Severe familial hypercholesterolemia impairs the regulation of coronary blood flow and oxygen supply during exercise

• Published in: Basic research in cardiology 2016-11, Vol.111 (6), p.61-61, Article 61
• Main Authors: Bender, Shawn B., de Beer, Vincent J., Tharp, Darla L., Bowles, Douglas K., Laughlin, M. Harold, Merkus, Daphne, Duncker, Dirk J.
• Format: Article
• Language: English
• Subjects: Animals; Cardiology; Coronary Artery Disease - physiopathology; Coronary Circulation; Disease Models, Animal; Endothelium, Vascular - physiopathology; Hemodynamics - physiology; Hyperlipoproteinemia Type II - physiopathology; Medicine; Medicine & Public Health; Original Contribution; Oxygen Consumption - physiology; Physical Conditioning, Animal - physiology; Swine
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-016-0579-9

Accelerated development of coronary atherosclerosis is a defining characteristic of familial hypercholesterolemia (FH). However, the recent data highlight a significant cardiovascular risk prior to the development of critical coronary stenosis. We, therefore, examined the hypothesis that FH produces coronary microvascular dysfunction and impairs coronary vascular control at rest and during exercise in a swine model of FH. Coronary vascular responses to drug infusions and exercise were examined in chronically instrumented control and FH swine. FH swine exhibited ~tenfold elevation of plasma cholesterol and diffuse coronary atherosclerosis (20–60 % plaque burden). Similar to our recent findings in the systemic vasculature in FH swine, coronary smooth muscle nitric oxide sensitivity was increased in vivo and in vitro with maintained endothelium-dependent vasodilation in vivo in FH. At rest and during exercise, FH swine exhibited increased myocardial O 2 extraction resulting in reduced coronary venous SO 2 and PO 2 versus control. During exercise in FH swine, the transmural distribution of coronary blood flow was unchanged; however, a shift toward anaerobic cardiac metabolism was revealed by increased coronary arteriovenous H + concentration gradient. This shift was associated with a worsening of cardiac efficiency (relationship between cardiac work and O 2 consumption) in FH during exercise owing, in part, to a generalized reduction in stroke volume which was associated with increased left atrial pressure in FH. Our data highlight a critical role for coronary microvascular dysfunction as a contributor to impaired myocardial O 2 balance, cardiac ischemia, and impaired cardiac function prior to the development of critical coronary stenosis in FH.