ST. PETER HIV-Alcohol, Protein Biomarkers and Cardiovascular Disease Risk

在人类免疫缺陷病毒感染(HIV+)人群中大量饮酒是常见的 与心力衰竭(HF)和冠心病(CHD)相关。一种尚未探索的潜在机制 因为这种联系涉及肠道微生物种群的变化(生物失调)，这种变化发生在 酗酒或感染艾滋病毒。生物失调可能会改变微生物基因组(微生物群)的平衡，以促进 三甲胺氮氧化物(TMAO)产量增加。TMAO升高与心血管疾病相关 疾病(CVD)事件，包括一般人群中的亚临床冠心病和心力衰竭的发病率和死亡率。然而， 还没有发表的研究评估酒精与TMAO或TMAO与亚临床心衰之间的联系 HIV+人群。我们假设，在HIV+酗酒者中，饮酒与更高水平的 TMAO，较高的TMAO水平与心衰的亚临床措施和生物标志物相关。我们会 在圣彼得堡测试这些假设。Peter HIV-CVD，一项将建立和补充的观察性研究 圣彼得艾滋病毒，一项随机临床试验(U01AA020780；2017年冬季开始招募)。圣彼得修道院 HIV临床试验正在测试varenicline与胞嘧啶在同时戒酒和吸烟方面的效果 在圣彼得堡，400名艾滋病毒+酗酒者(前一个月≥为5天大量饮酒)和每日吸烟者戒烟。 俄罗斯彼得堡。ST.的主要优势。Peter HIV-CVD是现有的互补 圣彼得艾滋病毒临床试验的资源/基础设施包括：1)招募参与者；2)验证自我 报告酒精消费；3)生物样品收集；4)专业知识和良好的合作历史 进行这项研究的美国和俄罗斯团队成员的酒精、艾滋病毒和心血管疾病研究。在圣彼得堡。彼得 HIV-CVD，我们建议在基线和3个月收集以下新数据：TMAO，超声心动图， B型利钠肽(BNP；心室舒缩生物标志物)、磷脂酰乙醇(PEH；酒精 生物标志物)和食物频率调查问卷。6个月后还将测量超声心动图。使用 这些现有的和新的数据，我们将处于独特的地位，以实现以下目标： 目标1：评估重度饮酒(酒精使用障碍识别测试，AUDIT≥20)是否：a) 横截面和b)与HIV+重度饮酒者的TMAO水平纵向相关； 目的2：评估TMAO是否与该人群的心功能和BNP相关； 目的3：探讨TMAO是否介导了饮酒与亚临床心力衰竭风险之间的关系。 如果得到证实，我们的假设将确定一个生物标记物(TMAO)，以响应减少酒精的干预- HIV+酗酒者的相关心血管疾病风险。因为大量饮酒的干预并不完全成功， 开发新的酒精治疗策略，减少酒精对艾滋病毒携带者的负面健康影响 都是需要的。识别生物标记物及其所代表的途径(例如，生物失调)可能导致 干预研究和改进HIV+饮酒者心血管疾病风险预测的新目标。

Heavy alcohol use among human immunodeficiency virus infected (HIV+) people is common and associated with heart failure (HF) and coronary heart disease (CHD). An unexplored potential mechanism for this association involves changes in intestinal microbial populations (dysbiosis), which occur with heavy alcohol use or HIV infection. Dysbiosis may shift the balance of microbial genomes (microbiomes) to promote increased trimethylamine N-oxide (TMAO) production. Increased TMAO is associated with cardiovascular disease (CVD) events, including subclinical CHD and HF morbidity and mortality in the general population. Yet, no published studies have assessed the link between alcohol and TMAO or TMAO and subclinical HF among HIV+ people. We hypothesize that among HIV+ heavy drinkers, alcohol use is associated with higher levels of TMAO, and that higher TMAO levels are associated with subclinical measures and biomarkers of HF. We will test these hypotheses in ST. PETER HIV – CVD, an observational study that will be built on and complement St. PETER HIV, a randomized clinical trial (U01AA020780; begins enrollment Winter 2017). The St. PETER HIV clinical trial is testing the effects of varenicline vs. cytosine on simultaneous alcohol reduction and smoking cessation among 400 HIV+ heavy drinkers (≥5 heavy drinking days in prior month) and daily smokers in St. Petersburg, Russia. Major strengths of ST. PETER HIV - CVD are the existing complementary resources/infrastructure of the St. PETER HIV clinical trial including:1) participant recruitment; 2) validated self- report alcohol consumption; 3) biospecimen collection; 4) expertise and strong history of collaboration on alcohol, HIV and CVD research of the U.S. and Russia team members undertaking this study. In ST. PETER HIV – CVD, we propose to collect at baseline and 3 months the following new data: TMAO, echocardiography, B-type natriuretic peptide (BNP; biomarker of ventricular stretching), phosphatidylethanol (PEth; alcohol biomarker) and food frequency questionnaires. Echocardiography will be measured also at 6 months. With these existing and new data, we will be uniquely positioned to complete the following aims: AIM 1: To assess whether heavier alcohol use (Alcohol Use Disorders Identification Test, AUDIT≥20) is: a) cross-sectionally and b) longitudinally associated with TMAO levels among HIV+ heavy drinkers; AIM 2: To assess whether TMAO is associated with cardiac function and BNP in this population; and AIM 3: To explore whether TMAO mediates the association of alcohol use and subclinical HF risk. If confirmed, our hypotheses will identify a biomarker (TMAO) responsive to interventions that reduce alcohol- related CVD risk in HIV+ heavy drinkers. Because heavy alcohol use interventions do not succeed in all, developing new alcohol treatment strategies that reduce alcohol’s negative health impact among HIV+ people are needed. The identification of biomarkers and the pathways they represent (e.g., dysbiosis) could result in new targets for intervention studies and improve CVD risk prediction in HIV+ drinkers.