Ongoing clinical investigations suggest that MRI might have the potential to detect preclinical signs of cardiovascular disease, possibly opening the door to new therapeutic strategies aimed at disease prevention.
The investigations focus on imaging correlates of novel markers of cardiovascular risk. The markers include both biologic and physiologic characteristics that have been linked to an increased risk of atherosclerotic vascular disease.
"We're taking the next step beyond just finding a blockage," said Dr. Andrew Arai, an investigator at the National Heart, Lung, and Blood Institute in Bethesda, MD. "Once someone has a blockage, the disease is pretty far along and will require some sort of major procedure, such as coronary angioplasty, carotid endarterectomy, or coronary bypass surgery.
"We would like to find a better way to discriminate early on which patients have a pathologic process in the arterial wall, so that we might be able to intervene with medications or genetic therapy, or something else, before a major interventional procedure is necessary."
Arai's work focuses on MR correlates of arterial inflammation. A growing body of clinical and laboratory evidence indicates that inflammation plays a key role in the initiation and evolution of vascular disease. This line of research has grown rapidly following early studies that demonstrated increased levels of circulating pro-inflammatory proteins in patients with vascular disease and in atherosclerotic plaque. The markers of inflammation include C-reactive protein, adhesion molecules, interleukin-6, and E-selectin.
"MRI can detect inflammation associated with a variety of medical conditions, from brain lesions to arthritis to infection," Arai said. "Since there is growing evidence that inflammation is part of the atherosclerotic process, we thought we might be able to detect changes in the walls of blood vessels associated with inflammation."
In preliminary clinical studies of 27 patients, Arai and colleagues have used a 1.5-tesla magnet and double-inversion recovery fast spin-echo MR sequences to image the carotid arteries or aorta in 27 patients with and without elevated cholesterol or other risk factors for cardiovascular disease. MR revealed arterial inflammation in 15 of the 27, as evidenced by arterial wall contrast enhancement or wall thickening.
None of the patients in the study had serious stenoses-perhaps 20% at worst-and would not have been considered candidates for intervention. The 15 patients with evidence of arterial inflammation, however, had higher blood levels of inflammatory proteins when compared with the 12 patients who did not have arterial wall abnormalities on MR.
"On the basis of MRI findings that we predict should correlate with inflammation, we think we can distinguish patients who are at high and low risk for having these blood stream markers of inflammation, which have been associated with increased cardiovascular risk," Arai said.
"If we can rely on information about inflammation, then we have something that we can potentially use to monitor people before they have advanced disease, and with enough reliability to make some clinical decisions."
MRI has also shown potential to detect abnormal endothelial function, another emerging marker of increased cardiovascular risk. Abnormal function of the inner lining of arterial walls has been linked to thrombosis, inflammation, and impaired vasodilation, said Dr. Harry Silber, an assistant professor of medicine at Johns Hopkins School of Medicine.
"Abnormal endothelial function often predates development of overt atherosclerosis by many years. If we can find a way to screen for endothelial dysfunction in people who do not yet have atherosclerosis, we might be able to use therapies targeted to that population of patients," Silber said.
Ultrasound represents the noninvasive standard for evaluating endothelial dysfunction, typically reflected in abnormal vasodilation in response to hyperemia, which is simulated by inflation and deflation of a blood pressure cuff on the upper or lower arm.
"When we release the cuff, there is a rush of blood down the arm," Silber explained. "The rush of blood and the friction between the blood and the vessel wall causes vasodilation, due to endothelium-dependent mechanisms."
Endothelial dysfunction is a systemic marker of cardiovascular disease, he said.
"When dysfunction exists, it is not limited to areas of atherosclerosis, so that dysfunction in the brachial artery, for example, indicates dysfunction throughout the vascular system, including the coronary arteries," he said.
Silber and colleagues have been evaluating phase-contrast MR angiography as a potential alternative to ultrasound for assessment of endothelial function. Specifically, they have sought correlations between flow-mediated vasodilation (FMD) and vascular wall shear stress, which reflects the friction between circulating blood and the vessel wall.
The Johns Hopkins group has observed that FMD at one minute after cuff release correlated significantly with vascular wall shear stress in normal individuals (p = 0.0001). They also found that baseline vessel diameter is a significant predictor of the hyperemic response (p <0.0001). By providing information about vessel diameter and wall shear stress, MRA improves noninvasive assessment of endothelial function, they concluded.
Endothelial dysfunction is associated with traditional coronary risk factors such as elevated cholesterol and smoking. Treatments for traditional risk factors tend to improve or normalize endothelial function. No studies to date have shown that normalization of endothelial function in isolation from improvement in coronary risk factors reduces the risk of cardiovascular morbidity and mortality, Silber said.
"However, a lot of people are coming around to believing that endothelial function is the final common pathway for treatments that improve vascular disease and for conditions that exacerbate vascular disease," he said.
