Abstract
Abstract 14661: A Novel Mini-Pig Genetic Model of Hypertrophic Cardiomyopathy (HCM) Exhibits Reduced Myocardial Capillary Density, Impaired Myocardial Flow Reserve, and Chronic Injury
Circulation (New York, N.Y.), Vol.138(Suppl_1 Suppl 1), pp.A14661-A14661
11/06/2018
Abstract
IntroductionHCM is a disease of heart muscle associated with heart failure and sudden death, usually caused by mutations in sarcomere protein genes. The mechanisms by which mutations cause disease are uncertain, partly because of the lack of model systems amenable to integrated translational studies.MethodsWe generated Yucatan minipigs with heterozygous knockin of the human HCM MYH7 R403Q mutation. We conducted serial serum biomarker analyses, cardiac imaging and histologic and omic analyses of LV biopsy samples of wildtype and R403Q pigs (n=14/group).ResultsCardiac MRI (CMR) and echocardiography showed heterogeneity in the pattern of hypertrophy in R403Q pigs (concentric vs asymmetric), similar to humans. Histology showed lower capillary density (x10/mm) in R403Q vs WT pigs (13.0±0.0.9 vs 10.1±0.4, p<0.01). CMR showed regional myocardial flow reserve (FR) in response to dipyridamole was decreased in R403Q pigs and was negatively correlated with the severity of hypertrophy (FigurePanel A shows a plot of all pigs; Panel B shows an R403Q pig with greater impairment of FR in the hypertrophic septum than the relatively normal posterior wall). Serum TnI (ng/L) was elevated in R403Q vs WT pigs at ages 1 month (167.3±20.1 vs 90.5±9.9, p<0.01), 3 months (202.0±30.6 vs 20.0±4.3, p<0.01), 6 months (134.5±69.6 vs 6.7±8.3, p<0.01), and 9 months (206.1±66.8 vs 0.0±0.0, p<0.001). There was increased fibrosis (% area) in R403Q vs WT pigs at ages 3 months (11.4±5.2 vs 2.9±3.1, p<0.01) and 9 months (15.7±8.5 vs 3.5±3.1, p<0.01), with increased myocyte disarray. Intramyocardial arterioles in R403Q pigs showed intimal hyperplasia with decreased luminal diameters. RNAseq and proteomic analyses showed upregulation of pro-fibrotic pathways.ConclusionsThis first large-animal genetic model of HCM allows studies such as FR not possible in rodents. Our data suggest that a limitation in perfusion of hypertrophic myocardium leads to chronic injury and fibrosis.
Details
- Title: Subtitle
- Abstract 14661: A Novel Mini-Pig Genetic Model of Hypertrophic Cardiomyopathy (HCM) Exhibits Reduced Myocardial Capillary Density, Impaired Myocardial Flow Reserve, and Chronic Injury
- Creators
- Eric Green - NA, MyoKardia, South San Francisco, CADavid Meyerholz - University of IowaCarlos del Rio - NA, MyoKardia, South San Francisco, CALindsey Gifford - University of IowaFrank Rohret - Exemplar GeneticsJessica Sieren - University of IowaChristopher Rogers - Exemplar GeneticsAbhay Divekar - University of Missouri–Kansas CityRobert Weiss - University of IowaFerhaan Ahmad - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.138(Suppl_1 Suppl 1), pp.A14661-A14661
- Publisher
- by the American College of Cardiology Foundation and the American Heart Association, Inc
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 11/06/2018
- Academic Unit
- Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Pathology; Internal Medicine
- Record Identifier
- 9984201123202771
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