Coronary atherogenesis begins before clinically manifest coronary artery disease (CAD) appears. The genesis of arterial plaque composition remain poorly understood. Preclinical coronary artery plaque can be detected using methods, where calcified and uncaicified lesions can be quantified. Known biological pathways associated with stable and unstable """"""""preclinical"""""""" arterial plaque in different forms may be elucidated by examining biomarkers from biological pathways and related genes. Gene discovery can be enhanced by examining genome wide associations with plaque morphologic phenotypes detected by computed tomographic (CT) methods. Specifically, we hypothesize that biomarkers and genes related to inflammation, lipid metabolism, cell-signaling, and vascular remodeling have differential effects on calcified and noncalcified plaque morphology. Dr. Krai proposes a study designed to examine """"""""preclinical"""""""" forms of arterial plaque in 2 generational kindreds identified from premature CAD probands participating in the 25 year old prospective Johns Hopkins Sibling and Family Heart Study. All subjects have been genotyped for mechanism-driven CAD-related candidate genes and have had a 1 million single nucleotide polymorphism genome-wide association scan (GWAS).The proposed research has these major aims: 1) to determine the extent to which calcified and noncalcified plaque are associated with genotypes or haplotypes from biologically driven models of vascular calcification, vascular function, inflammation, cell-signaling, platelet function, thrombosis, and lipoprotein metabolism, 2) determine the extent to which genetic associations can be accounted for by risk factors and biomarkers, and 3) to determine novel loci associated with the relative total, calcified, and noncalcified plaque volumes using GWAS data. Dr. Krai is a cardiology fellow with a successful history in clinical cardiology research. His long term goal is to develop an independent novel program of genomic and mechanism-derived research directed toward high risk populations, and to improve early detection and attendant preventive therapy. He has assembled a team of senior mentors in genetics, epidemiology, cardiology, and imaging, and will accrue requisite skills in advanced didactic coursework.

Public Health Relevance

Clinical detection of coronary artery plaque calcfication is common practice for risk stratification, although the mechanisms remain unclear. The identification of genes associated with plaque morphology based on biological models or novel genes may have a significant impact on the understanding of atherogenesis and plaque calcification and may lead to tailored diagnostics and therapeutics in preventing CAD events.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL094747-04
Application #
8299539
Study Section
Special Emphasis Panel (ZHL1-CSR-R (M1))
Program Officer
Papanicolaou, George
Project Start
2009-09-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$138,803
Indirect Cost
$9,428
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kral, Brian G; Kalyani, Rita R; Yanek, Lisa R et al. (2016) Relation of Plasma Lipoprotein(a) to Subclinical Coronary Plaque Volumes, Three-Vessel and Left Main Coronary Disease, and Severe Coronary Stenoses in Apparently Healthy African-Americans With a Family History of Early-Onset Coronary Artery Disease. Am J Cardiol 118:656-61
Qayyum, Rehan; Becker, Diane M; Yanek, Lisa R et al. (2015) Greater collagen-induced platelet aggregation following cyclooxygenase 1 inhibition predicts incident acute coronary syndromes. Clin Transl Sci 8:17-22
Nyquist, Paul A; Bilgel, Murat; Gottesman, Rebecca et al. (2015) Age differences in periventricular and deep white matter lesions. Neurobiol Aging 36:1653-8
Zimmerman, Stefan L; Kral, Brian G; Fishman, Elliot K (2014) Diagnostic quality of dual-source coronary CT examinations performed without heart rate control: importance of obesity and heart rate on image quality. J Comput Assist Tomogr 38:949-55
Kral, Brian G; Becker, Lewis C; Vaidya, Dhananjay et al. (2014) Noncalcified coronary plaque volumes in healthy people with a family history of early onset coronary artery disease. Circ Cardiovasc Imaging 7:446-53
Kral, Brian G; Nyquist, Paul; Vaidya, Dhananjay et al. (2013) Relation of subclinical coronary artery atherosclerosis to cerebral white matter disease in healthy subjects from families with early-onset coronary artery disease. Am J Cardiol 112:747-52
Vaidya, Dhananjay; Kral, Brian G; Yanek, Lisa R et al. (2013) The association of brachial artery diameter with noncalcified coronary plaque burden in apparently healthy individuals. Coron Artery Dis 24:657-62
Kral, Brian G; Becker, Diane M; Vaidya, Dhananjay et al. (2012) Severity of inducible myocardial ischemia predicts incident acute coronary syndromes in asymptomatic individuals with a family history of premature coronary artery disease. J Nucl Cardiol 19:28-36
Kral, Brian G; Becker, Lewis C; Vaidya, Dhananjay et al. (2011) Silent myocardial ischaemia and long-term coronary artery disease outcomes in apparently healthy people from families with early-onset ischaemic heart disease. Eur Heart J 32:2766-72
Kral, Brian G; Mathias, Rasika A; Suktitipat, Bhoom et al. (2011) A common variant in the CDKN2B gene on chromosome 9p21 protects against coronary artery disease in Americans of African ancestry. J Hum Genet 56:224-9