Left Ventricular Structural, Physiological, and Transcriptomic Abnormalities in a Novel Porcine Hypertrophic Cardiomyopathy Model.
9 affiliations
- 1MyoKardia / Bristol Myers Squibb, Brisbane, California, USA.
- 2Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA; Division of Cardiology, Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
- 3Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
- 4Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
- 5Exemplar Genetics, Coralville, Iowa, USA.
- 6Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
- 7Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa College of Pharmacy, Iowa City, Iowa, USA.
- 8Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
- 9Division of Cardiology, Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Abstract
Hypertrophic cardiomyopathy (HCM) is a disease of heart muscle commonly caused by variants in genes encoding sarcomere-associated proteins. The mechanisms by which these variants lead to the phenotype are uncertain, partly because of the lack of model systems amenable to integrated translational studies. We generated Yucatan minipigs with heterozygous knockin of the human HCM R403Q variant in MYH7. MYH7 R403Q pigs exhibited hypertrophy similar to humans on cardiac imaging. Relative to wild-type, MYH7 R403Q pigs showed increased interstitial fibrosis, increased myocyte disarray, lower capillary density, and intimal hyperplasia of intramyocardial arterioles with decreased luminal diameters. Bulk RNA sequencing and single nuclear RNA sequencing analyses showed upregulation of profibrotic and proinflammatory pathways. MYH7 R403Q hearts showed hypercontractility, elevated end-diastolic pressures, blunted β-adrenergic enhancement of systolic and diastolic function, and increased Ca²⁺ sensitivity. The cardiac myosin inhibitor MYK-581 reduced hypercontractility and improved diastolic function. Data from this large animal genetic model of HCM strengthen the mechanistic link between genetic variants and in vivo phenotypes and elucidate the mechanisms of myofilament-targeted therapies.
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BibTeX
@article{green2026left,
title = {{Left Ventricular Structural, Physiological, and Transcriptomic Abnormalities in a Novel Porcine Hypertrophic Cardiomyopathy Model.}},
author = {Eric M Green and Carlos Del Rio and Kamel Shibbani and David K Meyerholz and Joshua Gorham and Seong Kim and Daniel M DeLaughter and Marcus P Henze and Christopher S Rogers and Lindsey M Gifford and Melissa Kafa and Frank Rohret and J Adam Goeken and Jared M McLendon and Ryan L Boudreau and Christine E Seidman and Jessica C Sieren and Robert M Weiss and Jonathan G Seidman and Abhay Divekar and Ferhaan Ahmad},
journal = {JACC. Basic to translational science},
year = {2026},
month = oct,
doi = {10.1016/j.jacbts.2026.101696},
url = {https://europepmc.org/article/MED/42854668},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Left Ventricular Structural, Physiological, and Transcriptomic Abnormalities in a Novel Porcine Hypertrophic Cardiomyopathy Model.
AU - Eric M Green
AU - Carlos Del Rio
AU - Kamel Shibbani
AU - David K Meyerholz
AU - Joshua Gorham
AU - Seong Kim
AU - Daniel M DeLaughter
AU - Marcus P Henze
AU - Christopher S Rogers
AU - Lindsey M Gifford
AU - Melissa Kafa
AU - Frank Rohret
AU - J Adam Goeken
AU - Jared M McLendon
AU - Ryan L Boudreau
AU - Christine E Seidman
AU - Jessica C Sieren
AU - Robert M Weiss
AU - Jonathan G Seidman
AU - Abhay Divekar
AU - Ferhaan Ahmad
PY - 2026
DA - 2026/10/09
JO - JACC. Basic to translational science
DO - 10.1016/j.jacbts.2026.101696
UR - https://europepmc.org/article/MED/42854668
AB - Hypertrophic cardiomyopathy (HCM) is a disease of heart muscle commonly caused by variants in genes encoding sarcomere-associated proteins. The mechanisms by which these variants lead to the phenotype are uncertain, partly because of the lack of model systems amenable to integrated translational studies. We generated Yucatan minipigs with heterozygous knockin of the human HCM R403Q variant in MYH7. MYH7 R403Q pigs exhibited hypertrophy similar to humans on cardiac imaging. Relative to wild-type, MYH7 R403Q pigs showed increased interstitial fibrosis, increased myocyte disarray, lower capillary density, and intimal hyperplasia of intramyocardial arterioles with decreased luminal diameters. Bulk RNA sequencing and single nuclear RNA sequencing analyses showed upregulation of profibrotic and proinflammatory pathways. MYH7 R403Q hearts showed hypercontractility, elevated end-diastolic pressures, blunted β-adrenergic enhancement of systolic and diastolic function, and increased Ca²⁺ sensitivity. The cardiac myosin inhibitor MYK-581 reduced hypercontractility and improved diastolic function. Data from this large animal genetic model of HCM strengthen the mechanistic link between genetic variants and in vivo phenotypes and elucidate the mechanisms of myofilament-targeted therapies.
SN - 2452-302X
ER -