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

成人高血压患者的线粒体健康、心血管风险和血压目标

基本信息

批准号：
10679021
负责人：
Vasantha Kolavennu Jotwani
金额：
$ 70.28万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679021
关键词：
Acute Renal Failure with Renal Papillary Necrosis Adoption Adult Adverse effects Affect Age Aging Animal Model Antihypertensive Agents Benefits and Risks Bioenergetics Blood Blood Pressure Body Composition Calibration Cardiovascular Diseases Cardiovascular system Cessation of life Chronic Kidney Failure Clinical Clinical Data DNA Dementia Diabetes Mellitus Discrimination Disease Elderly Electrolytes Energy Metabolism Equilibrium Event Fresh Tissue Genomic Instability Genomics Glean Goals Guidelines Health Heart Diseases Human Hypertension Hypotension Impaired cognition Individual Individual Differences Inherited Intervention Trial Knowledge Link Machine Learning Measures Methods Mitochondria Mitochondrial DNA Modeling Mutation Nerve Degeneration Neurodegenerative Disorders Nuclear Observational Study Organelles Outcome Participant Pathway interactions Performance Persons Physical Function Play Recommendation Risk Risk Factors Risk Reduction Role Safety Stress Stroke Structure Subgroup Syncope Technology Testing United States National Institutes of Health Variant Work adverse event risk adverse outcome age related blood pressure control blood pressure elevation blood pressure intervention blood pressure reduction cardiovascular disorder risk cardiovascular risk factor clinical risk cognitive function data integration falls frailty functional status genomic data heart disease risk high risk hypertension treatment hypertensive hypoperfusion innovation insight lifestyle intervention machine learning method mild cognitive impairment mitochondrial DNA mutation mitochondrial dysfunction mitochondrial genome mitochondrial metabolism mortality mortality risk neural network next generation sequencing novel patient subsets personalized intervention personalized medicine precision medicine randomized trial response risk prediction risk prediction model risk stratification stressor tool treatment effect walking speed

项目摘要

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.

项目摘要收缩压干预试验（SPRINT）表明强化血压（BP）目标大大降低了心血管疾病（CVD）和死亡率的风险，导致了新的指南建议较低的BP目标<130/80 mm Hg。但是，密集的BP目标可能会增加降压治疗的不良事件。随着新的BP指南的广泛采用，有迫切需要评估是否有一些患者的子组可能具有不利的平衡强化BP降低的益处和危害。我们提出了一种创新的风险分层方法将传统风险因素与线粒体DNA（mtDNA）收集的新信息相结合。线粒体是细胞内细胞器，对于能量代谢和胁迫适应至关重要。在动物模型，线粒体功能障碍在衰老，CVD和神经退行性中起着基本作用疾病。因为线粒体代谢对于积极适应生物能胁迫（例如BP）至关重要降低线粒体健康的度量可能有助于预测有益和不利结果成年人接受高血压治疗。最近的观察性研究与小说有关 MTDNA具有多种与年龄相关的结果的测量，包括CVD的风险，高血压，死亡，痴呆，痴呆症，并降低功能状态。但是，用于整合线粒体的数据的最佳方法基因组尚未建立，也没有先前的研究调查了mtDNA措施的实用性识别可能从密集的BP目标中获得最大收益或损害的亚组。该建议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，以预测CVD风险，死亡率风险和认知和纵向变化老年人的身体机能。我们的第一个目的将在健康，衰老和身体组成研究的参与者（健康ABC； n = 3,075）和生活方式长老研究的干预措施和独立性（Life; n = 1,755），以发展两个mtDNA风险评分 CVD以及认知和身体功能结果的预测，同时考虑到竞争风险死亡。我们的第二和第三目标将在评估的两个具有里程碑意义的试验中验证这些mtDNA风险评分密集型与标准BP目标对心血管结局的影响：Sprint（n = 9,361）和动作对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评分评估的风险，修改了BP干预措施的功效或安全性。这项工作将： 1）开发用于分析线粒体基因组数据的创新方法； 2）提供新颖的假设关于连接线粒体健康，CVD风险和功能状况的途径； 3）探索潜力 MTDNA对老年人个性化健康干预措施的措施。