This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-HL-101: Identify and Validate Clinically Relevant, Quantifiable Biomarkers of Diagnostic and Therapeutic Responses to Blood, Vascular, Cardiac, and Respiratory Tract Dysfunction. Each year 1.4 million individuals have an acute coronary syndrome (ACS). Their prognosis is highly variable and therapeutic options broad. Circulating biomarkers of necrosis such as troponin have proven invaluable in aiding not only with diagnosis but also prognosis. However, limitations to the analytical performance of current assays at very low concentrations have constrained our ability to risk stratify a substantial number of patients. New, ultrasensitive troponin assays are being developed that have far greater precision at very low concentrations. Our group has led initial studies with these assays, which are 1-2 orders of magnitude more sensitive than current commercial assays, and found that they allow for the identification of myocardial ischemia earlier and in more patients than conventional assays do. In addition to cardiomyocyte-derived proteins released during myocardial injury, there is also growing interest in circulating biomarkers that reliably reflect other relevant pathobiologies central to ACS including inflammation, thrombosis, and ventricular wall stress. Moreover, recent advances in metabolic profiling technologies have enabled the monitoring of hundreds of metabolites (""""""""metabolomics""""""""), that may be deranged very early in disease states. We believe the combination of an ultrasensitive assay for a cardiomyocyte-specific structural protein plus proteins and metabolite markers from relevant pathobiological pathways offers the best chance to develop a comprehensive biomarker panel that offers significant advances in risk assessment. Moreover, such biomarkers hold the promise of enabling clinicians to tailor therapy so as to minimize morbidity and mortality. Thus, the overall goal of this proposal is to validate the ability of state-of-the-art biomarkers to predict major adverse cardiovascular outcomes and benefit of therapy in ACS. To achieve this goal, we will leverage the strength of our TIMI Study Group clinical trials, which offer (1) large numbers of carefully phenotyped patients and adjudicated clinical outcomes, (2) a wealth of additional data including Holter monitoring for ischemia, angiograms, and multiple traditional biomarkers, and (3) randomized allocation to specific pharmacotherapies.
In Aim 1, we will investigate the prognostic significance of ultrasensitive troponin measurements for adverse cardiovascular outcomes (a) at the time of presentation, (b) after clinical stabilization, and (c) following percutaneous coronary intervention (PCI).
In Aim 2 we will investigate the prognostic significance of novel circulating protein and metabolic biomarkers.
In Aim 3 we will test the association between levels of novel biomarkers and the benefit of specific pharmacotherapies. Public Health Relevance: The prognosis in patients suffering a heart attack is highly variable and the therapeutic options broad. We believe extremely sensitive blood tests for damage to heart muscle plus other novel blood tests for inflammation, heart muscle stress, and clotting offer the potential to improve a clinician's ability to determine a patient's prognosis and to tailor therapy so as to minimize the complications of a heart attack.

Public Health Relevance

The prognosis in patients suffering a heart attack is highly variable and the therapeutic options broad. We believe extremely sensitive blood tests for damage to heart muscle plus other novel blood tests for inflammation, heart muscle stress, and clotting offer the potential to improve a clinician's ability to determine a patient's prognosis and to tailor therapy so as to minimize the complications of a heart attack.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
5RC1HL099692-02
Application #
7933931
Study Section
Special Emphasis Panel (ZRG1-CVRS-B (58))
Program Officer
Przywara, Dennis
Project Start
2009-09-30
Project End
2011-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$498,462
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Bonaca, Marc P; O'Malley, Ryan G; Murphy, Sabina A et al. (2015) Prognostic performance of a high-sensitivity assay for cardiac troponin I after non-ST elevation acute coronary syndrome: Analysis from MERLIN-TIMI 36. Eur Heart J Acute Cardiovasc Care 4:431-40
Grinstein, Jonathan; Bonaca, Marc P; Jarolim, Petr et al. (2015) Prognostic implications of low level cardiac troponin elevation using high-sensitivity cardiac troponin T. Clin Cardiol 38:230-5
Bonaca, Marc P; Bhatt, Deepak L; Braunwald, Eugene et al. (2014) Design and rationale for the Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial. Am Heart J 167:437-444.e5
Bohula May, Erin A; Bonaca, Marc P; Jarolim, Petr et al. (2014) Prognostic performance of a high-sensitivity cardiac troponin I assay in patients with non-ST-elevation acute coronary syndrome. Clin Chem 60:158-64
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
Bonaca, Marc P; Ruff, Christian T; Kosowsky, Joshua et al. (2013) Evaluation of the diagnostic performance of current and next-generation assays for cardiac troponin I in the BWH-TIMI ED Chest Pain Study. Eur Heart J Acute Cardiovasc Care 2:195-202
Kohli, Payal; Bonaca, Marc P; Kakkar, Rahul et al. (2012) Role of ST2 in non-ST-elevation acute coronary syndrome in the MERLIN-TIMI 36 trial. Clin Chem 58:257-66