Cardiac Innervation Research Articles

Vasovagal syncope: poorly understood, but well handled

This editorial refers to ‘Cardiac autonomic disturbances in patients with vasovagal syndrome: comparison between iodine-123-metaiodobenzylguanidine myocardial scintigraphy and heart rate variability’ by G. Kochiadakis et al ., on page 1352 In this issue of the Journal, Kochiadakis and co-workers from Heraklion University Hospital in Athens report on autonomic regulation in patients with vasovagal syncope (VVS) diagnosed with tilt table testing.1 They measured heart rate variability (HRV) and assessed cardiac sympathetic innervation using 123-I-meta-iodobenzylguanidine (MIBG) scintigraphy. The main finding of this study was that adrenergic cardiac innervation showed defects in the left ventricle in patients with VVS. This finding was not associated with the type of response (cardioinhibitory or vasodepressor) during tilt table testing. However, the study critics may object that the infrequent blood pressure measurements rather than continuous non-invasive blood pressure measurement during tilt table testing did not allow the accurate classification of the response. In contrast to this finding, HRV, as a marker of the resulting efferent vasomotor activity at the level …

Ontogeny of Cardiac Sympathetic Innervation and Its Implications for Cardiac Disease

The vertebrate heart is innervated by the sympathetic and parasympathetic components of the peripheral autonomic nervous system, which regulates its contractile rate and force. Understanding the mechanisms that control sympathetic neuronal growth, differentiation, and innervation of the heart may provide insight into the etiology of cardiac arrhythmogenesis. This review provides an overview of the cell signaling pathways and transcriptional effectors that regulate both the noradrenergic gene program during sympathetic neurogenesis and regional nerve density during cardiac innervation. Recent studies exploring transcriptional regulation of the bHLH transcription factor Hand1 in developing sympathetic neurons are explored, and how the Hand1 sympathetic neuron-specific cis-regulatory element may be used further to assess the contribution of altered sympathetic innervation to human cardiac disease is discussed.

Protocolo diagnóstico del dolor torácico con sospecha de origen esofágico

Chest pain with esophageal origin is a symptom whose prevalence is over 10% in our setting. Esophageal and cardiac innervation have common nociceptive pathways and characteristics that require a differential diagnosis for cardiac causes, fundamentally of the ischemic heart disease, in many of the cases. Among the digestive causes, the most frequent are gastroesophageal reflux, esophageal motor disorders and esophageal hyperalgesia. However, a differential diagnosis should be made of other conditions, such as musculoskeletal disorders and pulmonary diseases. The clinical history followed by physical examination will orient the diagnostic decision making, it being possible to choose a treatment test period with high proton pump inhibitors for 1–4 weeks in the mild cases. This will help to discriminate some cases of gastroesophageal reflux disease (GERD) and will avoid the following complementary tests that include oral panendoscopy, 24–48 hour esophageal pHmetry and/or impedance pHmetry, stimulation tests combined with the esophageal manometry that will lead to the final diagnosis in most of the cases.

Cardiac Function, Perfusion, Metabolism, and Innervation following Autologous Stem Cell Therapy for Acute ST-Elevation Myocardial Infarction. A FINCELL-INSIGHT Sub-Study with PET and MRI

Purpose: Beneficial mechanisms of bone marrow cell (BMC) therapy for acute ST-segment elevation myocardial infarct (STEMI) are largely unknown in humans. Therefore, we evaluated the feasibility of serial positron emission tomography (PET) and MRI studies to provide insight into the effects of BMCs on the healing process of ischemic myocardial damage. Methods: Nineteen patients with successful primary reteplase thrombolysis (mean 2.4 h after symptoms) for STEMI were randomized for BMC therapy (2.9 × 106 CD34+ cells) or placebo after bone marrow aspiration in a double-blind, multi-center study. Three days post-MI, coronary angioplasty, and paclitaxel eluting stent implantation preceded either BMC or placebo therapy. Cardiac PET and MRI studies were performed 7–12 days after therapies and repeated after 6 months, and images were analyzed at a central core laboratory. Results: In BMC-treated patients, there was a decrease in [11C]-HED defect size (−4.9 ± 4.0 vs. −1.6 ± 2.2%, p = 0.08) and an increase in [18F]-FDG uptake in the infarct area at risk (0.06 ± 0.09 vs. −0.05 ± 0.16, p = 0.07) compared to controls, as well as less left ventricular dilatation (−4.4 ± 13.3 vs. 8.0 ± 16.7 mL/m2, p = 0.12) at 6 months follow-up. However, BMC treatment was inferior to placebo in terms of changes in rest perfusion in the area at risk (−0.09 ± 0.17 vs. 0.10 ± 0.17, p = 0.03) and infarct size (0.4 ± 4.2 vs. −5.1 ± 5.9 g, p = 0.047), and no effect was observed on ejection fraction (p = 0.37). Conclusion: After the acute phase of STEMI, BMC therapy showed only minor trends of long-term benefit in patients with rapid successful thrombolysis. There was a trend of more decrease in innervation defect size and enhanced glucose metabolism in the infarct-related myocardium and also a trend of less ventricular dilatation in the BMC-treated group compared to placebo. However, no consistently better outcome was observed in the BMC-treated group compared to placebo.

Detailed Comparative Anatomy of the Extrinsic Cardiac Nerve Plexus and Postnatal Reorganization of the Cardiac Position and Innervation in the Great Apes: Orangutans, Gorillas, and Chimpanzees

To speculate how the extrinsic cardiac nerve plexus (ECNP) evolves phyletically and ontogenetically within the primate lineage, we conducted a comparative anatomical study of the ECNP, including an imaging examination in the great apes using 20 sides from 11 bodies from three species and a range of postnatal stages from newborns to mature adults. Although the position of the middle cervical ganglion (MG) in the great apes tended to be relatively lower than that in humans, the morphology of the ECNP in adult great apes was almost consistent with that in adult humans but essentially different from that in the lesser apes or gibbons. Therefore, the well-argued anatomical question of when did the MG acquire communicating branches with the spinal cervical nerves and appear constantly in all sympathetic cardiac nerves during primate evolution is clearly considered to be after the great apes and gibbons split. Moreover, a horizontal four-chambered heart and a lifted cardiac apex with a relatively large volume in newborn great apes rapidly changed its position downward, as seen in humans during postnatal growth and was associated with a reduction in the hepatic volume by imaging diagnosis and gross anatomy. In addition, our observation using a range of postnatal stages exhibits that two sympathetic ganglia, the middle cervical and cervicothoracic ganglia, differed between the early and later postnatal stages.

Abstract 8823: Abnormal Cardiac Innervation in Ventricular Fibrillation Patients with and Without Brugada Syndrome

Abnormal cardiac innervation in patients with ventricular fibrillation (VF) has been reported. We investigated autonomic function in 48 successfully resuscitated VF patients using heart rate variability (HRV) as measured by Holter ECG and 123 I-metaiodobenzylguanidine ( 123 I-MIBG) scintigraphy. Eight patients were excluded because of hypertrophic cardiomyopathy (N = 2), arrhythmogenic right ventricular cardiomyopathy (N = 3), catecholamine-sensitive ventricular tachycardia (N = 1), and long QT syndrome (N = 2). Patients who could not discontinue internal remedies (N = 5) were also excluded. Fifteen patients (42 ± 14 years, 15 males) were diagnosed with Brugada syndrome (BS), and the remaining 20 patients (47 ± 6 years, 8 males) were diagnosed with idiopathic VF (IVF). QTc time was longer in the IVF patients than in the BS patients (450.1 ± 10.1 ms vs. 389.4 ± 21.0 ms, P < 0.05). RMS40 was lower in the BS patients than in the IVF patients (13.9 ± 2.2 mV vs. 20.9 ± 3.6 mV, P < 0.05). Parameters of HRV were similar in both groups, but abnormal circadian variations of HRV were observed in 53.3% of BS patients and 13.3% of IVF patients. The washout ratio was higher in the IVF patients than in the BS patients (36.3 ± 4.3 vs. 26.0 ± 2.1). The 123 I-MIBG uptake was increased in lateral regions in BS patients. Regionally reduced 123 I-MIBG uptake was observed with many variations in all patients, but no significant difference was observed between groups. These results demonstrated impairment of sympathetic innervation or enhanced activity of the sympathetic nervous system in patients with VF, particularly indicating sympathetic hypertonia in IVF and imbalance of circadian HRV in BS. These findings may have an impact on the arrhythmogenesis of such patients.

Sudden cardiac death in multiple sclerosis caused by active demyelination of the medulla oblongata

Cardiovascular autonomic dysfunction is not uncommon in multiple sclerosis (MS) and is related to the involvement of the vegetative areas of cardiac innervations in the medulla oblongata. It has been suggested that this may contribute to the occurrence of sudden death in MS. In this case report, we present a patient with active relapsing–remitting MS who died unexpectedly due to the sudden onset of cardiac arrythmias. Post-mortem examination showed the presence of active demyelinating lesions in the medulla oblongata. As far as we know, this is the first case report clearly linking sudden cardiac death to active MS on the histopathological level.

Diagnostic Accuracy of Combined FP-CIT, IBZM, and MIBG Scintigraphy in the Differential Diagnosis of Degenerative Parkinsonism: A Multidimensional Statistical Approach

In vivo molecular imaging of pre- and postsynaptic nigrostriatal neuronal degeneration and sympathetic cardiac innervation with SPECT is used to distinguish idiopathic Parkinson disease (PD) from atypical parkinsonian disorder (APD). However, the diagnostic accuracy of these imaging approaches as stand-alone procedures is often unsatisfying. The aim of this study was therefore to evaluate to which extent diagnostic accuracy can be increased by their combined use together with a multidimensional statistical algorithm. The SPECT radiotracers (123)I-(S)-2-hydroxy-3-iodo-6-methoxy-N-[1-ethyl-2-pyrrodinyl)-methyl]benzamide (IBZM), (123)I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropan (FP-CIT), and meta-(123)I-iodobenzylguanidine (MIBG) were used to assess striatal postsynaptic D(2) receptor binding, striatal presynaptic dopamine transporter binding, and myocardial adrenergic innervation, respectively. Thirty-one PD and 17 APD patients were prospectively investigated. PD and APD diagnoses were established using consensus criteria and reevaluated after 37.4 ± 12.4 and 26 ± 11.6 mo in PD and APD, respectively. Test accuracy (TA) for PD-APD differentiation was computed for all logical (Boolean) combinations of imaging modalities by receiver-operating-characteristic analysis--that is, after multidimensional optimization of cutoff values. Analysis showed moderate TA for PD-APD differentiation using each molecular approach alone (IBZM, 79%; MIBG, 73%; and FP-CIT, 73%). For combined use, the highest TA resulted under the assumption that at least 2 of the 3 biologic markers had to be positive for APD using the following cutoff values: 1.46 or less for IBZM, less than 2.10 for FP-CIT, and greater than 1.43 for MIBG. This algorithm distinguished APD from PD with a sensitivity of 94%, specificity of 94% (TA, 94%), positive predictive value of 89%, and negative predictive value of 97%. Results suggest that the multidimensional combination of FP-CIT, IBZM, and MIBG scintigraphy is likely to significantly increase TA in differentiating PD from APD. The differential diagnosis of degenerative parkinsonism may thus be facilitated.

Adrenergic effects on force-frequency relationship: a pivotal role for the cardiac intrinsic systems

The force-frequency relationship (F-FR) is an important intrinsic regulatory mechanism of cardiac contractility. The involvement of autonomic nervous system in this physiological aspect of cardiac control remains unclear. The aim of the study was to evaluate the role of extrinsic and intrinsic cardiac adrenergic innervations on the heart rate (HR)-related positive inotropic response. Twenty-four dogs were anesthetized and acutely instrumented to monitor and record ECG, systemic and left ventricular pressures and derivatives, and to pace the heart at 130, 150, 170, 190 and 210 bpm, in order to construct the F-FR curve. Animals were randomly assigned to four groups (n = 6 each): vehicle (V), ganglion-blocked (G-B), β-blocked (β-B) and ganglion-blocked plus β-blocked (G-B + β-B). Vehicle treated animals presented the classical F-FR. In the β-B group F-FR was blunted, but never fully suppressed. The G-B treated animals showed a bell-shape response curve of the induced inotropic effect with the zenith at 170 bpm: the first part of the curve resembling the control one, followed by a rapid decline toward baseline value. The co-administration of G-B and β-B agents reversed the contractile response to HR rise with a curve resembling the negative F-FR curve observed in the failing heart. The F-FR appeared to be constituted by two consecutive mechanisms: first depolarization-rate dependent, and a second catecholamine-dependent. The natural consequence of these observations is that the full expression of F-FR needs an intact adrenergic system.

A region-specific quantitative profile of autonomic innervation of the canine left atrium and pulmonary veins

The aim of the present study was to determine and quantify the cardiac autonomic innervation of the canine atria and pulmonary vein. Tissue specimens were taken from the canine pulmonary veins (PVs), posterior left atrium (PLA), left atrial roof (LAR), anterior left atrium (ALA), interatrial septum (IAS), and left atrial appendage (LAA) respectively for immunohistochemical analysis and nerve density determination. Both sympathetic and parasympathetic nerve densities decreased in the order: PLA>PV>IAS>LAR>ALA>LAA. For sympathetic nerve, multiple comparisons between any two regions showed a significant difference (P<0.05–P<0.01) except for PV vs. PLA, IAS vs. LAR, and LAR vs. ALA; for parasympathetic nerve, all the differences between any pair of regions were statistically significant (P<0.05–P<0.01) with the exception of PV vs. PLA, IAS vs. LAR, LAR vs. ALA, and ALA vs. LAA. For both nerve types, there was a decreasing gradient of nerve densities from the external to internal layer (P<0.001, for each comparisons). Nerve density at the ostia for either nerve type was significantly higher than at the distal segments of PVs (P<0.001). In summary, the LA and PVs are innervated by sympathetic and parasympathetic nerves in a regionally heterogeneous way, which may be important for the pathophysiological investigation and ablation therapy of atrial fibrillation (AF).

Remodeling of cardiac cholinergic innervation and control of heart rate in mice with streptozotocin-induced diabetes

Cardiac autonomic neuropathy is a frequent complication of diabetes and often presents as impaired cholinergic regulation of heart rate. Some have assumed that diabetics have degeneration of cardiac cholinergic nerves, but basic knowledge on this topic is lacking. Accordingly, our goal was to evaluate the structure and function of cardiac cholinergic neurons and nerves in C57BL/6 mice with streptozotocin-induced diabetes. Electrocardiograms were obtained weekly from conscious control and diabetic mice for 16weeks. Resting heart rate decreased in diabetic mice, but intrinsic heart rate was unchanged. Power spectral analysis of electrocardiograms revealed decreased high frequency and increased low frequency power in diabetic mice, suggesting a relative reduction of parasympathetic tone. Negative chronotropic responses to right vagal nerve stimulation were blunted in 16-week diabetic mice, but postjunctional sensitivity of isolated atria to muscarinic agonists was unchanged. Immunohistochemical analysis of hearts from diabetic and control mice showed no difference in abundance of cholinergic neurons, but cholinergic nerve density was increased at the sinoatrial node of diabetic mice (16weeks: 14.9±1.2% area for diabetics versus 8.9±0.8% area for control, P<0.01). We conclude that disruption of cholinergic function in diabetic mice cannot be attributed to a loss of cardiac cholinergic neurons and nerve fibers or altered cholinergic sensitivity of the atria. Instead, decreased responses to vagal stimulation might be caused by a defect of preganglionic cholinergic neurons and/or ganglionic neurotransmission. The increased density of cholinergic nerves observed at the sinoatrial node of diabetic mice might be a compensatory response.

Artificial gravity with ergometric exercise as a countermeasure against cardiovascular deconditioning during 4 days of head-down bed rest in humans

We have shown previously that combined short-arm centrifuge and aerobic exercise training preserved several physiologically important cardiovascular functions in humans. We hypothesized that artificial gravity (AG) and exercise is effective to prevent changes of physical problems during head-down bed rest (HDBR). To test this hypothesis, 12 healthy male subjects had undergone 4 days of 6° HDBR. Six of them were exposed to AG of an alternating 2-min intervals of +1.0 and +2.0 Gz at foot level for 30 min twice per day with ergometric exercise of 40 W as a countermeasure during bed rest (CM group), while the remaining six served as untreated controls (no-CM group). Before and after 4 days of bed rest, leg venous hemodynamics was assessed by venous occlusion plethysmography and autonomic cardiovascular control estimated by power spectral analysis of blood pressure and heart rate. Further, orthostatic tolerance was evaluated by a 75° head-up tilt test and physical working capacity was surveyed by near maximal physical working capacity test before and after bed rest. The data showed that combined centrifuge and exercise applied twice daily for a total of 60 min during 4 days of HDBR prevented (a) a decrease in working capacity, (b) autonomic dysfunction (a decrease in the activity of parasympathetic cardiac innervation) and (c) an increase in leg venous flow resistance. The combination of a 30 min alternating of +1.0 and +2.0 Gz for twice per day of AG with 40 W ergometric exercise may offer a promising countermeasure to short duration simulated microgravity.

Low frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation

Power spectral analysis of heart rate variability is used to assess cardiac autonomic function. The relationship of low frequency (LF) power to cardiac sympathetic tone has been unclear. We reported previously that LF power may reflect baroreflex modulation. In this study we attempted to replicate our findings in additional subject cohorts, taking into account possible influences of respiration and using different methods to measure baroreflex-cardiovagal gain (BCG). We assessed relationships of LF power, including respiration-adjusted LF power (LFa), with cardiac sympathetic innervation and baroreflex function in subjects with or without neuroimaging evidence of cardiac sympathetic denervation. Values for LF power at baseline supine, seated, and during the Valsalva maneuver were compared between subject groups with low or normal myocardial concentrations of 6-[(18)F]fluorodopamine-derived radioactivity. BCG was calculated from the slope of cardiac interbeat interval vs. systolic pressure during Phase II of the Valsalva maneuver or after i.v. nitroglycerine injection (the Oxford technique). LF and LFa were unrelated to myocardial 6-[(18)F]fluorodopamine-derived radioactivity. During sitting rest and the Valsalva maneuver logs of LF and LFa correlated positively with the log of Phase II BCG (r = 0.61, p = 0.0005; r = 0.47, p = 0.009; r = 0.69, p < 0.0001; r = 0.60, p = 0.0006). Groups with Low BCG (≤ 3 ms/mmHg) had low LF and LFa regardless of cardiac innervation. The log of LF power during supine rest correlated with the log of Oxford BCG (r = 0.74, p < 0.0001). LF power, with or without respiratory adjustment, reflects baroreflex modulation and not cardiac sympathetic tone.

Autres applications de la MIBG : « applications de la scintigraphie de l’innervation myocardique à la 123-I-MIBG en neurologie »

Myocardial 123-I-metaiodobenzylguanidine (MIBG) imaging enables the assessment of postganglionic sympathetic cardiac innervation. Recently myocardial 123-I-MIBG scintigraphy has been found to be useful to distinguishing Parkinsońs disease (PD) from other akinetic rigid syndromes. The absence of published guidelines for cardiac 123-I-MIBG imaging makes standardization of procedures among individual users of this technique even more important. Cardiac MIBG study showed markedly decreased uptake in PD, dementia with Lewy bodies (DLB) and pure autonomic failure, which is a common feature of Lewy body disease. The cardiac MIBG uptake is severely impaired even in the early disease stage. Atypical parkinsonian syndromes, including Multiple System Atrophy, Progressive Supranuclear Palsy, and other, show modest reduction of cardiac MIBG uptake. The MIBG study can be used for differentiating patients with extrapyramidal signs and dementia, and might provide useful diagnostic information to discriminate DLB and Alzheimeŕs disease.

Cardiac Sympathetic Neuroimaging in Dementia with Lewy Bodies

J Neuroimaging 2012;22:109‐110.

The role of nuclear imaging in the failing heart: myocardial blood flow, sympathetic innervation, and future applications

Heart failure represents a common disease affecting approximately 5 million patients in the United States. Several conditions play an important role in the development and progression of heart failure, including abnormalities in myocardial blood flow and sympathetic innervation. Nuclear imaging represents the only imaging modality with sufficient sensitivity to assess myocardial blood flow and sympathetic innervation of the failing heart. Although nuclear imaging with single-photon emission computed tomography (SPECT) is most commonly used for the evaluation of myocardial perfusion, positron emission tomography (PET) allows absolute quantification of myocardial blood flow beyond the assessment of relative myocardial perfusion. Both techniques can be used for evaluation of diagnosis, treatment options, and prognosis in heart failure patients. Besides myocardial blood flow, cardiac sympathetic innervation represents another important parameter in patients with heart failure. Currently, sympathetic nerve imaging with 123-iodine metaiodobenzylguanidine (123-I MIBG) is often used for the assessment of cardiac innervation. A large number of studies have shown that an abnormal myocardial sympathetic innervation, as assessed with 123-I MIBG imaging, is associated with increased mortality and morbidity rates in patients with heart failure. Also, cardiac 123-I MIBG imaging can be used to risk stratify patients for ventricular arrhythmias or sudden cardiac death. Furthermore, novel nuclear imaging techniques are being developed that may provide more detailed information for the detection of heart failure in an early phase as well as for monitoring the effects of new therapeutic interventions in patients with heart failure.

Differential heart rate dynamics in transient left ventricular apical and midventricular ballooning

The aim of the present study was to assess potential differences in cardiac autonomic nervous modulation in patients with transient left ventricular apical ballooning syndrome (AB) and the midventricular variant (MB) of this syndrome. We hypothesized that differences in regional distribution of cardiac autonomic innervation in AB and MB may induce alterations in autonomic modulation, and we tested this assumption by using a combination of traditional and novel nonlinear parameters of heart rate variability (HRV). In a prospective single-center study, 49 consecutive patients with transient left ventricular dysfunction syndrome underwent Holter electrocardiographic recording on the third day after admission. A total of 27 recordings of patients with AB and 10 recordings of patients with MB were valid for analysis of HRV, nonlinear dynamic measures of HRV, detrended fluctuation analysis (DFA), and phase-rectified signal averaging (PRSA). There were no significant differences in baseline clinical characteristics between AB and MB patients. Patients with MB showed significantly lower values for mean RR interval (835 ± 104 ms vs. 908 ± 118 ms; P < .05), 1/f power law slope (-1.28 ± 0.2 vs. -1.13 ± 0.2; P < .01), and deceleration capacity (DC) (4.6 ± 1.4 ms vs. 6.0 ± 1.4 ms; P < .01), and significantly higher values for low-frequency (LF) spectral component (5.3 ± 0.5 ln ms(2)/Hz vs. 4.8 ± 0.5 ln ms(2)/Hz), LF/high-frequency (HF) (1.7 ± 0.9 ms vs. 1.3 ± 0.6 ms; P < .05), and DFA α1 (1.09 ± 0.1 vs. 0.99 ± 0.1; P < .01) than patients with AB. There were no significant correlations between parameters of HRV, DFA, 1/f power law slope, and PRSA. There are significant differences in heart rate dynamics between AB and MB syndromes. Patients with MB show stronger fractal correlations of heart rate dynamics. Thus, inhomogeneous efferent bilateral sympathetic coactivation and differences in reflex autonomic regulation may be underlying pathophysiological mechanisms for AB and MB syndromes.

EP News: Clinical

Boogers et al (J Am Coll Cardiol 2010;55:2769–2777, PMID 20538172) evaluated whether 123-iodine metaiodobenzylguanidine (123-I MIBG) imaging predicts ventricular arrhythmias causing appropriate implantable cardioverter-defibrillator (ICD) therapy (primary endpoint) and the composite of appropriate ICD therapy or cardiac death (secondary endpoint). Early and late 123-I MIBG imaging was performed to assess cardiac innervation. Appropriate ICD therapy was documented in 24 (21%) of 116 patients and appropriate ICD therapy or cardiac death in 32 (28%) patients. Late 123-I MIBG SPECT defect score was an independent predictor for both endpoints. Patients with a large late 123-I MIBG SPECT defect (summed score >26) showed significantly more appropriate ICD therapy (52% vs 5%, P <.01) and appropriate ICD therapy or cardiac death (57% vs 10%, P <.01) than did patients with a small defect (summed score ≤26) at 3-year follow-up. The authors conclude that cardiac sympathetic denervation predicts ventricular arrhythmias causing appropriate ICD therapy as well as the composite of appropriate ICD therapy or cardiac death.

Molecular Imaging of Cardiac Sympathetic Innervation by 11C-mHED and PET: From Man to Mouse?

Dysfunction of the sympathetic nervous system underlies many cardiac diseases and can be assessed by molecular imaging using PET in humans. Small-animal PET should enable noninvasive quantitation of the sympathetic nervous system in mouse models of human disease. For mice, however, the radioactivity needed to give acceptable image quality may be associated with a mass of unlabeled compound sufficient to block the binding of radioligand to its target. The present study assesses the feasibility of using [N-methyl-(11)C]meta-hydroxyephedrine ((11)C-mHED) to measure norepinephrine reuptake in humans, to determine cardiac innervation in mice. Anesthetized mice were placed in a small-animal PET scanner. (11)C-mHED (containing 18% precursor metaraminol) was injected via a tail vein into each animal simultaneously. Fifteen minutes later, animals were injected with saline or metaraminol which competes with mHED for norepinephrine reuptake. (18)F-FDG was injected at 60 min to identify heart regions. After reconstruction of the list-mode data, radioactivity in myocardial regions was computed using in-house software, and time-activity curves were plotted. Hearts were clearly visualized after injection of (11)C-mHED. Injection of metaraminol at doses less than 50 nmol x kg(-1) had no effect, whereas doses greater than 100 nmol x kg(-1) caused a dose-dependent loss of specifically bound radioactivity. (11)C-mHED was successfully used to visualize and assess myocardial innervation in mice. Uptake of (11)C-mHED is displaceable by the false transmitter metaraminol. The total molar dose of metaraminol and (11)C-mHED must be considered in the analysis of PET data.

Cardiac Sympathetic Denervation Assessed With 123-Iodine Metaiodobenzylguanidine Imaging Predicts Ventricular Arrhythmias in Implantable Cardioverter-Defibrillator Patients

The purpose of this study was to evaluate whether 123-iodine metaiodobenzylguanidine (123-I MIBG) imaging predicts ventricular arrhythmias causing appropriate implantable cardioverter-defibrillator (ICD) therapy (primary end point) and the composite of appropriate ICD therapy or cardiac death (secondary end point). Although cardiac sympathetic denervation is associated with ventricular arrhythmias, limited data are available on the predictive value of sympathetic nerve imaging with 123-I MIBG on the occurrence of arrhythmias. Before ICD implantation, patients underwent 123-I MIBG and myocardial perfusion imaging. Early and late 123-I MIBG (planar and single-photon emission computed tomography [SPECT]) imaging was performed to assess cardiac innervation (heart-to-mediastinum ratio, cardiac washout rate, and 123-I MIBG SPECT defect score). Stress-rest myocardial perfusion imaging was performed to assess myocardial infarction and perfusion abnormalities (perfusion defect scores). During follow-up, appropriate ICD therapy and cardiac death were documented. One-hundred sixteen heart failure patients referred for ICD therapy were enrolled. During a mean follow-up of 23 +/- 15 months, appropriate ICD therapy (primary end point) was documented in 24 (21%) patients and appropriate ICD therapy or cardiac death (secondary end point) in 32 (28%) patients. Late 123-I MIBG SPECT defect score was an independent predictor for both end points. Patients with a large late 123-I MIBG SPECT defect (summed score >26) showed significantly more appropriate ICD therapy (52% vs. 5%, p < 0.01) and appropriate ICD therapy or cardiac death (57% vs. 10%, p < 0.01) than patients with a small defect (summed score </=26) at 3-year follow-up. Cardiac sympathetic denervation predicts ventricular arrhythmias causing appropriate ICD therapy as well as the composite of appropriate ICD therapy or cardiac death.