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1 Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3; 2 The Water and Salt Research Center, Department of Physiology, Faculty of Medicine, University of Aarhus, 8000 Aarhus C, Denmark; 3 Department of Clinical Pathology, McDonald Research Laboratories, The iCAPTURE Center, St Paul's Hospital, Vancouver, British Columbia, Canada V62 1Y6; 4 Division of Cardiology, University of Colorado Health Sciences Center, Denver 80262; and 5 Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309
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 
-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.
sudden cardiac death; acetylcholine; endothelin; myogenic tone
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