Background The aim of this study was to noninvasively measure regional contributions of vasculature in the human body using magnetohydrodynamic voltages (V MHD ) obtained from electrocardiogram (ECG) recordings performed inside MRI’s static magnetic field (B 0 ). Integrating the regional V MHD over the S wave -T wave segment of the cardiac cycle (V segment ) provides a noninvasive method for measuring regional blood volumes, which can be rapidly obtained during MRI without incurring additional cost. Methods V MHD was extracted from 12-lead ECG traces acquired during gradual introduction into a 3T MRI. Regional contributions were computed utilizing weights based on B 0 ’s strength at specified distances from isocenter. V segment mapping was performed in six subjects and validated against MR angiograms (MRA). Results Fluctuations in V segment , which presented as positive trace deflections, were found to be associated with aortic-arch flow in the thoracic cavity, the main branches of the abdominal aorta, and the bifurcation of the common iliac artery. The largest fluctuation corresponded to the location where the aortic arch was approximately orthogonal to B 0 . The smallest fluctuations corresponded to areas of vasculature that were parallel to B 0 . Significant correlations (specifically, Spearman’s ranked correlation coefficients of 0.96 and 0.97 for abdominal and thoracic cavities, respectively) were found between the MRA and V segment maps (p < 0.001). Conclusions A novel non-invasive method to extract regional blood volumes from ECGs was developed and shown to be a rapid means to quantify peripheral and abdominal blood volumes.

Background We assessed the contribution of endothelium-derived hyperpolarizing factors (EDHFs) to resting and agonist-stimulated vasodilator tone in health and disease. Tetraethylammonium chloride (TEA) was employed to inhibit K+Ca channel activation and fluconazole to inhibit cytochrome P450 2C9-mediated epoxyeicosatrienoic acid synthesis. We hypothesized that 1) EDHFs contribute to resting vascular tone by K+Ca channel activation and epoxyeicosatrienoic acid release, and 2) EDHFs compensate for reduced nitric oxide bioavailability at rest and with endothelium-dependent vasodilators. Methods and Results In 103 healthy subjects and 71 non-hypertensive subjects with multiple risk factors, resting forearm blood flow (FBF) was measured using venous occlusion plethysmography before and after intra-arterial infusions of NG-monomethyl-L-arginine (L-NMMA), TEA, fluconazole, and their combination. The effects of these antagonists on resting FBF, and on bradykinin- and acetylcholine-mediated vasodilation was studied. Resting FBF decreased with TEA and L-NMMA in all subjects (P<0.001), however, the vasoconstrictor response to L-NMMA was greater (p=0.04) and to TEA lower (p=0.04) in healthy subjects compared to those with risk factors. Fluconazole decreased resting FBF in all subjects and addition of TEA further reduced FBF after fluconazole, suggesting that cytochrome P450 metabolites and other hyperpolarizing factor(s) activate K+Ca channels. Both L-NMMA and TEA attenuated bradykinin-mediated vasodilation in healthy and hypercholesterolemic subjects (P<0.001). In contrast, acetylcholine-mediated vasodilation remained unchanged with TEA in healthy subjects, but was significantly attenuated in hypercholesterolemia (P<0.04). Conclusions Firstly, EDHFs by activating TEA inhibitable K+Ca channels together with NO contribute to resting microvascular dilator tone. The contribution of K+Ca channel activation compared to NO is greater in those with multiple risk factors compared to healthy subjects. Second, activation of K+Ca channels is only partly through epoxyeicosatrienoic acid release, indicating presence of other hyperpolarizing mechanisms. Third, bradykinin, but not acetylcholine stimulates K+Ca channel-mediated vasodilation in healthy subjects, whereas in hypercholesterolemia, K+Ca channel-mediated vasodilation compensates for the reduced NO activity. Thus, enhanced EDHF activity in conditions of NO deficiency contributes to maintenance of resting and agonist-stimulated vasodilation. Clinical Trial Registration Information: http://clinicaltrials.gov/, Identifier: NCT00166166

Objectives The primary objective of this study was to elucidate mechanisms underlying the link between vitamin D status and cardiovascular disease by exploring the relationship between 25-hydroxyvitamin D (25-OH D), an established marker of vitamin D status, and vascular function in healthy adults. Background Mechanisms underlying vitamin D deficiency-mediated increased risk of cardiovascular disease remain unknown. Vitamin D influences endothelial and smooth muscle cell function, mediates inflammation, and modulates the renin-angiotensin-aldosterone axis. We investigated the relationship between vitamin D status and vascular function in humans, with the hypothesis that vitamin D insufficiency will be associated with increased arterial stiffness and abnormal vascular function. Methods We measured serum 25-OH D in 554 subjects. Endothelial function was assessed as brachial artery flow-mediated dilation, and microvascular function was assessed as digital reactive hyperemia index. Carotid-femoral pulse wave velocity and radial tonometry-derived central augmentation index and subendocardial viability ratio were measured to assess arterial stiffness. Results Mean 25-OH D was 31.8 ± 14 ng/ml. After adjustment for age, sex, race, body mass index, total cholesterol, low-density lipoprotein, triglycerides, C-reactive protein, and medication use, 25-OH D remained independently associated with flow-mediated vasodilation (β = 0.1, p = 0.03), reactive hyperemia index (β = 0.23, p < 0.001), pulse wave velocity (β = −0.09, p = 0.04), augmentation index (β = −0.11, p = 0.03), and subendocardial viability ratio (β = 0.18, p = 0.001). In 42 subjects with vitamin D insufficiency, normalization of 25-OH D at 6 months was associated with increases in reactive hyperemia index (0.38 ± 0.14, p = 0.009) and subendocardial viability ratio (7.7 ± 3.1, p = 0.04), and a decrease in mean arterial pressure (4.6 ± 2.3 mm Hg, p = 0.02). Conclusions Vitamin D insufficiency is associated with increased arterial stiffness and endothelial dysfunction in the conductance and resistance blood vessels in humans, irrespective of traditional risk burden. Our findings provide impetus for larger trials to assess the effects of vitamin D therapy in cardiovascular disease.

Background Left ventricular dyssynchrony is an adverse consequence of ST-elevation myocardial infarction (STEMI) and bears an unfavorable prognosis. Mechanical dyssynchrony as measured by phase analysis from gated single photon emission computed tomography (GSPECT) correlates well with other imaging methods of assessing dyssynchrony but has not been studied in STEMI. We hypothesized that systolic dyssynchrony as measured by GSPECT would correlate with adverse remodeling after STEMI. Methods In 28 subjects suffering STEMI, GSPECT with technetium-99m sestamibi was performed immediately after presentation (day 5) and remotely (6 months). Parameters of left ventricular dyssynchrony (QRS width, histogram bandwidth (HBW) and phase standard deviation (PSD)) were measured from GSPECT using the Emory Cardiac Toolbox. Left ventricular volumes, ejection fraction (LVEF) and infarct size were also assessed. Results After successful primary percutaneous coronary intervention to the infarct-related artery, subjects had an LVEF of 46.4% ± 11% and a resting perfusion defect of 27.4% ± 16% at baseline. Baseline QRS width was normal (91.5 ± 17.5 ms). Subjects with STEMI had dyssynchrony compared with a cohort of 22 normal subjects (age 57.2 ± 10.6 years, <5% perfusion defect) by both HBW (100.3° ± 70.7° vs 26.5° ± 5.3°, P < .0001) and PSD (35.3° ± 16.9° vs 7.9° ± 2.1°, P < .0001). Baseline HBW correlated with resting perfusion defect size (r = 0.67, P < .001), end-systolic volume (r = 0.72, P < .001), end-diastolic volume (r = 0.63, P = .001), and inversely with LVEF (r =−0.74, P < .001). HBW and PSD improved over the follow-up period (−24.1 ± 35.9 degrees, P = .003 and −8.7° ± 14.6°, P = .006, respectively), and improvement in HBW correlated with reduction in LV end-systolic volumes (r = 0.43, P = .034). Baseline HBW and PSD, however, did not independently predict LVEF at 6 months follow-up. Conclusions After STEMI, subjects exhibit mechanical dyssynchrony as measured by GSPECT phase analysis without evidence of electrical dyssynchrony. Improvement in mechanical dyssynchrony correlates with beneficial ventricular remodeling. The full predictive value of this measure in post-infarct patients warrants further study.

The role of endothelium-derived hyperpolarizing factor (EDHF) in either the healthy circulation or in those with hypercholesterolemia is unknown. In healthy and hypercholesterolemic subjects, we measured forearm blood flow (FBF) using strain-gauge plethysmography at rest, during graded handgrip exercise, and after sodium nitroprusside infusion. Measurements were repeated after l-NMMA, tetraethylammonium (TEA), and combined infusions. At rest, l-NMMA infusion reduced FBF in healthy but not hypercholesterolemic subjects. At peak exercise, vasodilation was lower in hypercholesterolemic compared to healthy subjects (274% vs 438% increase in FBF, p=0.017). TEA infusion reduced exercise-induced vasodilation in both healthy and hypercholesterolemic subjects (27%, p<0.0001 and -20%, p<0.0001, respectively). The addition of l-NMMA to TEA further reduced FBF in healthy (-14%, p=0.012) but not in hypercholesterolemic subjects, indicating a reduced nitric oxide and greater EDHF-mediated contribution to exercise-induced vasodilation in hypercholesterolemia. In conclusion, exercise-induced vasodilation is impaired and predominantly mediated by EDHF in hypercholesterolemic subjects. Clinical Trial Registration Identifier: NCT00166166.

Bradykinin (BK) stimulates tissue plasminogen activator (t-PA) release from human endothelium. Although BK stimulates both nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) release, the role of EDHF in t-PA release remains unexplored. This study sought to determine the mechanisms of BK-stimulated t-PA release in the forearm vasculature of healthy human subjects. Methods: In 33 healthy subjects (age 40.3 ± 1.9 years), forearm blood flow (FBF) and t-PA release were measured at rest and after intra-arterial infusions of BK (400 ng/min) and sodium nitroprusside (3.2 mg/min). Measurements were repeated after intra-arterial infusion of tetraethylammonium chloride (TEA; 1 μmol/min), fluconazole (0.4 μmol·min^-1·l^-1), and N^G-monomethyl-L-arginine (L-NMMA, 8 μmol/min) to block nitric oxide, and their combination in separate studies. Results: BK significantly increased net t-PA release across the forearm (p < 0.0001). Fluconazole attenuated both BK-mediated vasodilation (-23.3 ± 2.7% FBF, p < 0.0001) and t-PA release (from 50.9 ± 9.0 to 21.3 ± 8.9 ng/min/100 ml, p = 0.02). TEA attenuated FBF (-14.7 ± 3.2%, p = 0.002) and abolished BK-stimulated t-PA release (from 22.9 ± 5.7 to -0.8 ± 3.6 ng/min/100 ml, p = 0.0002). L-NMMA attenuated FBF (p < 0.0001), but did not inhibit BK-induced t-PA release (nonsignificant). Conclusion: BK-stimulated t-PA release is partly due to cytochrome P<inf>450</inf>-derived epoxides and is inhibited by K⁺<inf>Ca</inf> channel blockade. Thus, BK stimulates both EDHF-dependent vasodilation and t-PA release.

Objective-Abnormalities in nitric oxide (NO) bioavailability have been reported in blacks. Whether there are differences in endothelium-derived hyperpolarizing factor (EDHF) in addition to NO between blacks and whites and how these affect physiological vasodilation remain unknown. We hypothesized that the bioavailability of vascular NO and EDHF, at rest and with pharmacological and physiological vasodilation, varies between whites and blacks. Approach and Results-In 74 white and 86 black subjects without known cardiovascular disease risk factors, forearm blood flow was measured using plethysmography at rest and during inhibition of NO with NG-monomethyl-L-arginine and of K +Ca channels (EDHF) with tetraethylammonium. The reduction in resting forearm blood flow was greater with NG-monomethyl-L- arginine (P=0.019) and similar with tetraethylammonium in whites compared with blacks. Vasodilation with bradykinin, acetylcholine, and sodium nitroprusside was lower in blacks compared with whites (all P<0.0001). Inhibition with NG-monomethyl-L-arginine was greater in whites compared with blacks with bradykinin, acetylcholine, and exercise. Inhibition with tetraethylammonium was lower in blacks with bradykinin, but greater during exercise and with acetylcholine. Conclusions-The contribution to both resting and stimulus-mediated vasodilator tone of NO is greater in whites compared with blacks. EDHF partly compensates for the reduced NO release in exercise and acetylcholine-mediated vasodilation in blacks. Preserved EDHF but reduced NO bioavailability and sensitivity characterizes the vasculature in healthy blacks.