Heinrich R. Schelbert

Reversibility of cardiac wall-motion abnormalities predicted by positron tomography.

Positron emission tomography (PET) can be used with nitrogen-13-ammonia (13NH3) to estimate regional myocardial blood flow, and with fluorine-18-deoxyglucose (18FDG) to measure exogenous glucose uptake by the myocardium. We used PET to predict whether preoperative abnormalities in left ventricular wall motion in 17 patients who underwent coronary-artery bypass surgery were reversible. The abnormalities were quantified by radionuclide or contrast angiography or both, before and after grafting. PET images were obtained preoperatively. Abnormal wall motion in regions in which PET images showed preserved glucose uptake was predicted to be reversible, whereas abnormal motion in regions with depressed glucose uptake was predicted to be irreversible. According to these criteria, abnormal contraction in 35 of 41 segments was correctly predicted to be reversible (85 percent predictive accuracy), and abnormal contraction in 4 of 26 regions was correctly predicted to be irreversible (92 percent predictive accuracy). In contrast, electrocardiograms showing pathological Q waves in the region of asynergy predicted irreversibility in only 43 percent of regions. We conclude that PET imaging with 13NH3 to assess blood flow and 18FDG to assess the metabolic viability of the myocardium is an accurate method of predicting potential reversibility of wall-motion abnormalities after surgical revascularization.

Noninvasive quantification of regional blood flow in the human heart using N-13 ammonia and dynamic positron emission tomographic imaging

Evaluation of regional myocardial blood flow by conventional scintigraphic techniques is limited to the qualitative assessment of regional tracer distribution. Dynamic imaging with positron emission tomography allows the quantitative delineation of myocardial tracer kinetics and, hence, the measurement of physiologic processes such as myocardial blood flow. To test this hypothesis, positron emission tomographic imaging in combination with N-13 ammonia was performed at rest and after pharmacologically induced vasodilation in seven healthy volunteers. Myocardial and blood time-activity curves derived from regions of interest over the heart and ventricular chamber were fitted using a three compartment model for N-13 ammonia, yielding rate constants for tracer uptake and retention. Myocardial blood flow (K1) averaged 88 +/- 17 ml/min per 100 g at rest and increased to 417 +/- 112 ml/min per 100 g after dipyridamole infusion (0.56 mg/kg) and handgrip exercise. The coronary reserve averaged 4.8 +/- 1.3 and was not significantly different in the septal, anterior and lateral walls of the left ventricle. Blood flow values showed only a minor dependence on the correction for blood metabolites of N-13 ammonia. These data demonstrate that quantification of regional myocardial blood flow is feasible by dynamic positron emission tomographic imaging. The observed coronary flow reserve after dipyridamole is in close agreement with the results obtained by invasive techniques, indicating accurate flow estimates over a wide range. Thus, positron emission tomography may provide accurate and noninvasive definition of the functional significance of coronary artery disease and may allow the improved selection of patients for revascularization.

Quantitative Relation Between Myocardial Viability and Improvement in Heart Failure Symptoms After Revascularization in Patients With Ischemic Cardiomyopathy

BACKGROUND Studies of patients with coronary artery disease and left ventricular dysfunction have shown that preoperative quantification of myocardial viability may be clinically useful to identify those patients who will benefit most from revascularization both functionally and prognostically. However, the relation between preoperative extent of viability and change in heart failure symptoms has not been documented carefully. We assessed the relation between the magnitude of improvement in heart failure symptoms after coronary artery bypass surgery (CABG) and the extent of myocardial viability as assessed by use of quantitative analysis of preoperative positron emission tomography (PET) images. METHODS AND RESULTS We studied 36 patients with ischemic cardiomyopathy (mean left ventricular ejection fraction, 28 +/- 6%) undergoing CABG. Preoperative extent and severity of perfusion abnormalities and myocardial viability (flow-metabolism mismatch) were assessed by use of quantitative analysis of PET images with 13N ammonia and fluorine-18-deoxyglucose. Each patients functional status was determined before and after CABG by use of a Specific Activity Scale. Mean perfusion defect size and severity were 63 +/- 13% and 33 +/- 12%, respectively. Total extent of a PET mismatch correlated linearly and significantly with percent improvement in functional status after CABG (r = .87, P < .0001). A blood flow-metabolism mismatch > or = 18% was associated with a sensitivity of 76% and a specificity of 78% for predicting a change in functional status after revascularization. Patients with large mismatches (> or = 18%) achieved a significantly higher functional status compared with those with minimal or no PET mismatch (< 5%) (5.7 +/- 0.8 versus 4.9 +/- 0.7 metabolic equivalents, P = .009). This resulted in an improvement of 107% in patients with large mismatches compared with only 34% in patients with minimal or no PET mismatch. CONCLUSIONS In patients with ischemic cardiomyopathy, the magnitude of improvement in heart failure symptoms after CABG is related to the preoperative extent and magnitude of myocardial viability as assessed by use of PET imaging. Patients with large perfusion-metabolism mismatches exhibit the greatest clinical benefit after CABG.

Identification and differentiation of resting myocardial ischemia and infarction in man with positron computed tomography, 18F-labeled fluorodeoxyglucose and N-13 ammonia.

Studies have shown that the extraction of glucose per unit flow is increased in moderately ischemic myocardium primarily due to anaerobic glucose metabolism manifested as lactate production, whereas myocardial infarction is characterized by the loss of metabolically active myocardium. To determine the feasibility of demonstrating these metabolic abnormalities reflecting both ischemia and infarction, we used positron computed tomography (PCT) to evaluate relative regional myocardial exogenous glucose utilization and perfusion in 15 patients with recent myocardial infarction. The positron-emitting tracers of glucose metabolism and perfusion, 18F-2-fluoro-2-deoxyglucose (FDG) and N-13 ammonia, respectively, were used. Fourteen of 19 documented infarctions were demonstrated by PCT to have concordantly decreased glucose utilization and perfusion. However, in an additional 11 regions, glucose utilization was disproportionately increased relative to perfusion, consistent with ischemic glucose consumption. These findings correlated with the presence of postinfarction angina, the site of ischemic electrocardiographic changes during chest pain, and the presence of regional left ventricular dysfunction and severe coronary artery disease. Because three ECG infarct zones not detected by PCT demonstrated ischemic glucose utilization, only two of 19 electrocardiographically defined infarctions had no detectable metabolic abnormality.We conclude that the changes in regional FDG and N-13 ammonia concentrations detected with PCT in patients who had had a recent myocardial infarction are consistent with regional exogenous glucose utilization and perfusion in moderately ischemic and irreversibly infarcted myocardium. This approach has the potential to identify and differentiate resting myocardial ischemia from infarction and to assess tissue viability after an ischemic event.

Noninvasive assessment of coronary stenoses with myocardial perfusion imaging during pharmacologic coronary vasodilatation. V. Detection of 47 percent diameter coronary stenosis with intravenous nitrogen-13 ammonia and emission-computed tomography in intact dogs.

To determine the minimal coronary lesions detectable with perfusion imaging, 16 stenoses of 43 to 66 percent diameter narrowing were applied to the left circumflex coronary artery of three chronically instrumented intact dogs. Orthogonal diastolic coronary arteriograms, obtained on cut film by triggering X-ray exposures from the electrocardiogram while injecting contrast medium through a chronically implanted coronary arterial catheter, were analyzed quantitatively by computer. Fifteen millicuries of nitrogen-13 ammonia was injected intravenously during resting conditions, and emission-computed tomography was performed without electrocardiographic gating. One hour later, after residual nitrogen-13 ammonia had decayed, 15 mg of intravenous dipyridamole was given followed by a second dose of intravenous nitrogen-13 ammonia and repeat performance of emission-computed tomography. The cross-sectional tomographs of the heart were of high quality and revealed in the images obtained with dipyridamole definite perfusion defects with coronary stenoses of 47 percent or greater diameter narrowing. Stenoses of 45 percent diameter narrowing or less did not produce perfusion defects. Quantitative perfusion abnormalities approximated the quantitative severity of stenoses. It is concluded that noninvasive myocardial emission-computed tomography with nitrogen-13 ammonia during dipyridamole-induced coronary vasodilatation detects mild coronary stenoses for purposes of potential medical intervention.

Anatomic versus physiologic assessment of coronary artery disease. Role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making.

Angiographic severity of coronary artery stenosis has historically been the primary guide to revascularization or medical management of coronary artery disease. However, physiologic severity defined by coronary pressure and/or flow has resurged into clinical prominence as a potential, fundamental change from anatomically to physiologically guided management. This review addresses clinical coronary physiology-pressure and flow-as clinical tools for treating patients. We clarify the basic concepts that hold true for whatever technology measures coronary physiology directly and reliably, here focusing on positron emission tomography and its interplay with intracoronary measurements.

Long-term survival of patients with coronary artery disease and left ventricular dysfunction: Implications for the role of myocardial viability assessment in management decisions

OBJECTIVES Our purpose was to evaluate the long-term benefit of myocardial viability assessment for stratifying risk and selecting patients with low ejection fraction for coronary artery bypass grafting and to determine the relation between the severity of anginal symptoms, the amount of ischemic myocardium, and clinical outcome. METHODS We studied 93 consecutive patients with severe coronary artery disease and low ejection fraction (median, 25%) who underwent positron emission tomography to delineate the extent of perfusion-metabolism mismatch (reflecting hibernating myocardium) for potential myocardial revascularization. Median follow-up was 4 years (range, 0 to 6.2 years). RESULTS Fifty patients received medical therapy, and 43 patients underwent bypass grafting. In Cox survival models, heart failure class, prior myocardial infarction, and positron emission tomographic mismatch were the best predictors of survival. Patients with positron emission tomographic mismatch receiving bypass grafting had improved 4-year survival compared with those on medical therapy (75% versus 30%; P =.007) and a significant improvement in angina and heart failure symptoms. In patients without positron emission tomographic mismatch, bypass grafting tended to improve survival and symptoms only in those patients with severe angina (100% versus 60%; P =.085), whereas no survival advantage was apparent in patients with minimal or no anginal symptoms (63% versus 52%; P =.462). CONCLUSIONS Patients with low ejection fraction and evidence of viable myocardium by positron emission tomography have improved survival and symptoms with coronary bypass grafting compared with medical therapy. In patients without evidence of viability, survival and symptom improvement with bypass grafting are apparent only among those patients with severe angina.

13N ammonia myocardial imaging at rest and with exercise in normal volunteers. Quantification of absolute myocardial perfusion with dynamic positron emission tomography.

Positron emission tomography (PET) was applied to the measurement of myocardial perfusion using the perfusion tracer 13N-labeled ammonia. 13N ammonia was delivered intravenously to 13 healthy volunteers both at rest and during supine bicycle exercise. Dynamic PET imaging was obtained in three cross-sectional planes for 10 minutes commencing with each injection. The left ventricle was divided into eight sectors, and a small region of interest was assigned to the left ventricular blood pool to obtain the arterial input function. The net extraction of 13N ammonia was obtained for each sector by dividing the tissue 13N concentration at 10 minutes by the integral of the input function from the time of injection to 10 minutes. With this approach for calculating net extractions, rest and exercise net extractions were not significantly different from each other. To obviate possible overestimation of the true 13N ammonia input function by contamination by 13N-labeled compounds other than 13N ammonia or by spillover from myocardium into blood pool, the net extractions were calculated using only the first 90 seconds of the blood and tissue time-activity curves. This approach for calculating net extractions yielded significant differences between rest and exercise, with an average ratio of exercise to rest of 1.38 +/- 0.34. Nonetheless, the increase was less than predicted from the average 2.7-2.8-fold increase in double product at peak exercise or the 1.7-fold increase in double product at 1 minute after exercise. However, when the first 90 seconds of dynamic data were fit with a two compartment tracer kinetic model, average perfusion rates of 0.75 +/- 0.43 ml/min/g at rest and 1.50 +/- 0.74 ml/min/g with exercise were obtained. This average increase in perfusion of 2.2-fold corresponded to similar average increases in double product. Thus, the noninvasive technique of PET imaging with 13N ammonia shows promise for future applications in determining absolute flows in patients with coronary artery disease.

Positron emission tomography detects tissue metabolic activity in myocardial segments with persistent thallium perfusion defects

Positron emission tomography with 13N-ammonia and 18F-2-deoxyglucose was used to assess myocardial perfusion and glucose utilization in 51 myocardial segments with a stress thallium defect in 12 patients. Myocardial infarction was defined by a concordant reduction in segmental perfusion and glucose utilization, and myocardial ischemia was identified by preservation of glucose utilization in segments with rest hypoperfusion. Of the 51 segments studied, 36 had a fixed thallium defect, 11 had a partially reversible defect and 4 had a completely reversible defect. Only 15 (42%) of the 36 segments with a fixed defect and 4 (36%) of the 11 segments with a partially reversible defect exhibited myocardial infarction on study with positron tomography. In contrast, residual myocardial glucose utilization was identified in the majority of segments with a fixed (58%) or a partially reversible (64%) thallium defect. All of the segments with a completely reversible defect appeared normal on positron tomography. Apparent improvement in the thallium defect on delayed images did not distinguish segments with ischemia from infarction. Thus, positron emission tomography reveals evidence of persistent tissue metabolism in the majority of segments with a fixed or partially resolving stress thallium defect, implying that markers of perfusion alone may underestimate the extent of viable tissue in hypoperfused myocardial segments.

Coronary Circulatory Dysfunction in Insulin Resistance, Impaired Glucose Tolerance, and Type 2 Diabetes Mellitus

Background—Abnormal coronary endothelial reactivity has been demonstrated in diabetes and is associated with an increased rate of cardiovascular events. Our objectives were to investigate the presence of functional coronary circulatory abnormalities over the full spectrum of insulin resistance and to determine whether these would differ in severity with more advanced states of insulin resistance. Methods and Results—Myocardial blood flow (MBF) was measured with positron emission tomography and 13N-ammonia to characterize coronary circulatory function in states of insulin resistance without carbohydrate intolerance (IR), impaired glucose tolerance (IGT), and normotensive and hypertensive type 2 diabetes mellitus (DM) compared with insulin-sensitive (IS) individuals. Indices of coronary function were total vasodilator capacity (mostly vascular smooth muscle–mediated) during pharmacological vasodilation and the nitric oxide–mediated, endothelium-dependent vasomotion in response to cold pressor testing. Total vasodilator capacity was similar in normoglycemic individuals (IS, IR, and IGT), whereas it was significantly decreased in normotensive (−17%) and hypertensive (−34%) DM patients. Compared with IS, endothelium-dependent coronary vasomotion was significantly diminished in IR (−56%), as well as in IGT and normotensive and hypertensive diabetic patients (−85%, −91%, and −120%, respectively). Conclusions—Progressively worsening functional coronary circulatory abnormalities of nitric oxide–mediated, endothelium-dependent vasomotion occur with increasing severity of insulin-resistance and carbohydrate intolerance. Attenuated total vasodilator capacity accompanies the more clinically evident metabolic abnormalities in diabetes.