Document text
Principal Investigator: Vasantha Kolavennu Jotwani
Organization: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
Fiscal Year: 2024
Award: $663,944
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <21+ years old><Acute Renal Failure with Renal Papillary Necrosis><Adoption><Adult><Adult Human><Adverse effects><Affect><Age><Aging><Amentia><Animal Model><Animal Models and Related Studies><Anti-Hypertensive Agents><Anti-Hypertensive Drugs><Anti-Hypertensives><Apoplexy><BP control><BP management><BP reduction><Benefits and Risks><Bioenergetics><Blood><Blood Pressure><Blood Reticuloendothelial System><Body Composition><Brain Vascular Accident><Calibration><Cardiac Diseases><Cardiac Disorders><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cessation of life><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical><Clinical Data><Cognitive Discrimination><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><DNA><Death><Degenerative Neurologic Disorders><Dementia><Deoxyribonucleic Acid><Diabetes Mellitus><Discrimination><Disturbance in cognition><Elderly><Electrolytes><Energy Expenditure><Energy Metabolism><Equilibrium><Event><Fainting><Fresh Tissue><Genetic Alteration><Genetic Change><Genetic defect><Genome Instability><Genomic Instability><Genomics><Glean><Goals><Guidelines><Health><Heart Diseases><Heart Vascular><Hereditary><Human><Hypertension><Hypotension><Hypotensive Agent><Hypotensive Drugs><Impaired cognition><Individual><Individual Differences><Inherited><Intervention Trial><Interventional trial><Knowledge><Link><Low Blood Pressure><Machine Learning><Measures><Methods><Mitochondria><Mitochondrial DNA><Modeling><Modern Man><Mutation><NGS Method><NGS system><NIH><National Institutes of Health><Nerve Degeneration><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Nuclear><Observation research><Observation study><Observational Study><Observational research><Organelles><Outcome><Participant><Pathway interactions><Performance><Persons><Physical Function><Play><Predicting Risk><Randomization trial><Recommendation><Risk><Risk Factors><Risk Reduction><Role><Safety><Stress><Stroke><Structure><Subgroup><Syncope><Technology><Testing><United States National Institutes of Health><Variant><Variation><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vascular Hypotensive Disorder><Work><acute kidney injury><adulthood><advanced age><adverse consequence><adverse event risk><adverse outcome><age associated><age associated disease><age associated disorder><age associated impairment><age correlated><age dependent><age dependent disease><age dependent disorder><age dependent impairment><age linked><age related><age related human disease><age specific><age-related disease><age-related disorder><age-related impairment><ages><aging associated><aging related><anti-hypertension><balance><balance function><blood pressure control><blood pressure elevation><blood pressure intervention><blood pressure management><blood pressure reduction><brain attack><cardiac disease risk><cardiac disorder risk><cardiovascular disease risk><cardiovascular disorder><cardiovascular disorder risk><cardiovascular risk><cardiovascular risk factor><cerebral vascular accident><cerebrovascular accident><chronic kidney disease><circulatory system><clinical risk><cognitive dysfunction><cognitive function><cognitive loss><data integration><death risk><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><diabetes><elevated blood pressure><falls><forecasting risk><frailty><functional status><genome mutation><genomic data><genomic data-set><genomic dataset><geriatric><hallmarks of aging><heart disease risk><heart disorder><heart disorder risk><high blood pressure><high risk><hyperpiesia><hyperpiesis><hypertension treatment><hypertensive><hypertensive disease><hypertensive disorder><hypoperfusion><increase in blood pressure><increased blood pressure><innovate><innovation><innovative><insight><life style intervention><lifestyle intervention><lower BP><lower blood pressure><lowers blood pressure><machine based learning><machine learning based method><machine learning method><machine learning methodologies><mild cognitive disorder><mild cognitive impairment><mitochondrial><mitochondrial DNA mutation><mitochondrial dysfunction><mitochondrial genome><mitochondrial metabolism><model of animal><mortality><mortality risk><mtDNA><mtDNA mutation><neural degeneration><neural network><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neuronal degeneration><next gen sequencing><next generation sequencing><nextgen sequencing><novel><older adult><older adulthood><pathway><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><personalization of treatment><personalized health intervention><personalized intervention><personalized medicine><personalized therapy><personalized treatment><pillars of aging><precision interventions><precision medicine><precision-based medicine><predict risk><predict risks><predicted risk><predicted risks><predicting risks><predictive risk><predicts risk><randomized trial><reduce BP><reduce blood pressure><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><reduction in BP><reduction in blood pressure><response><risk prediction><risk prediction algorithm><risk prediction model><risk predictions><risk stratification><risk-reducing><senior citizen><social role><stratify risk><stressor><stroked><strokes><tool><treatment effect><walking pace><walking speed>