EDITORIAL COMMENT
Testing coronary flow reserve without a provocative stress
A "BOLD" approach*
Francis J. Klocke, MD, MACC*,* and
Debiao Li, PhD*
* Feinberg Cardiovascular Research Institute and the Departments of Medicine, Radiology, and Biomedical Engineering, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
* Reprint requests and correspondence: Dr. Francis J. Klocke, Tarry 12-703 (T233), The Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, Illinois 60611-3008, USA.
f-klocke{at}northwestern.edu
The importance of identifying clinically important coronary stenoses noninvasively continues to stimulate interest in improved and/or less complex techniques for evaluating regional limitations in coronary flow reserve. The electrocardiographic, echocardiographic, and radionuclide approaches used in routine practice all employ exercise or pharmacologic stress to "unmask" areas of myocardium having normal resting perfusion but limited vasodilatory reserve. The possibility of identifying clinically important reductions in regional reserve without a provocative stress has intrigued several investigators and is addressed in coronary patients in this issue of the Journal in the study by Wacker et al. (1) using blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI).
The BOLD imaging capitalizes on the fact that deoxygenated hemoglobin in blood changes proton signals in a fashion that can be imaged to reflect the level of blood oxygenation (2). Increases in O2 saturation increase the BOLD imaging signal (T2* in this study), whereas decreases diminish it. Efforts to utilize BOLD imaging in the heart have previously focused on responses to pharmacologically induced coronary vasodilation (3–6). Because the increase in coronary flow produced by adenosine and dipyridamole usually occurs without a major increase in myocardial oxygen demand, coronary venous oxygen saturation normally increases from its usual value of 20% to 30% to 70% to 80%. When autoregulatory coronary vasodilation is required to counteract the effect of a proximal stenosis under resting conditions, regional coronary reserve is reduced and the increment in venous oxygen saturation during pharmacologic vasodilation is less than in areas without stenosis. The resultant regional differences in blood oxygen level (i.e., regional differences in deoxyhemoglobin concentration) are detected as regional differences in T2*.
The BOLD imaging signal is also affected by the amount of blood contained within the left ventricular vasculature, which this discussion will refer to as coronary blood volume (CBV). Coronary blood volume normally makes up 6% to 15% of left ventricular mass (7). As CBV increases, each unit volume of ventricle, that is, each voxel in a myocardial image, contains a slightly higher proportion of blood and a correspondingly smaller proportion of heart tissue. Thus, even at a stable level of oxygenation, the number of deoxygenated hemoglobin molecules within a voxel increases as CBV increases, causing a proportionate decrease in T2*. When CBV increases during pharmacologic vasodilation, the net effect on T2* reflects the increase caused by the increased level of blood oxygenation counterbalanced by any decrease resulting from the change in CBV. In the current study, increases in T2* in response to dipyridamole averaged 10 ± 5(SD)% in apparently healthy volunteers (1).
Several groups have now reported that CBV is also increased under resting conditions in areas supplied by stenotic coronary arteries (8–11). Using high-speed computed tomography in a canine model of epicardial coronary stenosis, Ritman’s laboratory found that CBV increased by  25% in response to an epicardial stenosis producing a 40-mm trans-stenotic pressure gradient (but no change in resting myocardial blood flow) (Fig. 5 in Wu et al. [9]). Coronary blood volume decreased slightly, but remained substantially elevated above its original value, as the trans-stenotic pressure gradient was increased to >100 mm Hg (and resting flow was impaired). Lindner et al. (10) and Wu et al. (11) subsequently reported that autoregulatory-induced increases in CBV could also be quantified using myocardial contrast echocardiography. In addition, Lindner et al. (10) confirmed that CBV increases progressively with the degree of stenosis until autoregulatory vasodilator reserve is exhausted.
Bauer, Ertl, Wacker, and colleagues (1,5,12) in Wuerzburg have contributed significantly to the study of myocardial applications of BOLD imaging. They have now examined regional values of T2* under resting conditions as well as during dipyridamole-induced vasodilation in 16 patients with clinically evident angina, single-vessel coronary artery disease (>70% stenosis), normal resting left ventricular wall motion and positive stress echocardiographic studies (1). Their data under resting conditions (Fig. 3, left panel in Wacker et al. [1]) are noteworthy. A regional reduction in T2*, corresponding to a relative increase in deoxyhemoglobin, was apparent in the area perfused by the stenotic artery in every case illustrated. Values of T2* in stenotic areas averaged 31 ± 9% less than in nonstenotic areas. Thus, clinically meaningful stenoses in these patients were apparent without a provocative stress.
This finding presumably resulted from increases in CBV associated with autoregulatory vasodilation required to maintain normal blood flow under resting conditions. The morphologic studies of Kassab et al. (13) indicate that 36% of the total left ventricular CBV normally resides in vessels <200 µm in diameter. Because of their relative length, capillaries appear to account for 90% of the blood contained within these vessels (13). Because autoregulation occurs primarily in arterioles <100 µm (14), autoregulatory increases in CBV involve capillaries and capillary recruitment. Capillary recruitment may also involve changes in microvessel hematocrit and flux of erythrocytes through capillaries. By increasing the proportion of blood in each voxel imaged, the autoregulatory increases in CBV apparently increased the amount of deoxyhemoglobin contained in capillaries and venules in voxels within the stenotic area.
Findings during dipyridamole-induced global coronary vasodilation were compatible with the expending of normal vasodilator reserve to maintain resting flow. Although regional differences in T2* between normal and stenotic areas increased on average to 43 ± 21%, responses in individual patients were quite variable (Fig. 3, right panel in Wacker et al. [1]). The variability no doubt reflected different degrees of residual flow reserve in individual stenotic beds. The several patients who showed no clear change presumably had lesions that required utilization of nearly all vasodilator reserve under resting conditions. Indeed, dipyridamole precipitated angina in five individuals.
As Wacker et al. (1) carefully point out, this investigation is a pilot study demonstrating that a noncontrast MRI technique can detect regional differences in BOLD signal in patients with isolated coronary stenoses of sufficient severity to produce clinical angina and abnormal responses to stress echocardiography. Its applicability to the broad spectrum of coronary disease merits further examination, particularly in regard to findings under resting conditions. However, the degree to which BOLD imaging technology can continue to be improved may be a major consideration as studies proceed. Several relevant issues, such as superimposed susceptibility artifacts, are discussed by Wacker et al (1). In addition, although a linear relationship between BOLD signal and regional differences in flow has been demonstrated over the full range of pharmacologic vasodilation in a canine preparation, the degree of scatter in the relationship remains problematic (6) (Fig. 6 in Wright et al. [6]). The degree to which higher field strength magnets and other potential improvements can improve the sensitivity and specificity that can be achieved using clinical MRI systems may determine the ultimate role of BOLD imaging in the noninvasive evaluation of coronary artery disease.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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