Regulation of pyruvate dehydrogenase activity and glucose metabolism in post-ischaemic myocardium.

Pyruvate dehydrogenase (PDH) is regulated both by covalent modification and through modulation of the active enzyme by metabolites. In the isolated heart, post-ischaemic inhibition of PDH, leading to uncoupling of glycolysis and glucose oxidation and a decrease in cardiac efficiency, has been described. In vivo, post-ischaemic reperfusion leads to metabolic abnormalities consistent with PDH inhibition, but the effects of ischaemia/reperfusion on PDH are not well characterized. We therefore investigated PDH regulation following transient ischaemia in vivo. In 33 open-chest dogs, the left anterior descending (LAD) was occluded for 20 min followed by 4 h reperfusion. In 17 dogs, dichloroacetate (DCA) was injected prior to reperfusion, while 16 dogs served as controls. In dogs without DCA, glucose oxidation and lactate uptake were lower in reperfused than in remote tissue, suggesting reduced flux through PDH. However, percent active and total PDH measured in myocardial biopsies were similar in both territories, excluding covalent enzyme modification or loss of functional enzyme. DCA activated PDH activity similarly in both regions and abolished differences in glucose oxidation and lactate uptake. Thus, decreased PDH flux in reperfused myocardium does not result from covalent modification or loss of total enzyme activity, but more likely from metabolite inhibition of the active enzyme. DCA leads to essentially complete activation of PDH, increases overall glucose utilization and abolishes post-ischaemic inhibition of glucose oxidation.

Abnormal longitudinal, base-to-apex myocardial perfusion gradient by quantitative blood flow measurements in patients with coronary risk factors.

BACKGROUND: A longitudinal, base-to-apex myocardial perfusion gradient has been described in patients with coronary artery disease (CAD) and was attributed to diffuse coronary luminal narrowing. We asked whether an abnormal perfusion gradient also existed in patients without CAD but with coronary risk factors. We measured myocardial blood flow (MBF) with (13)N-ammonia and PET at rest and during hyperemia in patients with coronary risk factors but without CAD. METHODS AND RESULTS: Regional MBF was measured in absolute units with (13)N-ammonia and PET at rest and during dipyridamole hyperemia in 36 patients with coronary risk factors (age, 55+/-10 years) and in 36 age-matched (age, 53+/-10 years) and in 28 young (age, 25+/-5 years) normal subjects. MBF was determined globally, for each of the 3 coronary territories, and in the mid and mid-to-apical sections of the left ventricle (LV). Myocardial perfusion on qualitative analysis was normal at rest and during hyperemia, and no flow defects were present. MBF in absolute units was similar in the 3 coronary territories. However, hyperemic MBFs in the mid-to-apical LV section were lower than in the mid LV section in the "at-risk" group (2.04+/-0.61 versus 1.71+/-0.40 mL. min(-1). g(-1); P<0.004) but not in the age-matched or in the young normal subjects. CONCLUSIONS: The abnormal longitudinal, base-to-apex perfusion gradient observed during dipyridamole MBF suggests the presence of a functional and/or structural alteration of the coronary circulation associated with coronary risk factors, possibly reflecting developing coronary atherosclerosis or preclinical CAD.

Prevalence of myocardial viability as detected by positron emission tomography in patients with ischemic cardiomyopathy.

BACKGROUND: Detection of myocardial viability is important in patients with ischemic cardiomyopathy. Restoration of blood flow to viable myocardium is associated with improved left ventricular function and improved patient prognosis. However, the prevalence of viable myocardium in patients with ischemic cardiomyopathy is unknown. METHODS AND RESULTS: To determine the prevalence of myocardial viability, clinical [13N]ammonia/18F-deoxyglucose PET studies performed in 283 patients (age, 63+/-10 years) with ischemic heart disease (mean ejection fraction, 26+/-8%) were visually analyzed for the presence and extent of viable and nonviable myocardium. The myocardium was divided into 19 segments. The extent of viable myocardium was considered "functionally" significant if >/=5 segments ( approximately 25% of the left ventricular myocardium) exhibited a blood flow/metabolism mismatch and "prognostically" significant if 1 to 4 left ventricular segments did so. Of all patients, 41% had no evidence of viable myocardium, 55% had viable myocardium, and 4% had normal blood flow and metabolism within an enlarged left ventricle. Functionally significant viability was found in 27% and prognostically significant viability in 28% of the patients. Multivariate analysis revealed the presence of angina to be the only clinical parameter associated with the presence of functionally significant viability. CONCLUSIONS: Revascularization might improve patient prognosis in 55% and result in improved left ventricular function in 27% of all patients with ischemic cardiomyopathy.

Positron computed tomography and its applications in the young.

Positron computed tomography is a new method for the external quantification of regional myocardial blood flow, substrate fluxes and biochemical reaction rates. It takes advantage of positron emitting tracers, metabolically active tracers, tracer kinetic principles and the quantitative imaging capabilities of the tomograph. To date, the technique has been used primarily for the study of ischemic heart disease and cardiomyopathies in adults. However, initial studies in infants and adolescents with regional cardiomyopathies provide evidence for its potential value in detecting disease at the biochemical level or at a stage that antedates clinical manifestations and cardiac dysfunction. Positron computed tomography is likely to contribute to our understanding of metabolic abnormalities associated with cyanotic or congenital heart disease and of the heart's maturation, and may become useful for optimal timing of corrective surgery. It allows the study of intrinsic myocardial disease in children, clarification of disease mechanisms and diagnosis of congenital metabolic disorders. It also might become useful for detecting disease when it is still confined to biochemical derangements and permit institution of therapy that may halt progression or even reversal of disease before irreversible morphologic changes develop. The high cost of equipment purchase and operation has precluded widespread use, but new technologic developments may make it possible to perform these studies at a cost comparable with that of other noninvasive procedures. Positron computed tomography may then become available as a routine diagnostic tool for studying pediatric cardiac disorders.

Dobutamine positron emission tomography: absolute quantitation of rest and dobutamine myocardial blood flow and correlation with cardiac work and percent diameter stenosis in patients with and without coronary artery disease.

OBJECTIVES: This study sought to measure myocardial blood flow at rest and during dobutamine infusion and to correlate flow with cardiac work and severity of coronary artery disease. BACKGROUND: Dobutamine is used with cardiac imaging to induce possible ischemia in patients with known or suspected coronary artery disease. Positron emission tomography permits noninvasive quantitation of myocardial blood flow. METHODS: Fifteen patients with quantitative coronary arteriography were studied at rest and during dobutamine infusion using nitrogen-13 ammonia flow imaging with positron emission tomography. Myocardial blood flow was determined in regions corresponding to the three major coronary arteries for myocardium with and without dobutamine flow defects and with and without a > 50% diameter stenosis. RESULTS: Eight patients had at least one dobutamine flow defect; four of whom had a previous myocardial infarction. One patient with > 50% diameter stenosis had no flow defects, and one with < 50% diameter stenosis (48%) had one defect. Dobutamine significantly increased myocardial blood flow in regions with and without a dobutamine flow defect or > 50% diameter stenosis, with a greater increase when a defect or > 50% diameter stenosis was not present. Rest and dobutamine flows in regions without > 50% diameter stenosis were 0.93 +/- 0.20 (mean +/- SD) and 2.16 +/- 0.52 ml/min per g (p < 0.01), respectively. The corresponding flows in regions without a defect were 0.94 +/- 0.21 and 2.17 +/- 0.53 ml/min per g (p < 0.01), respectively. This 2, 4-fold increase in flow was significantly correlated (p < 0.001) with a 2.2-fold increase in rate-pressure product induced by dobutamine. The rest and dobutamine flows for regions subtended by a vessel with > 50% diameter stenosis were 0.70 +/- 0.33 and 1.20 +/- 0.54 ml/min per g (p < 0.05), respectively, whereas the corresponding values for regions with a dobutamine flow defect were 0.69 +/- 0.33 ml/min per g at rest and 1.23 +/- 0.54 ml/min per g during dobutamine (p < 0.05). Dobutamine increased flow inversely proportional to percent diameter stenosis. The rest flow for regions with a dobutamine flow defect were not significantly different from that in regions without defects. CONCLUSIONS: Dobutamine resulted in a significant increase in myocardial blood flow that correlated significantly with both increased cardiac work and degree of stenosis.

Regional myocardial dysfunction in patients with angina at rest and response to isosorbide dinitrate assessed by phase analysis of radionuclide ventriculograms.

Left and right ventricular synchrony was assessed in 15 patients with angina at rest but no previous infarction by phase analysis of equilibrium radionuclide ventriculograms. Transient thallium-201 perfusion defects were noted in all during angina at rest and coronary vasospasm was documented in nine of the patients. Radionuclide ventriculograms were performed at control, during the ischemic episodes and after intravenous isosorbide dinitrate. Left and right ventricular phase histograms were quantified by the standard deviation from the mean of the peak (SD). Left ventricular ejection fraction averaged 65 +/- 11% (mean +/- standard deviation) at control, decreased in all patients during angina at rest to 49 +/- 14% (p less than 0.01) and increased in all patients after isosorbide dinitrate to 66 +/- 12%. However, ejection fraction during ischemia was abnormal in only nine patients and changed in two by less than 5% from the control value. Regional wall motion abnormalities were noted in all patients during the ischemic episodes but resolved after isosorbide dinitrate administration. Control left ventricular SD was 14.5 +/- 4 degrees, increased in all patients to 22.8 +/- 5 degrees during angina at rest (p less than 0.01) and returned to control values after isosorbide dinitrate administration (14.2 +/- 4 degrees). In contrast, right ventricular SD did not significantly change during ischemia as compared with control and isosorbide dinitrate. It is concluded that in angina at rest, a normal left ventricular ejection fraction does not exclude severe regional dysfunction; separate left and right ventricular SD is a sensitive index in detecting transient left ventricular dysfunction, and relief of ischemia is associated with rapid normalization of regional left ventricular function.

Dynamic positron tomographic imaging with nitrogen-13 glutamate in patients with coronary artery disease: comparison with nitrogen-13 ammonia and fluorine-18 fluorodeoxyglucose imaging.

This study was designed to test the usefulness of nitrogen-13 (N-13) glutamate imaging with positron emission tomography in defining myocardial ischemia in humans. Seventeen patients who had undergone coronary arteriography were studied with N-13 glutamate at peak supine exercise using a bicycle ergometer, as well as with the flow tracer N-13 ammonia at peak exercise during a second similar exercise test. Six of the patients also underwent imaging with N-13 glutamate at rest before exercise testing; in the remaining 11 patients imaging with fluorine-18 (F-18) fluorodeoxyglucose was performed to assess glucose metabolism after the second exercise test. Seven patients had classic metabolism-flow mismatches consistent with ischemia (that is, decreased N-13 ammonia uptake in a region with relatively increased F-18 fluorodeoxyglucose uptake). There was no evidence of increased N-13 glutamate uptake in the ischemic mismatched regions in any of these patients. In all 17 patients, the uptake of N-13 glutamate during exercise paralleled the uptake of N-13 ammonia during exercise, suggesting that N-13 glutamate behaves as a flow tracer rather than as a metabolic marker of ischemia in humans.

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.

Quantification of absolute myocardial perfusion at rest and during exercise with positron emission tomography after human cardiac transplantation.

The maximal exercise capacity of cardiac transplant recipients is reduced compared with that of normal subjects. To determine if this reduced exercise capacity is related to inadequate myocardial perfusion during exercise, myocardial perfusion was measured noninvasively with use of positron emission tomography and nitrogen (N)-13 ammonia. Twelve transplant recipients with no angiographic evidence of accelerated coronary atherosclerosis were studied. Serial N-13 ammonia imaging was performed at rest and during supine bicycle exercise. The results were compared with those from 10 normal volunteers with a low probability of having cardiac disease. A two-compartment kinetic model for estimating myocardial perfusion was applied to the data. Transplant recipients achieved a significant lower exercise work load than did the volunteers (42 +/- 16 vs. 128 +/- 22 W), but a higher venous lactate concentration (31.3 +/- 14.9 vs. 13.7 +/- 4.1 mg/100 ml). Despite the difference in exercise work load, there was no significant difference in the cardiac work achieved by transplant recipients and normal subjects as evidenced by similar rate-pressure products of 24,000 +/- 3,400 versus 21,300 +/- 2,800 betas/min per mm Hg, respectively. In addition, myocardial blood flow during exercise was not significantly different between the two groups (1.70 +/- 0.60 vs. 1.56 +/- 0.71 ml/min per g, respectively). This study demonstrates that the myocardial flow response to the physiologic stress of exercise is appropriate in transplant recipients and does not appear to explain the decreased exercise capacity in these patients.

Measurement of regional myocardial blood flow with N-13 ammonia and positron-emission tomography in intact dogs.

N-13 ammonia mimics certain properties of microspheres. It rapidly clears from blood into myocardium where it becomes fixed in proportion to myocardial blood flow. Used with positron emission tomography as a means for quantifying in vivo myocardial indicator concentrations, N-13 ammonia may be useful for noninvasive determination of myocardial blood flow with the arterial reference sampling technique. This possibility was examined in 27 experiments in 10 chronically instrumented dogs at control, high and low blood flows. Myocardial blood flow was calculated in vivo from the myocardial N-13 tissue activity concentrations derived from serial cross-sectional images of the heart, the 2 minute arterial input function and the withdrawal rate of arterial blood. These calculations were compared with blood flow determined by the standard microsphere technique. Blood flow determined in vivo with N-13 ammonia and positron emission tomography correlated with microsphere blood flow by y = -36.2 + 1.53x -0.0027x2 (r = 0.94 with a standard error of the estimate of 16 ml/min per 100 g). For flows from 44 to 200 ml/min per 100 g, the relation between in vivo and in vitro measured myocardial blood flow was nearly linear but reached a plateau at flows higher than 200 ml/min per 100 g. These results indicate that in dogs, blood flow in the physiologic range can be quantified in vivo with N-13 ammonia and positron emission tomography.

Regional myocardial blood flow and metabolism at rest in mildly symptomatic patients with hypertrophic cardiomyopathy.

Previous observations and clinical manifestations suggest the presence of ischemia in the disproportionately thickened septum of patients with hypertrophic cardiomyopathy. Metabolic consequences of ischemia can be demonstrated with positron emission tomography. Therefore, 10 patients with hypertrophic cardiomyopathy and an echocardiographic septum to posterior wall thickness ratio of 1.8 +/- 0.4 cm (range 1.3 to 2.5) were studied with the use of nitrogen (N)-13 ammonia, carbon (C)-11 palmitate and fluoro (F)-18 2-deoxyglucose as tracers of myocardial blood flow, fatty acid metabolism and exogenous glucose utilization. The results of positron emission tomography in 9 patients with hypertrophic cardiomyopathy were compared with those in 10 normal volunteers. In the hypertrophic cardiomyopathy group, observed myocardial activity of N-13 ammonia and C-11 palmitate in the septum was similar to that in the lateral wall. Septum to lateral wall tissue activity ratios averaged 1.04 +/- 0.15 for N-13 ammonia and 1.04 +/- 0.18 for C-11 palmitate, and were similar to those in the normal volunteers (0.98 +/- 0.07 and 0.98 +/- 0.03, respectively; p = NS). Myocardial clearance half-time and residual fraction of C-11 palmitate did not differ significantly between the septum and lateral wall. However, F-18 2-deoxyglucose uptake was significantly lower in the septum than in the lateral wall (15,768 +/- 4,314 versus 19,818 +/- 5,234 counts/pixel; p less than 0.003). The mean septum to lateral wall activity ratio of 0.83 +/- 0.21 was less than that observed in normal volunteers (0.92 +/- 0.07; p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Blood flow-metabolism imaging with positron emission tomography in patients with diabetes mellitus for the assessment of reversible left ventricular contractile dysfunction.

OBJECTIVES: The purpose of this study was to evaluate the predictive accuracy of positron emission tomography (PET) blood flow-F-18 fluorodeoxyglucose (FDG) imaging in coronary artery disease (CAD) patients with diabetes mellitus (DM). BACKGROUND: Positron emission tomography accurately predicts the postrevascularization improvement in left ventricular dysfunction in unselected patients with CAD. In diabetic patients, however, poor myocardial glucose utilization may limit the accuracy of the approach. METHODS: Forty patients (64+/-10 years old; 19 with DM = group I; 21 without DM = group II) with reduced left ventricular ejection fraction (LVEF = 29+/-6%) were studied with N-13 ammonia and FDG PET before coronary revascularization. Studies were performed after intravenous injection of regular insulin (group I) or oral glucose administration (group II). Blood flow-FDG mismatches and matches were identified by polar map analysis in the three vascular territories of the left anterior descending, left circumflex and right coronary artery. Wall motion and LVEF were assessed by two-dimensional echocardiography before and 158+/-123 days after revascularization. RESULTS: Of 107 vascular territories analyzed, 46 were classified as mismatch, 29 as match and 32 as normal. The FDG image quality, assessed by F-18 myocardium to blood pool activity ratios, and the predictive accuracy were similar in both groups; presence of a blood flow/FDG mismatch had a sensitivity of 92% (group I) and 94% (group II) and a specificity of 85% (group I) and 79% (group II) for an improvement in regional left ventricular function. A postrevascularization improvement in global left ventricular function was related to the extent of blood flow/FDG mismatch; LVEF increased from 30+/-7% to 35+/-7% (p = 0.017) in patients with one mismatch and from 27+/-4% to 41+/-7% (p < 0.001) in those with two mismatches. CONCLUSIONS: The predictive accuracy of blood flow/FDG imaging is maintained in patients with DM when a clinically acceptable study protocol, which guarantees good FDG image quality, is used. The extent of a blood flow/metabolism mismatch is correlated with the magnitude of the postrevascularization improvement in global left ventricular function.

Comparison of maximal myocardial blood flow during adenosine infusion with that of intravenous dipyridamole in normal men.

OBJECTIVE: This study compared quantitatively the efficacy of intravenous adenosine and dipyridamole for pharmacologic induction of myocardial hyperemia. BACKGROUND: Pharmacologic vasodilation is used increasingly for induction of myocardial hyperemia in conjunction with radionuclide imaging of myocardial blood flow. Although both intravenous dipyridamole and adenosine have been used, the magnitude of hyperemia induced by these agents and the hyperemia to baseline blood flow ratios have not been quantified and compared. METHODS: Twenty normal volunteers were studied with dynamic positron emission tomography (PET) and intravenous nitrogen-13 ammonia. Myocardial blood flow was quantified with a two-compartment tracer kinetic model. RESULTS: Myocardial blood flow at rest averaged 1.1 +/- 0.2 ml/min per g and increased significantly to 4.4 +/- 0.9 ml/min per g during adenosine and 4.3 +/- 1.3 ml/min per g after dipyridamole administration. Hyperemia to baseline flow ratios averaged 4.3 +/- 1.6 for adenosine and 4.0 +/- 1.3 for dipyridamole. The average flow ratios and the maximal flows achieved were similar for both agents, but there was considerable variation in the individual response to these agents, as indicated by the range of hyperemia to baseline flow ratios (from 2.0 to 8.4 for adenosine and from 1.5 to 5.8 for dipyridamole). In addition, the hyperemic responses to dipyridamole and to adenosine differed by greater than 1 ml/min per g in nine subjects. CONCLUSIONS: Despite these inter- and intraindividual differences, we conclude that both agents are equally effective in producing myocardial hyperemia.

Blood flow-dependent uptake of indium-111 monoclonal antimyosin antibody in canine acute myocardial infarction.

OBJECTIVES: The relation of myocardial blood flow and indium-111 (111In) antimyosin antibody uptake was studied by inducing myocardial infarction in 18 dogs, 8 with closed chest left anterior descending artery balloon occlusion for 3 h followed by reperfusion (group A) and 10 dogs with open chest left anterior descending artery ligation (without reperfusion, group B). BACKGROUND: The relation of antimyosin uptake to myocardial injury has been documented. However, its relation to tracer delivery by myocardial blood flow has not been studied and has been assumed to be independent. METHODS: Indium-111 antimyosin antibody, 2 mCi, was injected 20 min after reperfusion and 3 h after coronary artery ligation in groups A and B, respectively. Regional blood flows were determined by radiolabeled microspheres during occlusion and 24 h later in both groups. On day 2, dogs were killed after risk zone delineation with gentian violet. The heart was excised and stained with triphenyltetrazolium chloride solution and graded for increasing severity of tissue injury based on extent of staining. Microsphere activity and 111In antimyosin activity were measured in control tissue (grade 1), noninfarct tissue at risk (grade 2), mixed tissue (grade 3), infarct tissue (grade 4) and hemorrhagic infarct tissue (grade 5, present only in group A dogs). Count activity was normalized to that of the mean value in control tissue (grade 1) and expressed as a ratio of activity. RESULTS: Indium-111 antimyosin activity was high in triphenyltetrazolium chloride grade 4 tissue in both groups but was attenuated in grade 4 tissue in group B dogs (10.6 +/- 5.1 vs. 5.0 +/- 4.5; p < 0.05 group A vs. group B), which had lower blood flow on day 2 (0.51 +/- 0.36 vs. 0.23 vs. 0.22; p < 0.01). Normalizing 111In antimyosin activity for blood flow on day 2 resulted in equivalent 111In antimyosin uptake for infarct tissue (32.6 +/- 21.6 vs. 36.6 +/- 29.8 for group A vs. group B; p = NS). CONCLUSIONS: Thus, 111In antimyosin uptake is a specific marker of necrotic tissue with a high signal ratio in reperfused tissue. However, its uptake is dependent on residual blood flow in the infarct territory. Indium-111 antimyosin could potentially serve as a suitable tracer for infarct sizing if myocardial blood flow in the same region were factored simultaneously.

Afterload reduction with vasodilators and diuretics decreases mitral regurgitation during upright exercise in advanced heart failure.

In advanced heart failure, mitral regurgitation increases the burden of the failing ventricle and decreases effective stroke volume. Although tailored afterload reduction decreases mitral regurgitation at rest, it is not known if this benefit is maintained during upright exercise. Simultaneous radionuclide ventriculography and thermodilution stroke volumes were compared to measure the forward ejection fraction in 10 patients during upright bicycle exercise before and after therapy with vasodilators and diuretics tailored to decrease pulmonary capillary wedge pressure and systemic vascular resistance. Ventricular volumes, total ejection fraction and the forward ejection fraction did not change during exercise at baseline. At rest, tailored therapy decreased average pulmonary capillary wedge pressure from 36 to 19 mm Hg (p less than 0.01), systemic vascular resistance from 1,570 to 1,210 dynes.s.cm-5 (p less than 0.05), and left ventricular volume index from 251 to 177 ml/m2 (p less than 0.01), while increasing the forward ejection fraction from 0.53 to 0.85 (p less than 0.01) without change in total ejection fraction (0.18 from 0.17). During steady state exercise at low work load, tailored therapy decreased left ventricular volume index from 279 to 213 (p less than 0.05) and increased forward ejection fraction from 0.52 to 0.79 (p less than 0.01) without change in total ejection fraction (0.20 from 0.19). The total stroke volume during exercise was not increased after therapy; the increase in forward stroke volume after therapy appeared to result instead from the decrease in mitral regurgitant flow. The benefits of tailored afterload reduction are maintained throughout upright exercise.

Sustained regional abnormalities in cardiac metabolism after transient ischemia in the chronic dog model.

Positron emission tomography allows noninvasive assessment of myocardial blood flow and metabolism, and may aid in defining the extent and severity of an ischemic injury. This hypothesis was tested by studying, in chronically instrumented dogs, regional blood flow and metabolism during and after a 3 hour balloon occlusion of the left anterior descending coronary artery. The metabolic findings after ischemia were compared with the recovery of regional function over a 4 week period. N-13 ammonia was used as a blood flow tracer, and C-11 palmitic acid and F-18 deoxyglucose as tracers of fatty acid and glucose metabolism, respectively. Regional myocardial function was monitored with ultrasonic crystals implanted subendocardially. Regional function improved most between 24 hours and 1 week after reperfusion, but was still attenuated at 4 weeks. The slow functional recovery was paralleled by sustained metabolic abnormalities, reflected by segmentally delayed clearance of C-11 activity from myocardium and increased uptake of F-18 deoxyglucose. Absence of blood flow and C-11 palmitic acid uptake at 24 hours of reperfusion correlated with extensive necrosis as evidenced by histologic examination. Conversely, uptake of C-11 palmitic acid with delayed C-11 clearance and increased F-18 deoxyglucose accumulation identified reversibly injured tissue that subsequently recovered functionally and revealed little necrosis. Thus, recovery of metabolism after 3 hours of ischemia is slow in canine myocardium and paralleled by slow recovery of function. Metabolic indexes by positron tomography early after reperfusion can identify necrotic and reversibly injured tissue. Positron tomography may therefore aid in defining the extent and prognosis of an ischemic injury in patients undergoing reperfusion during evolving myocardial infarction.

Positron emission tomography demonstrates that coronary sinus retroperfusion can restore regional myocardial perfusion and preserve metabolism.

Positron emission tomography was used to image blood flow and metabolic tracers in risk zone myocardium after left anterior descending coronary artery occlusion during synchronized coronary venous retroperfusion. Six control and seven intervention open chest dogs had occlusion of the mid left anterior descending coronary artery. Synchronized retroperfusion commenced 25 min later. Flow tracers (rubidium-82 and nitrogen-13 ammonia) were injected retrogradely. Three hours after coronary occlusion, fluorine-18 (F-18) deoxyglucose uptake in the control and treatment groups was compared. At 200 min of occlusion, infarct size was assessed. Retrograde flow tracer uptake was observed in the risk zone in the seven intervention dogs. Fluorine-18 deoxyglucose uptake in the risk zone was increased in five of the six intervention dogs but was reduced in five of the six control dogs. The risk zone to normal zone F-18 deoxyglucose count ratio was higher in the intervention than the control group (1.13 +/- 0.39 vs. 0.59 +/- 0.51; p less than 0.05). The endocardial subsegment risk zone to normal zone F-18 deoxyglucose count ratio was also significantly higher in the intervention group. Percent infarction in the risk zone was 70% lower in the group treated with synchronized retroperfusion than in the control group (18.4 +/- 22.6% vs. 61.2 +/- 25.4%; p less than 0.02). Thus, positron emission tomography revealed that retroperfusion could deliver oxygenated blood and maintain metabolism in risk zone myocardium. Infarct size was limited to 30% of that of control. In acute closure of the left anterior descending coronary artery, synchronized retroperfusion might be considered for maintaining viability of the jeopardized myocardium if the artery cannot be reopened rapidly.

A quantitative index of regional blood flow in canine myocardium derived noninvasively with N-13 ammonia and dynamic positron emission tomography.

To derive a quantitative index of regional myocardial blood flow, the arterial input function of the flow tracer N-13 ammonia and the regional myocardial N-13 activity concentrations were noninvasively determined in 29 experiments in eight dogs. N-13 ammonia was administered intravenously and cross-sectional images were acquired dynamically using an ECAT III positron emission tomograph with an effective in-plane resolution of 13.46 mm full-width half-maximum. Time-activity curves were derived from the serial images by assigning regions of interest to the left ventricular myocardium and left ventricular blood pool. Tracer net extractions were estimated from the myocardial time-activity concentrations at various times after tracer injection and the integral of the arterial input function. Myocardial blood flow was altered by intravenous dipyridamole, morphine, propranolol and partial or complete occlusion of the left anterior descending coronary artery, and ranged from 9 to 860 ml/min per 100 g. Estimates of tracer net extractions were most accurate when determined from the myocardial N-13 activity concentrations at 60 s divided by the integral of the arterial input function to that time. These estimates correlated with regional myocardial blood flows determined independently by the microsphere technique by y = x (1 - 0.64(e-114/x); SEE = 22.9; r = 0.94). First pass extraction fractions of N-13 ammonia determined noninvasively with this approach declined with higher flows in a nonlinear fashion and were similar to those determined invasively by direct intracoronary N-13 ammonia injections. The findings indicate that an accurate index of regional myocardial blood flow can be obtained noninvasively by high temporal sampling of arterial and myocardial tracer activity concentrations with positron emission tomography. They also provide a basis for the in vivo application of tracer kinetic principles to derive quantitatively and noninvasively regional rates of functional processes in human myocardium.

Differentiating cardiomyopathy of coronary artery disease from nonischemic dilated cardiomyopathy utilizing positron emission tomography.

To determine if imaging of blood flow (using N-13 ammonia) and glucose metabolism (using F-18 2-deoxyglucose) with positron emission tomography can distinguish cardiomyopathy of coronary artery disease from nonischemic dilated cardiomyopathy, 21 patients with severe left ventricular dysfunction who were evaluated for cardiac transplantation were studied. The origin of left ventricular dysfunction had been previously determined by coronary angiography to be ischemic (11 patients) or nonischemic (10 patients). Images were visually analyzed by three observers on a graded scale in seven left ventricular segments and revealed fewer defects in dilated cardiomyopathy compared with ischemic cardiomyopathy for N-13 ammonia (2.7 +/- 1.6 versus 5 +/- 0.6; p less than 0.03) and F-18 deoxyglucose (2.8 +/- 2.1 versus 4.6 +/- 1.1; p less than 0.03). An index incorporating extent and severity of defects revealed more homogeneity with fewer and less severe defects in subjects with nonischemic than in those with ischemic cardiomyopathy as assessed by imaging of flow (2.8 +/- 1.8 versus 9.2 +/- 3; p less than 0.001) and metabolism (3.8 +/- 3.3 versus 8.5 +/- 3.6; p less than 0.005). Diagnostic accuracy for distinguishing the two subgroups by visual image analysis was 85%. Using previously published circumferential count profile criteria, patients with dilated cardiomyopathy had fewer ischemic segments (0.4 +/- 0.8 versus 2.5 +/- 2 per patient; p less than 0.01) and infarcted segments (0.1 +/- 0.3 versus 2.4 +/- 1.4 per patient; p less than 0.001) than did patients with cardiomyopathy of coronary artery disease. The sensitivity for differentiating the two clinical subgroups using circumferential profile analysis was 100% and the specificity 80%. An index incorporating both number and severity of defects derived from circumferential profile analysis was significantly lower in subjects with dilated cardiomyopathy than in ischemic cardiomyopathy (0.3 +/- 0.8 versus 2.7 +/- 2.4; p less than 0.005). Thus, noninvasive positron emission tomographic imaging with N-13 ammonia and F-18 deoxyglucose is helpful in distinguishing patients with severe left ventricular dysfunction secondary to coronary artery disease from those with nonischemic cardiomyopathy, and a semiquantitative index such as circumferential profile analysis is superior to that of visual analysis alone.

Retention and clearance of C-11 palmitic acid in ischemic and reperfused canine myocardium.

Free fatty acids are the major energy source for cardiac muscle. Oxidation of fatty acid decreases or even ceases during ischemia. Its recovery after transient ischemia remains largely unexplored. Using intracoronary carbon-11 palmitic acid as a tracer of myocardial fatty acid metabolism in an open chest dog model, retention and clearance of tracer in myocardium were evaluated at control, during ischemia and after reperfusion following a 20 minute occlusion of the left anterior descending coronary artery. Myocardial C-11 time-activity curves were analyzed with biexponential curve-fitting routines yielding fractional distribution and clearance half-times of C-11 palmitic acid in myocardial tissue. In animals with permanent occlusion and intracoronary injection of C-11 palmitic acid distal to the occlusion site, the relative size and half-time of the early clearance curve component differed markedly from control values and did not change with ongoing ischemia. Conversely, in animals with only 20 minutes of coronary occlusion, the relative size of the early C-11 clearance phase was still significantly depressed at 20 and 90 minutes of reperfusion but returned to control level at 180 minutes. Tissue C-11 clearance half-times remained significantly prolonged throughout the reperfusion period. Regional function in reperfused myocardium monitored with ultrasonic crystals recovered slowly and was still less than control after 3 hours of reperfusion. The data indicate that after transient ischemia, myocardial fatty acid metabolism fails to recover immediately. Because the metabolic recovery occurs in parallel with recovery of regional function, C-11 palmitic acid in conjunction with positron tomography may be useful for studying regional fatty acid metabolism noninvasively after an ischemic injury, and may be helpful in identifying reversible tissue injury.