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Purpose: Cardiac sympathetic nervous system (SNS) dysfunction is associated with poor prognosis in chronic heart failure patients. This study characterized the reproducibility and repeatability of [ 11 C]meta-hydroxyephedrine (HED) positron emission tomography (PET) quantification of cardiac SNS innervation, regional denervation, and myocardial blood flow (MBF)., Methods: Dynamic HED PET-CT scans were performed 47 ± 22 days apart in 20 patients with stable heart failure and reduced ejection fraction. Three observers, blinded to clinical data, used FlowQuant® to evaluate the test-retest repeatability and inter- and intra-observer reproducibility of HED tracer uptake and clearance rates to measure global (LV-mean) retention index (RI), volume of distribution (V T ), and MBF. Values were also compared with and without regional partial-volume correction. Regional denervation was quantified as %LV defect size of values < 75% of the LV-maximum. Test-retest repeatability and observer reproducibility were evaluated using intra-class-correlation (ICC) and Bland-Altman coefficient of repeatability (NPC)., Results: Intra- and inter-observer correlations of both V T and RI were excellent (ICC = 0.93-0.99). Observer reproducibility (NPC = 3-13%) was lower than test-retest repeatability (NPC = 12-61%). Both regional (%LV defect size) and global (LV-mean) measures of sympathetic innervation were more repeatable using the simple RI model compared to V T (NPC = 12% vs. 19% and 30% vs. 54%). Using either model, quantification of regional denervation (defect size) was consistently more reliable than the global LV-mean values of RI or V T . Regional partial-volume correction degraded repeatability of both the global and regional V T measures by 2-12%. Test-retest repeatability of MBF estimation was relatively poor (NPC = 30-61%) compared with the RI., Conclusions: Quantitative measures of global and regional SNS innervation were most repeatable using the simple RI method of analysis compared with the more complex V T . Observer variability was significantly lower than the test-retest repeatability using a highly automated analysis program. These results support the use of the simple RI method for reliable analysis of HED PET images in clinical research studies for future evaluation of new therapies and for risk stratification in patients with heart failure.

Background: Heart failure with reduced ejection fraction and obstructive sleep apnea (OSA), 2 states of increased metabolic demand and sympathetic nervous system activation, often coexist. Continuous positive airway pressure (CPAP), which alleviates OSA, can improve ventricular function. It is unknown whether this is due to altered oxidative metabolism or presynaptic sympathetic nerve function. We hypothesized that short-term (6-8 weeks) CPAP in patients with OSA and heart failure with reduced ejection fraction would improve myocardial sympathetic nerve function and energetics., Methods and Results: Forty-five patients with OSA and heart failure with reduced ejection fraction (left ventricular ejection fraction 35.8±9.7% [mean±SD]) were evaluated with the use of echocardiography and 11C-acetate and 11C-hydroxyephedrine positron emission tomography before and ≈6 to 8 weeks after randomization to receive short-term CPAP (n=22) or no CPAP (n=23). Work metabolic index, an estimate of myocardial efficiency, was calculated as follows: (stroke volume index×heart rate×systolic blood pressure÷Kmono), where Kmono is the monoexponential function fit to the myocardial 11C-acetate time-activity data, reflecting oxidative metabolism. Presynaptic sympathetic nerve function was measured with the use of the 11C-hydroxyephedrine retention index. CPAP significantly increased hydroxyephedrine retention versus no CPAP (Δretention: +0.012 [0.002, 0.021] versus -0.006 [-0.013, 0.005] min(-1); P=0.003). There was no significant change in work metabolic index between groups. However, in those with more severe OSA (apnea-hypopnea index>20 events per hour), CPAP significantly increased both work metabolic index and systolic blood pressure (P<0.05)., Conclusions: In patients with heart failure with reduced ejection fraction and OSA, short-term CPAP increased hydroxyephedrine retention, indicating improved myocardial sympathetic nerve function, but overall did not affect energetics. In those with more severe OSA, CPAP may improve cardiac efficiency. Further outcome-based investigation of the consequences of CPAP is warranted., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00756366., (© 2014 American Heart Association, Inc.)

Background: Positron emission tomography (PET) studies have demonstrated reduced sympathetic neuronal integrity in high-fat diet fed streptozotocin insulin-resistant diabetic rats in parallel with abnormal early-to-atrial transmitral velocity. We hypothesized that administration of anti-glycemic drugs early after diabetes induction would prevent sympathetic neuronal dysfunction., Methods and Results: Male Sprague-Dawley rats fed high-fat diet were administered streptozotocin (45 mg·kg(-1), ip, n = 23) to induce diabetes or vehicle alone (n = 6). Diabetic rats were randomized to receive insulin (4 U·day(-1)), metformin (650 mg·kg(-1)·day(-1)), rosiglitazone (4 mg·kg(-1)·day(-1)), or no treatment 1 week after streptozotocin. Small animal PET imaging using the norepinephrine analog [(11)C]meta-hydroxyephedrine (HED) at baseline and 8 weeks of diabetes determined sympathetic neuronal integrity. Echocardiography assessed cardiac function. Plasma norepinephrine levels were determined in parallel. Ex vivo immunoblotting was performed at the end of the experiment to compare the relative expression of various proteins involved in metabolic and noradrenergic signaling. Insulin restored blood glucose and lipid levels to normal. Despite improved plasma lipid levels, neither metformin nor rosiglitazone reduced blood glucose. At 8 weeks, untreated and treated diabetics displayed a 39%-42% reduction in myocardial HED standardized uptake values (P < .05). In all diabetic groups, plasma norepinephrine was elevated (2.3- to 3.3-fold, P < .05) and norepinephrine reuptake transporter expression reduced (28%-35%, P < .05) compared to non-diabetics. Doppler echocardiography revealed delayed development of prolonged mitral valve deceleration and elevated early-to-atrial filling velocity ratio among treated diabetic rats., Conclusion: Early glycemic treatment of insulin-resistant diabetic rats did not prevent deterioration of sympathetic neuronal integrity though ventricular filling abnormalities were delayed.

Background: Diabetes is associated with increased sympathetic activity, elevated norepinephrine, impaired heart rate variability, and the added risk of cardiovascular mortality. The temporal development of sympathetic neuronal dysfunction, response to therapy, and relation to ventricular function is not well characterized., Methods and Results: Sympathetic neuronal integrity was serially investigated in high fat diet-fed streptozotocin diabetic rats using [(11)C]meta-hydroxyephedrine (HED) positron emission tomography at baseline, 8 weeks of diabetes, and after a further 8 weeks of insulin or insulin-sensitizing metformin therapy. Myocardial HED retention was reduced in diabetic rats (n = 16) compared to non-diabetics (n = 6) at 8 weeks by 52-57% (P = .01) with elevated plasma and myocardial norepinephrine levels. Echocardiography pulse-wave Doppler measurements demonstrated prolonged mitral valve deceleration and increased early-to-atrial filling velocity, consistent with diastolic dysfunction. Insulin but not metformin evoked recovery of HED retention and plasma norepinephrine (P < .05), whereas echocardiography measurements of diastolic function were not improved by either treatment. Relative expressions of norepinephrine reuptake transporter and β-adrenoceptors were lower in metformin-treated as compared to insulin-treated diabetic and non-diabetic rats. Diabetic rats exhibited depressed heart rate variability and impaired diastolic function which persisted despite insulin treatment., Conclusions: HED imaging provides sound estimation of sympathetic function. Effective glycemic control can recover sympathetic function in diabetic rats without the corresponding recovery of echocardiography indicators of diastolic dysfunction. HED positron emission tomography imaging may be useful in stratifying cardiovascular risk among diabetic patients and in evaluating the effect of glycemic therapy on the heart.

Background: Diabetes mellitus is strongly associated with cardiovascular dysfunction, derived in part from impairment of sympathetic nervous system signaling. Glucose, insulin, and non-esterified fatty acids are potent stimulants of sympathetic activity and norepinephrine (NE) release. We hypothesized that sustained hyperglycemia in the high fat diet-fed streptozotocin (STZ) rat model of sustained hyperglycemia with insulin resistance would exhibit progressive sympathetic nervous dysfunction in parallel with deteriorating myocardial systolic and/or diastolic function., Methods: Cardiac sympathetic nervous integrity was investigated in vivo via biodistribution of the positron emission tomography radiotracer and NE analogue [11C]meta-hydroxyephedrine ([11C]HED). Cardiac systolic and diastolic function was evaluated by echocardiography. Plasma and cardiac NE levels and NE reuptake transporter (NET) expression were evaluated as correlative measurements., Results: The animal model displays insulin resistance, sustained hyperglycemia, and progressive hypoinsulinemia. After 8 weeks of persistent hyperglycemia, there was a significant 13-25% reduction in [11C]HED retention in myocardium of STZ-treated hyperglycemic but not euglycemic rats as compared to controls. There was a parallel 17% reduction in immunoblot density for NE reuptake transporter, a 1.2 fold and 2.5 fold elevation of cardiac and plasma NE respectively, and no change in sympathetic nerve density. No change in ejection fraction or fractional area change was detected by echocardiography. Reduced heart rate, prolonged mitral valve deceleration time, and elevated transmitral early to atrial flow velocity ratio measured by pulse-wave Doppler in hyperglycemic rats suggest diastolic impairment of the left ventricle., Conclusions: Taken together, these data suggest that sustained hyperglycemia is associated with elevated myocardial NE content and dysregulation of sympathetic nervous system signaling in the absence of systolic impairment.

Background: Altered sympathetic nervous system signaling is known to play a role in the cardiotoxicity of the anthracycline chemotherapeutic agents, but the interaction of pre- and postsynaptic function is not well understood., Methods and Results: Our aim was to study the noradrenergic signaling in an established rat model of adriamycin cardiotoxicity (15 mg/kg administered i.p. over 2 weeks) using radiotracers having potential applicability for imaging with positron emission tomography (PET). Ex vivo biodistribution was performed 1 and 3 weeks post-adriamycin treatment with the noradrenaline analogue [(11)C]meta-hydroxyephedrine ([(11)C]HED), beta-adrenergic receptor antagonist [(3)H]CGP12177, and phosphodiesterase-4 inhibitor (R)-[(11)C]rolipram. Cardiac function (echocardiographic parameters) and heart/body weight ratio were not affected. Myocardial retention of [(11)C]HED, [(3)H]CGP12177, and (R)-[(11)C]rolipram were unchanged 1 week post-adriamycin. Compared to controls, 3 weeks post-treatment [(3)H]CGP12177 uptake decreased (left ventricle free wall and septum; P < 0.05), while [(11)C]HED and (R)-[(11)C]rolipram uptake were unaffected. Following acute increase in myocardial noradrenaline levels with desipramine treatment, (R)-[(11)C]rolipram retention increased in the left atrium, right ventricle, left ventricle free wall and septum (P < 0.05) in vehicle-, but not adriamycin-treated animals., Conclusion: Our results suggest that adriamycin-induced toxicity exhibits no change in presynaptic noradrenaline uptake, but decreased beta-adrenergic receptors in cardiac tissues, supporting a role for PET imaging of noradrenaline signaling in the study of anthracycline cardiotoxicity.

Purpose: Cardiac sympathetic nervous system (SNS) dysfunction is associated with poor prognosis in chronic heart failure patients. This study characterized the reproducibility and repeatability of [11C]meta-hydroxyephedrine (HED) positron emission tomography (PET) quantification of cardiac SNS innervation, regional denervation, and myocardial blood flow (MBF). Methods: Dynamic HED PET-CT scans were performed 47 ± 22 days apart in 20 patients with stable heart failure and reduced ejection fraction. Three observers, blinded to clinical data, used FlowQuant® to evaluate the test-retest repeatability and inter- and intra-observer reproducibility of HED tracer uptake and clearance rates to measure global (LV-mean) retention index (RI), volume of distribution (VT), and MBF. Values were also compared with and without regional partial-volume correction. Regional denervation was quantified as %LV defect size of values < 75% of the LV-maximum. Test-retest repeatability and observer reproducibility were evaluated using intra-class-correlation (ICC) and Bland-Altman coefficient of repeatability (NPC). Results: Intra- and inter-observer correlations of both VT and RI were excellent (ICC = 0.93–0.99). Observer reproducibility (NPC = 3–13%) was lower than test-retest repeatability (NPC = 12–61%). Both regional (%LV defect size) and global (LV-mean) measures of sympathetic innervation were more repeatable using the simple RI model compared to VT (NPC = 12% vs. 19% and 30% vs. 54%). Using either model, quantification of regional denervation (defect size) was consistently more reliable than the global LV-mean values of RI or VT. Regional partial-volume correction degraded repeatability of both the global and regional VT measures by 2–12%. Test-retest repeatability of MBF estimation was relatively poor (NPC = 30–61%) compared with the RI. Conclusions: Quantitative measures of global and regional SNS innervation were most repeatable using the simple RI method of analysis compared with the more complex VT. Observer variability was significantly lower than the test-retest repeatability using a highly automated analysis program. These results support the use of the simple RI method for reliable analysis of HED PET images in clinical research studies for future evaluation of new therapies and for risk stratification in patients with heart failure. [ABSTRACT FROM AUTHOR]

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The article provides information on a study which assessed in vivo myocardial sympathetic nervous system (SNS) innervation in rats with type II diabetes mellitus (DM). Pretreatment with the uptake-I inhibitor desipramine was used to determine specific retention of [11C]meta-hydroxyephedrine (HED) which measures presynaptic SNS innervation. The findings show the presence of cardiac SNS dysinnervation in type II diabetic rats.

Aims Reduced cardiac β-adrenoceptors (β-AR) and cardiovascular (CV) dysfunction occur in diabetes mellitus (DM) and can be normalized by insulin. It is unclear how the duration of untreated hyperglycemia prior to intervention impacts insulin's effects. This study assesses insulin's effect on reduced myocardial β-AR and CV function, comparing insulin therapy at the onset of hyperglycemia and after a sustained period of hyperglycemia in streptozotocin (STZ) rats. Main methods Ex vivo biodistribution experiments with [ 3 H]CGP12177 were performed in high-fat fed STZ rats after 8 weeks of hyperglycemia evaluating cardiac β-AR expression. Western blotting of β-AR subtypes was completed in parallel. Serial echocardiography at 0, 6, and 8 weeks post-STZ investigated CV function. Sub-groups of hyperglycemic rats were treated with insulin early, at 1 week post-STZ (InsE) for 7 weeks, or late at 6 weeks post-STZ (InsL) for 2 weeks to observe how the duration of hyperglycemia prior to insulin impacts its effects. Key findings Reduced myocardial [ 3 H]CGP12177 binding occurred 8 weeks post-STZ in hyperglycemics, but was normal in both insulin treatments. Western blotting supported reduced β 1 -AR in hyperglycemics, but not in either treatment. InsE and InsL treatments improved prolonged mitral valve deceleration (MVD) observed in hyperglycemic animals, but hyperglycemic and InsL still displayed reduced heart rates (HR). Significance This work supports that glycemic control with insulin normalizes cardiac β-AR effectively regardless of prior hyperglycemia but HR may not recover as readily, indirectly supporting the utility of [ 11 C]CGP12177 positron emission tomography (PET) in assessing cardiac β-AR and their modulation with glycemic therapy. [ABSTRACT FROM AUTHOR]