Cardiac Sympathetic Nervous System Activity Research Articles

Cardiac sympathetic innervation, assessed with 123I-MIBG SPECT, predicts left ventricular function improvement in patients with newly diagnosed dilated cardiomyopathy

Abstract Introduction Beta-blockers (BB) are commonly prescribed medications for heart failure (HF) due to their ability to counteract the increased sympathetic nervous system (SNS) activity seen in HF, resulting in downregulation and desensitization of β-receptors. In patients with dilated cardiomyopathy (DCM), the introduction of BB therapy can lead to left ventricular ejection fraction (LVEF) improvement in 30-50% of cases. Single-photon emission computed tomography (SPECT) with 123I-meta-iodobenzylguanidine (MIBG) is a useful tool for assessing cardiac SNS activity. Healthy individuals typically exhibit high SPECT-MIBG uptake and low washout rate (WR) due to normal β-receptor levels and low norepinephrine (NE) levels, respectively (Fig 1A). While better SPECT-MIBG results have been associated with LVEF improvement in the general HF population, less data is available for DCM patients. Purpose This study aimed to evaluate the predictive value of MIBG-SPECT for LVEF improvement in newly diagnosed DCM patients. Methods Twenty-one DCM patients (mean age 47 ± 10 years, 90% male, baseline LVEF 29.5 ± 8.7%, left ventricular end-diastolic volume (LVEDV) 114 ± 36 ml/m2) with stable HF symptoms (NYHA class 1.8 ± 0.6) and newly diagnosed DCM underwent baseline MIBG-SPECT and echocardiography. HF therapy was initiated and up-titrated, and echocardiography was repeated at 6 months. Semi-quantitative parameters from MIBG-SPECT, including the MIBG uptake ratio from the heart and mediastinum (H/M) at 15 minutes (-15) and 4 hours (-4), as well as the WR [WR = (H/M-15 - H/M-4) / H/M-15], were evaluated. Patients were stratified based on median WR - 8.79 (IQR 5.17-12.90). Results After 6-months of HF therapy up-titration, 18 patients improved LVEF, and the mean LVEF increase was 7.7 ± 10.4%. Although, patients with WR > median did not differ in terms of baseline LVEF (30.2 ± 7.0 vs. 27.7 ± 9.6, p=0.52), they had worse LVEF at 6 months (32.0 ± 11.0 vs. 40.6 ± 9.2%, p=0.04). Moreover, WR at baseline strongly correlated with 6-month LVEF (R=-0.51, p=0.01) and was a significant predictor of 6-month LVEF (β=-0.55 ± 0.19, p=0.009). Moreover, WR could successfully predict LVEF improvement ≥ 10% (OR 1.27 [95%CI 1.01-1.61], p=0.03; AUC 0.82 [95%CI 0.63-0.99], p<0.001) with a cut-off point of 8.0 (sensitivity 88%, specificity 77%) (Fig 1B). Conclusion Most DCM patients demonstrated LVEF improvement during 6 months of HF therapy up-titration. Baseline WR from MIBG-SPECT was found to be a reliable predictor of significant LVEF improvement in this patient population.Fig1.A-SPECT-MIBG results. B-ROC curve.

Alleviation of physiological stress response by apple aroma

ABSTRACT Objective The study evaluated the potential of apple aroma to alleviate physiological stress response induced by a short-term cognitive stressor. It investigated the effects of apple aroma on cardiac and peripheral autonomic nervous system activity under stressful conditions. Methods Within-subject experiments were conducted with 25 healthy male university students with a 30-minute calculation task under three conditions: Apple, Chamomile (CHA), and Di propylene glycol (DPG) (scentless air). The aroma administration was precisely controlled and counterbalanced. Cardiac activity on electrocardiograms and nose tip temperature were recorded throughout the experiment. A visual analog scale and a scent questionnaire were subjective measures. Results Apple aroma demonstrated a significantly smaller increase in heart rate (t [24] = 3.36, p = 0.008 vs. DPG, t [24] = 4.06, p = 0.001 vs. CHA), and a decrease in the high-frequency component of heart rate variability (t [24] = 2.81, p = 0.029 vs. DPG, t [24] = 3.48, p = 0.006 vs. CHA) compared to the other conditions, representing a smaller enhancement of cardiac sympathetic nervous system activity and smaller suppression of cardiac parasympathetic nervous system activity respectively. Conclusion Apple aroma showed efficacy in alleviating the physiological stress response in terms of cardiac activity. Apple was also considered significantly preferable and comfortable compared to the other conditions, which would be beneficial in the context of aromatherapy.

Chronic Expression of Interleukin-10 Transgene Modulates Cardiac Sympathetic Ganglion Resulting in Reduced Ventricular Arrhythmia.

The cardiac autonomic nervous system (CANS) is intimately connected to the regulation of electrophysiology and arrhythmogenesis in cardiac systems. This work aimed at investigating whether interleukin-10 (IL-10) could effectively modulate CANS and suppress ischemia-induced ventricular arrhythmia (VA) through chronically acting on the cardiac sympathetic ganglion (CSG). Using an adeno-associated virus (AAV), we achieved local chronic overproduction of IL-10 in the CSG, left stellate ganglion (LSG). As a result, in the IL-10 group, we observed a decreased number of tyrosine hydroxylase-positive (TH+) cells in the LSG. IL-10 markedly downregulated the nerve growth factor, synaptophysin, as well as growth-associated protein 43 expression. In vivo, results from ambulatory electrocardiography showed that IL-10 overexpression significantly inhibited the cardiac sympathetic nervous system activity and improved heart rate variability. Meanwhile, we observed decreased LSG function as well as prolonged ventricular effective refractory period and suppressed VA after myocardial infarction (MI) in the IL-10 group. In addition, IL-10 overexpression attenuated inflammation and decreased norepinephrine levels in the myocardium after acute MI. In conclusion, our data suggest that chronic IL-10 overexpression modulates cardiac sympathetic nerve remodeling and suppresses VA induced by MI. Neuromodulation through AAV-mediated IL-10 overexpression may have the characteristics of and advantages as a potential neuroimmunotherapy for preventing MI-induced VAs.

Metabolism regulator adiponectin prevents cardiac remodeling and ventricular arrhythmias via sympathetic modulation in a myocardial infarction model.

The stellate ganglia play an important role in cardiac remodeling after myocardial infarction (MI). This study aimed to investigate whether adiponectin (APN), an adipokine mainly secreted by adipose tissue, could modulate the left stellate ganglion (LSG) and exert cardioprotective effects through the sympathetic nervous system (SNS) in a canine model of MI. APN microinjection and APN overexpression with recombinant adeno-associated virus vector in the LSG were performed in acute and chronic MI models, respectively. The results showed that acute APN microinjection decreased LSG function and neural activity, and suppressed ischemia-induced ventricular arrhythmia. Chronic MI led to a decrease in the effective refractory period and action potential duration at 90% and deterioration in echocardiography performance, all of which was blunted by APN overexpression. Moreover, APN gene transfer resulted in favorable heart rate variability alteration, and decreased cardiac SNS activity, serum noradrenaline and neuropeptide Y, which were augmented after MI. APN overexpression also decreased the expression of nerve growth factor and growth associated protein 43 in the LSG and peri-infarct myocardium, respectively. Furthermore, RNA sequencing of LSG indicated that 4-week MI up-regulated the mRNA levels of macrophage/microglia activation marker Iba1, chemokine ligands (CXCL10, CCL20), chemokine receptor CCR5andpro-inflammatory cytokine IL6, and downregulated IL1RN and IL10 mRNA, which were reversed by APN overexpression. Our results reveal that APN inhibits cardiac sympathetic remodeling and mitigates cardiac remodeling after MI. APN-mediated gene therapy may provide a potential therapeutic strategy for the treatment of MI.

Reclassification of Heart Failure with Preserved Ejection Fraction Following Cardiac Sympathetic Nervous System Activation: A New Cutoff Value of 58.

Heart failure (HF) with preserved left ventricular ejection fraction (LVEF) is a heterogeneous syndrome. An LVEF of 50% is widely used to categorize patients with HF; however, this is controversial. Previously, we have reported that patients with an LVEF of ≥ 58% have good prognoses. Further, cardiac sympathetic nervous system (SNS) activation is a feature of HF. In this retrospective, observational study, the cardiac SNS activity of HF patients (n = 63, age: 78.4 ± 9.6 years; male 49.2%) with LVEF ≥ 58% (n = 15) and LVEF < 58% (n = 48) were compared using 123I-metaiodobenzylguanidine scintigraphy. During the follow-up period (median, 3.0 years), 18 all-cause deaths occurred. The delayed heart/mediastinum (H/M) ratio was significantly higher in the LVEF ≥ 58% group than in the LVEF < 58% group (2.1 ± 0.3 vs. 1.7 ± 0.4, p = 0.004), and all-cause mortality was significantly lower in patients in the former than those in the latter group (log-rank, p = 0.04). However, when these patients were divided into LVEF ≥ 50% (n = 22) and LVEF < 50% (n = 41) groups, no significant differences were found in the delayed H/M ratio, and the all-cause mortality did not differ between the groups (log-rank, p = 0.09). In conclusion, an LVEF of 58% is suitable for reclassifying patients with HF according to cardiac SNS activity.

Blood Pressure Regulation by the Carotid Sinus Nerve: Clinical Implications for Carotid Body Neuromodulation.

Chronic carotid sinus nerve (CSN) electrical modulation through kilohertz frequency alternating current improves metabolic control in rat models of type 2 diabetes, underpinning the potential of bioelectronic modulation of the CSN as a therapeutic modality for metabolic diseases in humans. The CSN carries sensory information from the carotid bodies, peripheral chemoreceptor organs that respond to changes in blood biochemical modifications such as hypoxia, hypercapnia, acidosis, and hyperinsulinemia. In addition, the CSN also delivers information from carotid sinus baroreceptors—mechanoreceptor sensory neurons directly involved in the control of blood pressure—to the central nervous system. The interaction between these powerful reflex systems—chemoreflex and baroreflex—whose sensory receptors are in anatomical proximity, may be regarded as a drawback to the development of selective bioelectronic tools to modulate the CSN. Herein we aimed to disclose CSN influence on cardiovascular regulation, particularly under hypoxic conditions, and we tested the hypothesis that neuromodulation of the CSN, either by electrical stimuli or surgical means, does not significantly impact blood pressure. Experiments were performed in Wistar rats aged 10–12 weeks. No significant effects of acute hypoxia were observed in systolic or diastolic blood pressure or heart rate although there was a significant activation of the cardiac sympathetic nervous system. We conclude that chemoreceptor activation by hypoxia leads to an expected increase in sympathetic activity accompanied by compensatory regional mechanisms that assure blood flow to regional beds and maintenance of hemodynamic homeostasis. Upon surgical denervation or electrical block of the CSN, the increase in cardiac sympathetic nervous system activity in response to hypoxia was lost, and there were no significant changes in blood pressure in comparison to control animals. We conclude that the responses to hypoxia and vasomotor control short-term regulation of blood pressure are dissociated in terms of hypoxic response but integrated to generate an effector response to a given change in arterial pressure.

The value of cardiac sympathetic nervous system activity in the prognosis of atrial fibrillation radiofrequency ablation

Abstract Background Atrial fibrillation (AF) is one of the widest spread forms of arrhythmia worldwide. To date, radiofrequency catheter ablation (RFCA) of AF is a valuable treatment option. So far there are no clear predictors of the effectiveness of AF ablation. Nowadays, the association of cardiac sympathetic nervous system and the development and maintenance of AF has been showed. However, the association between sympathetic innervation disturbances and AF RFCA effectiveness remains inconclusive. Purpose To study the prognostic significance of cardiac sympathetic activity assessed by 123I-MIBG scintigraphy in AF RFCA efficacy. Methods The study included 46 patients. All patients were divided into 3 groups: I group - persistent AF (n=20), II group - long-standing persistent AF (LSPAF) (n=16), III group - sinus rhythm patients (n=10). All patients underwent 123I-MIBG and 99mTc-MIBI scintigraphy (planar and SPECT) to evaluate the cardiac sympathetic activity and myocardial perfusion, respectively. Echocardiography was performed in all patients to assess the cardiac contractile function. The effectiveness of interventional treatment was assessed in one year by 24 hour Holter monitoring. Results During a median follow-up of 12±6 month, arrhythmia recurrence was observed in 7 (35%) PAF patients and in 8 (50%) LSPAF patients. The univariate regression analysis showed that in patients with PAF the left atrial diameter (LAD), 123I-MIBG washout rate (WR), delayed 123I-MIBG defect score, and 123I-mIBG/99mTc-MIBI mismatch score were predictors of AF recurrence. In this group only the WR was a multivariate predictor of AF recurrence (odds ratios: 1.668, 95% confidence interval: 1.093–2.548, p=0.018). The receiver operator characteristics curve (ROC) analysis indicated the potential diagnostic value of WR to predict recurrence of AF after RFCA in PAF patients with an area under the curve of 0.968 (P&amp;lt;0.05; sensitivity = 100%, specificity = 45%), and an optimum cut-off value of 20.8%. The univariate regression analysis showed that in patients with LSPAF the LAD, WR, delayed 123I-MIBG defect score, rest perfusion defect score and 123I-MIBG/99mTc-MIBI mismatch score were predictors of AF recurrence. According to multivariate analysis only the 123I-MIBG/99mTc-MIBI mismatch score was an independent predictor of AF recurrence in this group of patients (odds ratios: 2.155, 95% confidence interval: 1.192–3.897, p=0.011). ROC analysis gave an optimum cut-off value of 12.5% for the 123I-MIBG/99mTc-MIBI mismatch score with an area under the curve of 0.942 to predict recurrence of AF after RFCA in LSPAF patients (p&amp;lt;0.05, sensitivity = 81%, specificity = 28%). Conclusions In AF patients the incidence of arrhythmia recurrence after RFCA is associated with impaired sympathetic nervous activity. The prognosis of AF recurrence in LSPAF patients has a link with rest myocardial perfusion disturbances which may reflect the severer structural change of myocardium. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Russian Science Foundation

EXPRESS: Cardiac Sympathetic Dysfunction in Pulmonary Arterial Hypertension: Lesson from Left-sided Heart Failure.

Sympathetic nervous system hyperactivity has a well-recognized role in the pathophysiology of heart failure with reduced left ventricular ejection fraction. Alterations in sympathetic nervous system have been related to the pathophysiology of pulmonary arterial hypertension, but it is unclear whether cardiac sympathetic nervous system is impaired and how sympathetic dysfunction correlates with hemodynamics and clinical status in pulmonary arterial hypertension patients. The aim of this study was to evaluate the cardiac sympathetic nervous system activity by means of 123Iodine-metaiodobenzylguanidine nuclear imaging in pulmonary arterial hypertension patients and to explore its possible correlation with markers of disease severity. Twelve consecutive pulmonary arterial hypertension patients (nine women, median age 56.5 (17.8), eight idiopathic and four connective tissue-associated pulmonary arterial hypertension) underwent cardiac 123Iodine-metaiodobenzylguanidine scintigraphy. The results were compared with those of 12 subjects with a negative history of cardiovascular or pulmonary disease who underwent the same nuclear imaging test because of a suspected paraganglioma or pheochromocytoma, with a negative result (controls), and 12 patients with heart failure with reduced left ventricular ejection fraction. Hemodynamics, echocardiography, six-minute walking distance, cardiopulmonary exercise testing, and N-terminal pro brain natriuretic peptide were collected in pulmonary arterial hypertension patients within one week from 123Iodine-metaiodobenzylguanidine scintigraphy. Cardiac 123Iodine-metaiodobenzylguanidine uptake, assessed as early and late heart-to-mediastinum ratio, was significantly lower in pulmonary arterial hypertension compared to controls (p = 0.001), but similar to heart failure with reduced left ventricular ejection fraction. Myocardial 123Iodine-metaiodobenzylguanidine turnover, expressed as washout rate, was similar in pulmonary arterial hypertension and heart failure with reduced left ventricular ejection fraction and significantly higher compared to controls (p = 0.016). In the pulmonary arterial hypertension group, both early and late heart-to-mediastinum ratios and washout rate correlated with parameters of pulmonary arterial hypertension severity including pulmonary vascular resistance, right atrial pressure, tricuspid annular plane systolic excursion, N-terminal pro brain natriuretic peptide, and peak VO2. Although we evaluated a small number of subjects, our study showed a significant impairment in cardiac sympathetic nervous system in pulmonary arterial hypertension, similarly to that observed in heart failure with reduced left ventricular ejection fraction. This impairment correlated with indices of pulmonary arterial hypertension severity. Cardiac sympathetic dysfunction may be a contributing factor to the development of right-sided heart failure in pulmonary arterial hypertension.

Sympathetic cardiac function in early sepsis: Noninvasive evaluation with [123I]-meta-iodobenzylguanidine (123I-MIBG) in vivo SPECT imaging

BackgroundSympathetic system abnormalities have been reported in sepsis-related cardiac dysfunction. The present study aimed at evaluating the potential of the norepinephrine radiolabeled analogue [123I]-meta-iodobenzylguanidine (123I-MIBG) for the noninvasive assessment of modifications in cardiac sympathetic activity occurring in lipopolysaccharide (LPS)-induced experimental acute sepsis by single-photon emission computed tomographic imaging (SPECT). Methods and ResultsSepsis was induced in male Wistar rats by intraperitoneal injection of 10 mg·kg−1 lipopolysaccharide (n = 16), whereas control animals (n = 7) were injected with vehicle (NaCl 0.9%). Echocardiography in LPS-injected animals (n = 8) demonstrated systolic and diastolic cardiac dysfunction. 123I-MIBG was injected 1 hour after LPS or vehicle administration (n = 8 and 7, respectively), and in vivo SPECT imaging was performed early and late (20 and 180 minutes) after tracer injection prior to animal euthanasia and ex vivo assessment of 123I-MIBG biodistribution. Global and 17-segment SPECT image analysis indicated that early 123I-MIBG activity was not affected by LPS treatment, whereas late cardiac tracer activity was significantly decreased in LPS-treated animals. Consequently, the cardiac washout of 123I-MIBG was significantly higher in LPS-treated (63.3% ± 4.0%) than that in control animals (56.7% ± 5.8%) (P < .05). ConclusionSepsis-induced modifications in cardiac sympathetic nervous system activity were evidenced by noninvasive in vivo 123I-MIBG SPECT imaging.

Trajectories of sleep and cardiac sympathetic activity indexed by pre-ejection period in childhood.

Fragmented and insufficient sleep has been implicated in disrupted autonomic nervous system activity during resting state conditions in typically developing children. Towards explication of these relations over development, the current study tested reciprocal relations between the development of sleep parameters (efficiency, duration, latency) and cardiac sympathetic nervous system (SNS) activity indexed by pre-ejection period (PEP) during waking-resting state conditions throughout middle and late childhood. Whether sleep derives changes in PEP or vice versa was examined. A longitudinal design was employed and latent growth modelling was used to examine the research questions. During the first assessment, 282 children aged 9.44years (65% European American, 35% African American) participated. Two more assessments followed, with a 1-year lag between consecutive study waves. Sleep was examined with 7 nights of actigraphy in the child's home. Controlling for many potential confounds (sex, race/ethnicity, body mass index and family socioeconomic status), higher sleep efficiency and more sleep minutes predicted increases in PEP (less SNS activity) over 3years. PEP did not predict changes in sleep efficiency or duration over time and there were no significant effects for sleep latency. Findings highlight the probable direction of effects between these two key bioregulatory systems. High levels of cardiac SNS activity are associated with many negative health outcomes, and thus these findings may have important implications.

Impact of aging on cardiac sympathetic innervation measured by 123I-mIBG imaging in patients with systolic heart failure.

Sympathetic nervous system (SNS) hyperactivity is a salient characteristic of chronic heart failure (HF) and contributes to the progression of the disease. Iodine-123 meta-iodobenzylguanidine (123I-mIBG) imaging has been successfully used to assess cardiac SNS activity in HF patients and to predict prognosis. Importantly, SNS hyperactivity characterizes also physiological ageing, and there is conflicting evidence on cardiac 123I-mIBG uptake in healthy elderly subjects compared to adults. However, little data are available on the impact of ageing on cardiac sympathetic nerve activity assessed by 123I-mIBG scintigraphy, in patients with HF. We studied 180 HF patients (age = 66.1 ± 10.5years [yrs]), left ventricular ejection fraction (LVEF = 30.6 ± 6.3%) undergoing cardiac 123I-mIBG imaging. Early and late heart to mediastinum (H/M) ratios and washout rate were calculated in all patients. Demographic, clinical, and echocardiographic data were also collected. Our study population consisted of 53 patients aged >75years (age = 77.7 ± 4.0year), 67 patients aged 62-72years (age = 67.9 ± 3.2years) and 60 patients aged ≤61year (age = 53.9 ± 5.6years). In elderly patients, both early and late H/M ratios were significantly lower compared to younger patients (p < 0.05). By multivariate analysis, H/M ratios (both early and late) and washout rate were significantly correlated with LVEF and age. Our data indicate that, in a population of HF patients, there is an independent age-related effect on cardiac SNS innervation assessed by 123I-mIBG imaging. This finding suggests that cardiac 123I-mIBG uptake in patients with HF might be affected by patient age.

Ambulatory measurement of the ECG T-wave amplitude.

Ambulatory recording of the preejection period (PEP) can be used to measure changes in cardiac sympathetic nervous system (SNS) activity under naturalistic conditions. Here, we test the ECG T-wave amplitude (TWA) as an alternative measure, using 24-h ambulatory monitoring of PEP and TWA in a sample of 564 healthy adults. The TWA showed a decrease in response to mental stress and a monotonic decrease from nighttime sleep to daytime sitting and more physically active behaviors. Within-participant changes in TWA were correlated with changes in the PEP across the standardized stressors (r = .42) and the unstandardized naturalistic conditions (mean r = .35). Partialling out changes in heart rate and vagal effects attenuated these correlations, but they remained significant. Ambulatory TWA cannot replace PEP, but simultaneous recording of TWA and PEP provides a more comprehensive picture of changes in cardiac SNS activity in real-life settings.

CARVEDILOL PREVENTS THE ETHANOL-INDUCED VENTRICULAR ARRHYTHMIAS BY MODIFYING THE GAP JUNCTION REMODELLING IN RATS

ObjectivesOur previous studies showed carvedilol blocked the abrupt termination of an ethanol regimen promoted the cardiac sympathetic predominance and the life-threatening ventricular arrhythmias in rats. However, the mechanisms by which...

650 Insulin treatment normalizes noradrenaline levels and cardiac sympathetic innervation in diabetic rats

650 Insulin treatment normalizes noradrenaline levels and cardiac sympathetic innervation in diabetic rats

Iodine-123 mIBG Imaging for Predicting the Development of Atrial Fibrillation

we investigated whether cardiac sympathetic nervous system (SNS) activity measured by iodine-123 meta-iodobenzylguanidine ((123)I-mIBG) imaging would be associated with both the occurrence of heart failure (HF) and the transit to permanent atrial fibrillation (AF) in patients with paroxysmal AF. atrial fibrillation occurs suddenly and transiently and can persist, and results in the occurrence of HF. An important feature of AF and HF is their propensity to coexist not only because they share antecedent risk factors, but also because the one may directly predispose the heart to the other. However, a useful modality for predicting the occurrences of both those has not been established in patients with paroxysmal AF. the (123)I-mIBG scintigraphy was performed to evaluate cardiac SNS activity presented as the heart/mediastinum ratio in 98 consecutive patients (age 66 ± 13 years, 63.3% male) with idiopathic paroxysmal AF and preserved left ventricular ejection fraction (≥ 50%). during 4 ± 3.6 years of follow-up, the transit to permanent AF was associated with the occurrence of HF (34.3% in 12 of 35 patients with permanent AF vs. 6.3% in 4 of 63 patients without, p < 0.0001). Lower heart/mediastinum ratio and lower left ventricular ejection fraction were the independent predictors of the transit to permanent AF with adjusted hazard ratios of 3.44 (95% confidence interval [CI]: 1.9 to 6.2, p < 0.0001) and 1.04 (95% CI: 1.01 to 1.08, p = 0.014). Further, these factors and higher plasma brain natriuretic peptide concentration were the independent predictors of the occurrence of HF with permanent AF, with adjusted hazard ratios of 5.08 (95% CI: 1.5 to 17.5, p = 0.011), 1.11 (95% CI: 1.03 to 1.19, p = 0.004), and 1.004 (95% CI: 1.001 to 1.008, p = 0.014). cardiac SNS abnormality was associated with the occurrence of both HF and permanent AF in paroxysmal AF patients, and (123)I-mIBG imaging may be a useful modality for predicting the development of AF.

Sympathetic-leptin relationship in obesity: effect of weight loss

Obese patients have high plasma leptin concentrations that do not induce the expected responses on weight regulation, suggesting a leptin resistance in obesity. Elevated leptin levels are also thought to be related to a high sympathetic nervous system (SNS) activity. This effect could be preserved, lowered, or even abolished in obesity. We planned to investigate the possible association in a longitudinal study. Ninety-five normotensive healthy women, aged 40.4 ± 11.4 years and body mass index of 33.2 ± 2.3 kg/m 2, were studied. Baseline leptin, fat mass, and heart rate variability were measured and included in a 6-month longitudinal study. Body composition was measured by dual-energy x-ray absorption. Time domain heart rate variability, QT dynamicity, and spectral components on ambulatory electrocardiographs were analyzed. Dietary advice was given by a dietitian to the patient (maximum caloric reduction of 30%), and subjects were randomized in 3 treatment groups: sibutramine 10 mg, sibutramine 20 mg, or placebo. At baseline, low frequencies (LF) and the LF–high frequencies (HF) ratio, mainly related to the SNS, were negatively correlated to leptin concentration ( r = −0.30, P = .002 and r = −0.36, P < .001) and to the leptin–fat mass ratio ( r = −0.28, P = .004 and r = − 0.33, P = .0007), thus explaining 38% of the LF variance and 33% of the LF/HF variance. Diastolic blood pressure was also negatively correlated to leptin concentrations (−0.20, P = .04) and to the leptin–fat mass ratio (−0.22, P = .022). In contrast, no consistent correlations between leptin and the time domain components related to vagal activity were observed. At 6 months, after completion of the weight loss program, LF significantly decreased (−7.7% ± 7.9%, P < .001), whereas HF was higher than the initial value (+20% ± 5.2%). The leptin–fat mass ratio remained negatively correlated to the LF ( r = −0.34, P = .030) and to LF/HF ( r = −0.35, P = .021) values, explaining 21% of the LF variation. None of the pairwise comparisons between the 2 sibutramine groups and the placebo group were statistically significant for heart rate variability. High leptin concentration is associated with low indexes of cardiac SNS activity and with a lower diastolic blood pressure in normotensive obese women. Our results imply therefore that the relationship between leptin and the autonomic nervous system is disturbed in normotensive obese subjects.

Effect of acute exposure to 3660 m altitude on orthostatic responses and tolerance.

Orthostatic reflexes were examined at 375 m and after 60 min of exposure in a hypobaric chamber at 3660 m using a 20-min 70 degrees head-up tilt (HUT) test. Mean arterial blood pressure, R wave-R wave interval (RRI), and mean cerebral blood flow velocity (MFV) were examined with coarse-graining spectral analysis. Of 14 subjects, 7 at 375 m and 12 at 3660 m were presyncopal. Immediately on arrival to high altitude, breathing frequency and MFV increased, and endtidal PCO2, RRI, RRI complexity, and the parasympathetic nervous system indicator decreased. MFV was similar in HUT at both altitudes. The sympathetic nervous system indicator increased with tilt at 3660 m, whereas parasympathetic nervous system indicator decreased with tilt at both altitudes. Multiple regression analysis of supine variables from either 375 or 3660 m and the time to presyncope at 3660 m indicated that, after 1 h of exposure, increased presyncope at altitude was the result of 1). ineffective peripheral vasoconstriction, despite increased cardiac sympathetic nervous system activity with HUT, and 2). insufficient cerebral perfusion owing to cerebral vasoconstriction as the result of hypoxic hyperventilation-induced hypocapnia.

若齢男性における持久性トレーニングおよび脱トレーニングが安静時心臓自律神経系活動に及ぼす影響

The effects of endurance training and detraining on cardiac autonomic nervous system activity were studied by using the power spectral analysis of heart rate (HR) variability. Twenty-one sedentary male subjects were trained for 8 weeks using cycle ergometer exercise [70% of maximal oxygen uptake (VO2max), 60 min, 3.4 times/wk]. Resting HR for 5 min was recorded before the training , after the 8-week training period, and after the 2-week and 4-week detraining period. The indices of cardiac parasympathetic and sympathetic nervous system activity were determined by Mem-Calc method, as the high frequency power (HF : 0.15•`0.50 Hz) and the ratio of the low frequency power (LF :0.04•`0.15 Hz) to the HF (LF/HF), respectively. The V02max after the training and 4 weeks detraining period were significantly higher than the initial value (before training : 41 •} 1 ml/kg/min ; after training:48•}2, P<0.0001; after detraining:46•}2, P<0.001). The HF was significantly increased by the training (P<0.05), and maintained the increased level for the 2-week detraining period (before training : 6.4•}0.3 In ms2 ; after training: 7.0•}0.2, P<0.01; after 2-week detraining: 7.0•}0.2, P<0.05). The increase in the HF, however, disappeared after the 4-week detraining period (6.8•}0.31n ms2). The LF/HF did not show any significant changes during the training and detraining period. These results suggest that an endurance exercise with moderate intensity enhances cardiac parasympathetic nervous system activity, but not cardiac sympathetic nervous system activity. The enhanced cardiac parasympathetic nervous system activity, however, may regress rapidly during detraining period. (Jpn. J. Phys. Fitness Sports Med. 2000, 49:121•`128) key words : heart rate variability, power spectral analysis, parasympathetic nervous system, sympathetic nervous system, maximal oxygen uptake

Plasma leptin level is associated with myocardial wall thickness in hypertensive insulin-resistant men.

Leptin, the product of the ob gene, has been shown to increase heart rate and blood pressure through a stimulation of cardiac sympathetic nervous system activity, a phenomenon also involved in the pathogenesis of left ventricular hypertrophy in hypertensives. Thus, we hypothesize that plasma leptin concentration is associated with left ventricular hypertrophy. Forty hypertensive males and 15 healthy male subjects underwent anthropometric and echocardiographic evaluations, assessment of insulin sensitivity through euglycemic glucose clamp combined with indirect calorimetry, and determination of fasting plasma leptin concentration. Fasting plasma leptin levels were higher in hypertensives than in controls (6.48+/-2.9 versus 4. 62+/-1.5 ng/mL, P<0.05); these results were unchanged after adjustment for body mass index (P<0.05). In the whole group of patients (n=55), fasting plasma leptin concentration was correlated with body mass index (r=0.46, P<0.001) and waist/hip ratio (r=0.50, P<0.001); independent of body mass index and waist/hip ratio, fasting plasma leptin concentration was correlated (n=55) with whole-body glucose disposal (r=-0.27, P<0.04), interventricular septum thickness (r=0.34, P<0.001), posterior wall thickness (r=0.38, P<0.003), and the sum of wall thicknesses (r=0.68, P<0.001). In a multivariate analysis (n=55), age, body mass index, fasting plasma leptin concentration, plasma Na(+) concentration, whole-body glucose disposal, and diastolic blood pressure explained 68% of the variability of the sum of wall thicknesses with fasting plasma leptin concentration (P<0.03), whole body glucose disposal (P<0.002), and diastolic blood pressure (P<0.001), which were significantly and independently associated with the sum of wall thicknesses. In conclusion, our study demonstrates that fasting plasma leptin levels are associated with increased myocardial wall thickness independent of body composition and blood pressure levels in hypertensives.

Comparison of [ 123I]metaiodobenzylguanidine kinetics with heart rate variability and plasma norepinephrine level

Background. [ 123I]Metaiodobenzylguanidine (MIBG) imaging has been used to assess cardiac sympathetic nerve abnormalities. We evaluated the clinical significance of myocardial MIBG imaging as a measure of cardiac sympathetic nervous system function by comparing it to heart rate variability and plasma norepinephrine level. Methods and Results. In 211 subjects, we analyzed heart rate variability with 24-hour electrocardiography, performed scintigraphy with MIBG, and measured plasma norepinephrine levels. Time and frequency domain measures of heart rate variability were calculated with the Marquette heart rate variability program (Marquette Electronics, Milwaukee, Wis.). Early and late myocardial MIBG uptakes were measured at 15 and 150 minutes after injection, respectively. MIBG clearance rate from the heart and heart-to-lung and heart-to-mediastinum ratios of MIBG activities were calculated. On the whole, heart rate variability, including low-frequency power, correlated positively, but modestly so, with late MIBG uptake and negatively with MIBG clearance rate. The plasma norepinephrine level correlated negatively with late MIBG uptake and with heart rate variability, including low-frequency power, and positively with MIBG clearance rate. Similar correlations were also observed in patient subgroups with coronary artery disease, diabetes mellitus, and renal failure, but these correlations were weak ( R 2 < 0.5). Conclusions. Increased cardiac sympathetic nervous system activity may be associated with increased myocardial MIBG clearance and decreased heart rate variability, including low-frequency power. Because these associations were not strong, however, the combination of heart rate variability with MIBG may allow an interactive assessment of the cardiac autonomic nervous system.