title: Coronary vasomotor responses to isometric handgrip exercise are primarily mediated by nitric oxide: a noninvasive MRI test of coronary endothelial function.
abstract: Endothelial cell release of nitric oxide (NO) is a defining characteristic of nondiseased arteries, and abnormal endothelial NO release is both a marker of early atherosclerosis and a predictor of its progression and future events. Healthy coronaries respond to endothelial-dependent stressors with vasodilatation and increased coronary blood flow (CBF), but those with endothelial dysfunction respond with paradoxical vasoconstriction and reduced CBF. Recently, coronary MRI and isometric handgrip exercise (IHE) were reported to noninvasively quantify coronary endothelial function (CEF). However, it is not known whether the coronary response to IHE is actually mediated by NO and/or whether it is reproducible over weeks. To determine the contribution of NO, we studied the coronary response to IHE before and during infusion of N(G)-monomethyl-l-arginine (l-NMMA, 0.3 mg·kg(-1)·min(-1)), a NO-synthase inhibitor, in healthy volunteers. For reproducibility, we performed two MRI-IHE studies ~8 wk apart in healthy subjects and patients with coronary artery disease (CAD). Changes from rest to IHE in coronary cross-sectional area (%CSA) and diastolic CBF (%CBF) were quantified. l-NMMA completely blocked normal coronary vasodilation during IHE [%CSA, 12.9 ± 2.5 (mean ± SE, placebo) vs. -0.3 ± 1.6% (l-NMMA); P < 0.001] and significantly blunted the increase in flow [%CBF, 47.7 ± 6.4 (placebo) vs. 10.6 ± 4.6% (l-NMMA); P < 0.001]. MRI-IHE measures obtained weeks apart strongly correlated for CSA (P < 0.0001) and CBF (P < 0.01). In conclusion, the normal human coronary vasoactive response to IHE is primarily mediated by NO. This noninvasive, reproducible MRI-IHE exam of NO-mediated CEF promises to be useful for studying CAD pathogenesis in low-risk populations and for evaluating translational strategies designed to alter CAD in patients.
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland;
authors.forename: Allison G
authors.initials: AG
authors.lastname: Hays
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland; Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland;
authors.forename: Micaela
authors.initials: M
authors.lastname: Iantorno
authors.affiliation: Division of Magnetic Resonance Research, Department of Radiology, Johns Hopkins University, Baltimore, Maryland; Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, Maryland; and.
authors.forename: Sahar
authors.initials: S
authors.lastname: Soleimanifard
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland;
authors.forename: Angela
authors.initials: A
authors.lastname: Steinberg
authors.affiliation: Division of Magnetic Resonance Research, Department of Radiology, Johns Hopkins University, Baltimore, Maryland;
authors.forename: Michael
authors.initials: M
authors.lastname: Schär
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland;
authors.forename: Gary
authors.initials: G
authors.lastname: Gerstenblith
authors.affiliation: Division of Magnetic Resonance Research, Department of Radiology, Johns Hopkins University, Baltimore, Maryland; Department of Radiology, Centre Hospitalier Universitaire Vaudois, Center for Biomedical Imaging and University of Lausanne, Lausanne, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Stuber
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland; Division of Magnetic Resonance Research, Department of Radiology, Johns Hopkins University, Baltimore, Maryland; rweiss@jhmi.edu.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Weiss
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000503:physiopathology*; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000378:metabolism / Q000502:physiology* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015444:Exercise; D005260:Female; D018737:Hand Strength; D006334:Heart Function Tests / Q000379:methods; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D014661:Vasoconstriction; D014664:Vasodilation; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III
keywords: coronary artery disease; endothelial function; magnetic resonance imaging
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