Mitochondrial health, cardiovascular risk, and blood pressure targets in hypertensive adults

项目总结 收缩压干预试验(Sprint)表明，强化血压(BP) 显著降低心血管疾病(CVD)风险和死亡率的目标，导致新的指导方针 建议的较低血压目标为&lt；130/80 mm Hg。然而，密集的BP目标可能会增加 抗高血压治疗的不良事件。随着新的BP指南的广泛采用，有 迫切需要评估是否有亚组患者可能有不利的平衡 密集降压的好处和坏处。我们提出了一种创新的风险分层方法 将传统的风险因素与从线粒体DNA(MtDNA)收集的新信息结合起来。 线粒体是细胞内的细胞器，对能量代谢和压力适应是必不可少的。在……里面 动物模型中，线粒体功能障碍在衰老、心血管疾病和神经退行性变中起重要作用 疾病。因为线粒体新陈代谢对于积极适应生物能量应激是至关重要的，例如BP 降低，衡量线粒体健康的指标可能有助于预测 正在接受高血压强化治疗的成年人。最近的观察性研究将小说 线粒体DNA测量与几个年龄相关的结果，包括心血管疾病、高血压、死亡、痴呆症的风险， 和降低的功能状态。然而，跨线粒体整合数据的最佳方法 基因组尚未建立，先前的研究也没有调查mtDNA测量对 确定谁可能从密集的BP目标中获得最大的好处或损害的子组。 该计划将利用下一代测序技术和机器学习分析来开发和 验证mtDNA风险评分，预测心血管疾病风险、死亡风险以及认知和 老年人的身体机能。我们的第一个目标是实现一个生物信息神经网络 健康、老龄化和身体成分研究(Health ABC；N=3,075)和生活方式的参与者 老年人干预和独立性研究(LIFE；N=1,755)为以下人群开发两个mtDNA风险评分 预测心血管疾病以及认知和身体功能结果，同时考虑到 死亡。我们的第二个和第三个目标将在两个里程碑式的试验中验证这些mtDNA风险分数 强化与标准血压目标对心血管结局的影响：Sprint(N=9,361)和行动 控制糖尿病的心血管风险(ACCORD；N=2,488)。然后我们将检查线粒体是否 通过这些mtDNA评分来评估风险，可以改变BP干预的有效性或安全性。这项工作将： 1)开发分析线粒体基因组数据的创新方法；2)提出新的假说 关于连接线粒体健康、心血管疾病风险和功能状态的途径；以及3)探索潜在的 对老年人进行个性化健康干预的线粒体DNA测量。

PROJECT SUMMARY The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive blood pressure (BP) targets significantly reduced risks of cardiovascular disease (CVD) and mortality, leading to new guidelines recommending a lower BP target of <130/80 mm Hg. However, intensive BP targets may increase the risk of adverse events from antihypertensive therapy. With widespread adoption of the new BP guidelines, there is an urgent need to evaluate whether there are subgroups of patients who may have an unfavorable balance of benefits and harms from intensive BP lowering. We propose an innovative approach to risk stratification that integrates traditional risk factors with novel information gleaned from mitochondrial DNA (mtDNA). Mitochondria are intracellular organelles that are essential for energy metabolism and stress adaptation. In animal models, mitochondrial dysfunction plays a fundamental role in aging, CVD, and neurodegenerative diseases. Because mitochondrial metabolism is vital to adapt positively to bioenergetic stressors such as BP lowering, measures of mitochondrial health may help to predict beneficial and adverse outcomes among adults undergoing intensive treatment for hypertension. Recent observational studies have linked novel mtDNA measures with several age-related outcomes, including risks of CVD, hypertension, death, dementia, and reduced functional status. However, the optimal methods for integrating data across the mitochondrial genome have not been established, nor have prior studies investigated the utility of mtDNA measures for identification of subgroups who may derive greatest benefits or harms from intensive BP targets. This proposal will leverage next-gen sequencing technology and machine learning analytics to develop and validate mtDNA risk scores that predict CVD risk, mortality risk, and longitudinal changes in cognitive and physical function in older adults. Our first Aim will implement a biologically-informed neural network among participants of the Health, Aging, and Body Composition Study (Health ABC; N=3,075) and the Lifestyle Interventions and Independence for Elders Study (LIFE; N=1,755) to develop two mtDNA risk scores for prediction of CVD and cognitive and physical function outcomes, while accounting for the competing risk of death. Our second and third Aims will validate these mtDNA risk scores in two landmark trials that evaluated the impact of intensive vs standard BP targets on cardiovascular outcomes: SPRINT (N=9,361) and Action to Control Cardiovascular Risk in Diabetes (ACCORD; N=2,488). We will then examine whether mitochondrial risk, assessed by these mtDNA scores, modifies the efficacy or safety of the BP interventions. This work will: 1) develop innovative methods for analysis of mitochondrial genomic data; 2) provide novel hypotheses regarding pathways linking mitochondrial health, CVD risk and functional status; and 3) explore the potential of mtDNA measures for personalized health interventions in older adults.