Incidence of major cardiovascular events in black patients with normal myocardial stress perfusion study results.

BACKGROUND: Previous studies have shown that the risk of major cardiovascular events at 1 year is less than 1% in patients with normal myocardial stress perfusion study results. However, the racial distribution of patients enrolled in these studies is not known. Hence, the prognostic value of normal stress perfusion study results in black patients is not well established. Our objective was to determine the incidence of major cardiovascular events in black patients with normal stress perfusion study results over a 12-month period. METHODS AND RESULTS: We searched the nuclear cardiology database at our institution for all black patients who had normal stress perfusion study results between January 1990 and December 1996. We excluded patients with a history of coronary revascularization, valvular heart disease, cardiomyopathy, congenital heart disease, left bundle branch block, or pre-excitation syndrome. Patients were followed up for at least 12 months from the time of inclusion. A total of 592 patients were enrolled and were followed up for 18 +/- 6 months (mean +/- SD). Of these, 388 underwent treadmill exercise testing, 155 underwent dipyridamole stress testing, and the remainder underwent dobutamine stress testing. Perfusion studies were performed in all patients with thallium 201 single photon emission computed tomography imaging. During the follow-up period, 11 cardiac deaths and 7 myocardial infarctions (MIs) occurred. The incidence of cardiac deaths was 1.2% per year, and that of nonfatal MIs was 0.8% per year. The total incidence of major cardiovascular events was 2% per year. In patients who underwent treadmill exercise testing, the incidence of major cardiovascular events was 1% per year. Performance of a pharmacologic stress test and a prior MI were significantly associated with death or nonfatal MI (P <.05). CONCLUSIONS: The overall incidence of major cardiovascular events in black patients after normal exercise perfusion study results were obtained was low (1%). However, black patients who had normal perfusion study results but underwent pharmacologic stress testing or had a history of MI were at intermediate risk. These patients require close surveillance for major cardiovascular events.

Enalaprilat attenuates ischemic rises in intracellular sodium in the isolated rat heart via the bradykinin receptor.

PURPOSE: Angiotensin-converting enzyme (ACE) inhibitors have been shown to have beneficial effects on ischemic myocardium. We examined whether the ACE inhibitor, enalaprilat (EN), improves intracellular sodium homeostasis during myocardial ischemia and the relationship of this effect to bradykinin. METHODS: EN (3.2 nM) was administered to isolated rat hearts that were subjected to ischemia and reperfusion. Intracellular sodium and pH were monitored using magnetic resonance spectroscopy (MRS). The specific bradykinin B2 receptor antagonist, HOE 140 (10 nM), was administered with EN in some hearts to determine the effect of bradykinin blockade on EN-mediated effects. RESULTS: EN blunted the rise in ischemic intracellular sodium, measured using MRS. With reperfusion, EN-treated hearts recovered 80% of their preischemic ventricular function, compared with negligible recover, in controls. These beneficial effects of EN were blocked when the bradykinin receptor antagonist, HOE 140, was coadministered with EN. HOE 140 also blocked EN-mediated attenuation of ischemic intracellular acidosis. CONCLUSIONS: These results suggest that EN exerts beneficial effects on ischemic intracellular sodium and pH homeostasis via the bradykinin receptor. These effects of EN may provide a mechanism for the beneficial actions of this agent during ischemia.

Protection of ischemic myocardium in diabetics by inhibition of electroneutral Na+-K+-2Cl- cotransporter.

Diabetes increases both the incidence of cardiovascular disease and complications of myocardial infarction and heart failure. Studies using diabetic animals have shown that changes in myocardial sodium transporters result in alterations in intracellular sodium (Na(i)) homeostasis. Because the changes in sodium homeostasis can be due to increased entry of Na+ via the electroneutral Na+-K+-2Cl- cotransporter (NKCC), we conducted experiments in acute diabetic hearts to determine if 1) net inward cation flux via NKCC is increased, 2) this cotransporter contributes to a greater increase in Na(i) during ischemia, and 3) inhibition of NKCC limits injury and improves function after ischemia-reperfusion. These issues were investigated in perfused type I diabetic and nondiabetic rat hearts subjected to ischemia and 60 min of reperfusion. A group of diabetic and nondiabetic hearts was perfused with 5 microM of bumetanide, an inhibitor of NKCC. Flux via NKCC, Na(i), and ATP was measured in each group with the use of radiotracer 86Rb, 23Na, and 31P nuclear magnetic resonance spectroscopy, respectively, whereas ischemic injury was assessed by measuring creatine kinase release on reperfusion. Cation flux via NKCC, as measured by 86Rb uptake, was significantly increased in diabetic hearts. Inhibition of NKCC significantly reduced ischemic injury in diabetic hearts, improved functional recovery on reperfusion, attenuated the ischemic rise in Na(i), and conserved ATP during ischemia-reperfusion. Parallel studies in nondiabetic hearts showed that NKCC inhibition was not cardioprotective. These findings demonstrate that flux via NKCC is increased in type I diabetic hearts and that inhibition with bumetanide attenuates changes in Na(i) and ATP during ischemia and protects against ischemic injury. The data suggest a therapeutic role for pharmacological agents that inhibit flux via NKCC in diabetic patients with myocardial ischemia.

Protection of ischemic hearts perfused with an anion exchange inhibitor, DIDS, is associated with beneficial changes in substrate metabolism.

OBJECTIVE: Metabolic interventions that promote glucose use during ischemia have been shown to protect the myocardium and improve functional recovery on reperfusion. In this study we evaluated if cardioprotection can be accomplished by inhibiting fatty acid uptake, which would be expected to increase glycolytic metabolism. METHODS: Diisothiocyanostilbene sulfonic acid (DIDS), commonly used to inhibit Band-3 mediated anion exchanger, and has also been demonstrated to inhibit fatty acid transport in adipocytes, was used to inhibit fatty acid uptake prior to ischemia. Isolated rat hearts were perfused with buffer containing 5 mM glucose, 70 mU/l insulin, 0.4 mM palmitate, and 0.4 mM albumin, paced at 300 beats/min, and subjected to 50 min of low-flow ischemia followed by 60 min of reperfusion. RESULTS: Ischemic injury, as assessed by creatine kinase release, was diminished in hearts perfused with DIDS (334+/-72 in DIDS vs. 565+/-314 IU/g dry wt in controls, P<0.04). Increases in LVEDP during ischemia were attenuated (8+/-3 mmHg in DIDS vs. 15+/-18 mmHg in controls, P<0.03) and the % recovery of LV function with reperfusion was enhanced in DIDS-treated hearts (78+/-10% of baseline in DIDS vs. 62+/-19% of baseline in controls, P<0.04). These beneficial effects of DIDS were associated with increased glucose metabolism and ATP content during ischemia and reperfusion. Furthermore, treatment with DIDS lowered the accumulation of long chain acyl carnitines. CONCLUSIONS: This study demonstrates that DIDS protects ischemic myocardium, and is associated with inhibition of fatty acid uptake, improved glucose metabolism, and enhanced functional recovery on reperfusion. The data presented here suggest a potential role for therapeutic agents that lower fatty acid uptake as a metabolic adjunct in the treatment of myocardial ischemia.

Failure of right precordial electrocardiography during stress testing to identify coronary artery disease.

BACKGROUND: It has been reported that the use of right precordial leads results in the same diagnostic accuracy as thallium-201 exercise scintigraphy for the detection of coronary artery disease (CAD). The aim of this study was to evaluate the utility of right precordial leads in the detection of CAD. METHODS AND RESULTS: We evaluated 900 consecutive patients (514 men, 386 women) ranging in age from 39 to 84 years (mean +/- SD, 64 +/- 11 years). Seven hundred forty patients underwent treadmill exercise testing, and 160 underwent pharmacologic stress testing for the diagnosis of chest pain or dyspnea. All received either Tl-201 or technetium-99m sestamibi during stress. During stress testing, the ECG was recorded every minute with 12 limb and left precordial leads and 3 right precordial leads (V(3)R, V(4)R, and V(5)R). The electrocardiogram was considered positive when the ST segment was either elevated or depressed by at least 0.1 mV at 80 ms after the J point, and results were also compared with single photon emission computed tomography myocardial perfusion imaging results. Of the 900 patients, 158 had significant positive changes in the limb or left precordial leads. Only 4 patients had positive changes in the right precordial leads (Fisher exact test, P <.001). Of the patients who had positive electrocardiographic changes, 95 (60%) had abnormal myocardial perfusion scans, with 91 in patients with normal right precordial leads. All 4 patients with ischemic changes in the right precordial leads had abnormal scans, but the left leads were also positive. Three hundred seventy-three of 900 patients (41%) had abnormal scans with no electrocardiographic evidence of ischemia. CONCLUSIONS: Our experience is far different than that published and suggests that the use of right precordial leads during stress testing fails to provide the same diagnostic accuracy as either the standard left-sided electrocardiography or myocardial perfusion imaging for the detection of CAD.

Protection of ischemic hearts by high glucose is mediated, in part, by GLUT-4.

Metabolic interventions that promote glucose use during ischemia have been shown to protect ischemic myocardium and improve functional recovery on reperfusion. We evaluated whether the cardioprotection afforded by high glucose during low-flow ischemia is associated with changes in the sarcolemmal content of glucose transporters, specifically GLUT-4. Isolated rat hearts were paced at 300 beats/min and perfused under normal glucose (5 mM) or high glucose (10 mM) conditions in buffer containing 0.4 mM albumin, 0.4 mM palmitate, and 70 mU/l insulin and subjected to 50 min of low-flow ischemia and 60 min of reperfusion. To determine the importance of insulin-sensitive glucose transporters in mediating cardioprotection, a separate group of hearts were perfused in the presence of cytochalasin B (10 microM), a preferential inhibitor of insulin-sensitive glucose transporters. Ischemic contracture during low-flow ischemia and creatine kinase release on reperfusion was decreased, and the percent recovery of left ventricular function with reperfusion was enhanced in hearts perfused with high glucose (P < 0.03). Hearts perfused with high glucose exhibited increased GLUT-4 protein expression in the sarcolemmal membrane compared with control hearts under baseline conditions, and these changes were additive with low-flow ischemia. In addition, high glucose did not affect the baseline distribution of sarcolemmal GLUT-1 and blunted any changes with low-flow ischemia. These salutary effects were abolished when glucose transporters are blocked with cytochalasin B. These data demonstrate that protection of ischemic myocardium by high glucose is associated with increased sarcolemmal content of the insulin-sensitive GLUT-4 and suggest a target for the protection of jeopardized myocardium.

Improving PET-based physiological quantification through methods of wavelet denoising.

The goal of this study was to evaluate methods of multidimensional wavelet denoising on restoring the fidelity of biological signals hidden within dynamic positron emission tomography (PET) images. A reduction of noise within pixels, between adjacent regions, and time-serial frames was achieved via redundant multiscale representations. In analyzing dynamic PET data of healthy volunteers, a multiscale method improved the estimate-to-error ratio of flows fivefold without loss of detail. This technique also maintained accuracy of flow estimates in comparison with the "gold standard," using dynamic PET with O15-water. In addition, in studies of coronary disease patients, flow patterns were preserved and infarcted regions were well differentiated from normal regions. The results show that a wavelet-based noise-suppression method produced reliable approximations of salient underlying signals and led to an accurate quantification of myocardial perfusion. The described protocol can be generalized to other temporal biomedical imaging modalities including functional magnetic resonance imaging and ultrasound.

Measurement of myocardial blood flow with PET using 1-11C-acetate.

UNLABELLED: 11C-acetate has been used extensively for the noninvasive assessment of myocardial oxygen consumption and viability with PET. The use of early uptake of acetate by the heart to measure myocardial perfusion has been proposed. This study evaluated the application of 11C-acetate for absolute measurement of myocardial blood flow using a simple compartmental model that does not require blood sampling. METHODS: Eight healthy volunteers and 13 subjects with concentric left ventricular hypertrophy were studied under resting conditions with both 11Cacetate and 15O-water. Myocardial blood flow with 11C-acetate was obtained by fitting the first 3 min of the blood and tissue tracer activity curves to a two-compartment model. Flows obtained were compared with a validated approach using 15O-water. RESULTS: In healthy volunteers, regional myocardial perfusion at rest estimated with 11C-acetate was comparable with values obtained with 15O-water (1.06 +/- 0.25 and 0.96 +/- 0.12 mL/g/min, respectively). Perfusion in subjects with left ventricular hypertrophy was also comparable if the recovery coefficient (FMM) used was corrected for ventricular mass. If a fixed FMM was used, flow was greatly overestimated. FMM could be estimated from left ventricular mass (FMM = 0.46 + 0.002 x mass, r = 0.86, P < 0.0001). CONCLUSION: The results of this study suggest that 11C-acetate can be applied to quantitatively estimate myocardial perfusion under resting conditions using a two-compartment model without the need for blood sampling, provided that an appropriate FMM is chosen. This approach should increase the usefulness of this tracer and obviate administration of a separate tracer to independently measure perfusion.

Use of wavelet transforms in analysis of time-activity data from cardiac PET.

UNLABELLED: Because of its intrinsic quantitative properties, PET permits measurement of myocardial perfusion and metabolism in absolute terms (i.e., mL/g/min). However, quantification has been limited by errors produced in image acquisition, selection of regions of interest, and data analysis. The goal of this study was to evaluate a newly developed, novel, wavelet-based noise-reduction approach that can objectively extract biologic signals hidden within dynamic PET data. METHODS: Quantification of myocardial perfusion using dynamic PET imaging with 82Rb, H2(15)O, and 13NH3 was selected to evaluate the effects of the wavelet-based noise-reduction protocol. Dynamic PET data were fitted to appropriate mathematic models before and after wavelet-based noise reduction to get flow estimates. Time-activity curves, precision, accuracy, and differentiating capacity derived from the wavelet protocol were compared with those obtained from unmodified data processing. A total of 84 human studies was analyzed, including 43 at rest (18 82Rb scans, 18 H2(15)O scans, and 7 13NH3 scans) and 41 after coronary hyperemia with dipyridamole (17 82Rb scans, 17 H2(15)O scans, and 7 13NH3 scans). RESULTS: For every tracer tested under all conditions, the wavelet method improved the shape of blood and tissue time-activity curves, increased estimate-to-error ratios, and maintained fidelity of flow in regions as small as 0.85 cm3. It also improved the accuracy of flow estimates derived from 82Rb to the level of that achieved with H2(15)O, which was not affected markedly by the wavelet process. In studies of patients with coronary disease, regional heterogeneity of myocardial perfusion was preserved and flow estimates in infarcted regions were differentiated more easily from normal regions. CONCLUSION: The wavelet-based noise-reduction method effectively and objectively extracted tracer time-activity curves from data with low signal-to-noise ratios and improved the accuracy and precision of measurements with all tracer techniques studied. The approach should be generalizable to other image modalities such as functional MRI and CT and, therefore, improve the ability to quantify dynamic physiologic processes.

Quantification of myocardial perfusion in human subjects using 82Rb and wavelet-based noise reduction.

UNLABELLED: Quantification of myocardial perfusion with 82Rb has been difficult to achieve because of the low signal-to-noise ratio of the dynamic data curves. This study evaluated the accuracy of flow estimates after the application of a novel multidimensional wavelet-based noise-reduction protocol. METHODS: Myocardial perfusion was estimated using 82Rb and a two-compartment model from dynamic PET scans on 11 healthy volunteers at rest and after hyperemic stress with dipyridamole. Midventricular planes were divided into eight regions of interest, and a wavelet transform protocol was applied to images and time-activity curves. Flow estimates without and with the wavelet approach were compared with those obtained using H2(15)O. RESULTS: Over a wide flow range (0.45-2.75 mL/g/min), flow achieved with the wavelet approach correlated extremely closely with values obtained with H2(15)O (y = 1.03 x -0.12; n = 23 studies, r = 0.94, P < 0.001). If the wavelet noise-reduction technique was not used, the correlation was less strong (y = 1.11 x + 0.24; n = 23 studies, r = 0.79, P < 0.001). In addition, the wavelet approach reduced the regional variation from 75% to 12% and from 62% to 11% (P < 0.001 for each comparison) for resting and stress studies, respectively. CONCLUSION: The use of a wavelet protocol allows near-optimal noise reduction, markedly enhances the physiologic flow signal within the PET images, and enables accurate measurement of myocardial perfusion with 82Rb in human subjects over a wide range of flows.

Absolute quantitation of coronary steal induced by intravenous dipyridamole.

OBJECTIVE: The study was done to determine whether coronary steal (defined as an absolute decrease in perfusion from resting blood flow) is induced by intravenous (IV) dipyridamole in patients with severe coronary artery disease (CAD). BACKGROUND: Myocardial ischemia during coronary vasodilation is usually attributed to coronary steal. However, there is limited data on the absolute magnitude of coronary steal in humans. METHODS: Eighteen patients with multivessel CAD underwent dynamic positron emission tomography (PET) imaging with 13NH3 at rest and after infusion of IV dipyridamole. Eight myocardial sectors were analyzed per short axis slice and myocardial blood flow calculated with a two-compartment model in absolute terms. RESULTS: Coronary steal occurred in 8 of the 18 patients. In the 8 patients with coronary steal, myocardial blood flow decreased from 90 +/- 18 ml/100 g/min at rest to 68 +/- 27 ml/100 g/min following dipyridamole in the segments with steal, and increased from 87 +/- 19 to 138 +/- 16 ml/100 g/min following dipyridamole in the segments without steal. Significant clinical correlates of coronary steal were either ST elevation or the combination of ST depression and angina. CONCLUSIONS: Coronary vasodilation with IV dipyridamole is associated with significant reductions in blood flow to collateral-dependent myocardium consistent with coronary steal in about 45% of patients with severe CAD.

Characterization of altered myocardial fatty acid metabolism in patients with inherited cardiomyopathy.

Inherited defects in myocardial long-chain fatty acid metabolism are increasingly recognized as a cause of cardiomyopathy and sudden death in children. To evaluate whether the phenotypic expression of these genetic diseases could be delineated using positron emission tomography (PET), 11 patients with inherited defects in fatty acid metabolism were evaluated and results were compared with those of 6 nonaffected siblings. Myocardial perfusion, myocardial oxygen consumption (MVO2), and long-chain fatty acid metabolism were determined noninvasively with PET using quantitative mathematical models. There were no differences in haemodynamics, perfusion, MVO2 or plasma substrate levels between groups. Patients with defects in enzymes of fatty acid beta-oxidation (acyl-CoA dehydrogenase and 3-hydroxyacyl-CoA dehydrogenase deficiencies) (n = 5) had diminished myocardial palmitate oxidation compared with healthy siblings (3.2 +/- 3.0 vs. 13.0 +/- 5.6 nmol/g per min, p < 0.03) and a decrease in the percentage of MVO2 accounted for by palmitate (2% +/- 3% vs. 9% +/- 5%, p < 0.04). In these patients, extracted palmitate was shunted into a slow-turnover compartment (predominantly reflecting esterification to triglycerides) with expansion of palmitate in that pool (185 +/- 246 compared with 27 +/- 67 nmol/g in healthy siblings,p < 0.02). In contrast, myocardium of patients with carnitine deficiency (n = 6) (all on oral carnitine therapy) had normal palmitate extraction but expansion of the interstitial/cytosolic fatty acid pool (617 +/- 399 vs. 261 +/- 73 nmol/g in healthy siblings, p < 0.04), suggesting different mechanisms for handling upstream fatty acyl intermediates. Thus, PET can be used to noninvasively assess abnormal myocardial handling of fatty acids in patients with inherited defects of metabolism. This approach should be useful in the assessment of altered myocardial fatty acid metabolism associated with cardiomyopathy as well as for evaluating the efficacy of therapeutic interventions in affected patients.

Fructose-2,6-bisphosphate, a potent stimulator of phosphofructokinase, is increased by high exogenous glucose perfusion.

BACKGROUND: We have previously demonstrated that perfusion of isolated hearts with high concentrations of glucose results in increased glycolysis during ischemia, diminished ischemic injury, and improved functional recovery with reperfusion. OBJECTIVE: To evaluate a possible mechanism by which glucose conferred this protection. We examined the hypothesis that increased exogenous glucose concentrations results in increased concentrations of fructose-2,6-bisphosphate, a potent activator of phosphofructokinase-1, and thus increases glycolysis. METHODS: Perfused rabbit hearts were subjected to 60 min of low-flow ischemia. Control hearts were perfused with buffer containing 0.4 mmol/l palmitate, 5 mmol/l glucose, and 70 mU/l insulin, and treated hearts were perfused with buffer containing 0.4 mmol/l palmitate, 15 mmol/l glucose and 210 mU/l insulin. RESULTS: Ischemic contracture was attenuated by perfusion of high concentrations of glucose (high glucose) (P < 0.05 compared with control). Glucose uptake and lactate production were greater in hearts perfused with high glucose, as was the ATP concentration at the end of ischemia (P < 0.05 compared with controls). Exogenous glucose uptake and lactate production correlated well with fructose-2,6-bisphosphate content (P = 0.007). CONCLUSIONS: Enhancement of glycolysis in hearts perfused with high glucose may be the result of stimulation of phosphofructokinase-1 by fructose-2,6-bisphosphate. Accordingly, this may serve as an important mechanism by which cardioprotection may be achieved.

Normal limits for left ventricular ejection fraction and volumes estimated with gated myocardial perfusion imaging in patients with normal exercise test results: influence of tracer, gender, and acquisition camera.

BACKGROUND: Myocardial imaging with tracers such as technetium-99m sestamibi or thallium-201 is extensively used as a means of measuring myocardial perfusion. With gated acquisition, these tracers can also be used as a means of measuring left ventricular ejection fraction (EF) and end diastolic and end systolic volumes (EDV and ESV, respectively). The objective of this study was to determine the normal range of EF, EDV, and ESV and to evaluate differences caused by either the tracer used, the gender of the patient, or the acquisition camera used. METHODS AND RESULTS: A total of 1513 consecutive patients (mean age, 60+/-12 years [SD]) who had normal results on Bruce exercise tests had either Tc-99m sestamibi (n = 884) or Tl-201 (n = 629) injected at peak stress. Although all patients were referred for the evaluation of chest pain or dyspnea and many had cardiac risk factors, all had normal exercise capacity corrected for age, no electrocardiographic signs of ischemia, normal results on perfusion scans, and normal wall motion determined by means of quantitated gated single photon emission computed tomography (QGS). Scans were acquired on 1 of 3 different cameras. The mean EF for all patients who had gated Tc-99m sestamibi scans was 63% +/- 9%, not different from patients who had gated Tl-201 scans (63% +/- 9%). However, when the gender of the patient was considered, the mean EF for women was 66% +/- 8% with Tc-99m sestamibi (n = 519), higher than the mean EF for men (58% +/- 8%, n = 365, P<.0001). Similarly, the mean EF for women studied with Tl-201 (67% +/- 8%, n = 326) was higher than that of men (59% +/- 7%, n = 303,P<.0001). Patients with diabetes mellitus (n = 153) had a slightly reduced EF (62% +/- 10%, P<.001). In a subset of 240 patients, 140 patients studied with Tc-99m sestamibi and 100 studied with Tl-201, the EDV and ESV for women (n = 124) was estimated by means of QGS to be lower (57 +/- 17 mL and 19 +/- 11 mL, respectively) than those for men (74 +/- 22 mL-and 29 +/- 13 mL, respectively; n = 116; P<.001 for each comparison). No clinically significant differences in EF or volumes were noted based on tracers used or acquisition camera. For patients with normal results on exercise treadmill tests and perfusion imaging, the lower limit of normal for EF with gated perfusion imaging with QGS was 50% for women and 43% for men. For EDV and ESV, the upper limit of normal was 91 mL and 40 mL, respectively, for women and 119 mL and 55 mL, respectively, for men. CONCLUSIONS: No significant differences related to either tracer or acquisition camera used were noted for EF, suggesting equivalency for clinical trials for patients with normal results on exercise tests. However, EF, EDV, and ESV determined by means of gated perfusion imaging need to be corrected for gender.