The complications of myocardial infarction contribute to 550,000 cases of heart failure (HF) and 300,000 cases of sudden cardiac arrest (SCA) annually. HF and SCA are mechanistically linked to the closely related processes of mechanical and electrical remodeling of the heart following infarction. Markers of adverse remodeling are widely used to risk-stratify post-MI patients for medical or device therapies. However, current risk-stratification strategies lack adequate sensitivity and specificity. Thus, development of complementary biomarkers to predict adverse outcomes post-MI is needed for the appropriate and cost-effective applications of these advanced therapies. Cellular micro-RNAs (miRNAs) regulate entire gene networks in human cardiovascular diseases and circulating miRNAs can be used as integrative biomarkers. We now propose to identify novel circulating miRNA signatures that can prognosticate susceptibility to arrhythmia/SCA and HF post-MI and to integrate these biomarkers into a digital PCR-based assay readily translatable into the clinic. Our group of investigators spanning multiple discipline within cardiovascular research will test the central hypothesis that (1) unbiased profiling of circulating plasma using RNA-seq will identify novel miRNAs associated with the development of adverse mechanical and electrical remodeling in a cohort of extensively-phenotyped post-MI patients;(2) mechanistic animal and cell culture models will complement the clinical discovery efforts by helping prioritize those markers that play a functional role in disease pathobiology, and (3) the assessment of miRNA signatures of adverse remodeling will enable accurate prediction of clinical outcomes, notably SCA and HF, in a large cohort of patients with CAD and MI. We believe that our results will lay the foundation for a novel strategy of risk-stratificationfor post-MI patients that would allow for identification of patients at high risk of adverse electrical and mechanical remodeling, who may benefit from more aggressive monitoring and interventions with medications and ICDs.

Public Health Relevance

The complications of a myocardial infarction (heart attack) such as heart failure and lethal arrhythmias lead to significant morbidity and mortality. Current tests to predict which patients are at risk of these complications are imperfect. We seek to develop novel blood tests to identify patients at risk of developing these complications so that they can be treated prophylactically.

Agency
National Institute of Health (NIH)
Institute
National Center for Advancing Translational Sciences (NCATS)
Type
Exploratory/Developmental Cooperative Agreement Phase I (UH2)
Project #
5UH2TR000901-02
Application #
8710366
Study Section
Special Emphasis Panel (ZRG1-GGG-R (51))
Program Officer
Tagle, Danilo A
Project Start
2013-08-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
$500,000
Indirect Cost
$169,106
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Bezzerides, Vassilios J; Platt, Colin; Lerchenmüller, Carolin et al. (2016) CITED4 induces physiologic hypertrophy and promotes functional recovery after ischemic injury. JCI Insight 1:
Danielson, Kirsty M; Estanislau, Jessica; Tigges, John et al. (2016) Diurnal Variations of Circulating Extracellular Vesicles Measured by Nano Flow Cytometry. PLoS One 11:e0144678
Freedman, Jane E; Gerstein, Mark; Mick, Eric et al. (2016) Diverse human extracellular RNAs are widely detected in human plasma. Nat Commun 7:11106
Xiao, Junjie; Sluijter, Joost P G; Das, Saumya et al. (2015) A snapshot of genetic and epigenetic basis of arrhythmia and heart failure. Front Genet 6:74
Wei, Xin; Liu, Xiaojun; Rosenzweig, Anthony (2015) What do we know about the cardiac benefits of exercise? Trends Cardiovasc Med 25:529-36
Liu, Xiaojun; Xiao, Junjie; Zhu, Han et al. (2015) miR-222 is necessary for exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell Metab 21:584-95
Kwong, Raymond Y; Heydari, Bobak; Abbasi, Siddique et al. (2015) Characterization of Cardiac Amyloidosis by Atrial Late Gadolinium Enhancement Using Contrast-Enhanced Cardiac Magnetic Resonance Imaging and Correlation With Left Atrial Conduit and Contractile Function. Am J Cardiol 116:622-9
Melman, Yonathan F; Shah, Ravi; Danielson, Kirsty et al. (2015) Circulating MicroRNA-30d Is Associated With Response to Cardiac Resynchronization Therapy in Heart Failure and Regulates Cardiomyocyte Apoptosis: A Translational Pilot Study. Circulation 131:2202-16
Simonson, Bridget; Das, Saumya (2015) MicroRNA Therapeutics: the Next Magic Bullet? Mini Rev Med Chem 15:467-74
Danielson, Kirsty M; Das, Saumya (2014) Extracellular Vesicles in Heart Disease: Excitement for the Future ? Exosomes Microvesicles 2: