Background Coronary endothelial function (endoFx) is abnormal in patients with established coronary artery disease (CAD) and was recently shown by MRI to relate to the severity of luminal stenosis. Recent advances in MRI now allow the non-invasive assessment of both anatomic and functional (endoFx) changes that previously required invasive studies. We tested the hypothesis that abnormal coronary endoFx is related to measures of early atherosclerosis such as increased coronary wall thickness (CWT). Methods and Results Seventeen arteries in fourteen healthy adults and seventeen arteries in fourteen patients with non-obstructive CAD were studied. To measure endoFx, coronary MRI was performed before and during isometric handgrip exercise, an endothelial-dependent stressor and changes in coronary cross-sectional area (CSA) and flow were measured. Black blood imaging was performed to quantify CWT and other indices of arterial remodeling. The mean stress-induced change in CSA was significantly higher in healthy adults (13.5%±12.8%, mean±SD, n=17) than in those with mildly diseased arteries (-2.2±6.8%, p<0.0001, n=17). Mean CWT was lower in healthy subjects (0.9±0.2mm) than in CAD patients (1.4±0.3mm, p<0.0001). In contrast to healthy subjects, stress-induced changes in CSA, a measure of coronary endoFx, correlated inversely with CWT in CAD patients (r= -0.73, p=0.0008). Conclusions There is an inverse relationship between coronary endothelial function and local CWT in CAD patients but not in healthy adults. These findings demonstrate that local endothelial-dependent functional changes are related to the extent of early anatomic atherosclerosis in mildly diseased arteries. This combined MRI approach enables the anatomic and functional investigation of early coronary disease.

Hays AG, Iantorno M, Soleimanifard S, Steinberg A, Schär M, Gerstenblith G, Stuber M, Weiss RG. Coronary vasomotor responses to isometric handgrip exercise are primarily mediated by nitric oxide: a noninvasive MRI test of coronary endothelial function. Am J Physiol Heart Circ Physiol 308: H1343-H1350, 2015. First published March 27, 2015 doi:10.1152/ajpheart.00023.2015.-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 Ϫ1 ·min Ϫ1 ), a NO-synthase inhibitor, in healthy volunteers. For reproducibility, we performed two MRI-IHE studies ϳ8 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 Ϯ 2.5 (mean Ϯ SE, placebo) vs. Ϫ0.3 Ϯ 1.6% (L-NMMA); P Ͻ 0.001] and significantly blunted the increase in flow [%CBF, 47.7 Ϯ 6.4 (placebo) vs. 10.6 Ϯ 4.6% (L-NMMA); P Ͻ 0.001]. MRI-IHE measures obtained weeks apart strongly correlated for CSA (P Ͻ 0.0001) and CBF (P Ͻ 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. endothelial function; coronary artery disease; magnetic resonance imaging ENDOTHELIAL CELL RELEASE of nitric oxide (NO) is a defining characteristic of nondiseased vascular tissue; it inhibits platelet aggregation, attenuates inflammation, decreases cellular proliferation, and induces local vascular smooth muscle vasodilation (4). Most classic and novel cardiovascular risk factors converge to impair endothelial function, including dyslipidemia, insulin resistance, inflammation, tobacco abuse, and oxidative stress, as well as hemodynamic and genetic factors (4, 33). Critically, endothelial dysfunction is a marker for subclinical disease, an independent predictor of adverse cardiovascular events, and a potential target for medical interventions (21,24,28).Traditionally, coronary endothelial function (CEF) is assessed by the directi...