title: Coronary artery myogenic response in a genetic model of hypertrophic cardiomyopathy.
abstract: Hypertrophic cardiac myopathy (HCM) is the leading cause of mortality in young athletes. Abnormalities in small intramural coronary arteries have been observed at autopsy in such subjects. The walls of these intramural vessels, especially in the ventricular septum, are thickened, and the lumen frequently appears narrowed. Whether these morphological characteristics have functional correlates is unknown. We studied coronary myogenic tone in a transgenic mouse model of HCM that has mutations in the cardiac alpha-myosin heavy chain gene. This transgenic mouse has a cardiac phenotype that resembles that occurring in humans. We examined the possible vascular contributions to the pathology of HCM. Septal arteries from 3- and 11-mo-old wild-type (WT) and transgenic (TG) mice were studied on a pressure myograph. The myogenic response to increased intravascular pressure in older animals was significantly reduced [maximal constriction: 32 +/- 4% (TG) and 46 +/- 4% (WT), P < 0.05]. After inhibition of endothelin receptors with bosentan, both WT and TG mice had similar increases in myogenic constriction. The sensitivity to exogenous endothelin was significantly reduced in TG mice, suggesting that the reduced myogenic constriction in HCM was due to reduced receptor sensitivity. In conclusion, we show for the first time that 1) myogenic tone in the coronary septal artery of the mouse is regulated by a basal release of endothelin, and 2) pressure-induced myogenic activation is attenuated in HCM, possibly consequent to a reduction in endothelin responsiveness. The associated reduction in coronary vasodilatory reserve may increase susceptibility to ischemia and arrhythmias.
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada V6T 1Z3.
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Petersen
authors.forename: Jonathan
authors.initials: J
authors.lastname: Choy
authors.forename: Brian
authors.initials: B
authors.lastname: Stauffer
authors.forename: Farzad
authors.initials: F
authors.lastname: Moien-Afshari
authors.forename: Christian
authors.initials: C
authors.lastname: Aalkjaer
authors.forename: Leslie
authors.initials: L
authors.lastname: Leinwand
authors.forename: Bruce M
authors.initials: BM
authors.lastname: McManus
authors.forename: Ismail
authors.initials: I
authors.lastname: Laher
mesh_terms: D000367:Age Factors; D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000503:physiopathology; D005355:Fibrosis / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009129:Muscle Tonus / Q000187:drug effects / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D009929:Organ Size; D011188:Potassium / Q000494:pharmacology; D014654:Vascular Patency; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D024723:Ventricular Myosins / Q000235:genetics
chemical_list: D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains; D011188:Potassium