Simultaneous Noninvasive Assessment of Systemic and Coronary Endothelial Function

Abstract

Background: Normal endothelial function is a measure of vascular health and dysfunction is a predictor of coronary events. Nitric oxide-mediated coronary artery endothelial function, as assessed by vasomotor reactivity during isometric handgrip exercise (IHE), was recently quantified noninvasively with magnetic resonance imaging (MRI). Because the internal mammary artery (IMA) is often visualized during coronary MRI, we propose the strategy of simultaneously assessing systemic and coronary endothelial function noninvasively by MRI during IHE.

Methods and results: Changes in cross-sectional area and blood flow in the right coronary artery and the IMA in 25 patients with coronary artery disease and 26 healthy subjects during IHE were assessed using 3T MRI. In 8 healthy subjects, a nitric oxide synthase inhibitor was infused to evaluate the role of nitric oxide in the IMA-IHE response. Interobserver IMA-IHE reproducibility was good for cross-sectional area (R=0.91) and blood flow (R=0.91). In healthy subjects, cross-sectional area and blood flow of the IMA increased during IHE, and these responses were significantly attenuated by monomethyl-l-arginine (P<0.01 versus placebo). In patients with coronary artery disease, the right coronary artery did not dilate with IHE, and dilation of the IMA was less than that of the healthy subjects (P=0.01). The blood flow responses of both the right coronary artery and IMA to IHE were also significantly reduced in patients with coronary artery disease.

Conclusions: MRI-detected IMA responses to IHE primarily reflect nitric oxide-dependent endothelial function and are reproducible and reduced in patients with coronary artery disease. Endothelial function in both coronary and systemic (IMA) arteries can now be measured noninvasively with the same imaging technique and promises novel insights into systemic and local factors affecting vascular health.

Keywords: atherosclerosis; coronary artery disease; endothelium; magnetic resonance imaging; vasodilation.

Fig 1. MR anatomical and flow velocity images of right coronary artery and internal mammary artery at rest and during isometric handgrip exercise

A) Scout scan obtained parallel to the RCA and IMA in a healthy subject is shown together with the location for cross sectional imaging of the two vessels (red line). B) Cross-sectional image perpendicular to the RCA (green box) and IMA (red box) is shown. Magnified cross-sectional image of the RCA and the IMA (shown by green and red boxes, respectively) at rest (C) and during IHE (D). Magnified flow velocity image of the IMA in the same subject is shown at rest (E) and during IHE (F) during systole. Magnified coronary flow velocity image of the RCA in the same subject is shown at rest (G) and during IHE (H) in diastole. The signal phase is proportional to flow velocity with the darker pixels in the velocity phase contrast images during IHE indicating higher velocity in the caudal direction of the IMA and RCA.

Fig 2. Intravenous infusion of monomethyl-L-arginine, a nitric oxide synthase inhibitor, blocks isometric handgrip exercise-induced vasodilation and the increase in blood flow in the internal mammary artery of healthy volunteers

A) Diagram illustrating MRI L-NMMA study. B) Vasoreactive changes during IHE for placebo (blue striped) and L-NMMA (yellow) infusions showing that L-NMMA blocks IMA vasodilation and increase in velocity and blood flow with IHE. Comparisons of placebo- and L-NMMA responses were performed with a paired t-test. Abbreviations: L-NMMA: monomethyl-L-arginine; IHE: Isometric Handgrip Exercise

Fig 3. Inter-observer Reproducibility of Noninvasive MRI Measures of the IMA

(A-C) Linear regression showing strong correlation between % area change with IHE between observer 1 and observer 2 (A), % velocity (B) and % flow change (C) between first and second observer. D-F) Bland-Altman plots indicate good confidence of agreement and little variability between the two measures. Lines represent 95% confidence of agreement.

Fig 4. Peripheral and Coronary Endothelial Function in Healthy Volunteers and Patients with CAD-CSA Change

A) Protocol diagram illustrating MRI study. B) Summary results for mean CSA changes in the IMA (striped bars) and RCA (solid bars) during IHE for healthy volunteers (blue) and patients with CAD (red). Analysis performed with Kruskal-Wallis testing with Bonferroni adjustment for pair-wise comparisons.

Fig 5. Peripheral and Coronary Endothelial Function in Healthy Volunteers and Patients with CAD-Flow Change

A) Protocol diagram illustrating MRI study. Summary results for mean peak systolic velocity changes in the IMA and peak diastolic velocity changes in the RCA (B) and for mean blood flow changes with IHE (C) during IHE for healthy subjects (blue) and CAD patients (red). Analysis performed with Kruskal-Wallis testing with Bonferroni adjustment for pair-wise comparisons.

Fig 6. Relationship between Coronary and Internal Mammary Artery Endothelial Function

Individual results for IMA and RCA responses to IHE for CSA (A), flow velocity (B), and blood flow (C) changes in healthy subjects (blue) and CAD patients (red). When all participants were combined into a single group there was a statistically significant relationship between IMA and RCA responses (although the significance of the CSA relationship depended on one point remote from the others). However, the correlation between IMA and RCA responses were not significant for each group considered alone, suggesting the overall correlation was primarily related to group differences between healthy subjects and CAD patients rather than a close fundamental relationship between IMA and RCA responses.