R01HL151564

Mitochondrial Health, Cardiovascular Risk, and Blood Pressure Targets in Hypertensive Adults - 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 mmHg. 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 the identification of subgroups who may derive the 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 the 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 the 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.

Northern California Institute For Research And Education

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

California United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 07/31/25 to 07/31/26 and the total obligations have increased 325% from $757,768 to $3,222,133.