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Myocardial hibernation is hypoperfused dysfunctional myocardium that has the potential to recover function after coronary revascularization. Although recovery of regional function after revascularization is the gold standard for assessing the diagnostic accuracy of various techniques, improvements of EF, symptoms, and survival are fundamental end points. Despite important differences in the markers of viability by positron-emission tomography, single-photon emission tomography, two-dimensional echocardiography, and magnetic resonance imaging, their positive and negative predictive values in nonrandomized studies are fairly comparable. Assessment of myocardial viability may be clinically important in many patients but especially in those with EF < 30% and congestive heart failure. The degree of improvement in EF after coronary revascularization depends on the extent of hibernation, the suitability of coronary structure for revascularization, the lack of perioperative infarction, the completeness of revascularization, and the long-term patency of grafts.

Physical stress might modulate myocardial blood flow in near-maximally dilated coronary arteries by increasing coronary perfusion pressure, myocardial contractility, and heart rate. The net effect of these changes on hyperemic blood flows has not yet been defined in humans. To quantify the effect of physical exercise on pharmacologically induced hyperemia, myocardial blood flow was measured in 11 healthy volunteers. Measurements were performed with positron emission tomographic imaging with nitrogen-13 ammonia at rest, during intravenous (i.v.) adenosine administration (140 micrograms.kg-1.min-1 over 6 minutes), and during i.v. adenosine administration plus supine bicycle exercise with a maximal workload of 125 W. Myocardial blood flow was quantified by using a previously validated graphic analysis. Heart rate, systolic blood pressure, rate-pressure product, and mean aortic blood pressures were significantly higher during combined physical and pharmacologic stress than during pharmacologic stress alone. However, myocardial blood flow decreased from 2.6 +/- 0.4 to 2.2 +/- 0.4 ml.min-1.gm-1 with the addition of physical stress (p < 0.05). This decline was associated with a significant increase in coronary vascular resistance (35 +/- 6 vs 52 +/- 13 mm Hg.ml-1.gm.min; p < 0.05). Accordingly, myocardial flow reserve declined, from 5.0 +/- 0.9 to 4.3 +/- 1.0, with exercise supplementation (p < 0.05). Exercise in addition to pharmacologic stress increases coronary vascular resistance and thus significantly decreases hyperemic myocardial blood flow and flow reserve. This decrease results most likely from an increase in extravascular restrictive forces caused by higher ventricular pressures and contractility during physical stress.

To examine the effects of inotropic stimulation on regional myocardial blood flow (MBF), oxidative metabolism, and contractile function in stunned myocardium, nine closed-chest dogs were studied 2 hours postreperfusion after a 25 minute occlusion of the left anterior descending coronary artery (LAD). MBF was determined with microspheres, and regional myocardial oxygen consumption (MVO2) was estimated from the rate constant k1 of the rapid clearance phase of [1-11C] acetate time activity curves, recorded with dynamic positron emission tomography. Myocardium at risk was determined from [13N] ammonia images obtained during occlusion. Wall motion, assessed by two-dimensional echocardiography, was impaired in postischemic myocardium in all dogs 2 hours after reperfusion. Dobutamine infusion increased the rate pressure product by 70% +/- 31% and significantly improved contractile function in the postischemic region in all dogs. In remote myocardium, MVO2 increased from 5.7 +/- 1.2 to 8.6 +/- 1.6 mumol/gm/min, and blood flow from 0.87 +/- 0.16 to 1.52 +/- 0.42 ml/gm/min in response to dobutamine. In reperfused myocardium, MVO2 increased from 3.1 +/- 0.7 to 7.4 +/- 1.5 mumol/gm/min, and blood flow from 0.51 +/- 0.12 to 1.2 +/- 0.4 ml/gm/min. Oxygen extraction increased significantly in reperfused myocardium relative to remote myocardium consistent with a flow-limited response to dobutamine stimulation. The improvement in contractile function failed to correlate significantly with relative increases in MBF or MVO2, suggesting that mechanical function is not as tightly coupled as MBF and MVO2 in postischemic myocardium during inotropic stimulation.

Myocardial blood flow was evaluated in 31 subjects with not only visual but also, for the first time, circumferential profile analysis of rubidium 82 (82Rb) images acquired with positron emission tomography. Fifteen were control subjects and 16 subjects had significant coronary artery disease, defined as 50% or greater diameter stenosis in a major coronary artery or a first-order branch. Simultaneous 82Rb images at three myocardial levels were obtained before and after intravenous dipyridamole plus handgrip stress. In patients with significant coronary artery disease, visual analysis correctly identified significant disease in 26 (76%) of 34 arteries and its absence in 12 (86%) of 14 normal arteries. According to circumferential profile analysis, these numbers were 91% and 86%, respectively. Thus circumferential analysis of 82Rb images, obtained before and after intravenous dipyridamole plus handgrip stress, yielded improved sensitivity and comparable specificity compared with visual analysis.

Positron emission tomography has been employed in vivo to assess flow using N-13 (nitrogen-13) ammonia and glucose metabolism, with the glucose analog F-18 (fluorine-18) fluorodeoxyglucose. Flow metabolism mismatches in which glucose metabolism is increased with respect to flow have been used to define ischemic, but viable myocardium. The feasibility of detecting exercise-induced ischemia using this technique was explored. Eleven normal volunteers and 16 patients who had undergone coronary arteriography were studied with N-13 ammonia at rest and with bicycle exercise, and with F-18 fluorodeoxyglucose in the postexercise period. Each image was divided into 16 sectors. Comparison of absolute net extractions of N-13 ammonia at rest and with exercise was not sensitive in detecting functionally significant coronary artery lesions. Myocardial uptakes of F-18 fluorodeoxyglucose and exercise N-13 ammonia were normalized to the sector with the highest N-13 ammonia uptake (corresponding to the highest flow rate). The differences and ratios of these normalized uptakes were successfully used to objectively define flow metabolism mismatches and to identify functionally significant coronary artery disease. Our data suggest that exercise flow and metabolic imaging are superior to rest and exercise flow imaging, particularly in patients with prior myocardial infarctions.

Calculation of accurate stroke count ratios for the assessment of valvular regurgitation from equilibrium blood pool images has been difficult and did not permit computation of regurgitant fractions (RF) because of contamination of right ventricular (RV) stroke counts by right atrial activity. We describe a new approach to correct for this contamination by subtracting one half of the right atrial counts from the RV counts, assuming that in the standard or "modified" left anterior oblique projection commonly used about one half of the right atrial activity is superimposed to the RV. This new method was tested in 20 patients without valvular disease or shunts. Left ventricular (LV) to RV stroke count ratio approached unity (1.01 +/- 0.14). RV ejection fractions (EF) derived by this technique agreed well with those obtained by gated first-pass studies recorded in the right anterior oblique projection. In 9 normals and 17 patients with moderate severe or severe aortic (12 patients or mitral (7 patients) regurgitation, LVEF, RVEF, and RF were determined at rest and maximum exercise. In patients at rest, LVEF (56.0 +/- 6.4%) and RVEF (49.0 +/- 7.3%) did not differ significantly from LVEF (59.6 +/- 4.2%) and RVEF (52.5 +/- 6.4%) in normals. The calculated RF was negligible in normals (1.9 +/- 8.6%), but averaged 51.8 +/- 9.8% in patients with valvular disease. During exercise, LVEF fell significantly (p less than 0.001) to 44.1 +/- 7.2% in patients but increased to 70.5 +/- 3.8% in normals. RVEF increased in aortic regurgitation to 64.5 +/- 9.8% (NS to normals) but fell in mitral regurgitation to 36.6 +/- 5.9% (p greater than 0.001). In both patient subsets RF decreased with exercise to 25.4 +/- 15.0% in aortic and 39.1 +/- 12.7% in mitral regurgitation. The results indicate that this new approach permits assessment of RVEF and RF from gated equilibrium blood pool studies and is suitable to evaluate the hemodynamic response to physiologic and therapeutic interventions in patients with valvular regurgitation.

We have previously demonstrated that enhanced glucose utilization in reperfused myocardium as assessed by F-18 2-deoxyglucose (FDG) and positron tomography predicts functional recovery. In this study, we compared segmental uptake of F-18 FDG with that of Tl-201 and Tc-99m (Sn) pyrophosphate (Tc-99m PPi) as conventional markers of tissue viability in seven dogs after a 3-hour intracoronary balloon occlusion and 20 hours of reperfusion. Myocardial blood flow was determined with microspheres. Regional retention fractions were calculated from tracer tissue concentrations, the arterial input function, and blood flow. Ischemic injury was assessed by triphenyltetrazolium chloride (TTC) staining and histologic analysis. At 24 hours, blood flow was 22% lower in reperfused than in control myocardium (p less than 0.05). Uptake of Tl-201 was related linearly to blood flow (r = 0.92), while glucose utilization and Tc-99m PPi were 2.9 (p less than 0.01) and 4.7 (p less than 0.05) times higher in reperfused than in control myocardium. Retention fractions of Tc-99m PPi increased with the degree of ischemic injury, while F-18 FDG uptake was highest in segments with mild cell injury. Thus, in ischemically injured myocardium, Tl-201 primarily reflects blood flow. F-18 FDG as a marker of glucose utilization identifies ischemically injured but viable tissue. The admixture of necrotic cells can be determined with Tc-99m PPi. Our results indicate that a dual tracer approach might best characterize the presence and extent of reversibly and of irreversibly injured tissue in a given myocardial region.

The possibility of demonstrating noninvasively with C-11 palmitate and positron emission tomography (PET) changes in myocardial substrate metabolism in normal and diseased human myocardium in response to altered substrate availability in blood and disease-related abnormalities was examined in five normal volunteers and 16 patients with ventricular dysfunction. C-11 palmitate injection and serial PET imaging were performed after an overnight fast (control period) and again 2 hours later after oral glucose (50 gm). Myocardial C-11 time-activity curves from serial PET images revealed a biexponential clearance pattern. An early rapid phase, defined by relative size and clearance half-time, reflects C-11 palmitate oxidation and the late slow phase tracer deposition in the endogenous lipid pool. During the control period, the tracer fraction entering the early rapid phase averaged 47 +/- 13% (SD) in normal subjects and 45 +/- 12% in patients. Corresponding clearance half-times were 19 +/- 7 and 20 +/- 5 minutes, respectively. Heart rate and blood pressure remained unchanged after glucose, but plasma glucose levels rose by 72.5% in normal subjects and by 98.9% in patients, while free fatty acid levels fell by 72% and 42% (p less than 0.001), respectively. In normal subjects, the tracer fraction in the early rapid phase fell by 43% (p less than 0.005) and the clearance half-time increased by 46% (p less than 0.01). In patients, the response of C-11 palmitate tissue kinetics to glucose was variable. In nine patients, it was similar to that in normal subjects while in the other seven patients a "paradoxic" response occurred. The tracer fraction entering the rapid clearance phase increased after glucose by 30% (p less than 0.05) associated with a 36% (p less than 0.05) decline in clearance half-times. The paradoxic response was unrelated to disease etiology or plasma substrate levels but occurred mostly in left ventricles with more severely depressed function. Thus, PET and C-11 palmitate allow the noninvasive demonstration of the known response of substrate metabolism of the human heart to altered substrate availability. Glucose administration in fasted humans serves as a provocative test of substrate regulation which can be abnormal in myocardial disease and can be demonstrated noninvasively.

The value of phase analysis of multiple gated acquisition blood pool images for identifying wall motion abnormalities due to stress-induced ischemia was examined. Myocardial segments with an abnormal phase, i.e., delayed onset of wall motion, were localized on a phase distribution image of the LV and the synchrony of LV systolic wall motion was assessed from histograms of the LV phase distribution, i.e., the standard deviation (SD) from the mean of this peak, which was defined as SDP, its upper limits of normal at rest and exercise were established in seven normals as the mean +2 SD and were 12 degrees at rest and 10 degrees at maximum exercise. Of the 56 patients, 37 had coronary artery disease (CAD), 11 had valvular disease but normal coronary arteries, and eight had normal coronary arteries, no valvular disease, but had either cardiomyopathy or typical angina. In the CAD patients, SDP was abnormal in 95% during exercise while only 86% had an abnormal ejection fraction (EF) response and/Or exercise-induced wall motion abnormalities by visual interpretation. By contrast, in the 11 valvular heart disease patients, SDP was abnormal in only two despite exercise-induced wall motion abnormalities in five and an abnormal EF response in all 11. Thus, although an abnormal EF response to exercise is a sensitive indicator of cardiac disease, it is, however, like exercise-induced wall motion abnormalities, not specific for CAD. By contrast, phase analysis not only permitted separation of wall motion abnormalities induced by ischemia from those associated with valvular disease, but was also an objective, highly sensitive, and specific indicator of regional myocardial ischemia.

Positron-emission computed tomography (PCT) is a new means of studying regional myocardial metabolism. This new device permits quantitative, cross-sectional imaging of the tissue concentrations of positron-emitting tracers of blood flow and metabolism in the myocardium. To examine the potential value of PCT for evaluating regional alterations in myocardial metabolism, acute myocardial ischemia was induced by rapid atrial pacing in open-chest dogs with partial coronary stenoses. Regional myocardial glucose uptake and utilization of free fatty acids were examined with the glucose analog F-18 2-fluoro-2-deoxyglucose (FDG) and C-11-labeled palmitic acid. Myocardial blood flow was evaluated with N-13 ammonia. In the ischemic segment, uptake of C-11 palmitic acid was reduced in proportion to blood flow and its rate of clearance as an index of beta oxidation was delayed. There was a relative or absolute increase in FDG uptake (depending on the uptake of FDG in the normal myocardium). Similar observations were made in patients with ischemic heart disease and anginal symptoms at the time study. The observed alterations in the regional distribution of positron-emitting tracers of metabolic substrates in ischemic myocardium are in agreement with previously reported animal experimental studies in which a fall in free fatty acid utilization associated with an increase in glycolytic flux was observed. These studies indicate that metabolic alterations associated with acute myocardial ischemia observed previously in destructive animal experiments do indeed occur in humans and can now be demonstrated noninvasively in humans by PCT.

Phase analysis of radionuclide ventriculograms is used for identifying ischemic wall motion abnormalities. Myocardial segments with an abnormal phase, that is, delayed onset of wall motion, can be localized on a phase distribution image, and the synchronicity of left ventricular (LV) wall motion can be assessed from a histogram of LV phase distribution. The standard deviation of the LV peak on this histogram (SDP-LV) describes the width of the peak and is used as an index of the synchronicity of wall motion. We examined in this study the sensitivity of SDP-LV for identifying coronary artery disease (CAD) and its specificity in patients with normal and various degrees of LV impairment. A total of 84 patients were studied. Forty-five patients had CAD and 39 had congestive cardiomyopathy or valvular heart disease. Patients were grouped according to their LV ejection fraction (EF). In group I (37 patients) resting LVEF was equal to or greater than 50%, in group II (24 patients) it ranged from 35% to 50%, and in group III (23 patients) it was less than 25%. SDP-LV was highly specific in groups I and II for CAD with sensitivities of 48% and 89% at rest that increased with exercise to 88% and 100%. In group III patients, SDP-LV remained highly sensitive but was no longer specific for CAD. Therefore, in severe LV impairment, phase analysis does not aid in distinguishing CAD from other causes of ventricular dysfunction. By contrast, phase analysis is highly sensitive and specific for CAD in patients with normal or moderately depressed LV function.