Effects of Feeding-Related Peptides on Neuronal Oscillation in the Ventromedial Hypothalamus.

The ventromedial hypothalamus (VMH) plays an important role in feeding behavior, obesity, and thermoregulation. The VMH contains glucose-sensing neurons, the firing of which depends on the level of extracellular glucose and which are involved in maintaining the blood glucose level via the sympathetic nervous system. The VMH also expresses various receptors of the peptides related to feeding. However, it is not well-understood whether the action of feeding-related peptides mediates the activity of glucose-sensing neurons in the VMH. In the present study, we examined the effects of feeding-related peptides on the burst-generating property of the VMH. Superfusion with insulin, pituitary adenylate cyclase-activating polypeptide, corticotropin-releasing factor, and orexin increased the frequency of the VMH oscillation. In contrast, superfusion with leptin, cholecystokinin, cocaine- and amphetamine-regulated transcript, galanin, ghrelin, and neuropeptide Y decreased the frequency of the oscillation. Our findings indicated that the frequency changes of VMH oscillation in response to the application of feeding-related peptides showed a tendency similar to changes of sympathetic nerve activity in response to the application of these substances to the brain.

Thrombomodulin can predict the incidence of second events in patients with acute coronary syndrome: Single-center, retrospective cohort study.

BACKGROUND: Plasma levels of atherothrombosis-related markers such as endothelial biomarkers have been reported to predict the risk of first acute coronary syndrome (ACS) events. Percutaneous coronary intervention (PCI) by balloon angioplasty and stenting established as a treatment for ACS enabled early discharge and early clinic care. The procedure of PCI, however, may itself be associated with arterial injury with endothelial dysfunction. The clinical significance of those biomarkers for second events in patients after PCI has not yet been completely understood to identify patients who need strict follow-up. METHODS: After the exclusion of 100 patients (60 deaths during hospitalization, 40 severe renal failure), 400 ACS patients (291 males, 71.1±13.0 years) who had undergone successful PCI followed by biomarker assessment within the first postoperative hour were enrolled. We evaluated atherothrombosis-related biomarkers: thrombomodulin (TM), C-reactive protein (CRP), and D-dimer, prothrombin fragment F1+2, and plasminogen activator inhibitor-1, other than those assessed by routine biochemical tests. The outcome after PCI in ACS patients was assessed by the incidence of major adverse cardiovascular events (MACEs). RESULTS: MACEs occurred in 112 patients during the follow-up period (813.9±474.8 days). As in previous reports, patients with MACEs showed decreased left ventricular ejection fraction (LVEF) by echocardiography, elevated brain natriuretic peptide and HbA1c than patients without MACEs. Not only these markers but also TM were significantly associated with MACEs in multivariate analysis. There were no significant correlations between MACEs and CRP. The association between TM and MACEs was especially high (odds ratio 2.73) and unaffected by the stage of cardiac (≤40, 40

Modulation of sympathetic preganglionic neuron activity via adrenergic receptors.

The sympathetic preganglionic neurons (SPNs) play a key role in the sympathetic nervous system. Previous reports have suggested that norepinephrine (NE) directly affects SPNs via both inhibitory hyperpolarization interactions mediated by α2 receptors and excitatory depolarization interactions mediated by α1 receptors. It remains poorly understood, however, whether the excitability of SPNs can be inhibited indirectly (presynaptically) as well as directly (postsynaptically). We intracellularly recorded 41 SPNs using the whole-cell patch-clamp technique in spinal cord slice preparations of neonatal rats. We examined the effects of NE or dexmedetomidine hydrochloride (Dxm) (α2-adrenergic receptor agonist) on SPNs by analyzing the excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs). EPSPs were dominant in 15 SPNs (EPSP-SPNs) and IPSPs were dominant in 7 SPNs (IPSP-SPNs) at baseline. We were unable to analyze the postsynaptic potentials in the other 19 SPNs, due to high frequency of action potential firings (firing-SPNs). At baseline, the membrane potentials and resistances of each type of SPN were similar. NE (1 µM) gradually depolarized the EPSP-SPNs and IPSP-SPNs (P < 0.001) and NE significantly increased the EPSP frequency of the EPSP-SPNs (P < 0.05). Dxm (10 nM) after application of NE decreased the EPSP frequency of the EPSP-SPNs (P < 0.001) and the EPSP voltage and IPSP voltage of the IPSP-SPNs (P < 0.05). In 5 of the 19 firing-SPNs, NE induced membrane hyperpolarization (P < 0.05) and completely inhibited firings. Dxm had no effect in these neurons. The SPNs received inhibitory modulation through α2-adrenergic receptors. Some SPNs can be directly inhibited via effects independent of the α2 receptors.

Primary Pulmonary Artery Intimal Sarcoma Case with Elevated Coagulation Markers.

Primary Sarcoma of the Pulmonary Artery (PAS) is a very rare and miserable disease. The clinical signs and symptoms of PAS are non- specific, which usually prevents diagnosis before surgery or autopsy. The current guidelines for the diagnosis and treatment of PAS have not been well established. Several reported cases of PAS have been mistaken for Pulmonary Artery Thromboembolism (PTE), because the clinical signs and symptoms of PAS are non-specific. Elevated coagulation markers are generally absent in PAS and therefore, support a differential diagnosis of PTE. We herein report a patient with PAS who presented with elevated coagulation markers and later showed rapidly improved values mimicking response of PTE to anticoagulant therapy.

An in vitro experimental model for analysis of central control of sympathetic nerve activity.

Newborn rat brainstem-spinal cord preparations are useful for in vitro analysis of various brainstem functions including respiratory activity. When studying the central control of sympathetic nerve activity (SNA), it is important to record peripheral outputs of the SNA. We developed an in vitro preparation in which neuronal connections between the cardiovascular center in the medulla and SNA peripheral outputs are preserved. Zero- to 1-day-old rats were deeply anesthetized with isoflurane, and the brainstem and spinal cord were isolated with a partial right thoracic cage to record sympathetic nerve discharge from the right thoracic sympathetic nerve trunk (T9-T11). SNA in this preparation was strongly modulated by inspiratory activity. Single-shot electrical stimulation of the ipsilateral rostral ventrolateral medulla (RVLM) induced a transient increase of SNA. Bath application of angiotensin II induced an increase of SNA, and local ipsilateral microinjection of angiotensin II to the RVLM induced a transient increase of SNA. This preparation allows analysis of the central control of the SNA in vitro.

Predictors of Mortality, Rehospitalization for Syncope and Cardiovascular Events in Patients With Cardiovascular Syncope.

BACKGROUND: Predictors of poor outcomes remain unknown for cardiovascular syncope patients after discharge.Methods and Results:We reviewed the medical records of consecutive patients admitted to hospital with cardiovascular syncope. We then performed Cox stepwise logistic regression analysis to identify significant independent factors for death, rehospitalization for syncope, and cardiovascular events. The study group was 206 patients with cardiovascular syncope. Of them, bradycardia was diagnosed in 50%, tachycardia in 27%, and structural disease in 23%. During a 1-year follow-up period, 18 (8%) and 45 (23%) patients, respectively, were rehospitalized for syncope or a cardiovascular event, and 10 (4%) died. Independent predictors of cardiovascular events were systolic blood pressure <100 mmHg (odds ratio [OR] 3.25; 95%confidence interval [CI] 1.41-7.51, P=0.006) and implantation of a pacemaker (OR 0.19; 95% CI 0.05-0.51, P=0.0005) (inverse association). Drug-induced syncope (OR 4.57; 95% CI 1.54-12.8, P=0.007) was an independent risk factor for rehospitalization. Finally, a history of congestive heart failure (OR 11.0; 95% CI 2.78-54.7, P=0.0006) and systolic blood pressure <100 mmHg (OR 5.40; 95% CI 1.30-22.7, P=0.02) were identified as significant independent prognostic factors for death. CONCLUSIONS: Drug-induced syncope, hypotension, no indication for a pacemaker, and a history of congestive heart failure are risk factors post-discharge for patients with cardiovascular syncope and careful follow-up of these patients for at least 1 year is recommended.

Immediate discontinuation of ablation during pulmonary vein isolation remarkably decreases the incidence of esophageal thermal lesions even when using steerable sheaths.

BACKGROUND: Left atrial-esophageal fistulas (LAEFs) are serious complications with high mortality after atrial fibrillation radiofrequency ablation (AFRA). Decreasing the incidence of esophageal thermal lesions (EsoTLs) that may lead to LAEFs is important. The aim of this study was to suppress EsoTL development and determine the appropriate alarm setting for a temperature-monitoring probe by using steerable sheath (STS) methods. METHODS: We enrolled 82 consecutive patients (mean, 61.9±11.7 years; 75.6% men) who underwent AFRA, including pulmonary vein isolation for symptomatic, drug-refractory atrial fibrillation with esophageal temperature monitoring by using STS between January 2011 and April 2014. All patients underwent upper gastrointestinal endoscopy (UGE) 1-3 days after AFRA. The timing of ablation discontinuation in the first 17 patients was determined by each physician during AFRA (only monitoring group, OM). In the next 65 patients, physicians were to immediately discontinue ablation when an alarm set at 39 °C went off (instruction group, INS). We compared two groups with respect to the incidence of EsoTLs. RESULTS: Among the 82 patients, 5 (6.1%) had EsoTLs after AFRA. EsoTLs occurred in 3 of 17 patients (17.6%) and 2 of 65 patients (3.1%) in the OM and INS groups, respectively. The incidence of EsoTLs in the INS group was significantly lower than that in the OM group (p=0.0254). EsoTL did not occur at maximal temperature less than 39 °C, measured by using esophageal temperature-monitoring probe. CONCLUSIONS: Immediate discontinuation of ablation during pulmonary vein isolation remarkably decreased the incidence of EsoTLs, even when using STS.

Interaction between novel oscillation within the ventromedial hypothalamus and the sympathetic nervous system.

The ventromedial hypothalamus (VMH) is known to play an important role in feeding behavior and the control of sympathetic nerve activity (SNA). We report the identification of novel neuron groups that showed oscillations on both sides of the VMH in hypothalamus slice preparations from juvenile rats of postnatal days 5-14. We detected spontaneous rhythmic burst activity with a frequency of around 0.06Hz typically in the dorsolateral region of the VMH (i.e., VMH oscillation) using optical recordings (voltage and calcium imaging), field potential recordings and intracellular membrane potential recordings. The oscillation was also confirmed after isolation of the VMH from other hypothalamic structures. The frequency of oscillation was increased by lowering the glucose concentration of the superfusate. To evaluate the relation between VMH oscillation and SNA, we simultaneously recorded VMH oscillation, SNA from the thoracic sympathetic nerve trunk and phrenic nerve discharge (Phr) in the decerebrate and arterially perfused in situ preparation from juvenile rats of postnatal days 5-11. Power spectral analysis in the arterially perfused in situ rat preparation revealed similar peak values to those of slice preparations within the low-frequency range between the VMH oscillation and sympathetic nerve trunk activity. In addition, we analyzed cross-correlations between the VMH, SNA and Phr. The results revealed that a predominant positive correlation of the VMH activity with the SNA existed with an average time lag of 2.4s, suggesting the presence of functional couplings between the VMH and SNA (and respiratory center) in the lower brainstem and spinal cord. We hypothesize that the VMH oscillation might be involved in low-frequency modulation of the SNA.

Effects of Aging on the Coagulation Fibrinolytic System in Outpatients of the Cardiovascular Department.

BACKGROUND: Although clinical trials demonstrate that the elderly with atrial fibrillation have risks of thrombosis and bleeding, the relationship between aging and coagulation fibrinolytic system in "real-world" cardiology outpatients is uncertain. METHODS AND RESULTS: We retrospectively evaluated 773 patients (mean age: 58 years; 52% men; Asian ethnicity). To thoroughly investigate markers of coagulation and fibrinolysis, we simultaneously measured levels of D-dimer, prothrombin-fragment1+2 (F1+2), plasmin-α2 plasmin inhibitor complex (PIC), and thrombomodulin (TM). There were correlations between aging and levels of F1+2, D-dimer, PIC, and TM (R=0.61, 0.57, 0.49, and 0.30, respectively). We compared 3 age groups, which were defined as the Y group (<64 years), M group (65-74 years), and the O group (>75 years). Levels of markers were higher in older individuals (D-dimer: 1.0±0.8 vs. 0.8±0.8 vs. 0.6±0.4 µg/ml, F1+2: 281.8±151.3 vs. 224.6±107.1 vs. 155.5±90.0 pmol/L, PIC: 0.9±0.3 vs. 0.8±0.3 vs. 0.6±0.5 µg/ml, and TM: 2.9±0.8 vs. 2.7±0.7 vs. 2.5±0.7FU/ml). We performed logistic regression analysis to determine F1+2 and PIC levels. Multivariate analysis revealed that aging was the most important determinant of high F1+2 and PIC levels. CONCLUSIONS: Hypercoagulable states develop with advancing age in "real-world" cardiology outpatients. (Circ J 2016; 80: 2133-2140).

Recurrence of atrial fibrillation within three months after pulmonary vein isolation for patients with paroxysmal atrial fibrillation: Analysis using external loop recorder with auto-trigger function.

BACKGROUND: Pulmonary vein isolation (PVI) via catheter ablation has been shown to be a highly effective treatment option for patients with symptomatic paroxysmal atrial fibrillation (AF). The recurrence of AF within 3 months after PVI is not considered to be the result of ablation procedure failure, because early recurrence of AF is not always associated with late recurrence. We examined the usefulness of an external loop recorder with an auto-trigger function (ELR-AUTO) for the detection of atrial fibrillation following PVI to characterize early recurrence and to determine the implications of AF occurrence within 3 months after PVI. METHODS: Fifty-three consecutive symptomatic patients with paroxysmal AF (age 61.6±12.6 years, 77% male) who underwent PVI and were fitted with ELR-AUTO for 7±2.0 days within 3 months after PVI were enrolled in this study. RESULTS: Of the 33 (62.2%) patients who did not have AF recurrence within 3 months after PVI, only 1 patient experienced AF recurrence at 12 months. Seven (35%) of the 20 patients who experienced AF within 3 months of PVI experienced symptomatic AF recurrence at 12 months. The sensitivity, specificity, positive predictive value, and negative predictive value of early AF recurrence for late recurrence were 87.5%, 71.1%, 35.0%, and 96.9%, respectively. CONCLUSIONS: AF recurrence measured by ELR-AUTO within 3 months after PVI can predict the late recurrence of AF. Freedom from AF in the first 3 months following ablation significantly predicts long-term AF freedom. ELR-AUTO is useful for the detection of symptomatic and asymptomatic AF.

J-Wave in Patients With Syncope.

BACKGROUND: Syncope is a common occurrence. The presence of J-wave, also known as early repolarization, on electrocardiogram is often seen in the general population, but the relationship between syncope and J-wave is unclear. METHODS AND RESULTS: After excluding 67 patients with structural heart disease from 326 with syncope, we classified 259 patients according to the presence or absence of J-wave (≥1 mm) in at least 2 inferior or lateral leads. Head-up tilt test (HUT) was performed for 30 min. If no syncope or presyncope occurred, HUT was repeated after drug loading. Before tilt, 97/259 (37%) had J-wave (57 male, 47.6±22.5 years) and 162 patients had no remarkable change (89 male, 51.1±21.2 years). HUT-positive rate was higher in patients with J-wave, compared with patients without (P<0.0001). The combination of J-wave and descending/horizontal ST segment in the inferior leads was more strongly associated with positive HUT than J-wave with ascending ST segment (odds ratio, 3.23). CONCLUSIONS: Prevalence of J-wave in the inferior or lateral leads was high in patients with syncope and was associated with HUT-induced neurally mediated reflex syncope (NMRS). Furthermore, the combination of J-wave and descending/horizontal ST segment in the inferior leads could be associated with a much higher risk of NMRS.

Daily Dysfunction of Autonomic Regulation Based on Ambulatory Blood Pressure Monitoring in Patients with Neurally Mediated Reflex Syncope.

BACKGROUND: The onset of neurally mediated reflex syncope (NMRS) is associated with dysfunction of the autonomic regulatory system. Yet relatively little is known about the daily conditions of the autonomic regulation system in patients with NMRS. This study elucidated characteristics of daily autonomic function using ambulatory blood pressure monitoring (ABPM) and evaluated the utility of ABPM for NMRS diagnosis. METHODS: Patients with syncope underwent the head-up tilt test (HUT) (80°, 30 minutes). If no syncope occurred, the HUT was repeated with drug loading. ABPM was performed on a different day. RESULTS: The enrolled subjects were 152 consecutive patients with syncope and 12 controls. Sixty-four patients with other diseases related to autonomic dysfunction were excluded. HUT with/without drug loading was positive in 40 patients (Group P) and negative in 48 patients (Group N). The average systolic blood pressure (SBP) in daytime was lower in Groups P and N than in the control group (Group C) (P < 0.05). The average diastolic blood pressure in daytime was also lower in Group P than in Group C (P < 0.05). The average standard deviation-SBP at nighttime was higher in Groups P and N than in Group C (P < 0.05). In heart rate variability analysis, Group P had higher high frequency normalized unit in daytime than Groups C and N (P < 0.05, P < 0.1). Low frequency/high frequency was lower in Group P than in Group N in both daytime and nighttime (P < 0.1, P < 0.05). CONCLUSION: This study suggests that patients with NMRS present with daily vagal hyperactivity and sympathetic dysfunction. ABPM may support the diagnosis of NMRS.

Effects of α2-adorenoceptor agonist dexmedetomidine on respiratory rhythm generation of newborn rats.

Dexmedetomidine, an α2-adrenoceptor agonist which has a slight side effect on breathing, is clinically used as an analgesic and sedative agent. Previous studies have shown depressing or modest effects of α2-adorenoceptor agonists on respiratory rhythm generation in newborn rat preparation in vitro. In contrast, it was recently reported that dexmedetomidine induced long-lasting activation of respiratory rhythm in brainstem-spinal cord preparation isolated from neonatal mice. In the present study, we examined whether dexmedetomidine induces any effects on respiratory rhythm in brainstem-spinal cord preparation isolated from newborn rats. We also examined the effects of dexmedetomidine on reflex response in the spinal cord, which is presumed to be an indication of nociceptive response. We found that the administration of dexmedetomidine, at the range of 0.1-10µM, dose-dependently depressed respiratory rhythm and that the inhibitory effect was reversed by atipamezole, an α2-adorenoceptor antagonist. Spinal cord reflex responses were depressed by the application of dexmedetomidine at the range of 0.1-1nM, a lower concentration than that affecting respiratory rhythm. The inhibitory effect was also reversed by atipamezole. Our findings provide neuronal mechanisms that support the clinical use of dexmedetomidine, which shows sedative and antinociceptive effects with minimal side effects on breathing.

Single center experience in Japanese patients with syncope.

BACKGROUND AND PURPOSE: The present diagnostic method and features of syncope in Japan are unclear. Implantable loop recorder (ILR) and head-up tilt tests have recently become available for diagnosing syncope. The examination method and rates of diagnosing syncope may vary. This study aimed to clarify the present diagnostic method and features of syncope in a single Japanese medical center. METHODS AND RESULTS: We retrospectively reviewed the medical records of consecutive patients who were seen at our hospital from January 1, 2009, to December 31, 2012. A total of 547 patients (328 men, 60.4±21.5 years) with syncope were seen at our hospital. Reflex syncope was diagnosed in 29.1% of the cases, orthostatic hypotension in 11.7%, cardiac syncope in 34.0%, and unexplained syncope in 23.9% by initial and early evaluations. The number of patients with situational syncope and orthostatic hypotension that could be diagnosed in the initial evaluation of the first examination was significantly greater than that in subsequent evaluations. Forty-three percent of the unexplained syncope patients received an ILR. The consent rate for ILR implantations in the unexplained syncope patients with a suspected arrhythmia nature was 53.1%. The cumulative ILR diagnostic rates were 47% and 65% at 1 and 2 years after the ILR implantation, respectively. The estimated ILR diagnostic rates were significantly greater than that for conventional test without using an ILR. When patients with unexplained syncope could be diagnosed, the recurrent symptoms were greatly reduced. CONCLUSIONS: Syncope is induced by various causes in Japan. It is important that we understand the characteristics of each syncope cause. The consent rate for implanting an ILR in appropriate unexplained syncope patients is low. We need to educate these patients about the importance of making a diagnosis of syncope.

A temporal window of vulnerability for development of atrial fibrillation with advancing heart failure.

AIMS: Heart failure (HF) is associated with development of AF and life-threatening ventricular tachycardia and fibrillation (VT/VF). Vulnerability to development of AF and VT/VF at different stages of HF and the underlying pathophysiological mechanisms are poorly defined. The present study was designed to determine the time-course of development of electrical and structural remodelling of the atria and ventricles, and their contribution to induction of AF and VT/VF in a canine model of HF. METHODS AND RESULTS: Dogs were ventricular tachypaced (VTP) for 2-3 weeks or 5-6 weeks ('early' and 'late' HF, respectively). Electrophysiological studies were performed in isolated atrial and ventricular preparations and correlated with cardiac dimensions and haemodynamic parameters recorded in vivo. Vulnerability to programmed electrical stimulation-induced AF was greater in early vs. late stages of HF (78% vs. 38%). In contrast, VT/VF was inducible in late but not in early stages of HF (38% vs. 0%). The temporal distinction in atrial and ventricular arrhythmia susceptibility was associated with a much more rapid development of electrical and structural remodelling in atria. Vulnerability to AF developed following moderate electro-structural remodelling and waned with further progression to severe remodelling, which averted rapid atrial activation. CONCLUSIONS: A temporal window of vulnerability for AF appears relatively early during development of VTP-induced HF in dogs, whereas VT/VF vulnerability is observed at more advanced stages of HF. These findings, if confirmed in humans, may have clinical implications with regard to prognosis and approach to therapy of patients with HF.

Effect of Wenxin Keli and quinidine to suppress arrhythmogenesis in an experimental model of Brugada syndrome.

BACKGROUND: Wenxin Keli (WK), a Chinese herb extract, is reported to be effective in the treatment of atrial and ventricular cardiac arrhythmias. Recent studies suggest that WK inhibits the transient potassium outward current (I(to)). OBJECTIVE: To examine the effectiveness of WK, alone and in combination with quinidine, to suppress arrhythmogenesis in an experimental model of Brugada syndrome (BrS). METHODS: Action potential and electrocardiographic recordings were obtained from epicardial and endocardial sites of coronary-perfused canine right ventricular wedge preparations. The Ito agonist NS5806 (10-15 µM) was used to pharmacologically mimic a genetic predisposition to BrS. RESULTS: The Ito agonist induced Phase 2 reentry (P2R) in 13/19 preparations and polymorphic ventricular tachycardia (pVT) in 11/19 wedge preparations. WK (10 g/L) suppressed P2R and pVT in 100% (3/3) of preparations. A lower concentration of WK (5 g/L) suppressed P2R in 60% (3/5) and pVT in 50% (2/4), but in combination with a low concentration of quinidine (5 µM), was 100% effective in suppressing P2R and pVT. Quinidine alone suppressed P2R and pVT in 60% (3/5) and 50% (2/4), respectively, and in combination with WK (5 g/L) suppressed P2R and pVT by 80% (4/5) and 75% (3/4), respectively. WK reduced Ito, the L-type calcium current, and contractility in single cardiomyocytes, but dose-dependently increased contractility in intact wedge preparations, an effect mimicked by tyramine. CONCLUSIONS: Our data provide support for the hypothesis that WK, particularly in combination with quinidine, effectively suppresses arrhythmogenesis in an experimental model of BrS via inhibition of Ito and indirect adrenergic sympathomimetic effects.

Ionic and cellular mechanisms underlying the development of acquired Brugada syndrome in patients treated with antidepressants.

INTRODUCTION: Tricyclic antidepressants are known to induce cardiac arrhythmias at therapeutic or supratherapeutic doses. The tricyclic antidepressant, amitriptyline, is reported to induce ST segment elevation in the right precordial electrocardiogram (ECG) leads, thus unmasking Brugada syndrome (BrS). The mechanism by which antidepressants induce the BrS phenotype and associated sudden death is not well established. METHODS AND RESULTS: Action potentials (AP) were simultaneously recorded from epicardial and endocardial sites of isolated coronary-perfused canine right ventricular wedge preparations, together with a transmural pseudo-ECG. Amitriptyline alone (0.2 µM-1 mM) failed to induce a BrS phenotype. NS5806 (8 µM), a transient outward potassium channel current (I(to) ) agonist, was used to produce an outward shift of current mimicking a genetic predisposition to BrS. In the presence of NS5806, a therapeutic concentration of amitriptyline (0.2 µM) accentuated the epicardial AP notch leading to ST-segment elevation of the ECG. All-or-none repolarization at some epicardial sites but not others gave rise to phase-2-reentry and polymorphic ventricular tachycardia (VT) in 6 of 9 preparations. Isoproterenol (100 nM) or quinidine (10 µM) reversed the effects of amitriptyline aborting phase 2 reentry and VT (4/4). Using voltage-clamp techniques applied to isolated canine ventricular myocytes, 0.2 µM amitriptyline was shown to produce use-dependent inhibition of sodium channel current (I(Na) ), without significantly affecting I(to) (n = 5). CONCLUSIONS: Our data suggest that amitriptyline-induced inhibition of I(Na) unmasks the Brugada ECG phenotype and facilitates development of an arrhythmogenic substrate only in the setting of a genetic predisposition by creating repolarization heterogeneities that give rise to phase 2 reentry and VT.

Electrophysiological responses of sympathetic preganglionic neurons to ANG II and aldosterone.

The intermediolateral cell column (IML) of the spinal cord is an important area where sympathetic impulses propagate to peripheral sympathetic organs. ANG II and aldosterone are important components of the renin-angiotensin-aldosterone system (RAAS), which activate the sympathetic nervous system. Each is partly synthesized in the brain and plays a paracrine role in the regulation of blood pressure independently of RAAS in the periphery. Our purpose in the present study was to clarify the contributions of sympathetic preganglionic neurons in the IML (IML neurons) and the effects of ANG II and aldosterone on the sympathetic nervous system. To examine responses to ANG II and aldosterone, we intracellularly recorded 104 IML neurons using a whole cell patch-clamp technique in spinal cord slice preparations. IML neurons were classified into two types: silent and firing. Both neuron types were significantly depolarized by ANG II, and candesartan inhibited this depolarization. After pretreatment with TTX, firing neurons (but not silent neurons) were significantly depolarized by ANG II. Aldosterone significantly increased the number of excitatory postsynaptic potentials (EPSPs) in both neuron types, but this response disappeared after pretreatment with TTX. ANG II and aldosterone had no synergistic effects on the IML neurons. The silent neurons had large cell soma, and many more dendrites than the firing neurons. These results suggest that ANG II acts presynaptically and postsynaptically in IML neurons, while aldosterone acts mainly presynaptically. Thus, the physiological effects of these substances are likely to be transmitted via specific membrane receptors of IML and/or presynaptic neurons.

Hemodynamics changes after tilting and the efficacy of preventive drugs.

BACKGROUND: We investigated whether hemodynamics changes during head-up tilt test (HUT) predict the efficacy of preventive drugs in neurally mediated syncope (NMS) patients, in order to clarify the differences between drug responders and nonresponders. METHOD: In 402 patients with syncope, we examined HUT. In 66 patients with induced NMS, we administered propranolol when heart rate (HR) > 60 and systolic blood pressure (SBP) > 100 mmHg. When HR or= 100, we administered disopyramide. After administration of each drug we examined HUT test again. RESULTS: Propranolol prevented NMS in 9/20 patients (propranolol responder group (pro-res group)). In pro-res group, systolic blood pressure (SBP), diastolic BP (DBP), and total peripheral resistance (TPR) at upright position (UP) before propranolol were significantly increased as compared to those at supine position (SP) (P < 0.05). But in propranolol nonresponder (pro-nonres group) SBP was not increased. After propranolol, DBP and TPR at UP was not increased in pro-nonres group. Propranolol inhibited the increase of low-frequency/high-frequency ratio (LF/HF) after tilting in pro-res group. Disopyramide prevented NMS in 14/32 patients (disopyramide responder group (dis-res group)). In dis-res group, DBP and TPR at UP before disopyramide was significantly increased as compared to that at SP (DBP P < 0.0001, TPR P < 0.05). But in disopyramide nonresponder group (dis-nonres group), DBP and TPR were not increased. After disopyramide, DBP and TPR at SP were significantly increased as compared to that before disopyramide in dis-res group (P < 0.05). CONCLUSION: The hemodynamics changes after tilting during HUT predict the efficacy of two preventive drugs for NMS induced by HUT.

Combination therapy of renin angiotensin system inhibitors and bepridil is useful for maintaining sinus rhythm in patients with atrial fibrillation.

BACKGROUND: The present study evaluated the effect of treatment renin angiotensin system inhibitors (RAS-I) for maintaining sinus rhythm after conversion from persistent atrial fibrillation. As the efficacy of RAS-I in atrial fibrillation is unclear, our study evaluated conversion to and maintenance of sinus rhythm by combination therapy with RAS-I and bepridil in patients in atrial fibrillation. METHODS: Bepridil was administered to 125 consecutive patients with paroxysmal and persistent atrial fibrillations. Two groups of patients were compared: The bepridil group was treated with bepridil alone, the RAS-I group with bepridil plus angiotensin II receptor blockers or angiotensin converting enzyme inhibitors. The primary end point was length of time to first recurrence of atrial fibrillation. RESULTS: Maintenance of sinus rhythm was achieved in 25 patients (45%) in the bepridil group and 44 patients (63%) in the RAS-I group (persistent and paroxysmal atrial fibrillations). The difference between the bepridil group and the RAS-I group was significant (p < 0.05). Maintenance of sinus rhythm was achieved in 9 of 25 patients (36%) in the bepridil group, and in 22 of 35 patients (62%) in the RAS-I group with persistent atrial fibrillation. The difference between the bepridil group and the RAS-I group was significant (p < 0.05). Bepridil plus RAS-I was particularly effective at preventing the recurrence of atrial fibrillation in patients with left ventricular dysfunction (left ventricular ejection fraction < 50%). CONCLUSIONS: Combination therapy with RAS-I and bepridil may be useful for maintenance of sinus rhythm.