Publications

OBJECTIVE

Circulating angiogenic cells (CACs), also termed endothelial progenitor cells, play an integral role in vascular repair and are functionally impaired in coronary artery disease (CAD). The role of nitric oxide (NO) in CAC function is poorly understood. We hypothesized that CAC migration toward angiogenic signals is modulated by both NO synthase (NOS) expression and functional response to NO.

METHODS AND RESULTS

Similar to endothelial cells, CAC chemotaxis to vascular endothelial growth factor (VEGF) was blocked by inhibition of NOS, phosphatidylinositol 3-kinase, or guanylyl cyclase or by treatment with an NO scavenger. Addition of an NO donor (S-nitroso-N-acetylpenicillamine) and the NOS substrate l-arginine increased random cell migration (chemokinesis) and enhanced VEGF-dependent chemotaxis. Healthy CACs expressed endothelial NOS, but endothelial NOS was not detected in CAD patient CACs. Both chemokinesis and chemotaxis to VEGF of patient CACs were decreased compared with healthy CACs but were restored to healthy values by S-nitroso-N-acetylpenicillamine. In parallel, CAD patients exhibited lower flow-mediated vasodilation and plasma NO source nitrite than young, healthy subjects, indicating endothelial dysfunction with reduced NO bioavailability.

CONCLUSIONS

NOS activity is required for CAC chemotaxis. In CAD patients, impairment of NOS expression and NO bioavailability, rather than response to NO, may contribute to dysfunction of CACs and limit their regenerative capacity.

Based on in vitro rat and human hepatocyte uptake studies showing inhibition of warfarin uptake in the presence of the nonspecific organic anion-transporting polypeptide (OATP) inhibitor rifampin, a clinical study was conducted in 10 healthy volunteers to examine the in vivo relevance of OATP hepatic uptake on the pharmacokinetics of warfarin. In a randomized, single-dose, two-period, crossover design, subjects received a 7.5-mg dose of warfarin, either alone or immediately following a 600-mg intravenous dose of rifampin. Rifampin did not significantly alter the R- or S-warfarin area under the concentration-time curves (AUCs) from 0 to 12 h (period of hepatic OATP inhibition by rifampin) or the maximum plasma concentration (C(max)) value. AUC(0-∞) was decreased on days rifampin was administered, for both R-warfarin (25% reduction; P < 0.001) and S-warfarin (15% reduction; P < 0.05). No differences were seen in the area under the international normalized ratio (INR)-time curve. Our study suggests that hepatic uptake via OATPs may not be clinically important in the pharmacokinetics of warfarin.

OBJECTIVES

The purpose of this paper was to compare quantitative cardiac magnetic resonance (CMR) first-pass contrast-enhanced perfusion imaging to qualitative interpretation for determining the presence and severity of coronary artery disease (CAD).

BACKGROUND

Adenosine CMR can detect CAD by measuring perfusion reserve (PR) or by qualitative interpretation (QI).

METHODS

Forty-one patients with an abnormal nuclear stress scheduled for X-ray angiography underwent dual-bolus adenosine CMR. Segmental myocardial perfusion analyzed using both QI and PR by Fermi function deconvolution was compared to quantitative coronary angiography.

RESULTS

In the 30 patients with complete quantitative data, PR (mean +/- SD) decreased stepwise as coronary artery stenosis (CAS) severity increased: 2.42 +/- 0.94 for <50%, 2.14 +/- 0.87 for 50% to 70%, and 1.85 +/- 0.77 for >70% (p < 0.001). The PR and QI had similar diagnostic accuracies for detection of CAS >50% (83% vs. 80%), and CAS >70% (77% vs. 67%). Agreement between observers was higher for quantitative analysis than for qualitative analysis. Using PR, patients with triple-vessel CAD had a higher burden of detectable ischemia than patients with single-vessel CAD (60% vs. 25%; p = 0.02), whereas no difference was detected by QI (31% vs. 21%; p = 0.26). In segments with myocardial scar (n = 64), PR was 3.10 +/- 1.34 for patients with CAS <50% (n = 18) and 1.91 +/- 0.96 for CAS >50% (p < 0.0001).

CONCLUSIONS

Quantitative PR by CMR differentiates moderate from severe stenoses in patients with known or suspected CAD. The PR analysis differentiates triple- from single-vessel CAD, whereas QI does not, and determines the severity of CAS subtending myocardial scar. This has important implications for assessment of prognosis and therapeutic decision making.