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Positron Emission Tomography (PET)
Dr. M. F. Di CarliIntroduction
For more than 15 years, the experimental and clinical use of positron emission tomography (PET) has contributed significantly to our knowledge of cardiac physiology. As a result of the important clinical observations made in these investigations, the use of PET is emerging from the experimental arena and assuming an important role in clinical cardiology. PET imaging can accurately evaluate the presence and location of coronary stenoses in patients with suspected coronary artery disease (CAD). Further, the ability to measure coronary blood flow (ml/min/g) and coronary flow reserve allows a precise characterization of the physiologic severity of known coronary stenoses. In addition, the evaluation of cardiac metabolism permits the assessment of myocardial viability in patients with ischemic left ventricular dysfunction. This functional characterization complements the angiographic information and, thus, contributes to a more rational therapeutic management of patients with ischemic heart disease. The objective of this presentation is to provide a review of the role of PET in clinical cardiology, while recognizing that its clinical role is a subject of continued investigation.
Evaluation of Coronary Blood Flow and Flow Reserve in Patients With CAD
In normal epicardial coronary arteries, myocardial blood flow is primarily regulated by the resistance of the arteriolar vessels. As a stenosis develops in an epicardial vessel, the resistance to blood flow through the stenotic segment increases . Under this condition, resting myocardial blood flow is maintained at the expenses of compensatory arteriolar vasodilation whereas the maximal flow response to hyperemic stimulus becomes impaired with increasing stenosis severity . As a result, the ratio between hyperemic blood flow and resting blood flow (coronary flow reserve) distal to the coronary obstruction falls and continues to decline in an exponential fashion as the stenosis becomes more severe .
Coronary arteriography is the current "gold standard" for evaluating the severity of a coronary stenosis. Angiographic stenosis severity is usually expressed as percent diameter stenosis. However, this approach is limited because it does not include other lesion characteristics such as length, shape, and eccentricity which may also affect the impedance to blood flow. Gould and Kerkeeide and colleagues have proposed and validated the use of a single measure of coronary flow reserve on quantitative arteriography as a parameter which reflects all of the various anatomic factors influencing stenosis severity . Similarly, other investigators also have reported a close correlation between coronary flow reserve measured with intracoronary Doppler probes and luminal stenosis by quantitative arteriography . The physiologic significance of coronary lesions may also be assessed noninvasively by quantifying coronary blood flow and flow reserve with PET during pharmacologically induced coronary vasodilation .
Noninvasive assessment of coronary flow reserve in patients with CAD
Recent studies from our group and others have demonstrated excellent correlations between noninvasive measurements of coronary blood flow and the angiographic severity of coronary stenoses (Fig.1 A-B-C-D) .
Fig. 1 D
Coronary blood flow in myocardial regions supplied by coronary arteries with <50% luminal narrowing in patients with CAD was similar to that in age-matched normal volunteers both at rest and during maximal hyperemia. As a result, coronary flow reserve (peak flow/basal flow) was similar in both groups. However, PET estimates of coronary blood flow and flow reserve successfully differentiated coronary lesions of intermediate severity (50% to 70% and 70% to 90%). Quantitative PET estimates of hyperemic blood flow (r=0.81, p<0.00001), flow reserve (r=0.78, p<0.00001), and an index of the minimal coronary resistance (r=0.78, p<0.00001) were inversely and nonlinearly correlated with the percent area stenosis on angiography (Fig.2a-b-c) . Similar correlations were reported by Uren etal using [O-15]-labeled water and PET in patients with single vessel disease . These correlations between coronary blood flow and angiographic stenosis are virtually identical to previously published data in animal models confirming the universality of these relations utilizing different species and different methodologies for assessment of blood flow and arteriographic measurements .
Detection and localization of CAD
Previous myocardial perfusion studies with PET in patients with suspected CAD have demonstrated a high diagnostic accuracy (>90%) . Technical features such as routine attenuation correction (increased specificity), and the high spatial and contrast resolution, which combined with absolute measurements of coronary flow reserve allows detection of mild CAD (increased sensitivity) are the main reasons for the high diagnostic accuracy. Eight studies including a total of 647 patients have confirmed the high diagnostic ability of PET using [13N]-ammonia or Rubidium-82 (Table 1) . Two studies have directly compared in the same patient population the diagnostic accuracy of Rubidium-PET with Thallium-SPECT. In 202 pacientes, Go et al demonstrated a higher sensitivity with PET compared to SPECT (76% vs 93%), with a similar specificity for both modalities (80% vs 78%) . In another study, Stewart et al reported in 81 patients a higher specificity for PET (88% vs 53%), with a virtually identical sensitivity for both modalities (84%). The diagnostic accuracy was higher with PET than (89% vs 78%).
Assessment of progression and regression of CAD
Recent evidence suggest that aggressive reduction of serum cholesterol and risk factor modification can halt the progression of CAD and even produce a mild regression of disease . More importantly, this risk factor modification is associated with a significant improvement in clinical outcome, which is disproportionate to the modest regression of CAD . In addition, there is a substantial reduction in the severity of anginal pain. The marked clinical benefit in the context of a very modest regression of disease can be explained, at least in part, by the stabilization of atherosclerotic plaques and the improvement in microvascular function, which can be demonstrated by PET, that occur following aggressive risk factor modification. For example, Gould et al demonstrated a significant improvement in regional myocardial perfusion as assessed by PET in patients undergoing aggressive risk factor modification . Patients in the treated group showed a reduction in the size (-5.1±4.8%) and severity (-4.9±3.3%) of regional perfusion defects, which contrasts with the increase in the size (+10±5.6%) and severity (+8.8±2.3%) of perfusion abnormalities in the control group. This study has important clinical implications as it demonstrates the utility of noninvasive measurements of coronary flow reserve by PET for monitoring regression and progression of CAD.
Evaluation of Myocardial Viability in Patients With Ischemic Cardiomyopathy
Patients with CAD and severe LV dysfunction have a poor prognosis when treated with medical therapy alone . In selected patients, surgical revascularization appears to afford a long-term survival benefit . However, the selection of patients with low ejection fraction for revascularization remains controversial due to the high surgical risk. In some patients with coronary artery disease, left ventricular dysfunction results from myocardial infarction with attendant necrosis and scar formation. However, in many patients such myocardial dysfunction may be reversible with revascularization; this is otherwise referred to as hibernating and/or stunned myocardium . Consequently, the distinction of ventricular dysfunction caused by fibrosis from that arising from viable but dysfunctional myocardium has important implications for patients with low ejection fraction, in whom severe heart failure may be attributed to severe, widespread hibernation (or stunning or both) rather than to necrosis of a critical mass of myocardium. Failure to identify patients with these potentially reversible causes of heart failure may lead to progressive cellular damage, heart failure, and death (Fig 3) .
Detection of myocardial viability by PET imaging
Because dysfunctional myocardium that improves functionally after revascularization must retain sufficient blood flow and metabolic activity to sustain myocyte viability, the combined assessment of regional blood flow and glucose metabolism appears most attractive. With this approach, regional myocardial perfusion is first evaluated following the administration of [13N]-ammonia, 82Rb or [15O]-labeled water. Regional glucose uptake is then assessed with [18F]-deoxyglucose (FDG) (a marker of exogenous glucose uptake), providing an index of myocardial metabolism and, thus, cell viability.
Using this approach, three distinct perfusion-metabolism patterns can be observed in dysfunctional myocardium: (1) normal blood flow associated with normal FDG uptake; (2) reduced blood flow associated with preserved or enhanced FDG uptake (perfusion-metabolism mismatch); and (3) proportional reduction in blood flow and FDG uptake (perfusion-metabolism match) (Fig 4) . The patterns of normal blood flow and metabolism or of a PET mismatch identify potentially reversible myocardial dysfunction, whereas the match pattern identifies irreversible myocardial dysfunction.
Accuracy of PET for predicting functional recovery
The experience with the combined blood flow-FDG approach using PET or the PET-SPECT hybrid technique (SPECT perfusion with PET FDG imaging) has been extensively documented in 17 studies including 462 patients . Contractile dysfunction was predicted to be reversible after revascularization in regions with increased FDG uptake or a perfusion-metabolism mismatch, and irreversible in those with reduced FDG uptake or a perfusion-metabolism match pattern. Using these criteria, the average positive predictive accuracy for predicting improved segmental function after revascularization is 76 (range, 52% to 100%), whereas the average negative predictive accuracy is 82% (range, 67% to 100%) (Table 2).
Predicting improvement in global LV function
Several studies using different PET approaches have shown that the gain in global left ventricular systolic function after revascularization is related to the magnitude of viable myocardium assessed preoperatively (Table 3) . These data demonstrate that clinically meaningful changes in global LV function can be expected after revascularization only in patients with relatively large areas of hibernating and/or stunned myocardium (=17% of the left ventricular mass).
Selecting patients with low ejection fraction for myocardial revascularization
Recent studies have examined the relative efficacy of medical therapy versus revascularization in patients with moderate or severe LV dysfunction with and without evidence of viable myocardium, as assessed by the perfusion-metabolism PET mismatch pattern . They included patients with coronary artery disease and moderate or severe LV dysfunction (LV ejection fraction <40%). Most of these patients had a history of myocardial infarction and multivessel coronary artery disease. Approximately one third of the patients presented with angina and 20% to 68% of them had severe heart failure (NYHA class III-IV). In these studies, survival and recurrent ischemic events (myocardial infarction, unstable angina, and ventricular arrhythmia) were evaluated for an average of 12 to 17 months. In all three studies, the patients were grouped based on the presence (or absence) of a perfusion-metabolism PET mismatch, as evidence of viable myocardium. Treatment decisions (i.e., revascularization or medical therapy) in patients with and without a PET mismatch were made on clinical grounds. However, no significant differences in relevant clinical and angiographic variables known to affect prognosis were found between these two groups.
The results of these studies showed a quite consistent trend with respect to several points (Fig 5). In patients with PET mismatch, one year event-free survival was consistently poor with medical therapy. However, one-year event-free survival in patients with viable myocardium was improved significantly by early referral to revascularization. In contrast, one-year event-free survival in patients without viable myocardium was similar with either medical therapy or revascularization. Similar results have also been reported by others in patients with mild or moderate LV dysfunction (LV ejection fraction =40%) after myocardial infarction. The earlier observations with PET have also been confirmed by investigators using rest-redistribution thallium imaging for evaluating myocardial viability or dobutamine echocardiography .
Predicting improvement in symptoms and exercise capacity
Another important challenge in the management of patients with poor cardiac function under consideration for bypass surgery is to identify those in whom revascularization can provide a significant alleviation of anginal and heart failure symptoms, which is often their primary functional limitation. In one study of 23 patients with LV dysfunction and impaired functional capacity (70% in NYHA class II-III), investigators have shown that the amount of viable myocardium before revascularization was predictive of a significant improvement in exercise parameters after revascularization . More recently, our group demonstrated a significant linear correlation between the global extent of a preoperative perfusion-metabolism PET mismatch (reflecting hibernating myocardium) and the percent improvement in functional capacity after bypass surgery in 36 patients with ischemic cardiomyopathy . Patients with large areas of PET mismatch (=18% of the left ventricle), in particular those located in the territory served by the LAD coronary artery had the greatest clinical benefit. In these patients, exercise capacity improved by 107% after CABG compared to only 34% improvement in patients without significant viability (<5% of the left ventricle) (Fig 6).
Risks of revascularization and long-term outcome
Patients with low EF and clinical heart failure have a considerably higher perioperative risk than those with normal LV function . Thus, consideration of bypass surgery in such patients would be more attractive if there were objective evidence that such a patient has a high probability of improving LV function and, consequently, enhance exercise capacity and survival. Demonstration of preserved metabolic activity in a myocardial region with reduced perfusion at rest (perfusion-metabolism mismatch) on PET can provide such evidence. Using this approach, operative mortality rate ranges from 3% to 10% . These numbers represent an improvement over the initial results in patients with severe LV dysfunction, rendering revascularization a more acceptable treatment option in selected patients. Recent data suggest that despite the increased surgical risk, the survival benefit of revascularization in patients with PET mismatch is long-lasting regardless of their symptoms (Fig 7) . In patients without evidence of viability, however, revascularization appears to improve long-term survival over medical therapy only among those with severe angina, whereas no survival advantage is apparent in patients with minimal or no anginal symptoms (Fig 7). Importantly, long-term survival in patients with ischemic cardiomyopathy undergoing surgical revascularization appears to be comparable to that achieved with cardiac transplantation.
PET allows a precise assessment of the extent, severity and location of CAD. The average sensitivity and specificity for detection of CAD with PET is 90% and 95% respectively for both men and women. In addition, its ability to measure coronary blood flow and flow reserve allows a precise characterization of the physiologic severity of known coronary artery stenoses. These measurements are of special clinical interest for noninvasive monitoring progression/regression of CAD following medical interventions.
The clinical and experimental data presented above also indicate that preoperative PET imaging can effectively select patients with coronary artery disease and low ejection fraction who would benefit most following myocardial revascularization. The average positive and negative predictive accuracies of PET for predicting functional recovery are 76 % and 82%, respectively. Most importantly, patients with relatively large areas of hibernating myocardium have improved long-term outcome with prompt revascularization than with medical therapy alone. Long-term survival with revascularization in these patients is comparable to that achieved with cardiac transplantation. These observations suggest that noninvasive investigation of the amount of ischemic myocardium should be an important component of the diagnostic evaluation of patients with heart failure due to coronary artery disease. This approach will likely enhance the often difficult process of selecting patients with poor cardiac function in whom revascularization will likely improve both the quality and quantity of life.
Because the relative cost of PET is high, however, patients undergoing PET imaging must be selected carefully. The high sensitivity and, especially, specificity for detection of CAD makes it particularly useful in obese patients as well as in women with low-intermediate probability of CAD, in whom coronary arteriography is inappropriate. However, its routine use for assessment of myocardial viability in patients with ischemic cardiomyopathy seems justified as the relative cost of PET is small compared with the high cost of cardiac transplantation.Top