导致人类免疫缺陷病毒 1 型（HIV-1）感染者（PLWH）早期心力衰竭的分子病因仍未明确。本研究采用纵向超声心动图评估了用人造血干细胞（Hu-NSG 小鼠）重建的 NOD.Cg-Prkdc Il2rgt/SzJ 小鼠感染 HIV-1 是否能重现这种进行性人类疾病的显著特征。感染后 4 周，雌雄 Hu-NSG 小鼠均出现左心室（LV）舒张功能障碍（DD），其中 25%出现二尖瓣反流的 III/IV 级限制型 DD。感染后 8 周观察到整体纵向和圆周应变增加，LV 射血分数和缩短分数降低。感染 12 周后，33%的 Hu-NSG 小鼠出现 LV 运动障碍和不同步。感染后 17 周心脏的组织病理学分析显示冠状动脉微血管渗漏、纤维化和免疫细胞浸润到心肌。这些数据首次表明，HIV-1 感染的 Hu-NSG 小鼠可重现报道的 HIV-1 感染进展过程中人类 LV 心脏缺陷和病理生理变化的关键特征。结果还表明，HIV-1 感染的 Hu-NSG 小鼠可能是筛选用于减轻 PLWH 报道的 LV 功能障碍和相关病理生理原因的药理学药物的有用模型。
