The purpose of this proposal is to foster the candidate's development into a clinical investigator capable of translating metabolic signatures of myocardial ischemia and dysfunction into clinically applicable biomarkers. Dr. Lewis will couple training in mass-spectrometry based small molecule profiling and clinical research methodology through a unique, multi-disciplinary collaboration between the Broad Institute of Harvard &MIT and the Massachusetts General Hospital. There is an unmet clinical need for circulating biomarkers that provide biochemical proof ofmyocardial ischemia and early (troponin negative) myocardial infarction (Ml). Recent advances in metabolic profiling technologies have enhanced the feasibility of obtaining high throughput "snapshots" of a whole organism's metabolic state. Over the past 2 years, Dr. Lewis has played a central role in establishing a liquid chromatography-mass spectrometry platform to monitor over 400 metabolites per human plasma sample. He proposes to apply this platform to identify and validate metabolic signatures of myocardial ischemia and Ml.
Specific Aim 1 will be to identify metabolic changes of Ml and ischemia in two patient cohorts: 1) patients undergoing planned Ml to treat hypertrophic obstructive cardiomyopathy, and 2) patients experiencing myocardial ischemia during exercise treadmill testing (ETT). In both of these cohorts, the controlled nature of the myocardial insult permits samples to be obtained before and after the insult, allowing each patient to serve as his or her own biological control. Coronary sinus sampling will aid in localizing the source of metabolic changes in planned Ml.
Specific Aim 2 will be to prospectively validate the diagnostic utility of metabolic markers of myocardial ischemia in a second ETT cohort.
Specific Aim 3 will be to validate the diagnostic utility of these novel metabolic biomarkers in patients presenting to the emergency department with chest pain.
Specific Aim 4 will be to extend metabolic profiling beyond ischemia to identify metabolic modulators of ventricular dysfunction. The candidate will ultimately integrate training and results from this proposed award with his physiology training to define metabolic signatures of ischemia and heart failure.

Public Health Relevance

Blood tests that measure markers of heart damage play an important role in making the diagnosis of heart attack and in guiding appropriate treatments. Currently used markers, however, are not detectable in the blood for the first several hours after a heart attack. This proposal outlines a novelstrategy to capture rapid changes in circulating metabolites that occur in response to heart injury. These metabolites may serve as new markers of injury to help to guide prompt, appropriate treatments to correct metabolic abnormalities.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-R (M1))
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Scott, Jane
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Massachusetts General Hospital
United States
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Turer, Aslan T; Lewis, Gregory D; O'Sullivan, John F et al. (2014) Increases in myocardial workload induced by rapid atrial pacing trigger alterations in global metabolism. PLoS One 9:e99058
Magnusson, Martin; Lewis, Gregory D; Ericson, Ulrika et al. (2013) A diabetes-predictive amino acid score and future cardiovascular disease. Eur Heart J 34:1982-9
Saggar, R; Lewis, G D; Systrom, D M et al. (2012) Pulmonary vascular responses to exercise: a haemodynamic observation. Eur Respir J 39:231-4
Cheng, Susan; Rhee, Eugene P; Larson, Martin G et al. (2012) Metabolite profiling identifies pathways associated with metabolic risk in humans. Circulation 125:2222-31
Rhee, Eugene P; Cheng, Susan; Larson, Martin G et al. (2011) Lipid profiling identifies a triacylglycerol signature of insulin resistance and improves diabetes prediction in humans. J Clin Invest 121:1402-11
Chatterjee, Neal A; Lewis, Gregory D (2011) What is the prognostic significance of pulmonary hypertension in heart failure? Circ Heart Fail 4:541-5
Turer, Aslan T; Addo, Tayo A; Martin, Justin L et al. (2011) Myocardial ischemia induced by rapid atrial pacing causes troponin T release detectable by a highly sensitive assay: insights from a coronary sinus sampling study. J Am Coll Cardiol 57:2398-405
Chaudhry, Sundeep; Arena, Ross; Wasserman, Karlman et al. (2011) The utility of cardiopulmonary exercise testing in the assessment of suspected microvascular ischemia. Int J Cardiol 148:e7-9
Lewis, Gregory D; Murphy, Ryan M; Shah, Ravi V et al. (2011) Pulmonary vascular response patterns during exercise in left ventricular systolic dysfunction predict exercise capacity and outcomes. Circ Heart Fail 4:276-85
Murphy, Ryan M; Shah, Ravi V; Malhotra, Rajeev et al. (2011) Exercise oscillatory ventilation in systolic heart failure: an indicator of impaired hemodynamic response to exercise. Circulation 124:1442-51

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