Cardiac Pathology and Risk Prediction for Sudden Cardiac Death in Patients with HIV

HIV 患者心脏病理学和心脏性猝死的风险预测

• 批准号: 8847202
• 负责人: ZIAN H TSENG
• 金额: $ 79.81万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847202
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Address; Adverse effects; Affect; Aging; Alcohol or Other Drugs use; Antibiotics; Arrhythmia; Autopsy; CD4 Lymphocyte Count; Cardiac; Cardiovascular Diseases; Caring; Cessation of life; Clinical; Clinical Data; Cohort Studies; Collaborations; Complement; Data; Death Rate; Development; EFRAC; Electrocardiogram; Evaluation; Face; Fibrosis; Functional disorder; Gene Expression; Gene Expression Profiling; General Population; Goals; Gold; Guidelines; HIV; HIV risk; Health; Highly Active Antiretroviral Therapy; Hospitals; Immune; Immunohistochemistry; Implantable Defibrillators; Individual; Inflammatory; Left; Life; Malignant - descriptor; Measurable; Measurement; Medical Examiners; Medicare/Medicaid; Modeling; Morbidity - disease rate; Myocardium; National Heart, Lung, and Blood Institute; Pathogenesis; Pathologic; Pathology; Patients; Pattern; Persons; Pharmaceutical Preparations; Population; Prevention; Prevention strategy; Primary Prevention; Probability; Relative (related person); Risk; Risk Assessment; Risk Factors; Role; San Francisco; Sensitivity and Specificity; Stratification; Tissue Sample; Tissues; Ventricular; Veterans; Viral; Viral Genes; Viral Load result; Work; base; cardiovascular disorder risk; cohort; high risk; immunopathology; implantation; indexing; lifestyle factors; lymph nodes; macrophage; mortality; novel; prophylactic; public health relevance; screening; sudden cardiac death; virtual

 DESCRIPTION (provided by applicant): With the advent of HAART, HIV-infected (HIV+) individuals are living longer but face health challenges such as higher rates of cardiovascular disease (CVD) and CV mortality than HIV- people. Sudden cardiac death (SCD) is a leading cause of mortality in the general population. While many HIV+ persons still die of AIDS, we discovered a much higher HIV+ SCD rate than in the general population. Our new preliminary data confirm the association of HIV with higher SCD risk in a large, independent cohort (Veterans Aging Cohort Study Virtual Cohort [VACS-VC]). Although imperfect, left ventricular systolic dysfunction (LVSD) [stable ejection fraction (EF) d35%] is the major risk assessment criterion for SCD in the HIV- population. We recently demonstrated that left ventricular systolic dysfunction (LVSD) also increases HIV+ SCD risk, with even higher risk in combination with detectable viral load (VL). Implantable cardioverter-defibrillators (ICDs) are highly effective for SCD prevention in HIV- patients with LVSD and current guidelines recommend their use for primary prevention in patients with EFd35%, but no guidelines exist for the HIV+ population. Given the competing risk of AIDS death, it is unknown whether the same EF threshold for primary prevention ICD applies and whether unique HIV+ risk factors such as QT prolonging (QTP) HAART, VL, or other factors should affect this decision. Therefore, to reduce mortality in an aging HIV+ population, it is critical to identify persons at high SCD risk. Our ultimate goal is to reduce HIV+ SCD risk and inform ICD guidelines in this population. The objective of this application is to develop a prediction model for SCD in HIV+ patients to inform guidelines for ICD implantation and determine the cardiac pathologic substrate and immunopathology of HIV+ SCDs by autopsy. We will leverage work supported by the NHLBI in two ongoing studies by extending the scope of each. First, we will calculate SCD rates and risk in HIV+ and matched uninfected controls in VACS- VC, and evaluate the relative contributions of LVSD, ECG, viral, QTP HAART and other drugs, CVD risk factors, and substance use. We also plan to develop and validate a prediction model for SCD in HIV+ patients to inform ICD guidelines, accounting for indirect effects via competing risks. Second, we address the major limitation of all prior SCD studies the lack of gold-standard autopsy data to definitively establish cause and underlying pathology by leveraging a unique, ongoing collaboration with the Medical Examiner to perform autopsy and standardized cardiac pathologic evaluation on all consecutive, incident HIV+ SCDs in San Francisco, thereby avoiding referral bias. Third, our unique access to tissue in all HIV+ SCDs will allow us an unprecedented opportunity to study both cardiac pathology and HIV viral persistence, both of which will help elucidate underlying reasons for higher observed SCD rates. These data will fundamentally advance our understanding of risk factors, mechanisms, and preventive strategies for an important cause of mortality in an aging, HIV-infected population.

 描述（由申请人提供）：随着HAART的出现，HIV感染者（HIV+）的寿命更长，但面临着健康挑战，如心血管疾病（CVD）和CV死亡率高于HIV-人群。心源性猝死（SCD）是普通人群死亡的主要原因。虽然许多HIV+患者仍然死于艾滋病，但我们发现HIV+ SCD的发病率比一般人群高得多。我们新的初步数据证实了HIV与一个大型独立队列（退伍军人老龄化队列研究虚拟队列[VACS-VC]）中SCD风险较高的相关性。尽管不完全，但左心室收缩功能障碍（LVSD）[稳定射血分数（EF）d35%]是HIV人群中SCD的主要风险评估标准。我们最近证明，左心室收缩功能障碍（LVSD）也增加了HIV+ SCD的风险，与可检测的病毒载量（VL）相结合的风险甚至更高。植入式心脏复律除颤器（ICD）对以下方面非常有效： HIV-LVSD患者的SCD预防和当前指南建议将其用于EFd 35%患者的一级预防，但尚无HIV+人群的指南。考虑到艾滋病死亡的竞争风险，尚不清楚一级预防ICD是否适用相同的EF阈值，以及独特的HIV+风险因素（如QT延长（QTP）HAART、VL或其他因素）是否会影响这一决定。因此，为了降低老龄化HIV+人群的死亡率，识别SCD高风险人群至关重要。我们的最终目标是 降低HIV+ SCD风险，并为该人群的ICD指南提供信息。 本申请的目的是开发HIV+患者SCD的预测模型，为ICD植入提供指导，并通过尸检确定HIV+ SCD的心脏病理学基质和免疫病理学。我们将利用NHLBI支持的两项正在进行的研究中的工作，扩大每项研究的范围。首先，我们将计算VACS-VC中HIV+和匹配的未感染对照的SCD率和风险，并评估LVSD、ECG、病毒、QTP HAART和其他药物、CVD风险因素和物质使用的相对贡献。我们还计划开发和验证HIV+患者SCD的预测模型，以告知ICD指南，通过竞争风险解释间接影响。其次，我们解决了所有先前SCD研究的主要局限性 缺乏黄金标准的尸检数据来确定病因和潜在病理学 通过利用与医学检查员的独特持续合作，对旧金山弗朗西斯科所有连续发生的HIV+ SCD进行尸检和标准化心脏病理学评估，从而避免转诊偏倚。第三，我们对所有HIV+ SCD组织的独特访问将使我们有前所未有的机会研究心脏病理学和HIV病毒持续性，这两者都将有助于阐明观察到的SCD率较高的根本原因。这些数据将从根本上推进我们对老龄化、艾滋病毒感染人群死亡的重要原因的风险因素、机制和预防策略的理解。