CARDIAC DYSFUNCITON, AIDS AND COCAINE

心脏功能障碍、艾滋病和可卡因

• 批准号: 6390774
• 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/6390774
• 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。 突然的死亡和充血性心力衰竭是可卡因使用的严重后果。 心肌病（CM）已成为艾滋病的重要并发症。 不幸的是，可卡因的使用和艾滋病可能重合同一患者。 这表明添加剂或协同有害影响的可能性。 工作假设状态：心脏功能障碍发生在艾滋病和可卡因使用中。 当艾滋病和可卡因给药一起进行时，添加剂或协同作用会恶化心脏功能障碍，CM，并增加猝死的风险。 肿瘤坏死因子α（TNFALPHA）和内皮素-1（ET-1）在两种情况下都表达。 它们施加肾上腺素能反应性，钙处理以及导致心肌死亡和心肌纤维化的变化。 该项目的目的是：（1）定义艾滋病和可卡因给药的心脏性能改变和心律失常的改变； （2）定义心肌β-肾上腺素能受体（βAR）的密度和亚型表达的改变，Ca转运蛋白的表达以及艾滋病和可卡因给药中的重塑标记； （3）定义艾滋病和可卡因给药中的心脏病理特征。一种新型的转基因小鼠（TGS）的系统，具有无能的HIV-1，是一种精致的工具，可帮助定义可卡因给药的艾滋病中的病理生理事件。 TGS通过渗透微型蛋白酶的恒定输液接收可卡因。使用该系统的初步数据表明，与FVB/N野生类型相比，可卡因对TGS的心脏毒性更多。 它导致左心室肥大（LVH），心室重塑，肾上腺素能反应性降低，心房递衡因子的心室表达（ANF）和过早死亡。一种多学科方法解决了病理生理机制。 心电图遥测确定了可卡因在艾滋病中猝死的电生理原因。 串行超声心动图测量定义心室性能和腔室尺寸。 具有孤立工作的心脏的研究鉴定了收缩缺陷和负载的控制。 Betaar功能研究在生物化学上定义了心脏肾上腺素能的丰度和功能。 钙处理元素和LV重塑元件的mRNA丰度表明心脏分子变化。 毛，光显微镜（LM）和超微结构（TEM）病理学研究精确的心室重塑，心肌死亡以及纤维化和形态学上可以量化这些变化。免疫LM和免疫TEM鉴定细胞和亚细胞的改变。