CARDIAC DYSFUNCTION, AIDS AND COCAINE

心脏功能障碍、艾滋病和可卡因

• 批准号: 6527570
• 负责人: WILLIAM LEWIS
• 金额: $ 38万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-27 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527570
• 关键词: AIDS; atrial natriuretic peptide; beta adrenergic receptor; calcium flux; cardiotoxin; cocaine; comorbidity; disease /disorder proneness /risk; electrocardiography; endothelin; genetically modified animals; heart rhythm; histopathology; hypertrophic myocardiopathy; immunoelectron microscopy; laboratory mouse; light microscopy; telemetry; transmission electron microscopy; tumor necrosis factor alpha

This project defines how AIDS and cocaine use contribute to cardiac dysfunction. Sudden death and congestive heart failure as serious consequences of cocaine use. Cardiomyopathy (CM) has become an important complication of AIDS. Unfortunately, cocaine use and AIDS may coincide in the same patient. This suggests the possibility of additive or synergistic deleterious effects. The working hypothesis states: Cardiac dysfunction occurs in AIDS and in cocaine use. When AIDS and cocaine administration occur together, additive or synergistic effects worsen cardiac dysfunction, CM, and increase the risk of sudden death. Tumor necrosis factor alpha (TNFalpha) and endothelin-1 (ET-1) are expressed in both conditions. They exert changes in adrenergic responsiveness, calcium handling, and result in myocyte death and myocardial fibrosis. The AIMS of the project are: (1) to define altered cardiac performance and disturbed cardiac rhythm in AIDS and cocaine administration; (2) to define alterations in myocardial beta-adrenergic receptor (betaAR) density and subtype expression, expression of Ca transporters, and markers of remodeling in AIDS and cocaine administration; and (3) to define cardiac pathological features in AIDS and cocaine administration. A novel system of transgenic mice (TGs) that harbor replication- incompetent HIV-1 serves as an exquisite tool to help define pathophysiological events in AIDS with cocaine administration. TGs receive cocaine by constant infusion via osmotic minipumps. Preliminary data with this system indicate that cocaine is more cardiotoxic to AIDS TGs than to FVB/n wild types. It results in left ventricular hypertrophy (LVH), ventricular remodeling, decreased adrenergic responsiveness, ventricular expression of atrial natriuretic factor (ANF) and premature death. A multidisciplinary approach addresses pathophysiologic mechanisms. EKG telemetry identifies electrophysiological causes of sudden death from cocaine in AIDS. Serial echocardiographic measurements define ventricular performance, and chamber dimensions. Studies with isolated work-performing hearts identify contractile defects and control for load. BetaAR function studies biochemically define cardiac adrenergic receptor abundance and function. Abundance of mRNAs for elements of calcium handling and LV remodeling indicates cardiac molecular changes. Gross, light microscopic (LM) and ultrastructural (TEM) pathology studies pinpoint ventricular remodeling, myocyte death, and fibrosis and morphometrically quantitate these changes. Immuno-LM and immuno-TEM identify cellular and subcellular alterations.

该项目定义了艾滋病和可卡因的使用如何导致心脏功能障碍。 使用可卡因的严重后果是猝死和充血性心力衰竭。 心肌病（CM）已成为艾滋病的重要并发症。 不幸的是，可卡因使用和艾滋病可能同时发生在同一患者身上。 这表明可能存在累加或协同有害效应。 工作假设指出：心脏功能障碍发生在艾滋病和可卡因使用中。 当艾滋病和可卡因同时服用时，叠加或协同作用会加重心功能障碍、CM，并增加猝死的风险。 肿瘤坏死因子 α (TNFα) 和内皮素-1 (ET-1) 在这两种情况下均表达。 它们改变肾上腺素能反应性、钙处理，并导致心肌细胞死亡和心肌纤维化。 该项目的目标是：(1) 定义艾滋病和可卡因给药时心脏功能的改变和心律紊乱； (2) 定义心肌β-肾上腺素能受体（βAR）密度和亚型表达、Ca转运蛋白表达以及艾滋病和可卡因给药中重塑标志物的变化； (3) 明确艾滋病和可卡因给药中的心脏病理学特征。一种新的转基因小鼠（TG）系统，其携带无法复制的HIV-1，可以作为一种精致的工具来帮助确定可卡因给药引起的艾滋病的病理生理学事件。 TG 通过微型渗透泵持续输注来接收可卡因。该系统的初步数据表明，可卡因对 AIDS TG 的心脏毒性比对 FVB/n 野生型的心脏毒性更大。 它导致左心室肥厚（LVH）、心室重构、肾上腺素能反应性降低、心房钠尿因子（ANF）心室表达降低和过早死亡。多学科方法解决病理生理机制。 心电图遥测可识别艾滋病患者因可卡因猝死的电生理原因。 连续超声心动图测量可确定心室性能和心室尺寸。 对孤立的工作心脏进行的研究确定了收缩缺陷和负荷控制。 BetaAR 功能研究通过生化方法定义心脏肾上腺素受体的丰度和功能。 钙处理和左心室重塑元素的 mRNA 丰度表明心脏分子变化。 大体、光显微镜 (LM) 和超微结构 (TEM) 病理学研究可精确定位心室重塑、肌细胞死亡和纤维化，并通过形态学定量这些变化。免疫-LM 和免疫-TEM 可识别细胞和亚细胞改变。