Myocardial Sympathetic Nerve Function Research Articles

Determination of Impurities and Degradation Products/Causes for <i>m</i>-Iodobenzylguanidine Using HPLC-Tandem Mass Spectrometry

m-Iodobenzylguanidinium hemisulfate (MIBGHS) is a precursor in the preparation of radioiodine-labeled m-iodobenzylguanidine (MIBG), which is used as a radio-imaging and therapy agent for neuroendocrine tumors and myocardial sympathetic nerve function. To ensure the quality and efficacy of the medicine and prevent side effects, the precursor purity, source of impurity, and derivatives have to be determined. In this study, the purity of synthesized MIBGHS and the amount of contaminants therein were determined by high-performance liquid chromatography and ultraviolet detection, gradient eluted by ammonium formate aqueous solution and acetonitrile mobile phase on both C8 and phenyl type column. The impurities were identified on the basis of molecular and fragmented ion mass spectra using of electrospray ionization triple quadrupole tandem mass spectrometry. The results revealed the presence of process-related impurities including m-bromobenzylguanidine (MBrBG) and overreacted byproducts. Stress test results indicated that MIBGHS is stable under acidic and dry thermal conditions for at least 72 h but MIBG aqueous solution was deteriorated slowly when exposed to UV light, thermal, oxidative and alkaline environments. Thus, m-iodobenzylamine, the starting material intended for the synthesis of MIBGHS should be analyzed to ensure that it is free from m-bromobenzylamine impurity. Stored under normal condition (-18°C), MIBGHS is stable for at least 12 months. The chemically labile guanidine and amine groups in MIBGHS are the major causes of its instability, while iodide loss from the phenyl group is a minor cause.

Effects of short-term continuous positive airway pressure on myocardial sympathetic nerve function and energetics in patients with heart failure and obstructive sleep apnea: a randomized study.

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. 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). 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. http://www.clinicaltrials.gov. Unique identifier: NCT00756366.

ＩＤＷ法を用いた異なるガンマカメラシステムにおける｀１２３´Ｉ−ＭＩＢＧ Ｈ／Ｍ比のクロスキャリブレーションの検討

(123)I-MIBG Heart-to-Mediastinum activity ratio (H/M) is commonly used as an indicator of relative myocardial (123)I-MIBG uptake. H/M ratios reflect myocardial sympathetic nerve function, therefore it is a useful parameter to assess regional myocardial sympathetic denervation in various cardiac diseases. However, H/M ratio values differ by site, gamma camera system, position and size of region of interest (ROI), and collimator. In addition to these factors, 529 keV scatter component may also affect (123)I-MIBG H/M ratio. In this study, we examined whether the H/M ratio shows correlation between two different gamma camera systems and that sought for H/M ratio calculation formula. Moreover, we assessed the feasibility of (123)I Dual Window (IDW) method, which is a scatter correction method, and compared H/M ratios with and without IDW method. H/M ratio displayed a good correlation between two gamma camera systems. Additionally, we were able to create a new H/M calculation formula. These results indicated that the IDW method is a useful scatter correction method for calculating (123)I-MIBG H/M ratios.

Clinical Implications of Cardiac-MIBG SPECT in the Differentiation of Parkinsonian Syndromes

Background and Purpose123I cardiac meta-iodobenzylguanidine (MIBG), an analogue of norepinephrine, has been used to estimate myocardial sympathetic nerve function. We investigate whether cardiac-MIBG SPECT is clinically applicable in the differentiation of Parkinson's disease (PD) from parkinsonian syndromes.MethodsCardiac-MIBG scintigraphy was performed in 27 controls, in 40 patients with PD and in 52 patients with other parkinsonian syndromes comprising 23 with multiple system atrophy (MSA), 26 with drug-induced parkinsonism (DIP), and 3 with corticobasal degeneration (CBD). The heart to mediastinum (H/M) uptake ratio was calculated for each subjects. Patients who either had medical conditions that confused the MIBG SPECT results or who took medications that interfere with MIBG accumulation were excluded from the study.Results Both early and delayed H/M ratios were in patients with PD significantly lower than in controls (early, 1.34±0.15 vs 1.79±0.19; delayed, 1.29±0.15 vs 2.06±0.29, p<0.001). In patients with PD, both early and delayed H/M ratios were significantly lower than those in patients with MSA (early, 1.68±0.23; delayed, 1.80±0.34, p<0.001), DIP (early, 1.83±0.24; delayed, 2.07±0.4, p<0.001), or CBD (early, 1.85±0.01; delayed, 1.99±0.19, p<0.001). Two patients with DIP, who were within the range of patients with PD, showed clinically similar courses of PD.ConclusionsThis study demonstrates that cardiac-MIBG is a clinically powerful tools to differentiate PD from other parkinsonian syndromes.

Assessment of Takotsubo cardiomyopathy (transient left ventricular apical ballooning) using99mTc-tetrofosmin,123I-BMIPP,123I-MIBG and99mTc-PYP myocardial SPECT

We compared Takotsubo cardiomyopathy (transient left ventricular apical ballooning) with acute myocardial infarction (AMI) using two-dimensional echocardiography, 99mTc-tetrofosmin, 99mTc-PYP, 123I-BMIPP and 123I-MIBG myocardial SPECT. We examined 7 patients with Takotsubo cardiomyopathy and 7 with AMI at the time of emergency admission (acute phase), and 2-14 days (subacute phase), one month (chronic phase), and 3 months (chronic II phase) after the attack. The left ventricle was divided into nine regions on echocardiograms and SPECT images, and the degree of abnormalities in each region was scored according to five grades from normal (0) to severely abnormal (4). Coronary angiography showed the absence of stenotic regions in patients with Takotsubo cardiomyopathy, and severely stenotic and/or occlusive lesions in patients with AMI. The total ST segment elevation on electrocardiograms (mm) was 7.8 +/- 3.7 in those with Takotsubo cardiomyopathy, and 7.3 +/- 3.9 in patients with AMI. Abnormal wall motion scores on echocardiograms were 14.2 +/- 4.6, 4.7 +/- 4.0, 1.7 +/- 2.0 and 0.5 +/- 0.4 during the acute, subacute, chronic and chronic II phases, respectively, in patients with Takotsubo cardiomyopathy, and 14.0 +/- 4.3, 11.4 +/- 3.9, 8.8 +/- 3.6 and 5.2 +/- 4.8 in those with AMI. Abnormal myocardial perfusion scores on 99mTc-tetrofosmin images were 11.8 +/- 3.5, 3.2 +/- 3.0, 0.5 +/- 1.2 and 0.2 +/- 0.4 during the acute, subacute, chronic and chronic II phases, in patients with Takotsubo cardiomyopathy, and 16.2 +/- 4.3, 13.9 +/- 4.6, 7.9 +/- 4.6 and 5.0 +/- 4.5, respectively, in those with AMI. Abnormal myocardial fatty acid scores on 123I-BMIPP images were 12.6 +/- 3.7, 6.8 +/- 3.2 and 0.4 +/- 0.6 during the subacute, chronic and chronic II phases, respectively, in patients with Takotsubo cardiomyopathy, and 16.5 +/- 5.1, 14.7 +/- 4.8 and 7.5 +/- 4.5 in those with AMI. Abnormal myocardial sympathetic nerve function scores on 123I-MIBG images were 14.8 +/- 4.0, 8.8 +/- 4.0 and 0.4 +/- 0.6 during the subacute, chronic, chronic II phases, respectively, in patients with Takotsubo cardiomyopathy, and 18.6 +/- 6.5, 16.8 +/- 6.8 and 12.9 +/- 5.2 in those with AMI. Myocardial 99mTc-PYP uptake was abnormal not only in patients with AMI but also in those with Takotsubo cardiomyopathy during the acute phase. Takotsubo cardiomyopathy might represent a stunned myocardium caused by a disturbance of the coronary microcirculation.

Impairments of myocardial sympathetic activity may reflect the progression of myocardial damage or dysfunction in hypertrophic cardiomyopathy

Background. Abnormalities of myocardial sympathetic nerve function have been reported in hypertrophic cardiomyopathy (HCM). However, the mechanism of such abnormalities remains unknown. In part, the high plasma level of B-type natriuretic peptide (BNP) reportedly reflects myocardial damage in addition to hemodynamic disorder. Methods and Results. To assess myocardial sympathetic nerve function, we obtained metaiodobenzylguanidine (MIBG) images 15 and 180 minutes after the injection of iodine 123–MIBG at a dose of 111 MBq and calculated the heart-mediastinum count ratio (H/M) and the washout rate (WR) in 59 consecutive patients with HCM and age-matched normal control subjects (C, n = 23). The plasma levels of atrial natriuretic peptide (ANP), BNP, and norepinephrine (NE) were also measured. The left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF) were measured by echocardiographic study. H/M was significantly lower in patients with HCM (2.1 ± 0.3) than in control subjects (2.6 ± 0.4) (P < .01). WR was higher in patients with HCM (35 ± 6) than in control subjects (28 ± 3) (P < .01). H/M had a significant negative correlation with LVEF, LVMI, ANP, BNP, and NE. WR also had a significant positive relationship with the plasma levels of NE and BNP. Multivariate regression analysis was used with 5 variables (LVEF, LVMI, ANP, BNP, and NE). BNP (P = .0001) and LVMI (P = .0009) were independent and significant predictors of H/M. NE was an independent and significant predictor of WR (P = .0018). Conclusions. These findings indicate that impairments of myocardial sympathetic function may reflect the progression of myocardial damage or dysfunction in HCM. (J Nucl Cardiol 2002;9:407-12)

Analysis of sympathetic nerve activity in end-stage cardiomyopathy patients receiving left ventricular support

Background The left ventricular assist system (LVAS) has been used increasingly for patients with end-stage heart failure who are awaiting transplantation. Sympathetic nerve activity is known to correlate with cardiac function in chronic heart failure patients, but little is known about sympathetic nerve activity during LVAS support. In this study, we examined the status of sympathetic nerve activity in relation to mechanical support. Methods In this study, we included 10 consecutive patients with end-stage cardiomyopathy who were on LVAS support for at least 2 months (duration, 222 ± 59 days). None of these patients achieved enough functional recovery to be taken off LVAS. In these patients, we used iodine-125-metaiodobenzylguanidine ( 125I-MIBG) scintigraphy to examine the change of sympathetic nerve activity after LVAS implantation, and compared the results with the change of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels as well as with histologic optional findings. Samples for ANP and BNP measurement were obtained before and 30 days after LVAS implantation. Specimens for histologic analysis were obtained at the time of LVAS implantation and at the time of cardiac transplantation or autopsy. Results We observed marked decrease in serum levels of ANP and BNP 1 month after LVAS implantation. But myocardial sympathetic nerve function, which was evaluated with 125I-MIBG scintigraphy and expressed as the heart-to-mediastinum activity ratio, remained below normal even 2 months after the LVAS implantation (1.57 ± 0.19; normal, 2.34 ± 0.36). Serial histologic analysis in these 10 patients showed continuous increase in percentage of fibrosis and cell diameter despite ventricular unloading by the LVAS. Conclusions Sympathetic nerve function, which was evaluated on 125I-MIBG scintigraphy, did not improve during left ventricular support. Because none of the patients included in our study showed improvement in cardiac function or histologic findings, the recovery of myocardial sympathetic nerve function may be an important factor in myocardial recovery for cardiomyopathy patients on LVAS support.

Influence of drugs on myocardial iodine-123 metaiodobenzylguanidine uptake in rabbit myocardium.

About 15 years ago, iodine-123 metaiodobenzylguanidine (MIBG) myocardial imaging was introduced for the evaluation of myocardial sympathetic nerve function. Two uptake mechanisms for MIBG have so far been identified: uptake type I, a saturable, energy-dependent mechanism, and uptake type II, a non-saturable, energy-independent mechanism. We incubated isolated rabbit myocardial tissue samples with 123I-MIBG in order to assess the uptake characteristics and the influence of varying incubation conditions. Furthermore, we examined the effects of several drugs and uptake inhibitors on the myocardial uptake of MIBG. The in vitro myocardial uptake of MIBG reached a steady plateau at 23.87%+/-3.63% after 1 h, i.e. a concentration gradient of 10, in a thermo-independent manner within a concentration range from 1.5 to 1500 microM. This indicates an unsaturable uptake process in the tested concentrations. Preincubation with the following drugs caused a significant inhibitory effect on myocardial MIBG uptake: haloperidol, levomepromazine, metoprolol, labetalol and clomipramine. According to our findings, the uptake mechanism seems to be an unspecific process, but the concentration gradient of 10 makes passive diffusion unlikely. Further studies with uptake-II-blocking substances as well as with isolated myocardial cells will be needed to clarify the nature of the myocardial MIBG uptake mechanism.

Iodine-123 Metaiodobenzylguanidine Scintigraphic Assessment of Myocardial Sympathetic Innervation in Patients With Familial Amyloid Polyneuropathy

Objectives. This study attempted to assess myocardial sympathetic innervation using iodine-123 (I-123) metaiodobenzylguanidine (MIBG) imaging in patients with familial amyloid polyneuropathy.Background. Signs and symptoms of cardiac autonomic dysfunction are commonly seen in patients with cardiac amyloidosis. However, the incidence and magnitude of abnormalities in myocardial sympathetic nerve function by means of I-123 MIBG imaging and their relation to clinical findings, cardiac function and the results of thallium-201 (Tl-201) and technetium-99m pyrophosphate (Tc-99m PYP) myocardial scanning have not yet been clarified.Methods. We performed M-mode, two-dimensional and Doppler echocardiography and I-123 MIBG, Tl-201 and Tc-99m PYP imaging of the heart in 12 patients with familial amyloid polyneuropathy and biopsy-proved cardiac amyloidosis.Results. Ten of 12 patients had no clinical evidence of overt heart disease, but left ventricular (LV) wall thickening was observed in 4 of these 10. Left ventricular percent fractional shortening and Doppler transmitral flow velocity patterns were found to be normal in all 12 patients. Eight of 12 patients showed no myocardial MIBG accumulation, with limited uptake in the remaining 4 demonstrated only in the LV anterior wall. Diffuse but mild myocardial uptake of Tc-99m PYP occurred in only 4 of 12 patients, and all 12 had normal results on Tl-201 myocardial scanning. Complete defects on myocardial MIBG scans were found in five of eight patients with negative findings on Tc-99m PYP myocardial scanning. The incidence and magnitude of myocardial uptake of MIBG were independent of clinical findings, extent of endomyocardial amyloid deposition, electrocardiographic QRS voltage and ventricular wall thickness.Conclusions. Patients with familial amyloid polyneuropathy show a high incidence of myocardial adrenergic denervation with viable myocardium that can be identified very early in cardiac amyloidosis, before the development of clinically apparent heart disease, ventricular wall thickening, significant LV systolic and diastolic dysfunction and positive findings on Tc-99m PYP myocardial scanning.(J Am Coll Cardiol 1997;29:168–74)>