This study demonstrated that abnormal coronary endothelial function and increased coronary wall thickness can be detected during a single, non-invasive 3T MRI exam and, importantly, that abnormal coronary endothelial-dependent vasoreactivity is present locally in mildly diseased coronaries and related to the earliest non-invasive in vivo
measure of local coronary atherosclerosis, an increase in coronary artery wall thickness. We previously reported that coronary endothelial function was closely related to the degree of luminal stenosis.15
Our current pilot study in patients with non-obstructive CAD demonstrate that local functional and anatomic changes of the coronary arteries are closely related in early
atherosclerosis, before the development of significant luminal stenoses, a late occurrence in the progression of atherosclerotic disease.
The present study detected significantly higher mean coronary wall thickness, wall area, and normalized wall index in patients with mild CAD compared to those of healthy subjects. This increase in wall thickness in CAD patients relative to healthy subjects and preservation of luminal area is indicative of positive arterial remodeling.4
The values for coronary wall area, wall thickness, and coronary endothelial function reported here are similar to those previously reported using MRI6-8, 15
and invasive techniques2, 10, 30-32
in separate studies, although the endothelial-dependent stressors varied across studies. The observation that mild structural and/or functional coronary disease may contribute to reduced endothelial-dependent coronary flow supports earlier PET vasomotor flow studies.33, 34
However, the ability to measure both vessel wall remodeling and endothelial-dependent coronary vasoreactivity in a single non-invasive exam, demonstrated here for the first time, enables a more complete measure of early atherosclerotic disease than previously possible. Finally, the length of the coronary protocol makes it feasible to combine the imaging sequence with an MR evaluation of left ventricular structure or function, leading to a more comprehensive cardiac exam.
In a recent report, abnormal coronary endothelial function varied among arteries in a given CAD patient and was related to the severity of luminal stenosis.15
The observation here that coronary wall thickness and local endothelial function are associated in patients with mild, non-stenotic CAD is novel and demonstrates that anatomic and functional early atherosclerosis not only co-exist in coronary arteries but are also closely related. Although structural alterations in the arterial wall may impair flow-mediated epicardial vasodilation, we previously showed that the administration of nitroglycerin to patients with significant CAD dilated the same arteries that constricted with isometric handgrip exercise.15
That demonstration that endothelial-independent
mechanisms are intact shows that the likely mechanism for impaired epicardial vasodilation during isometric handgrip exercise is likely endothelial dysfunction rather than a mechanical disturbance such as may occur with heavy coronary calcification, especially in these patients with very mild atherosclerosis.
In contrast to the findings in CAD patients, there was no relationship between coronary endothelial function and CWT in healthy subjects. Though prior work demonstrated that stimuli like tobacco abuse or high circulating lipids35,36
can induce transitory abnormal endothelial function in healthy subjects, all such stimuli were avoided here by protocol design.
Although our study detected a relationship between endothelial-dependent coronary vasodilation (area change) and wall thickness in arteries with mild atherosclerosis, we found no apparent relationship between coronary velocity change with stress and early anatomic atherosclerosis in either group. These findings suggest that early local anatomic atherosclerotic changes are more closely related to measures of, and therefore, local coronary endothelial function (e.g. area change within the same epicardial coronary segment) than to endothelial function measures which incorporate non-local parameters (e.g. coronary flow velocity).
The extent of early anatomic atherosclerosis and endothelial function has been well characterized in peripheral arterial beds.37, 38
Several previous studies evaluated the relationship between brachial endothelial function (flow mediated dilation) and carotid intimal medial thickness using B-mode ultrasound and reported varying results.37-39
Although earlier studies found a positive relationship between carotid intimal medial thickness and peripheral endothelial function,37
more recent studies found no significant correlation between the two parameters.38, 39
Those findings may be explained by the fact that different vascular beds were evaluated for anatomic and functional measurements of atherosclerotic disease.
Although atherosclerosis is a systemic process, studies of different vascular territories have shown that vasoreactivity may not be uniform across vascular regions within the same individual. One study using MRI compared changes in flow and vessel radius before and during post-occlusion hyperemia in the upper (brachial) vs. lower (femoral) extremities and found that femoral but not brachial reactivity was impaired in patients with increased cardiovascular risk.40
Other data suggest that peripheral and coronary endothelial function measures may not be strongly related41, 42
possibly due to differences in vascular properties.43
Moreover, acute brachial arterial plaque rupture rarely occurs in contrast to acute coronary plaque rupture. Although peripheral and coronary endothelial vasoreactivity have not been directly compared using the same stressor and imaging modality, our previous data show significant heterogeneity of coronary endothelial function within the coronary tree.15
Thus, the non-invasive measurement of coronary endothelial function is likely more relevant for defining factors related to local coronary artery atherosclerosis and plaque progression.
human studies evaluating coronary
endothelial function and its relationship to early vessel remodeling have not been performed before, likely because invasive techniques were required. The most commonly used technique to identify positive coronary arterial remodeling has been intravascular ultrasound (IVUS).44,45
Traditionally, studies of coronary endothelial function have been performed during x-ray coronary angiography with acetylcholine or cold pressor testing as the endothelial-dependent stressor.2, 9
Those techniques, however, are not suitable for screening low risk and asymptomatic populations because of their invasive nature and associated risk. Although multi-detector computed tomography (MDCT) has been used to assess positive remodeling and plaque progression in patients with CAD,46
the exposure to ionizing radiation and contrast media limit repeated studies and its use in low risk populations. It is also unable to measure coronary velocity or flow for the assessment of endothelial function. Black blood coronary wall MRI can detect coronary arterial wall changes indicative of positive arterial remodeling6, 7
with good reproducibility.28, 29
Moreover, MRI studies of the coronaries may be safely applied to low risk populations to noninvasively quantify coronary vessel wall dimensions and to measure endothelial dependent vasoreactivity. There were no noteworthy variations in image quality with respect to BMI, heart rate or other clinical parameters and the sequences performed equally well with the RCA and LAD in most cases. Lastly, in our study, the use of an MRI contrast agent (gadolinium) was not necessary, which offers the ability to safely study patients with renal insufficiency.
One limitation to the current study is that the spatial resolution of MR imaging of the coronaries is not able to distinguish separate layers of the vessel wall or plaque components. Therefore, radiofrequency intravascular ultrasonography determination of early anatomical changes in the coronary arterial wall may be more sensitive at detecting and characterizing early disease than MRI, however, we were not able to ethically justify the risk associated with invasive coronary procedures in healthy and low risk subjects studied here as an alternative validation approach. In addition, we are currently limited in the choice of the coronary segment that can be imaged. Although we primarily focused on proximal and mid coronary segments of the RCA or LAD to evaluate stress-induced area changes, the ability to also measure coronary velocity and flow permits a more global assessment of downstream endothelial function that complements the measurement of local epicardial vasoreactivity. Therefore, technical developments designed to improve spatial resolution and volumetric coverage will likely advance endothelial function studies and permit greater flexibility in the choice of the imaging plane and local characterization of plaque morphology. Another limitation to this pilot study is the relatively small sample size. However, with only 34 coronary arteries investigated, we observed significant differences in both positive arterial remodeling and vasomotor responses to a known endothelial-dependent stressor between healthy and CAD subjects. Lastly, the two groups were not age-matched. However, on further statistical analysis of a subset of healthy subjects age-matched to the CAD patients, significant differences in CWT and exercise-induced change in CSA were still observed between mild CAD patients and healthy age-matched controls. Because of the small sample size, multivariate analysis with respect to coronary risk factors and age could not be performed.
In summary, the present findings demonstrate that local coronary endothelial function is inversely related to local positive arterial remodeling in patients with non-obstructive CAD. These findings indicate that early non-stenotic atherosclerosis is associated with abnormal local endothelial function and therefore that anatomic and physiologic indicators of coronary vascular pathology are related in patients at the earliest stages of coronary atherosclerosis that can be detected non-invasively in humans. Moreover, it would be feasible to combine this imaging protocol with an MRI evaluation of left ventricular function, leading to a more comprehensive evaluation of cardiac risk. This may contribute to improved detection and monitoring of atherosclerotic disease and its response to therapy at an early, preclinical stage as well as the ability to non-invasively investigate anatomic and functional predictors of disease progression.