By the direct comparison of the images obtained before and after an exercise test within two hours, the present study demonstrated a significant change of 18F-FDG uptake in CAD patients and stenotic coronaries. Previous studies have reported enhanced 18F-FDG uptake in patients with CAD under fasting conditions [3,4,5,6,7,8,9,10,11]. However, myocardial 18F-FDG uptake is spatially heterogeneous even under strict dietary control [13,14,15]. Patients without documented CAD can also have regional or global myocardial uptake, which is known as ‘non-specific’ or ‘physiological’. Physiological uptake is mostly localized on, but not confined to, the basal segments. Therefore, regional 18F-FDG uptake, even in the territory supplied by the stenotic coronary, may only be physiological. As a result, although 18F-FDG imaging had a relatively high sensitivity in the diagnosis of CAD, its specificity was rarely investigated and presumably poor . To clarify the specificity of 18F-FDG imaging, we had conducted exercise and resting 18F-FDG imaging in CAD patients during two sequential days . Resting imaging was 24 h after exercise imaging. We speculated that the ischemic uptake of 18F-FDG on exercise imaging should decrease or disappear on resting imaging. In that study, 87% of the patients with increased 18F-FDG uptake on exercise imaging showed decreased or no discernible uptake on resting imaging, which in part supported that 18F-FDG uptake was a specific marker for myocardial ischemia. The other 13% patients had persistent uptake which was interpreted as ischemic memory. However, several studies have found that normal myocardium could also show a significant change in 18F-FDG uptake among serial examinations [14, 15], which was considered as temporal heterogeneity. A number of known factors (hormones, dietary preparation, exercise, etc.) and unknown factors might influence myocardial 18F-FDG uptake, and it was difficult to modulate these conditions to the same level on different days. Contrary to the prior studies [14, 15], the two 18F-FDG imaging sessions in this study were performed within a very short interval of two hours, and only with a single administration of 18F-FDG. This could, to the greatest extent, alleviate the differences of the aforementioned factors between exercise and resting imaging. Catecholamines released during exercise stress suppress exogenous glucose metabolism in normal myocardium but do not alter anaerobic glucose metabolism in ischemic myocardium [12, 19], but no study has reported that that effect was spatially heterogeneous. Hence, the regionally increased uptake on exercise imaging in CAD patients was most likely induced by myocardial ischemia. The significance of the present study was, for the first time, providing unequivocal evidence in support of that myocardial ischemia can induce 18F-FDG uptake.
On the exercise imaging, the 18F-FDG uptake in ischemic myocardium was consistently increased. Contrarily, non-ischemic myocardium showed variable changes of 18F-FDG uptake and nearly half of them had decreased uptake. Moreover, the SUVblood consistently decreased on the exercise imaging both in CAD and normal patients. Therefore, the 18F-FDG distribution changes between resting and exercise imaging was due to the increased uptake ratio of ischemic to non-ischemic myocardium as well as the myocardium to background radioactivity.
Of note, some patients showed ischemic 18F-FDG uptake on resting and nearly half (7/15) of them had more segments involved on exercise imaging. Abnormal 18F-FDG uptake at rest may be induced by resting ischemia since 6 patients had perfusion abnormalities at rest in this study. Moreover, patients with unstable angina may have abnormal 18F-FDG uptake at rest due to ischemic memory, even without perfusion abnormalities, which had been validated in prior studies [11, 20].
To determine the abnormality of 18F-FDG uptake, we adopted the classification of 18F-FDG distribution patterns and defined the uptake of basal segments and papillary muscle as normal, as recommended recently for the ‘hot’ spot imaging for the heart . This study demonstrated this strategy was efficient for the detection of CAD. Overall, the diagnostic performance was comparable between 18F-FDG imaging and MPI. Especially, a favorable specificity was obtained on both patient and vascular levels. In this study, all patients with perfusion abnormalities showed abnormal 18F-FDG uptake on exercise imaging. Furthermore, 45.5% (5/11) of CAD patients with normal perfusion were detected by 18F-FDG imaging as well. This implied that 18F-FDG imaging may be more sensitive than MPI. It is important to note, the difference of the sensitivity between 18F-FDG imaging and MPI was merely borderline (P = 0.06) on the patient level. In contrast, previous studies have reported higher sensitivity of 18F-FDG imaging over MPI [7, 10]. There were two major differences between the present and prior studies. First, 18F-FDG was administered at peak exercise in previous studies. Contrarily, 18F-FDG was injected one hour prior to exercise in the present study. Due to the extraction by myocardium and other tissues, and clearance from urinary and digestive system, 18F-FDG in blood at the onset of exercise-induced ischemia was decreased. In addition, if physiological uptake of myocardium prior to exercise was too intense, new ischemic uptake might be masked. Second, only focally increased 18F-FDG uptake was defined as abnormal in this study, whereas diffuse but homogeneous uptake and basal (including papillary muscle) uptake were also considered abnormal in prior studies [3,4,5,6,7,8,9,10,11]. The current definitions inevitably decreased the sensitivity, but rendered an improved specificity. Recent studies have demonstrated that most individuals without heart disease showed a ‘none’ or ‘diffuse’ pattern, ‘focal’ or ‘focal on diffuse’ uptake was mostly observed in unstable angina [11, 16]. These findings suggested that the pattern, rather than the extent, of 18F-FDG uptake, is an indicator of myocardial involvement under fasting conditions. Therefore, we adopted these classifications in the present study. For the same reason, we did not consider quantitative evaluation of 18F-FDG uptake as the diagnostic criteria.
The secretion of insulin is impaired and/or there is insulin resistance for diabetic patients. Therefore, the utilization of glucose is decreased in these subjects. However, recent studies have proposed that ischemia and insulin would trigger independent pathways of the translocation of glucose transporters (GLUTs) in the myocardium, to increase glucose transport to the myocyte: ischemia leads to GLUT-4 translocation via a phosphatidylinositol 3-kinase (PI3-kinase)-independent mechanism, and insulin via a PI3-kinase-mediated pathway [21, 22]. These differential regulations of GLUT-4 translocation suggest that even in diabetic patients who have myocardial insulin resistance, would have increased glucose uptake when triggered by ischemic events. Moreover, due to the lower 18FDG uptake in non-ischemic myocardium demonstrated in this study, 18FDG myocardial ischemic imaging may have a higher specificity in diabetic patients than that in non-diabetic patients.
There are some limitations in this study. This study included a subgroup of patients with suspected unstable angina, who had a higher incidence and more severity of perfusion abnormalities on both resting and exercise imaging. This may result in the overestimation of the sensitivity of 18F-FDG imaging. However, we did not yet find significant differences in the diagnostic performance between stable and unstable angina (Fig. 7b). 18F-FDG was only injected once and one hour prior to the exercise test in this study. This may, as discussed above, lower the sensitivity of 18F-FDG imaging. Whether split dose (i.e., the 18F-FDG was divided into 2 parts, and was administered separately at rest and exercise testing) or one injection after exercise followed by two imaging session, can improve the sensitivity needs to be further studied. We only examined the glucose level at the baseline and no other hormones were checked. The difference of these hormones between resting and exercise imaging, and their effects on the myocardial uptake of 18F-FDG, could not be evaluated. Exercise perfusion images were acquired using SPECT equipped with ultra-high-energy collimators, which might have underestimated the sensitivity of MPI compared using SPECT equipped with low-energy collimators. Moreover, down-scatter of 18F to the 99mTc window might bring quantitation error. The ratio of 99mTc to 18F was more than 4–5 : 1 in this study, and the contribution of 18F was estimated to be less than 5% of the total counts in the 99mTc window . In addition to fasting, several other strategies have recently been developed to suppress the physiological uptake of 18F-FDG in myocardium . However, the application of these interventions in ischemic 18F-FDG imaging was scarce and required further investigation . Hence, we did not integrate them into our study protocol. We didn’t integrate functional evaluation of wall motion into the study protocol, hence we couldn’t correlate the metabolic abnormality with myocardial hypokinesis. Therefore, we couldn’t decide in which patient myocardial stunning was the underlying mechanism of metabolic abnormality. Finally, since this was a small and exploratory study, larger studies are necessary.