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

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Abstract

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 O2 extraction resulting in reduced coronary venous SO2 and PO2 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 O2 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 O2 balance, cardiac ischemia, and impaired cardiac function prior to the development of critical coronary stenosis in FH.

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Acknowledgments

We gratefully acknowledge the assistance of Pam Thorne, Dave Harah, Jan Ivey, Sherrie Neff, Dr. Richard McAllister, Elza D. van Deel, and Rob van Bremen. This work was supported by the National Institutes of Health Grants HL-52490 (to MHL) and AR-048523 (to SBB), European Commission FP9-Health-2010 Grant MEDIA-261409 (to DJD and DM), the Netherlands Cardiovascular Research Initiative: an initiative of the Dutch Heart Foundation [CVON2012-08 PHAEDRA to DM; CVON2014-11 RECONNECT to DM and DJD], and the Department of Veterans Affairs Biomedical Laboratory Research and Development CDA-2 IK2 BX002030 (to SBB). This work was supported with resources and the use of facilities at the Harry S Truman Memorial Veterans Hospital in Columbia, MO.

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Authors and Affiliations

  1. Research Service, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO, 65211, USA

    Shawn B. Bender

  2. Biomedical Sciences, University of Missouri, Columbia, MO, USA

    Shawn B. Bender, Darla L. Tharp, Douglas K. Bowles & M. Harold Laughlin

  3. Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA

    Shawn B. Bender, Douglas K. Bowles & M. Harold Laughlin

  4. Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, USA

    Douglas K. Bowles & M. Harold Laughlin

  5. Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands

    Vincent J. de Beer, Daphne Merkus & Dirk J. Duncker

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  1. Shawn B. Bender
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Bender, S.B., de Beer, V.J., Tharp, D.L. et al. Severe familial hypercholesterolemia impairs the regulation of coronary blood flow and oxygen supply during exercise. Basic Res Cardiol 111, 61 (2016). https://doi.org/10.1007/s00395-016-0579-9

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