In the present study, noninvasive coronary CMRA demonstrated impaired coronary artery vasodilation to NTG in a group of patients at increased risk for coronary artery disease. To our knowledge, this is the first study to use noninvasive imaging to directly assess impaired epicardial coronary vasodilation in this patient group.
Coronary Vasomotor Function and Atherosclerosis
Abnormal coronary vasomotor function occurs early in the development of atherosclerosis  and is typically assessed by studying endothelial- dependent epicardial coronary vasodilation by invasive methods [5, 17]. However, several x-ray coronary angiography studies [6, 10] have also found impairment of endothelial- independent coronary vasodilation to NTG in patients, with prognostic significance. In a study of 147 patients with risk factors for CAD (including 9% with diabetes and 84% with angiographic evidence of atherosclerosis) followed for a median 7.7 years, abnormal vasodilator response to acetycholine, cold pressor, and NTG were each independently associated with disease progression and increased cardiovascular events . Consistent with these findings, a study of 163 women (including 26% with diabetes and 45% without angiographic evidence of CAD) found impaired reactivity to NTG and acetycholine in subjects who had future cardiovascular events .
Impaired Coronary Vasomotor Function and Patients with DM and ESRD
Prospective data on coronary vasomotor function are limited in patients with DM  and ESRD . However, consistent with an increased cardiovascular risk, peripheral vasomotor dysfunction has been almost universally found in these patients [20–26]. Two studies in non-insulin-dependent DM have shown impaired brachial artery vasodilation to both endothelial-dependent and endothelial-independent stimuli [24, 26]. Interestingly, in a study using brachial ultrasound in subjects with no documented CAD (including 13.1% with DM), the only risk factor independently associated with impaired NTG-induced vasodilation was DM . Similar to findings in the peripheral vasculature, reduced coronary artery reactivity to NTG has been previously reported in patients with DM. In a study  of non-insulin-dependent DM using intravascular ultrasound, coronary artery distensibility and diastolic cross sectional luminal area after NTG were significantly lower in DM compared to controls.
Similar to patients with DM, patients with renal failure have impaired peripheral vasomotor function [19, 28, 29]. In a study of 28 patients with chronic renal failure (13 on hemodialysis), both flow-mediated and NTG-induced brachial artery vasodilation were impaired to comparable degrees . To date, there are no known studies on coronary vasoreactivity in patients with ESRD.
Our data show that patients with DM and ESRD have impaired NTG-induced coronary vasodilation compared to age-matched controls. The individual data (Figure 3b) reveal that patients generally fell into two groups: those with normal coronary vasodilation (~25%) and those with low coronary vasodilation (< 15%). Eighty percent (80%) of ESRD and 38% of DM patients fell below the 15% threshold, compared to only 6% of the controls.
Noninvasive Coronary Imaging
CMR [30, 31], computed tomography (CT) [32, 33], ultrasound [34–36], and nuclear techniques [37, 38] all offer alternative approaches to assess coronary artery disease noninvasively. By using sub-mm spatial resolution and analyzing the lumen cross-sectional area, CMR has been shown to have adequate resolution to detect coronary vasodilation to NTG in two prior studies [12, 13]. CMR can also directly image the coronary wall, with increased wall thickness demonstrated in patients with Type I DM  and non-obstructive CAD [39, 40]. CT can provide high-resolution structural imaging of the coronary lumen and wall , but the radiation and contrast involved make it suboptimal for serial imaging of coronary vasomotor changes. One recent study did look retrospectively at patients who had more than one coronary CT scan, where NTG was used in one and not in another, and did show significantly larger coronary diameter with NTG . The feasibility of transthoracic echocardiography for measuring epicardial coronary vasodilation has recently been shown in healthy men . The other main approach to assess coronary function noninvasively has been to measure coronary flow or perfusion reserve to a vasodilator stimulus (e.g., adenosine). This is primarily a measure of coronary microvascular function in the absence of epicardial stenoses. This can be performed by CMR [30, 31, 43], positron emission tomography (PET) [37, 38], and transthoracic Doppler techniques [34–36] and has been shown to be impaired in patients with coronary risk factors [31, 38], including DM[35, 38]. More data comparing the prognostic significance of epicardial vs. microvascular vasomotor function are needed.
A major study limitation is that only endothelium-independent coronary vasodilation with NTG was evaluated. Endothelium-dependent vasomotor function has been shown to be an earlier marker of atherosclerosis and may be more sensitive in patients with subclinical disease [2, 4, 16]. Future studies should focus on overcoming the challenges of performing a more endothelial-dependent stimulus in the magnetic resonance environment. A preliminary report  and a case report  on using the cold pressor test show promise . In addition, the size of the clinical cohort was small and recruitment was consecutive, which may have contributed to the significant differences in demographics (i.e., % female) between the two groups. This difference did not account for the finding of impaired vasodilation in the patients, as this finding remained significant even when the only males were analyzed. A study incorporating more female patients is needed to verify if the impaired coronary vasodilation applies to high-risk women. Finally, long-term clinical follow up is needed to determine the prognostic significance of these findings.