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Background: Measurement of myocardial blood flow (MBF) by dynamic nitrogen 13 ammonia (NH(3)) positron emission tomography (PET) uses tracer kinetic modeling to analyze time-activity curves. We compared 2 commonly used models with 2 compartments (2C) and 3 compartments (3C) for quantification of MBF and coronary flow reserve (CFR)., Methods and Results: Seventy-seven patients underwent NH(3) PET at rest and during hyperemia. Time-activity curves for blood pool and myocardial segments were obtained from short-axis images of dynamic sequences. Model fitting of the 2C and 3C models was performed to estimate regional MBF. MBF values calculated by 2C and 3C models were 0.98 +/- 0.31 mL.min(-1).g(-1) and 1.11 +/- 0.37 mL.min(-1).g(-1), respectively, at rest (P < .0001) and 2.79 +/- 1.18 mL.min(-1).g(-1) and 2.46 +/- 1.02 mL.min(-1).g(-1), respectively, during hyperemia (P < .01), resulting in a CFR of 3.02 +/- 1.31 and 2.39 +/- 1.15 (P < .0001), respectively. Significant correlation was observed between the 2 models for calculation of resting MBF (r = 0.78), hyperemic MBF (r = 0.68), and CFR (r = 0.68)., Conclusion: Measurements of MBF and CFR by 2C and 3C models are significantly related. However, quantification of MBF and CFR significantly differs between the methods. This difference needs to be considered when normal values are established or when measurements obtained with different methods need to be compared.

Estrogen has beneficial effects on markers of coronary heart disease (CHD) risk, but may increase overall CHD events. The effects of hormone therapy on vascular endothelial function have been mixed, and require further assessment. We studied the myocardial blood flow (MBF) response to postmenopausal combination hormone therapy (CHT) in postmenopausal women with risk factors for CHD. We performed dynamic [13N]ammonia positron emission tomography in 15 postmenopausal women in a 7-month placebo-controlled crossover trial of continuous conjugated equine estrogen/cyclical micronized progesterone. MBF was measured at rest, after sympathetic stimulation with the cold pressor test (CPT), and after i.v. adenosine infusion, to determine baseline, endothelium-dependent, and maximal flows, respectively. Response to CPT was neutral in all women at baseline (-0.51 +/- 27%). Adenosine induced a marked increase in MBF (161 +/- 111%). Treatment with 3 months of combined estrogen/progestin CHT did not change CPT or adenosine MBF responses. Myocardial flow reserve was unchanged as well. In this group of postmenopausal women at higher cardiovascular risk, no association was found between CHT assignment and change in MBF. Further study is needed to clarify the effects of CHT on the endothelium of women with presumably diseased vasculature.

Objectives: The purpose of this study was to assess myocardial blood flow (MBF) and flow reserve in systemic right ventricles (RV) in long-term survivors of the Mustard operation., Background: There is a high prevalence of systemic RV dysfunction and impaired exercise performance in long-term survivors of the Mustard operation. A mismatch between myocardial blood supply and systemic ventricular work demand has been proposed as a potential mechanism., Methods: We assessed MBF at rest and during intravenous adenosine hyperemia in 11 long-term survivors of a Mustard repair (age 18+/-5 years, median age at repair 0.7 years, follow-up after repair 17+/-5 years) and 13 healthy control subjects (age 23+/-7 years), using N-13 ammonia and positron emission tomography imaging., Results: There was no difference in basal MBF between the systemic RV of survivors of the Mustard operation and the systemic left ventricle (LV) of healthy control subjects (0.80+/-0.19 vs. 0.74+/-0.15 ml/g/min, respectively, p = NS). However, the hyperemic flows were significantly lower in systemic RVs than they were in systemic LVs (2.34+/-0.0.69 vs. 3.44+/-0.62 ml/g/min respectively, p < 0.01). As a result, myocardial flow reserve was lower in systemic RVs than it was in systemic LVs (2.93+/-0.63 vs. 4.74+/-1.09, respectively, p < 0.01)., Conclusions: Myocardial flow reserve is impaired in systemic RVs in survivors of the Mustard operation. This may contribute to systemic ventricular dysfunction in these patients.

Background: C ardiac sympathetic signals play an important role in the regulation of myocardial perfusion. We hypothesized that sympathetically mediated myocardial blood flow would be impaired in diabetics with autonomic neuropathy., Methods and Results: We studied 28 diabetics (43+/-7 years old) and 11 age-matched healthy volunteers. PET was used to delineate cardiac sympathetic innervation with [(11)C]hydroxyephedrine ([(11)C]HED) and to measure myocardial blood flow at rest, during hyperemia, and in response to sympathetic stimulation by cold pressor testing. The response to cardiac autonomic reflex tests was also evaluated. Using ultrasonography, we also measured brachial artery reactivity during reactive hyperemia (endothelium-dependent dilation) and after sublingual nitroglycerin (endothelium-independent dilation). Based on [(11)C]HED PET, 13 of 28 diabetics had sympathetic-nerve dysfunction (SND). Basal flow was regionally homogeneous and similar in the diabetic and normal subjects. During hyperemia, the increase in flow was greater in the normal subjects (284+/-88%) than in the diabetics with SND (187+/-80%, P=0.084) and without SND (177+/-72%, P=0.028). However, the increase in flow in response to cold was lower in the diabetics with SND (14+/-10%) than in those without SND (31+/-12%) (P=0.015) and the normal subjects (48+/-24%) (P<0.001). The flow response to cold was related to the myocardial uptake of [(11)C]HED (P<0.001). Flow-mediated brachial artery dilation was impaired in the diabetics compared with the normal subjects, but it was similar in the diabetics with and without SND., Conclusions: Diabetic autonomic neuropathy is associated with an impaired vasodilator response of coronary resistance vessels to increased sympathetic stimulation, which is related to the degree of SND.

Objectives: Myocardial blood flow (MBF) in children late after arterial switch operation (ASO) was investigated quantitatively by positron emission tomography (PET)., Background: In children with transposition of the great arteries (TGA), ASO is widely accepted as the management of choice. The long-term patency of coronary arteries after surgical transfer to the neo-aorta, however, remains a concern., Methods: Twenty-two normally developed, symptom-free children were investigated by PET with nitrogen-13 ammonia at rest and during adenosine vasodilation 10+/-1 years after ASO. A subgroup of 15 children (9+/-1 years; group A) had simple TGA and underwent ASO within 20 days after birth while 7 (13+/-3 years; group B) had complex TGA and underwent ASO and correction of associated anomalies later after birth. Ten young, healthy adults (26+/-6 years) served as the control group., Results: Resting MBF was not different between groups. After correction for the rate-pressure product as an index of cardiac work, younger children of group A had significantly higher MBF at rest compared to healthy adults (102+/-29 vs. 77+/-6 ml/100 g/min; p = 0.012) while flow in group B was not different from the other groups (85+/-22 ml/100 g/min; p = NS). Hyperemic blood flows were significantly lower in both groups after ASO compared to normals (290+/-42 ml/100 g/min for group A, 240+/-28 for group B, 340+/-57 for normals; p < 0.01); thus, coronary flow reserve was significantly lower in both groups after ASO compared to healthy adults (3.0+/-0.6 for group A, 2.9+/-0.6 for group B, 4.6+/-0.9 for normals; p < 0.01)., Conclusions: Blood flow measurements suggest decreased coronary reserve in the absence of ischemic symptoms in children late after arterial switch repair of TGA. The global impairment of stress flow dynamics may indicate altered vasoreactivity; however, the prognostic significance of these findings needs to be determined.

Objectives: Regional myocardial blood flow (MBF) and flow reserve measurements using nitrogen-13 (N-13) ammonia positron emission tomography (PET) were compared with quantitative coronary angiography to determine their utility in the detection of significant coronary artery disease (CAD)., Background: Dynamic PET protocols using N-13 ammonia allow regional quantification of MBF and flow reserve. To establish the diagnostic performance of this method, the sensitivity and specificity must be known for varying decision thresholds., Methods: MBF and flow reserve for three coronary territories were determined in 20 normal subjects and 31 patients with angiographically documented CAD by means of dynamic PET and a three-compartment model for N-13 ammonia kinetics. Ten normal subjects defined the normal mean and SD of MBF and flow reserve, and 10 normal subjects were compared with patients. PET flow obtained in the territory with the most severe stenosis in each patient was correlated with the angiographic assessment of the stenosis (severity > or = 50%, > or = 70%, > or = 90%). Receiver operating characteristic (ROC) curve analysis was performed for 1.5, 2.0, 2.5, 3.0 and 4.0 SD of flow abnormalities., Results: MBF and flow reserve values from the normal subjects and from territories with documented stenoses > or = 50% were significantly different (p < 0.05). A significant difference was found between normal subjects and angiographically normal territories of patients with CAD. High diagnostic accuracy and sensitivity, with moderately high specificity, were demonstrated for detection of all stenoses., Conclusions: Quantification of myocardial perfusion using dynamic PET and N-13 ammonia provides a high performance level for the detection and localization of CAD. The specificity of dynamic PET was excellent in patients with a low likelihood of CAD, whereas an abnormal flow reserve in angiographically normal territories was postulated to represent early functional abnormalities of vascular reactivity.

Background: The role of cardiac sympathetic nerves in regulating coronary blood flow is controversial. We sought to determine the degree to which cardiac efferent sympathetic signals modulate coronary blood flow. The heterogeneous sympathetic reinnervation in transplanted hearts provides a model for studying the vasomotor responses to adrenergic stimulation in reinnervated and denervated coronary territories of the same heart., Methods: We studied 14 cardiac-transplant recipients who had normal coronary arteries and no evidence of rejection and 8 normal subjects. We used positron-emission tomography with [(11)C]hydroxyephedrine, an analogue of norepinephrine, to delineate sympathetic innervation. Using [(13)N]ammonia, we measured myocardial blood flow at rest, during adenosine-induced hyperemia, and in response to sympathetic stimulation induced by cold pressor testing., Results: In the transplant recipients, the uptake of [(11)C]hydroxyephedrine was greater in the territory served by the left anterior descending artery (0.15+/-0.01) than in those served by the right coronary artery (0.07+/-0.01, P<0.001) or the circumflex artery (0.09+/-0.01, P<0.001). The basal flow was similar in all three regions, as was the percent increase in flow during hyperemia. However, the increase in flow in response to cold pressor testing was higher in the territory of the left anterior descending artery (46+/-10 percent) than in those of the right coronary artery (16+/-5 percent, P=0.01) or the circumflex artery (23+/-6 percent, P=0.06), although the changes in hemodynamics and levels of circulating catecholamines were similar. No such regional differences were observed in the normal subjects., Conclusions: Increases in coronary blood flow in response to sympathetic stimulation correlated with the regional norepinephrine content in the cardiac sympathetic-nerve terminals. These findings suggest that cardiac adrenergic signals play an important part in regulating myocardial blood flow.

Objectives: The purpose of this investigation was to determine whether myocardial blood flow and flow reserve, based on quantitative measurements derived from positron emission tomographic (PET) imaging, would be globally impaired in children with a previous history of Kawasaki disease and normal epicardial coronary arteries., Background: Kawasaki disease is an acute inflammatory process of the arterial walls that results in panvasculitis in early childhood. Children with a history of Kawasaki disease and normal epicardial coronary arteries were previously considered to have normal coronary flow reserve. However, recent studies have reported exercise-induced regional perfusion abnormalities on single-photon positron emission tomographic (SPECT) imaging., Methods: We assessed myocardial blood flow and flow reserve at rest and during adenosine stress with nitrogen-13 ammonia and PET in 10 children with a history of Kawasaki disease and in 10 healthy young adult volunteers. All children had acute Kawasaki disease 4 to 15 years before the PET study. None of the children had epicardial coronary artery abnormalities at the acute stage of the disease or during follow-up, as assessed by echocardiography., Results: Rest blood flows normalized to the rate-pressure product, an index of cardiac work, were similar in both the patients with Kawasaki disease and healthy adult volunteers (82 +/- 14 vs. 77 +/- 16 ml/100 g per min [mean +/- SD], p = NS). However, hyperemic blood flows were significantly lower in the patients with Kawasaki disease than in the control subjects (263 +/- 64 vs. 340 +/- 57 ml/100 g per min, p = 0.01). As a result, estimates of myocardial flow reserve were lower in the patients with Kawasaki disease than in the healthy young adult volunteers (3.2 +/- 0.7 vs. 4.6 +/- 0.9, p = 0.003). In addition, total coronary resistance was higher in the patients with Kawasaki disease than in the healthy adult volunteers (33 +/- 11 vs. 24 +/- 5 mm Hg/ml per g per min, p = 0.04). Quantitative analysis of perfusion images demonstrated no evidence of regional perfusion abnormalities., Conclusions: Children with a previous history of Kawasaki disease and normal epicardial coronary arteries exhibit normal rest myocardial blood flows but reduced hyperemic flows and flow reserve. The abnormal hyperemic blood flows and flow reserve suggest an impaired vasodilatory capacity, possibly due to residual damage of the coronary microcirculation.

Objectives: The aim of this study was to evaluate patients with coronary artery disease to 1) determine the relation between flow reserve measured by nitrogen-13 (N-13) ammonia kinetic modeling and stenosis severity assessed by quantitative angiography, and 2) examine whether flow reserve is impaired in regions supplied by vessels without significant angiographic disease., Background: With the advent of new therapeutic approaches for coronary disease, an accurate noninvasive approach for absolute quantification of flow and flow reserve is needed to evaluate functional severity and extent of atherosclerosis. Nitrogen-13 ammonia kinetic modeling may permit such evaluation., Methods: Twenty-seven subjects were classified into three groups: group 1 = 5 young volunteers: group 2 = 7 middle-aged volunteers; and group 3 = 15 patients with coronary artery disease. Dynamic N-13 ammonia positron emission tomographic imaging was performed at rest and during adenosine infusion. A three-compartment model was fit to regional N-13 ammonia kinetic data to determine myocardial flow. Group 3 patients underwent quantitative coronary angiography., Results: The regional blood flow results in patients with coronary disease were classified into four subgroups: no significant detectable disease and mild (50% to 69.9% area stenosis), moderate (70% to 94.9% area stenosis) or severe (95% to 100% area stenosis) coronary disease. Flow reserve was 2.95 +/- 0.65; 2.09 +/- 0.47; 2.02 +/- 0.51; 1.3 +/- 0.32, respectively (p < or = 0.01 except mild vs. moderate). Flow reserve was correlated with percent area stenosis (r = -0.56) and minimal lumen diameter (r = 0.75). In volunteers (groups 1 and 2), flow reserves were greater than in segments without detectable disease in group 3 patients (4.10 +/- 0.71 and 3.79 +/- 0.42, respectively, vs. 2.88 +/- 0.56, p < or = 0.02)., Conclusions: The functional severity of coronary disease measured by N-13 ammonia positron emission tomography varied for a given stenosis but was significantly related to angiographic severity. Among patients with coronary disease, myocardial regions without significant angiographic stenoses displayed reduced flow reserve than did regions in control subjects, indicating that vascular reactivity was more diffusely impaired in group 3 than was suggested by angiography. Noninvasive quantification of myocardial flow reserve using dynamic N-13 ammonia positron emission tomography yields important functional data that permit definition of the extent of disease even when disease is not apparent by angiography.

Background: Experimental studies have shown that positron emission tomography (PET) with 13N-labeled ammonia provides accurate quantification of regional myocardial blood flow (MBF) under rest and stress conditions. To establish the clinical utility of this method, the interobserver variability and the temporal variability of serial measurements of blood flow and coronary flow reserve (CFR) must be known. This study investigated the interobserver and temporal reproducibility of 13N-labeled PET for measurement of MBF and CFR., Methods and Results: Initial and follow-up 13N-labeled ammonia PET studies were performed at rest and during adenosine infusion in six normal volunteers and six patients with stable coronary artery disease. Two investigators analyzed dynamically acquired data from the initial studies and one investigator analyzed the follow-up studies. Time-activity curves of tissue tracer activity were derived by a semiautomated sampling routine. A three-compartment model and curve-fitting algorithm were used to determine estimates of MBF in five myocardial regions. The interobserver correlations for MBF and CFR were excellent (r = 0.96 and 0.93, respectively). The interstudy correlation was good for rest and stress MBF (r = 0.87). The estimates of CFR on the initial and follow-up studies demonstrated a fair correlation (r = 0.72). For individual myocardial regions, there was considerable interstudy variability of stress MBF and CFR, with a mean percent difference for CFR of 19% +/- 19% in normal volunteers and 38% +/- 16% in patients with coronary disease. In normal subjects, regional CFR was highly reproducible (95%) when the values were defined as either normal (> or = 2.5) or reduced (< 2.5)., Conclusions: The interobserver of reproducibility of 13N-labeled ammonia PET estimates of regional MBF was excellent. The temporal reproducibility of MBF and CFR was fair, with individual regions demonstrating substantial interstudy variability.

Background: The objective of this study was to compare coronary flow reserve (CFR) as a measure of vascular integrity in asymptomatic middle-aged men with family history of coronary artery disease (CAD) and a high-risk lipid profile with men without risk factors for CAD using positron emission tomography (PET). Previous studies suggested that the assessment of CFR is a sensitive means to detect vascular abnormalities before angiographic appearance of CAD. N-13 ammonia PET scanning allows noninvasive evaluation of regional and global myocardial blood flow and thereby quantification of CFR., Methods and Results: We used dynamic N-13 ammonia PET imaging in conjunction with intravenous adenosine to assess regional and global CFR in asymptomatic middle-aged men with high risk (group 1, n = 16) and men without any known risk factors (group 2, n = 11) for CAD. Group 1 patients were selected based on positive family history of CAD, one or more lipid abnormalities, and a normal stress test. No patient had history of diabetes or hypertension. A three-compartment tracer kinetic model developed and validated in our institution was used to calculate myocardial blood flow. Absolute myocardial blood flow (mL/100 g per minute) was calculated in five territories for each patient. CFR was defined as the ratio of blood flow during maximum pharmacological vasodilatation to blood flow at rest. Comparisons of CFR between the two groups of patients were performed. The mean age was similar between groups (group 1, 49.3 +/- 0.5 years; group 2, 48.1 +/- 8.7 years; P = NS). Group 1 had higher total cholesterol (mg/dL) (241 +/- 43 versus 173 +/- 34, P < .001), total cholesterol to high-density lipoprotein cholesterol ratio (6.4 +/- 1.6 versus 4.1 +/- 1.4, P < .001), and low-density lipoprotein cholesterol (mg/dL) (167 +/- 33 versus 107 +/- 32). No group 1 patient had evidence of ischemia by exercise ECG or exercise of pharmacological radionuclide perfusion studies. The mean global absolute myocardial blood flow at rest was not significantly different among groups (group 1, 76 +/- 18; group 2, 66 +/- 8; P = NS; (in mL/100 g per minute). However, blood flow after adenosine infusion was higher for group 2 (group 1, 217 +/- 56; group 2, 264 +/- 39; P < .001), which resulted in a larger CFR for group 2 (group 1, 2.93 +/- 0.86; group 2, 4.27 +/- 0.52; P < .001). Univariate linear regression analysis revealed significant negative correlation of CFR to total cholesterol (P < .05, r = -.41), low-density lipoprotein (P < .05, r = -.38), and total cholesterol to high-density lipoprotein cholesterol ratio (P < .05, r = -.47)., Conclusions: Noninvasive quantification of absolute myocardial blood flow by N-13 ammonia PET allows the detection of abnormal vasodilatory response to intravenous adenosine in male patients with family history of CAD and high-risk lipid profiles. Early assessment of alterations of vascular reactivity to adenosine in relation to high-risk lipid profiles in asymptomatic men may allow early detection of preclinical atherosclerosis and may initiate modification and/or elimination of risk factors that may slow, retard, or even reverse the progression of CAD.

In combination with PET, the tracer 13N-ammonia can be employed for the noninvasive quantification of myocardial perfusion at rest and after pharmacological stress. The purpose of this study was to develop an analysis method for the quantification of regional myocardial blood flow in the clinical setting. The algorithm includes correction for patient motion, an automated definition of multiple regions and display of absolute flows in polar map format. The effects of partial volume and blood to tissue cross-contamination were accounted for by optimizing the radial position of regions to meet fundamental assumptions of the kinetic model. In order to correct for motion artifacts, the myocardial displacement was manually determined based on edge-enhanced images. The obtained results exhibit the capability of the presented algorithm to noninvasively assess regional myocardial perfusion in the clinical environment.

Positron emission tomography has been shown to provide quantitative estimates of myocardial blood flow using 13N-ammonia and 15O-water. In a validation study, myocardial blood flow was noninvasively determined in 11 open-chest anesthetized dogs using dynamic positron emission tomography. The radiopharmaceuticals 13N-ammonia and 15O-water were intravenously administered and measurements were carried out at rest and following pharmacological vasodilation to assess blood flow over a range from 53 to 580 ml/100 g/min. Quantification of blood flow based on tracer kinetic modeling of 13N-ammonia data correlated closely with myocardial blood flow determined by microspheres (y = 0.944 x +7.22, r = 0.986) and with the 15O-water injection technique y = 1.054 x -15.8 (r = 0.99). The use of 13N-ammonia with positron emission tomography enables the accurate quantification of myocardial blood flow. Using this technique, uncomplicated study protocols simplify the measurement procedures while providing excellent qualitative and quantitative information.

Objectives: The aim of this study was to define the temporal changes in the relationship between technetium-99m teboroxime tissue retention and myocardial blood flow in a canine model., Background: Technetium-99m teboroxime is a new neutral lipophilic myocardial perfusion agent. It is known to be highly extracted by the myocardium but to have a rapid clearance rate., Methods: A wide range of myocardial blood flow was induced in each experiment by regional coronary occlusion and dipyridamole infusion. Myocardial retention of technetium-99m teboroxime was determined by in vitro tissue counting at 1, 2 or 5 min after injection of the tracer. Tracer retention was correlated with microsphere-determined blood flow and the data were fitted to nonlinear functions., Results: Correlation coefficients for these functions were 0.92, 0.95 and 0.95 at 1, 2, and 5 min, respectively. At 1 min after injection, the relationship of technetium-99m teboroxime retention to blood flow was linear over a wide flow range, becoming nonlinear at flow rates greater than 4.5 ml/min per g. After 5 min the retention-flow relationship was linear only to 2.5 ml/min per g, above which little change in retention was noted. Normalized myocardial retention, expressed as a percent of the retention at 1 ml/min per g, was also calculated. At flow rates of 1, 2, 3, 4 and 5 ml/min per g, normalized retention was 100, 169, 228, 277 and 317% at 1 min and 100, 171, 217, 239 and 237% at 5 min after injection., Conclusions: At 1 min after injection, the relationship of technetium-99m teboroxime myocardial retention to blood flow is well maintained over a wide range of flow. However, after only 5 min, tracer retention underestimates flow changes at moderate and high flow rates. Thus, rapid acquisition protocols are necessary to fully exploit the potential of this promising new tracer in the evaluation of myocardial perfusion.

Positron emission tomography (PET) represents an advanced imaging technology for the noninvasive evaluation of regional myocardial blood flow. Several blood flow tracers are available, including cyclotron-produced radiopharmaceuticals such as [15O]H2O and [13N]NH3 and generator-produced rubidium-82 ([82Rb]-) and copper-62 ([62Cu]-) pyruvaldehyde-bis-(N-4-methylthiosemicarbazone) (PTSM). 82Rb and [13N]NH3 are the most commonly employed tracers for the qualitative evaluation of regional myocardial perfusion. Their use allows the accurate detection of coronary artery disease in combination with pharmacologic stress. Initial comparative studies with thallium-201 (201Tl) single-photon emission computed tomography (SPECT) have shown that PET has a higher diagnostic accuracy. Beyond improved diagnostic performance, the quantitative flow measurements provided by PET represent an important advance in nuclear cardiology. The radiopharmaceuticals [15O]H2O and [13N]NH3 have been applied for the noninvasive determination of regional coronary reserve. Quantification of blood flow based on tracer kinetic modeling yields blood flow values in close agreement with determinations provided by invasive procedures. The noninvasive quantification of blood flow provides a useful research and clinical tool for the objective assessment of therapeutic interventions as well as pathophysiologic alterations of regional myocardial blood flow in various cardiac diseases.