Cardiovascular disease (CVD) is responsible for one third of all deaths in the United States, with the estimated costs anticipated to increase from $500 billion to $1,200 billion between 2015 and 2030. Given the societal burden of CVD, considerable attention has been directed at major risk factors for CVD. Recognition, understanding and widespread ascertainment of additional actionable CVD risk factors is necessary. Greater exercise capacity (e.g. cardiorespiratory fitness) is increasingly recognized to decrease the burden of chronic diseases, promote cardiovascular health, improve quality of life, and delay CVD and mortality. Although fitness has been shown to be among the most potent predictors of future CVD and overall health outcomes, it is currently one of the only major risk factors that is not routinely and regularly assessed in either general or specialized clinical settings. Beyond permitting quantification of fitness, brief (~10min) exposure to exercise can also unmask early forms of CVD. We and others have shown that simple measurements of heart rate and blood pressure during exercise in population studies are of incremental prognostic value over the same measurements made at rest. Recent technological advances now permit measurement of a broad array of circulating metabolites and gas exchange patterns that reflect the complex metabolic responses to exercise. The central hypothesis of this proposal is that precise measurements of metabolic responses to exercise through cardiopulmonary exercise testing (CPET) combined with metabolite profiling during exercise will relate to clinical and genetic traits as well as subclinical CVD, and will be of incremental value beyond standard CV risk factor assessment (in the resting state) for predicting future CVD and cardiometabolic disease.
Aim 1 will comprehensively determine how standard risk factors, life-style measures (including precise accelerometry-based physical activity measures), genetic variation and familial traits relate to metabolic responses to exercise, as measured by changes in gas exchange variables and metabolite levels in response to incremental exercise.
Aim 2 will determine how previously ascertained subclinical disease measures (conduit artery stiffness, coronary artery calcium, ventricular hypertrophy) relate to metabolic responses to exercise.
Aim 3 will determine whether easily acquired CPET gas exchange variables and changes in circulating metabolites in response to exercise will incrementally predict future cardiometabolic and CVD outcomes in the Framingham Heart Study and in a separate referral cohort. Overall, our proposal will help identify and characterize the spectrum of metabolic changes during exercise in the community, and assess their cross-sectional correlates and long-term prognostic significance. We hope to identify a minimally invasive means to test CV and metabolic reserve capacity that will identify and refine risk factors that can be targeted for interventions to prevet CVD.

Public Health Relevance

A person's ability to exercise is an important measure of heart and blood vessel health. By measuring new blood markers and patterns of oxygen use during exercise we aim to identify heart, blood vessel, and metabolic disorders at earlier stages than would be possible with standard resting measurements alone.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sholinsky, Phyliss
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Bailey, Cole S; Wooster, Luke T; Buswell, Mary et al. (2018) Post-Exercise Oxygen Uptake Recovery Delay: A Novel Index of Impaired Cardiac Reserve Capacity in Heart Failure. JACC Heart Fail 6:329-339
Wasfy, Meagan M; Bibbo, Courtney Foster; Brown, Marcel et al. (2018) Myocardial Metabolism in Endurance Exercise-Induced Left Ventricular Hypertrophy. JACC Cardiovasc Imaging 11:928-930
Field, Patrick A; Vasan, Ramachandran S (2018) LDL-Cholesterol Is Not the Only Clinically Relevant Biomarker for Coronary Artery Disease or Acute Coronary Syndrome. Clin Pharmacol Ther 104:232-234
Eisman, Aaron S; Shah, Ravi V; Dhakal, Bishnu P et al. (2018) Pulmonary Capillary Wedge Pressure Patterns During Exercise Predict Exercise Capacity and Incident Heart Failure. Circ Heart Fail 11:e004750
Houstis, Nicholas E; Eisman, Aaron S; Pappagianopoulos, Paul P et al. (2018) Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Diagnosing and Ranking Its Causes Using Personalized O2 Pathway Analysis. Circulation 137:148-161
Spartano, N L; Stevenson, M D; Xanthakis, V et al. (2017) Associations of objective physical activity with insulin sensitivity and circulating adipokine profile: the Framingham Heart Study. Clin Obes 7:59-69
Shah, Ravi; Yeri, Ashish; Das, Avash et al. (2017) Small RNA-seq during acute maximal exercise reveal RNAs involved in vascular inflammation and cardiometabolic health: brief report. Am J Physiol Heart Circ Physiol 313:H1162-H1167
Steiner, Johannes; Wiafe, Stephanie; Camuso, Janice et al. (2017) Predicting Success: Left Ventricular Assist Device Explantation Evaluation Protocol Using Comprehensive Cardiopulmonary Exercise Testing. Circ Heart Fail 10:
Shah, Ravi; Murthy, Venkatesh L; Colangelo, Laura A et al. (2017) Submaximal Blood Pressure Responses to Exercise in Young Adulthood and Long-Term Cardiovascular Health. J Am Coll Cardiol 70:1941-1943
Spartano, Nicole L; Himali, Jayandra J; Beiser, Alexa S et al. (2016) Midlife exercise blood pressure, heart rate, and fitness relate to brain volume 2 decades later. Neurology 86:1313-9

Showing the most recent 10 out of 14 publications