13NH3 Positron Emission Tomography Research Articles

MP-453090-11 HIBERNATING MYOCARDIUM IS ASSOCIATED WITH A LOWER INCIDENCE OF SUSTAINED VENTRICULAR ARRHYTHMIAS IN PATIENTS WITH ISCHEMIC CARDIOMYOPATHY

Prognostic markers for the prediction of major arrhythmic events (MAE) in patients with ischemic cardiomyopathy (ICM) are scarce. Although myocardial scar is associated with ventricular arrhythmias (VA), the role of hibernating myocardium (HM) is unclear. The aim of this study was to identify prognostic markers for MAE using positron emission tomography (PET) in patients with ICM. In this retrospective single-center study, consecutive patients with ICM confirmed by invasive coronary angiography undergoing both 13N-ammonia (NH3) and 18F-fluorodeoxyglucose (FDG) scan for evaluation of myocardial ischemia and HM were assessed for the occurrence of MAE after PET scan of sudden cardiac death (SCD), survived SCD, VA requiring external or ICD shock, antitachycardia pacing (ATP) or sustained VA during follow-up. PET scan was performed in 254 with ICM and they were followed up for a median of 5.4 years (IQR 3.6-9.8). Mean age was 65.6 years (±10.9), mean ejection fraction was 36.2% (±12.1), 69 patients (27%) had an ICD at baseline, 39 (56.5%) for primary prevention. PET scan revealed myocardial ischemia, scar (=NH3-PET resting perfusion defect) and HM in 94 (37%), 229 (90.2%) and 121 (47.6%) patients, respectively. Mean left ventricular (LV) scar size was 23.5% (±13.5) and mean HM size 8.1% (±7.6). MAE after PET scan occurred in 34 patients (13.4%); 18 patients (7%) suffered SCD, 19 patients had sustained VA, 4 (1.6%) an external, 4 (1.6%) an ICD shock and 12 (4.7%) received ATP. Median time to MAE was 2.5 years (IQR 1-3.9). Scar >10% detected by NH3-PET scan was associated with a higher incidence of MAE (HR 1.24, CI 1.21-9.82, p=0.02) compared to ≤10%. HM >10% detected by FDG-PET scan in patients with scars >10% had lower incidence of MAE (HR 0.89, CI 0.18-0.93, p=0.033) compared to HM ≤10% or scar ≤10%, even after adjusting for LVEF ≤35%. This association remained significant when patients (n=49) revascularized within 90 days of PET scan were censored at the time of revascularization. There was no significant association between MAE and myocardial ischemia (HR 0.84, CI 0.42-1.7, p=0.63), independent of any revascularization. Patients with large and non-viable myocardial scars are at increased risk for MAE. Large (>10% of LV), but viable scars carry similar risk of MAE as smaller (≤10% of LV) scars. The combination of cardiac NH3 and FDG PET scans may serve as a prognostic tool for the prediction of clinically important endpoints such as SCD and sustained VA.

Does quantification of [11C]meta-hydroxyephedrine and [13N]ammonia kinetics improve risk stratification in ischemic cardiomyopathy

BackgroundIn ischemic cardiomyopathy patients, cardiac sympathetic nervous system dysfunction is a predictor of sudden cardiac arrest (SCA). This study compared abnormal innervation and perfusion measured by [11C]meta-hydroxyephedrine (HED) vs [13N]ammonia (NH3), conventional uptake vs parametric tracer analysis, and their SCA risk discrimination. MethodsThis is a sub-study analysis of the prospective PAREPET trial, which followed ischemic cardiomyopathy patients with reduced left ventricular ejection fraction (LVEF ≤ 35%) for events of SCA. Using n = 174 paired dynamic HED and NH3 positron emission tomography (PET) scans, regional defect scores (%LV extent × severity) were calculated using HED and NH3 uptake, as well as HED distribution volume and NH3 myocardial blood flow by kinetic modeling. ResultsDuring 4.1 years follow-up, there were 27 SCA events. HED defects were larger than NH3, especially in the lowest tertile of perfusion abnormality (P < .001). Parametric defects were larger than their respective tracer uptake defects (P < .001). SCA risk discrimination was not significantly improved with parametric or uptake mismatch (AUC = 0.73 or 0.70) compared to HED uptake defect scores (AUC = 0.67). ConclusionQuantification of HED distribution volume and NH3 myocardial blood flow produced larger defects than their respective measures of tracer uptake, but did not lead to improved SCA risk stratification vs HED uptake alone.

Longitudinal [18F]FDG and [13N]NH3 PET/CT imaging of brain and spinal cord in a canine hemisection spinal cord injury model

To further understand the neurological changes induced by spinal cord injury (SCI) in its acute and subacute stages, we evaluated longitudinal changes in glucose and glutamate metabolism in the spinal cord and brain regions of a canine hemisection SCI model. [18F]FDG and [13N]NH3 positron-emission tomography (PET) with computed tomography (CT) was performed before SCI and at 1, 3, 7, 14, and 21 days after SCI. Spinal cord [18F]FDG uptake increased and peaked at 3 days post SCI. Similar changes were observed in the brain regions but were not statistically significant. Compared to the acute phase of SCI, [13N]NH3 uptake increased in the subacute stage and peaked at 7 days post SCI in all analyzed brain regions. But in spinal cord, no [13N]NH3 uptake was detected before SCI when the blood-spinal cord barrier (BSCB) was intact, then gradually increased when the BSCB was damaged after SCI. [13N]NH3 uptake was significantly correlated with plasma levels of the BSCB disruption marker, monocyte chemoattractant protein-1 (MCP-1). Overall, we showed that SCI induced in vivo changes in glucose uptake in both the spinal cord and the examined brain regions, and changes in glutamine synthetase activity in the latter. Moreover, our results suggest that [13N]NH3 PET may serve as a potential method for assessing BSCB permeability in vivo.

Coronary microvascular function is impaired in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Abstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; OMIM 125310) is a rare inherited disease, caused by NOTCH3 gene mutations. Main clinical manifestations of CADASIL include recurrent subcortical ischemic events, migraine, cognitive impairment and psychiatric disturbances. CADASIL is a systemic microangiopathy and cardiac involvement has been observed in a series of Dutch patients, presenting higher frequency of myocardial infarction compared to non-mutated relatives and general population. In particular, electron microscopic examination of myocardial tissue of a study participant demonstrated CADASIL characteristics. We sought to investigate the relationship between CADASIL and microvascular dysfunction (MVD). Seventeen patients with genetically-confirmed CADASIL, aged &amp;lt;60 years, with ≤1 cardiovascular risk factor (current smoke, diabetes, hypertension, dyslipidemia), recent (&amp;lt;3 months) neurological evaluation with neuropsychological tests and 3 Tesla brain magnetic resonance imaging (MRI) underwent 12-lead ECG, echocardiography, and measurement of maximal myocardial blood flow following Regadenoson infusion (Reg-MBF) by 13NH3positron emission tomography (PET), to investigate the presence of coronary microvascular dysfunction (CMD). Coronary flow reserve (CFR) was defined as Reg-MBF/resting MBF. PET results were compared to those of 15 healthy controls matched for age and sex recruited among a historical cohort of healthy patients. The study was approved by the institutional review board and all the subjects gave informed consent. Mean age was 40±9 years (range 28–57 years); 6 patients (35%) were male. One was a current smoker and 3 ex-smokers; 1 patient was on aspirin, 1 on acetazolamide and 2 on escitalopram, none was taking statins. 12 patients (71%) presented with migraine, 9 (53%) had psychiatric disturbances and 1 (6%) had a previous stroke. Brain MRI showed mild-moderate and severe leukoencephalopathy in 11 (65%) and 5 (29%) patients respectively, lacunes were present in 14 patients and microbleeds in 1; one patient had normal findings. Both Reg-MBF and CFR were blunted in CADASIL patients compared with controls (Reg-MBF 2.46±0.54 versus 3.09±0.44 ml/gr/min respectively, p&amp;lt;0.001; CFR 2.74±0.36 vs. 3.28±0.66, respectively, p&amp;lt;0.01). In 3 male patients (17%), CFR reduction was severe (&amp;lt;2). Segmental Reg-MBF analysis of left ventricular flow showed diffuse hypoperfusion, excluding preferential regional involvement. No correlations were found between Reg-MBF values and neuropsychological performance or cerebral lesion burden, suggesting that neurological and cardiac involvement might be independent in CADASIL. These data represent the first documentation of coronary microvascular involvement in a group of young and mildly symptomatic CADASIL patients, confirming the systemic nature of the disease. This proof of concept study expands our understanding of genetically-driven CMD. Funding Acknowledgement Type of funding source: None

Sub-endocardial and sub-epicardial measurement of myocardial blood flow using 13NH3 PET in man

BackgroundThis study examined whether measuring myocardial blood flow (MBF) in the sub-endocardial (SEN) and sub-epicardial (SEP) layers of the left ventricular myocardium using 13NH3 positron emission tomography (PET) and an automated procedure gives reasonable results in patients with known or suspected coronary artery disease (CAD). MethodsResting and stress 13NH3 dynamic PET were performed in 70 patients. Using ≥ 70% diameter stenosis in invasive coronary angiography (ICA) to identify significant CAD, we examined the diagnostic value of SEN- and SEP-MBF, and coronary flow reserve (CFR) vs. the corresponding conventional data averaged on the whole wall thickness. ResultsICA demonstrated 36 patients with significant CAD. Their global stress average [1.61 (1.26, 1.87) mL·min−1·g−1], SEN [1.39 (1.2, 1.59) mL·min−1·g−1] and SEP [1.22 (0.96, 1.44) mL·min−1·g−1] MBF were significantly lower than in the 34 no-CAD patients: 2.05 (1.76, 2.52), 1.72 (1.53, 1.89) and 1.46 (1.23, 1.89) mL·min−1·g−1, respectively, all P < .005. In the 60 CAD vs. the 150 non-CAD territories, stress average MBF was 1.52 (1.10, 1.83) vs. 2.06 (1.69, 2.48) mL·min−1·g−1, SEN-MBF 1.33 (1.02, 1.58) vs. 1.66 (1.35, 1.93) mL·min−1·g−1, and SEP-MBF 1.07 (0.80, 1.29) vs. 1.40 (1.12, 1.69) mL·min−1·g−1, respectively, all P < .05. Using receiver operating characteristics analysis for the presence of significant CAD, the areas under the curve (AUC) were all significant (P < .0001 vs. AUC = 0.5) and similar: stress average MBF = 0.79, SEN-MBF = 0.75, and SEP-MBF = 0.73. AUC was 0.77 for the average CFR, 0.75 for SEN, and 0.70 for SEP CFR. The stress transmural perfusion gradient (TPG) AUC (0.51) was not significant. However, stress TPG was significantly lower in segments subtended by totally occluded arteries vs. those subtended by sub-total stenoses: 1.10 (0.86, 1.33) vs. 1.24 (0.98, 1.56), respectively, P < .005. ConclusionAutomatic assessment of SEN- and SEP-MBF (and CFR) using 13NH3 PET gives reasonable results that are in good agreement with the conventional average whole wall thickness data. Further studies are needed to examine the utility of layer measurements such as in patients with hibernating myocardium or microvascular disease.

Diagnostic accuracy of 13N-ammonia PET, 11C-methionine PET and 18F-fluorodeoxyglucose PET: a comparative study in patients with suspected cerebral glioma

BackgroundThe treatment of patients with glioma depended on the nature of the lesion and on histological grade of the tumor. Positron emission tomography (PET) using 13N-ammonia (NH3), 11C-methionine (MET) and 18F-fluorodeoxyglucose (FDG) have been used to assess brain tumors. Our aim was to compare their diagnostic accuracies in patients with suspected cerebral glioma.MethodsNinety patients with suspicion of glioma based on previous CT/MRI, who underwent NH3 PET, MET PET and FDG PET, were prospectively enrolled in the study. The reference standard was established by histology or clinical and radiological follow-up. Images were interpreted by visual evaluation and semi-quantitative analysis using the lesion-to-normal white matter uptake ratio (L/WM ratio).ResultsFinally, 30 high-grade gliomas (HGG), 27 low-grade gliomas (LGG), 10 non-glioma tumors and 23 non-neoplastic lesions (NNL) were diagnosed. On visual evaluation, sensitivity and specificity for differentiating tumors from NNL were 62.7% (42/67) and 95.7% (22/23) for NH3 PET, 94.0% (63/67) and 56.5% (13/23) for MET PET, and 35.8% (24/67) and 65.2% (15/23) for FDG PET. On semi-quantitative analysis, brain tumors showed significantly higher L/WM ratios than NNL both in NH3 and MET PET (both P < 0.001). The sensitivity, specificity and the area under the curve (AUC) by receiver operating characteristic (ROC) analysis, respectively, were 64.2, 100% and 0.819 for NH3; and 89.6, 69.6% and 0.840 for MET. Besides, the L/WM ratios of NH3, MET and FDG PET in HGG all significantly higher than that in LGG (all P < 0.001). The predicted (by ROC) accuracy of the tracers (AUC shown in parentheses) were 86.0% (0.896) for NH3, 87.7% (0.928) for MET and 93.0% (0.964) for FDG. While no significant differences in the AUC were seen between them.ConclusionNH3 PET has remarkably high specificity for the differentiation of brain tumors from NNL, but low sensitivity for the detection of LGG. MET PET was found to be highly useful for detection of brain tumors. However, like FDG, high MET uptake is frequently observed in some NNL. NH3, MET and FDG PET all appears to be valuable for evaluating the histological grade of gliomas.

Fully quantitative cardiovascular magnetic resonance myocardial perfusion ready for clinical use: a comparison between cardiovascular magnetic resonance imaging and positron emission tomography

BackgroundRecent studies have shown that quantification of myocardial perfusion (MP) at stress and myocardial perfusion reserve (MPR) offer additional diagnostic and prognostic information compared to qualitative and semi-quantitative assessment of myocardial perfusion distribution in patients with coronary artery disease (CAD). Technical advancements have enabled fully automatic quantification of MP using cardiovascular magnetic resonance (CMR) to be performed in-line in a clinical workflow. The aim of this study was to validate the use of the automated CMR perfusion mapping technique for quantification of MP using 13N–NH3 cardiac positron emission tomography (PET) as the reference method.MethodsTwenty-one patients with stable CAD were included in the study. All patients underwent adenosine stress and rest perfusion imaging with 13N–NH3 PET and a dual sequence, single contrast bolus CMR on the same day. Global and regional MP were quantified both at stress and rest using PET and CMR.ResultsThere was good agreement between global MP quantified by PET and CMR both at stress (−0.1 ± 0.5 ml/min/g) and at rest (0 ± 0.2 ml/min/g) with a strong correlation (r = 0.92, p < 0.001; y = 0.94× + 0.14). Furthermore, there was strong correlation between CMR and PET with regards to regional MP (r = 0.83, p < 0.001; y = 0.87× + 0.26) with a good agreement (−0.1 ± 0.6 ml/min/g). There was also a significant correlation between CMR and PET with regard to global and regional MPR (r = 0.69, p = 0.001 and r = 0.57, p < 0.001, respectively).ConclusionsThere is good agreement between MP quantified by 13N–NH3 PET and dual sequence, single contrast bolus CMR in patients with stable CAD. Thus, CMR is viable in clinical practice for quantification of MP.

Sphingosine-1-phosphate receptor agonist, FTY720, restores coronary flow reserve in diabetic rats.

Impairment of coronary flow reserve (CFR) has been generally demonstrated in diabetic patients and animals with microvascular complications but without obvious obstructive coronary atherosclerosis. There have been few studies investigating CFR in cases of relatively well-controlled therapy. The purpose of this study is to evaluate the effect of treatment with a Sphingosine-1-phosphate (S1P) receptor potent agonist, FTY720, on early diabetic rats in terms of CFR. METHODS AND RESULTS: Male Sprague-Dawley (SD) rats were divided into 3 groups: (1) streptozotocin-uninjected rats (control rats); (2) streptozotocin-injected hyperglycemic rats (diabetic group); and (3) FTY720-fed and streptozotocin-injected hyperglycemic rats. FTY720 (1.25 mg/kg per day orally) was administrated for 9 weeks in SD rats (from 6 weeks old to 15 weeks old). CFR was evaluated by (13)NH3-positron emission tomography. No obvious pathological changes of macrovascular atherosclerosis were observed in each group. Diabetic rats had impaired CFR compared with the control group (1.39±0.26 vs. 1.94±0.24, P<0.05). Treatment with FTY720 for 9 weeks attenuated the heart histological changes and improved CFR in 32% of diabetic rats (1.84±0.36 vs. 1.39±0.26, P<0.05). In summary, long-term therapy with the Sphingosine-1-phosphate receptor agonist, FTY720, improved CFR by attenuating the heart histological changes, and it might have a beneficial effect on coronary microvascular function in diabetic rats.

P2927 Gated cardiac NH3-positron emission tomography for assessment of left-ventricular volumes, mass and ejection fraction: comparison with electrocardiogramgated 18F-fluorodeoxyglucose-positron emission tomography

P2927 Gated cardiac NH3-positron emission tomography for assessment of left-ventricular volumes, mass and ejection fraction: comparison with electrocardiogramgated 18F-fluorodeoxyglucose-positron emission tomography

Evaluation of coronary blood flow reserve by 13N-NH3 positron emission computed tomography (PET) with dipyridamole in the treatment of hypertension with the ACE inhibitor (Cilazapril).

The purpose of this study was to evaluate the effect of treatment with an angiotensin-converting enzyme (ACE) inhibitor (Cilazapril) for early hypertensive patients in terms of coronary blood flow reserve evaluated by 13NH3-positron emission tomography (PET). Before and after 12 weeks of ACE inhibitor treatment, 13NH3-PET with dipyridamole provocation test was performed, and definite myocardial perfusion and coronary flow reserve (CFR) were calculated. Compared to our normal subjects previously reported (2.61+/-0.74), average coronary flow reserve was decreased (1.70+/-0.64 in hypertensive patients), and improved after treatment (1.77+/-0.52), but not significantly. Of 12 patients, five (42%) showed improved coronary flow reserve from 1.34 to 1.99 without a significant change in the resting flow. Only one patient (8%) showed deterioration after the ACE inhibitor treatment. The coronary vascular resistance (CVR) after ACE inhibitor treatment of the patients with CFR < 2.0 decreased significantly compared with those with CFR> or = 2.0 (p < 0.03). These results indicate that hypertensive patients at the early stage show decreased coronary flow reserve despite having normal resting flow. Treatment with an ACE inhibitor (Cilazapril) for 12 weeks improved coronary flow reserve in 42% of our patients. The CVR of the patients with CFR < 2.0 showed improvement compared to those with CFR> or = 2.0. This result indicates that an ACE inhibitor (e.g., Cilazapril) should be one of the choices for improving CFR if hypertensive patients in early stage show signs of ischemia or diastolic dysfunction, which may be one of the sequels of reserve restriction.

901-103 Effects of Dual Chamber Pacing on Myocardial Ischemia in Hypertrophic Cardiomyopathy Studied with 13-N Ammonia and 18-FDG Positron Emission Tomography

Dual chamber (DDD) pacing improves symptoms of angina in most patients with hypertrophic cardiomyopathy (HCM). Besides reduction of outflow tract obstruction, other factors may be operative, since symptoms also improve in HCM without severe obstruction. We studied with positron emission tomography (PET) whether permanent DDD pacing would influence myocardial perfusion (MP) and myocardial perfusion reserve (MPR). Six patients (age 52 ± 7 yrs) were treated with DDD pacing for HCM with angina refractory to medication. Before and 3 months after DDD insertion MP and MPR (ratio of dipyridamole and resting perfusion) were studied with 13-NH3 PET at rest and during a dipyridamole stress test. Myocardial glucose uptake was studied with 18-fluoro-deoxy-glucose PET (FDG). All studies were performed off medication. Results were compared to 18 normals.Empty CellMP (ml/l00 g/min)MPRSeptal-FDG (ml/l00 g/min)Baseline173 ± 27*1.40 ± 0.27*665 ± 9.0*DDD102 ± 23*1.70 ± 0.18*48.8 ± 8.5*Normals96 ± 191.96 ± 0.3454.8 ± 14.7*P &lt; 0.05 P &lt; 0.05 Thus DDD pacing decreased baseline myocardial perfusion and increased perfusion reserve in HCM. The decrease in septal FDG uptake suggests a reduction of septal ischemia. This is probably due to a reduction in outflow tract obstruction in combination with early septal activation resulting in reduced septal fiber strain and a redistribution in blood flow.

頭頂葉性純粋失書 病変と症候の検討

Recently, several cases of pure agraphia caused by left parietal lobe lesion have been reported. Most of the reported cases were caused by space-occupying lesions, but clinical descriptions and anatomical correlations were not sufficiently detailed. The present authors investigated two cases of pure agraphia caused by left posterior parietal infarction. Detailed analyses of symptoms, CT scans and 13NH3 PET (Positron Emission Tomography) were performed. The characteristics of the symptoms in both cases were : 1) Agraphia was present with both hands. 2) Copying was not greatly disturbed as compared with spontaneous writing or dictation. 3) Agraphia was characterized mainly by paragraphia, non-reaction, omissions and wrong writing order of letters. 4) One patient who had much knowledge of English was examined as to his writing and oral spelling in English. The main lesions in the CT scan were found in the left supramarginal gyrus and the upper parietal lobe. The functional lesions seen in 13NH3 PET were much wider than those in CT scan but not extending to the frontal lobe. These observations suggest that pure agraphia may also be caused by left parietal lobe lesion.