Little attention has been paid to patient-centered health status outcomes such as angina, depression, and worse quality of life after myocardial infarction (MI) but these are often the factors that patients care about the most. More than 10 million people in the US suffer from angina and approximately 500,000 new cases occur each year at an estimated cost of $20 billion dollars annually. We propose to identify novel genomic and non- genomic factors that contribute to inter-individual variation in post-MI angina and health status outcomes by using the TRIUMPH population, and NIH-funded cohort with exquisite disease-specific health status assessments at admission, and 1-month, 6-months and 1-year post-MI, along with adjudicated 1-year major adverse cardiovascular events and 5-year mortality. The study group is particularly well qualified to perform this research, having expertis in genomics, pharmacogenomics, patient screening and risk profiling, acute MI management, clinical trials, outcomes research, and statistical genomics. Collectively, we will address the following Aims:
AIM 1. Identification and Validation of Novel Genomic and Non-Genomic Factors Contributing to Inter-individual Variation in Post-MI Angina There will be two ongoing stages of this AIM. The first is to continue to comprehensively identify genomic and non-genomic factors contributing to post-MI angina in a focused and sequential way. We propose to use novel statistical approaches including SMART-scan, growth curve estimation, and pleiotropy and collapsing methods to achieve this AIM. The second stage of this AIM is to validate the genomic predictors we have identified in the initial funding cycle and to continue thi validation for all newly identified genomic variants. We intend to use multiple validation cohorts to validate and extend our findings, including the INFORM, PREMIER, BARI 2D and GENESIS-PRAXY study.
AIM 2. Pilot Study to Test Genotype-guided Post-MI Therapy Aimed at Decreasing Post-MI Angina We propose to show the feasibility of incorporating genotype-guided therapy into post-MI therapy using the CHRNA5 rs16969968 variant as our pilot case and using a novel prognostic modeling tool (PRISMTM) which allows multivariable models to be run with patient-specific data to predict post-MI outcomes. This pilot study will lay the foundation for personalized, genotype-guided, post-MI therapy aimed at decreasing angina symptoms and improving the quality of life for post-MI patients. The successful execution of these AIMs will enable us to help implement the NINRs strategic plan and address several of the NINR's key themes, including personalized health strategies toward symptom management, improving quality of life for individuals with chronic diseases, and promoting health and preventing illness. In summary, we will use cutting edge experimental, statistical, and diagnostic methods to identify genomic and non-genomic factors associated with post-MI angina and initiate the first step towards personalized post-MI care with the overarching goal of reducing angina symptoms and improving outcomes.

Public Health Relevance

Sequence differences in genes may influence an individual's response to chest pain (angina) after a heart attack. This study proposes identifying specific gene sequence differences that predict more or less chest pain after heart attack and to determine how to best translate the findings into medical practice. The ultimate goal of this proposal is to advance personalized care for adults with coronary artery disease who have had a heart attack.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Research Project (R01)
Project #
5R01NR013396-07
Application #
9394726
Study Section
Nursing and Related Clinical Sciences Study Section (NRCS)
Program Officer
Tully, Lois
Project Start
2011-09-27
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Zewinger, Stephen; Kleber, Marcus E; Tragante, Vinicius et al. (2017) Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study. Lancet Diabetes Endocrinol 5:534-543
Doll, Jacob A; Tang, Fengming; Cresci, Sharon et al. (2016) Change in Angina Symptom Status After Acute Myocardial Infarction and Its Association With Readmission Risk: An Analysis of the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) Re J Am Heart Assoc 5:
Depta, J P; Lenzini, P A; Lanfear, D E et al. (2015) Clinical outcomes associated with proton pump inhibitor use among clopidogrel-treated patients within CYP2C19 genotype groups following acute myocardial infarction. Pharmacogenomics J 15:20-5
Do, Ron; Stitziel, Nathan O; Won, Hong-Hee et al. (2015) Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 518:102-6
Buchanan, Donna M; Arnold, Suzanne V; Gosch, Kensey L et al. (2015) Association of Smoking Status With Angina and Health-Related Quality of Life After Acute Myocardial Infarction. Circ Cardiovasc Qual Outcomes 8:493-500
Arnold, Suzanne V; Spertus, John A; Lipska, Kasia J et al. (2015) Association between diabetes mellitus and angina after acute myocardial infarction: analysis of the TRIUMPH prospective cohort study. Eur J Prev Cardiol 22:779-87
Labos, Christopher; Martinez, Sara C; Leo Wang, Rui Hao et al. (2015) Utility of a genetic risk score to predict recurrent cardiovascular events 1 year after an acute coronary syndrome: A pooled analysis of the RISCA, PRAXY, and TRIUMPH cohorts. Atherosclerosis 242:261-7
Cresci, Sharon; Depta, Jeremiah P; Lenzini, Petra A et al. (2014) Cytochrome p450 gene variants, race, and mortality among clopidogrel-treated patients after acute myocardial infarction. Circ Cardiovasc Genet 7:277-86
Myocardial Infarction Genetics Consortium Investigators; Stitziel, Nathan O; Won, Hong-Hee et al. (2014) Inactivating mutations in NPC1L1 and protection from coronary heart disease. N Engl J Med 371:2072-82
Chen, Li-Shiun; Bach, Richard G; Lenzini, Petra A et al. (2014) CHRNA5 variant predicts smoking cessation in patients with acute myocardial infarction. Nicotine Tob Res 16:1224-31

Showing the most recent 10 out of 13 publications