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Catheter ablation (CA) to isolate the pulmonary vein, which is an established treatment for atrial fibrillation (AF), is associated with left atrium reverse remodeling (LARR). The intrinsic cardiac autonomic nervous system includes the ganglion plexi adjacent to the pulmonary vein in the left atrium (LA). However, little is known about the effect of CA on the relationship between LARR and sympathetic nerve activity in patients with AF.This study enrolled 22 AF patients with a normal left ventricular ejection fraction (LVEF) aged 64.6 ± 12.9 years who were scheduled for CA. Sympathetic nerve activity was evaluated by direct recording of muscle sympathetic nerve activity (MSNA) before and 12 weeks after CA. Blood pressure, heart rate (HR), HR variability, and echocardiography were also measured.The heart rate increased significantly after CA (63 ± 10.9 vs. 70.6 ± 7.7 beats/min, p 0.01), but blood pressure did not change. A high frequency (HF) and low frequency (LF) of HR variability decreased significantly after ablation, but no significant change in LF/HF was observed. CA significantly decreased MSNA (38.9 ± 9.9 vs. 28 ± 9.1 bursts/min, p 0.01). Moreover, regression analysis revealed a positive correlation between the percentage change in MSNA and the LA volume index (r = 0.442, p 0.05).Our results show that CA for AF reduced MSNA and the decrease was associated with the LA volume index in AF patients with a normal LVEF. These findings suggest that LARR induced by CA for AF decrease sympathetic nerve activity.

Background Sodium‐glucose cotransporter 2 inhibitors improve cardiovascular outcomes in patients with diabetes with and without heart failure (HF). However, their influence on sympathetic nerve activity (SNA) remains unclear. The purpose of this study was to evaluate the effect of sodium‐glucose cotransporter 2 inhibitors on SNA and compare the responses of SNA to sodium‐glucose cotransporter 2 inhibitors in patients with type 2 diabetes with and without HF. Methods and Results Eighteen patients with type 2 diabetes, 10 with HF (65.4±3.68 years) and 8 without HF (63.3±3.62 years), were included. Muscle SNA (MSNA), heart rate, and blood pressure were recorded before and 12 weeks after administration of dapagliflozin (5 mg/day). Sympathetic and cardiovagal baroreflex sensitivity were simultaneously calculated. Brain natriuretic peptide level increased significantly at baseline in patients with HF than those without HF, while MSNA, blood pressure, and hemoglobin A1c did not differ between the 2 groups. Fasting blood glucose and homeostatic model assessment of insulin resistance did not change in either group after administering dapagliflozin. MSNA decreased significantly in both groups. However, the reduction in MSNA was significantly higher in patients with HF than patients with non‐HF (−20.2±3.46 versus −9.38±3.65 bursts/100 heartbeats; P =0.049), which was concordant with the decrease in brain natriuretic peptide. Conclusions Dapagliflozin significantly decreased MSNA in patients with type 2 diabetes regardless of its blood glucose‐lowering effect. Moreover, the reduction in MSNA was more prominent in patients with HF than in patients with non‐HF. These results indicate that the cardioprotective effects of sodium‐glucose cotransporter 2 inhibitors may, in part, be attributed to improved SNA.

BACKGROUND Obstructive sleep apnea syndrome (OSAS) is associated with augmented sympathetic nerve activity and cardiovascular diseases. However, the interaction between coronary artery plaque characteristics and sympathetic nerve activity remains unclear. The purpose of this study was to clarify the relationships between coronary artery plaque characteristics, sleep parameters and single- and multi-unit muscle sympathetic nerve activity (MSNA) in OSAS patients. Methods and Results: A total of 32 OSAS patients who underwent full-polysomnography participated in this study. The coronary plaque volume was calculated with 320-slice coronary computed tomography (CT). Single- and multi-unit MSNA were obtained during the daytime within 1 week from full-polysomnography. Patients were divided into 2 groups according to their apnea-hypopnea index (AHI) score (mild-moderate group, AHI

Objective We aimed to identify obstructive sleep apnea syndrome (OSAS) severity indices reflecting the anthropometric and metabolic characteristics of patients with OSAS. Methods A total of 76 patients with OSAS underwent nasal continuous positive airway pressure (nCPAP). We also investigated the effects of nCPAP on OSAS-associated muscle sympathetic nerve activity (MSNA), risk for cardiovascular diseases, and insulin secretion and sensitivity. Results Among the OSAS severity indices, HbA1c was significantly correlated with the apnea-hypopnea index, whereas HOMA-beta, HOMA-IR, and hepatic insulin resistance were significantly correlated with % SpO2

Background: Intestinal angina is characterized by recurrent postprandial abdominal pain and anorexia. Commonly, these symptoms are caused by severe stenosis of at least two vessels among the celiac and mesenteric arteries. However, intestinal perfusion is affected not only by the degree of arterial stenosis but also by systemic perfusion. We experienced a unique case of intestinal angina caused by relatively mild stenosis of the abdominal arteries complicated with hypertrophic obstructive cardiomyopathy. Case presentation: We report an 86-year old Japanese man with hypertrophic obstructive cardiomyopathy and advanced atrioventricular block who was diagnosed with intestinal angina. Computed tomography showed mild stenosis of the celiac artery and severe stenosis of the inferior mesenteric artery, and these lesions were relatively mild compared with other reports. A dual-chamber pacemaker with right ventricular apical pacing was implanted to improve the obstruction of the left ventricular outflow tract. After implantation, the patient's abdominal symptoms diminished markedly, and improvement of the left ventricular outflow tract obstruction was observed. Conclusions: Although intestinal angina is generally defined by severe stenosis of at least two vessels among the celiac and mesenteric arteries, the present case suggests that hemodynamic changes can greatly affect intestinal perfusion and induce intestinal angina in the presence of mild stenosis of the celiac and mesenteric arteries. © 2016 The Author(s).

IntroductionFamilial hypercholesterolaemia (FH) is an autosomal-dominant inherited genetic disease. It carries an extremely high cardiovascular risk associated with significantly elevated low-density lipoprotein (LDL) cholesterol. The diagnostic rate of this disease in some European nations is quite high, due to the presence of multiple prospective registries. On the other hand, few data—and in particular multicentre data—exist regarding this issue among Japanese subjects. Therefore, this study intends to assemble a multicentre registry that aims to comprehensively assess cardiovascular risk among Japanese FH patients while taking into account their genetic backgrounds.Methods and analysisThe Hokuriku-plus FH registry is a prospective, observational, multicentre cohort study, enrolling consecutive FH patients who fulfil the clinical criteria of FH in Japan from 37 participating hospitals mostly in Hokuriku region of Japan from April 2020 to March 2024. A total of 1000 patients will be enrolled into the study, and we plan to follow-up participants over 5 years. We will collect clinical parameters, including lipids, physical findings, genetic backgrounds and clinical events covering atherosclerotic and other important events, such as malignancies. The primary endpoint of this study is new atherosclerotic cardiovascular disease (ASCVD) events. The secondary endpoints are as follows: LDL cholesterol, secondary ASCVD events and the occurrence of other diseases including hypertension, diabetes and malignancies.Ethics and disseminationThis study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. This study protocol has been approved by the Institutional Review Board at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal.Trial registration numberUMIN000038210.

OBJECTIVE Calcium channel blockers (CCBs) are used as antihypertensive agents and have a strong vasodilatory effect; however, the sympathetic activation mediated by baroreflex might cause adverse effects. A recently developed CCB, azelnidipine, decreases the heart rate (HR) while lowering blood pressure (BP), possibly by inhibiting sympathetic nerve activity in animal models. In this study, we evaluated whether azelnidipine inhibited sympathetic nerve activity, compared to amlodipine, in primary hypertensive patients. DESIGN AND METHODS We conducted a prospective, randomized, open-label, and crossover study of 14 patients. We measured the patients' BP, HR and baroreflex sensitivity, and directly recorded muscle sympathetic nerve activity (MSNA), via microneurography, after treatment with either CCB for 8 weeks. RESULTS Although systolic and diastolic BPs did not differ between the azelnidipine and amlodipine groups, the HR in the azelnidipine group significantly decreased compared with that in the amlodipine group. MSNA was significantly reduced in the azelnidipine compared with the amlodipine group (47.7 ± 14.9 vs. 61.5 ± 10.7 bursts per 100 beats, P

Sympathetic activation in chronic heart failure (CHF) is greatly augmented at rest but the response to exercise remains controversial. We previously demonstrated that single-unit muscle sympathetic nerve activity (MSNA) provides a more detailed description of the sympathetic response to physiological stress than multi-unit nerve recordings. The purpose of this study was to determine whether the reflex response and discharge properties of single-unit MSNA are altered during handgrip exercise (HG, 30% of maximum voluntary contraction for 3 min) in CHF patients (New York Heart Association functional class II or III, n= 16) compared with age-matched healthy control subjects (n= 13). At rest, both single-unit and multi-unit indices of sympathetic outflow were augmented in CHF compared with controls (P < 0.05). However, the percentage of cardiac intervals that contained one, two, three or four single-unit spikes were not different between the groups. Compared to the control group, HG elicited a larger increase in multi-unit total MSNA (Δ1002 ± 50 compared with Δ636 ± 76 units min−1, P < 0.05) and single-unit MSNA spike incidence (Δ27 ± 5 compared with Δ8 ± 2 spikes (100 heart beats)–1), P < 0.01) in the CHF patients. More importantly, the percentage of cardiac intervals that contained two or three single-unit spikes was increased (P < 0.05) during exercise in the CHF group only (Δ8 ± 2% and Δ5 ± 1% for two and three spikes, respectively). These results suggest that the larger multi-unit total MSNA response observed during HG in CHF is brought about in part by an increase in the probability of multiple firing of single-unit sympathetic neurones.

Background It has been reported that sympathetic nerve activity (SNA) is associated with fibrinolysis, but the interaction between SNA and the fibrinolytic system with aging has not been elucidated in humans. The purpose of this study was to examine the effect of age-related SNA on the activity of plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (tPA) using muscle SNA (MSNA). Methods and Results This study included 16 young subjects (mean age 26.1 years) and 10 aged subjects (mean age 56.9 years). Lower body negative pressure (LBNP) was performed at -40 mmHg for 30 min. LBNP significantly increased both tPA and PAI-1 activity (from 5.2±0.5 to 7.3±1.2 IU/ml and from 2.85±0.68 to 4.06±0.73 U/ml, p

It has been shown that cigarette smoking increases blood pressure (BP) and heart rate (HR), and decreases muscle sympathetic nerve activity (MSNA) in healthy young smokers. The decrease in MSNA might be secondary to baroreflex responses to the pressor effect. We tested the hypothesis that cigarette smoking increases MSNA in smokers with impaired baroreflex function. The effects of cigarette smoking on BP, HR, forearm blood flow (FBF), forearm vascular resistance (FVR), and MSNA were examined in 14 patients with stable effort angina (59 ± 3 years, group CAD) and 10 healthy smokers (23 ± 1 years, group C). In group CAD, the arterial baroreflex sensitivity (BRS) was significantly lower than in group C (4.7 ± 0.8 versus 15.1 ± 2.2 msec/mmHg, P < 0.01). In both groups, cigarette smoking increased the plasma concentration of nicotine, systolic and diastolic BP, HR, and FVR significantly (P < 0.01), but decreased FBF significantly (P < 0.01). After smoking, MSNA was decreased significantly in group C (from 35.2 ± 3.5 to 23.5 ± 3.2 bursts/100 beats, P < 0.01), but increased significantly in group CAD (from 48.8 ± 5.4 to 57.3 ± 5.5 bursts/100 beats, P < 0.01). There was significant correlation between BRS and changes in MSNA (r = -0.62, P < 0.01). Cigarette smoking increased MSNA in smokers with impaired baroreflex function. This demonstrates that cigarette smoking stimulates sympathetic nerve activity by both a direct peripheral effect and a centrally mediated effect.

Background The number of the elderly patients with atrial fibrillation (AF) is increasing, but the current status of anticoagulation therapy for elderly patients with AF in Japan is not clear. Methods and Results Among the patients registered in the "Hokuriku Atrial Fibrillation Trial (HAT) 1", 365 AF patients aged ≥65 years were enrolled in this study. Warfarin was used for significantly less patients in the oldest group aged ≥85 years (36%) than in younger populations, but the percentage of antiplatelet use in this oldest population was largest (40%). The elderly group (≥85 years) was compared with a younger group aged between 75 and 84 years. Warfarin was given to 61% of the younger group compared with 36% in the elderly group. In the younger group, the more thromboembolic risks they had according to CHADS2 score, the more warfarin was used, whereas there was no clear trend in the usage of warfarin in the elderly group. Conclusions The number of elderly Japanese patients with AF taking warfarin is currently low, but because the population of elderly AF patients will increase in the future, there is a need for safe and suitable anticoagulation therapy for elderly patients. (Circ J 2008; 72: 2058 - 2061)

Obstructive sleep apnea syndrome (OSAS) is associated with augmented sympathetic nerve activity, as assessed by multi-unit muscle sympathetic nerve activity (MSNA). However, it is still unclear whether single-unit MSNA is a better reflection of sleep apnea severity according to the apnea-hypopnea index (AHI). One hundred and two OSAS patients underwent full polysomnography and single- and multi-unit MSNA measurements. Univariate and multivariate regression analysis were performed to determine which parameters correlated with OSAS severity, which was defined by the AHI. Single- and multi-unit MSNA were significantly and positively correlated with AHI severity. The AHI was also significantly correlated with multi-unit MSNA burst frequency (r = 0.437, p < 0.0001) and single-unit MSNA spike frequency (r = 0.632, p < 0.0001). Multivariable analysis revealed that SF was correlated most significantly with AHI (T = 7.27, p < 0.0001). The distributions of multiple single-unit spikes per one cardiac interval did not differ between patients with an AHI of 55. These results suggest that sympathetic nerve activity is associated with sleep apnea severity. In addition, single-unit MSNA is a more accurate reflection of sleep apnea severity with alternation of the firing pattern, especially in patients with very severe OSAS.

Diabetes-Related AF. Introduction: Diabetes mellitus is one of the significant independent risk factors for the development of atrial fibrillation (AF). However, the pathophysiological mechanisms of the relationship have not been fully elucidated. Methods and Results: The genetic type II diabetes (GK) rats and their original (Wistar) ones were subjected to electrophysiological (n = 8 per group) and histological (n = 7 per group) studies. At 40 weeks old, when GK rats had significantly (P < 0.01) more increased plasma glucose and HbA 1c values than Wistar rats, atrial electrical stimuli in the isolated-perfused hearts induced significantly greater number of repetitive atrial responses in GK rats than in Wistar rats (47.9 ± 17.5 vs 3.1 ± 1.3 beats, respectively, P < 0.01). GK rats showed significantly longer intra-atrial activation time than Wistar rats (18.3 ± 0.4 ms vs 15.9 ± 0.5 ms, P < 0.01) without any significant difference in the atrial refractoriness. The histological examination revealed significantly increased diffuse fibrotic deposition in GK rats atria compared with Wistar ones (P < 0.01). Conclusion: The present diabetic GK rat showed increased atrial arrhythmogenicity with intra-atrial conduction disturbance, and thus indicated that the structural remodeling of atrium characterized by diffuse interstitial fibrosis would be a major substrate for diabetes-related AF.

We speculated that the sphingosine-1-phosphate (S1P) receptor S1P(2), which uniquely inhibits cell migration, might mediate inhibitory effects on endothelial cell migration and angiogenesis, different from S1P(1) and S1P(3). Mouse vascular endothelial cells, which endogenously express S1P(2) and S1P(3), but not S1P(1), responded to S1P and epidermal growth factor (EGF) with stimulation of Rac, migration, and the formation of tube-like structures on the Matrigel. The S1P(3)-antagonist VPC-23019 abolished S1P-induced, G(i)-dependent Rac stimulation, cell migration, and tube formation, whereas the S1P(2)-antagonist JTE-013 enhanced these S1P-induced responses, suggesting that S1P(2) exerts inhibitory effects on endothelial Rac, migration, and angiogenesis. S1P(2) overexpression markedly augmented S1P-induced, G(i)-independent inhibition of EGF-induced migration and tube formation. Finally, the blockade of S1P(2) by JTE-013 potentiated S1P-induced stimulation of angiogenesis in vivo in the Matrigel implant assay. These observations indicate that in contrast to S1P(1) and S1P(3), S1P(2) negatively regulates endothelial morphogenesis and angiogenesis most likely through down-regulating Rac.

In order to determine the effect of pimobendan on sympathetic nerve activity and cardiopulmonary baroreflex (CPB), electrocardiogram, direct arterial pressure, central venous pressure (CVP) and cardiac output were recorded along with muscle sympathetic nerve activity (MSNA) in 8 healthy young men. CPB function was evaluated before and 60 min after oral administration of 5 mg pimobendan using the response of MSNA to lower body negative pressure (LBNP) of − 5 and − 10 mm Hg. The same protocol also was performed during handgrip exercise. Cardiac index, MSNA increased and CVP decreased significantly (p

Brugada Syndrome and Sodium Channel Blockade. Brugada syndrome is an inherited cardiac disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel a subunit, which can lead ventricular fibrillation and sudden death. Inattentive use of antiarrhythmic drugs potentially triggers fatal cardiac arrhythmias through further reduction of sodium current (I N a ). We studied the molecular mechanism underlying a case of Brugada syndrome that showed no response to a class Ic antiarrhythmic drug. Molecular genetic studies of a patient with Brugada syndrome identified a novel mutation in SCN5A, which causes substitution of serine for asparagine (N406S) in S6 of domain I (IS6). The provocation test with pilsicainide, a class Ic antiarrhythmic drug, failed to exacerbate ST-segment elevation in this case. Electrophysiological analyses of the N406S-mutant channel expressed together with the β1 subunit in HEK293 cells showed that the voltage dependence of activation was positively shifted by 16 mV and that intermediate inactivation was enhanced. Whereas tonic block by pilsicainide was not changed in the N406S channel, use-dependent block by pilsicainide was almost completely abolished, consistent with the clinical findings of the negative provocation test. In contrast, the N406S channel showed stronger use-dependent block by quinidine than the wild-type channel. We demonstrate a novel Brugada mutation N406S, which is associated with the discordant effects on blocking actions of antiarrhythmic drugs as well as the multiple channel gating defects. We emphasis that an antiarrhythmic drug may exert unpredicted effects in patients with channel mutations.

Central muscarinic receptors play an important role in the regulation of cardiac vagal nerve activity. We studied the inhibition of central muscarinic receptors and sympathetic nerve function in humans, since very little information is currently available on this subject. We examined the effects of graded doses of atropine (five doses, range 0.001 to 0.016 mg/kg) on heart rate, arterial pressure, heart rate variability, and muscle sympathetic nerve activity in 13 healthy young volunteers. Atropine caused biphasic effects on heart rate and the high-frequency (HF) power of R-R interval variability. At lower doses (< or =0.002 mg/kg for heart rate, 0.001 mg/kg for HF power), atropine decreased heart rate and increased HF power. In contrast, at higher doses, atropine increased heart rate and decreased HF power. Low-dose atropine significantly attenuated muscle sympathetic nerve activity, burst rate (bursts/min) by -30.5 +/- 6.0% and burst incidence (bursts/100 heart beats) by -23.8 +/- 6.9% at 0.002 mg/kg. Systolic and diastolic arterial pressure did not change with atropine infusion. Low-dose atropine (< or =0.002 mg/kg) did not significantly affect either low frequency (LF) power or LF/HF. These results suggest that central muscarinic receptors may modulate not only cardiac vagal nerve activity but also sympathetic nerve activity in the skeletal muscle vasculature.

Objective: The purpose of this study was to examine the feasibility of M-mode tissue Doppler imaging for localizing the accessory pathway in patients with Wolff-Parkinson-White (WPW) syndrome. Methods: Two-dimensional guided tissue Doppler M-mode was recorded at the mitral and tricuspid annular levels in 13 WPW patients. Time intervals were measured from the onset of the δ wave or the R wave to the beginning of the ventricular systolic motion. The earliest contraction site was defined as the site demonstrating the shortest time interval, and compared with the earliest activated site determined by body surface mapping and the successful ablation site. Results: In 6 patients with a left-sided pathway, tissue Doppler localization was identical to the ablation site. In 3 with a left-sided pathway and 3 with a right-sided pathway, localization was judged as an adjacent region of the ablation site. In 1 patient with a right lateral pathway, the pathway location was misdiagnosed. The tissue Doppler diagnosis for the left-sided pathways correlated well with the ablation site, in contrast to the right-sided pathways (p = 0.05). Prediction of the accessory pathway localization by tissue Doppler M-mode was equivalent to localization based on body surface mapping. Conclusions: In WPW syndrome, tissue Doppler M-mode can detect the earliest contraction sites and seems helpful in localizing the left-sided accessory pathways, but is of limited use for right-sided pathways.

The hypothesis that a coronary vasomotion disorder may exist in the entire coronary artery tree in patients with vasospastic angina was investigated by examining the coronary responses to atrial pacing (130 beats/min) before and after the administration of ergonovine (16 micrograms) into nonspastic coronary arteries. Seven patients with angiographically normal coronary arteries and focal spasm in the right coronary artery and 7 control patients with atypical chest pain and angiographically normal coronary arteries without spasm were studied. Great cardiac vein flow (GCVF) and left anterior descending coronary artery diameters (CDs) were measured by the thermodilution method and quantitative arteriography, respectively. Although the CDs before ergonovine were similar in the 2 groups, the pacing-induced increased in GCVF before ergonovine administration was smaller in patients with vasospastic angina than in control patients (22 +/- 4% vs 49 +/- 11%, respectively; p0.05). After ergonovine administration, pacing both increased GCVF and decreased anterior regional coronary resistance (ACR) to a lesser extent in patients with vasospastic angina than in control patients (GCVF, 16 +/- 4% vs 47 +/- 8%, respectively [p0.01]; ACR, -12 +/- 3% vs -29 +/- 3%, respectively [p0.01]). The decreases in CDs in patients with vasospastic angina observed after ergonovine administration were greater than those in control patients (-18 +/- 2% vs -9 +/- 2%, respectively; p0.05). Thus, not only epicardial, but also resistance coronary arteries are affected by the coronary vasomotion disorder in the nonspastic vascular bed in patients with vasospastic angina.

Two cases are presented in which angina pectoris associated with ST segment elevation occurred during either an ergonovine provocation test or coronary angioplasty, despite the absence of epicardial coronary artery obstruction. In both cases, no epicardial coronary spasm, thromboembolic occlusion, coronary air embolus, vessel dissection, or side-branch occlusion was observed. These findings suggest that transmural myocardial ischemia without epicardial coronary artery obstruction can occur owing to abnormalities of the coronary microcirculation. Microvascular vasoconstriction leading to transmural myocardial ischemia may be induced by ergonovine or by the release of potent vasocon strictors from disrupted coronary lesions during angioplasty.

A 25-year-old woman was admitted because of acute myocarditis. Echocardiogram revealed hypokinesis of the left ventricle with increased wall thickness, but on day 7, the wall motion normalized. Cyclic variation of myocardial integrated backscatter on day 1 was reduced to 1.8 dB (normal range, 2.9-5.3 dB) and normalized to 3.2 dB on day 3. The normalization of the cyclic variation of integrated backscatter in the myocardium preceded the recovery of the left ventricular wall contractility, suggesting the ability of tissue characterization to predict recovery of cardiac function. (Circ J 2002; 66: 416 - 418)

Sympathetic activation in chronic heart failure (CHF) is greatly augmented at rest but the response to exercise remains controversial. We previously demonstrated that single-unit muscle sympathetic nerve activity (MSNA) provides a more detailed description of the sympathetic response to physiological stress than multi-unit nerve recordings. The purpose of this study was to determine whether the reflex response and discharge properties of single-unit MSNA are altered during handgrip exercise (HG, 30% of maximum voluntary contraction for 3 min) in CHF patients (New York Heart Association functional class II or III, n = 16) compared with age-matched healthy control subjects (n = 13). At rest, both single-unit and multi-unit indices of sympathetic outflow were augmented in CHF compared with controls (P0.05). However, the percentage of cardiac intervals that contained one, two, three or four single-unit spikes were not different between the groups. Compared to the control group, HG elicited a larger increase in multi-unit total MSNA (Delta1002 +/- 50 compared with Delta636 +/- 76 units min(-1), P0.05) and single-unit MSNA spike incidence (Delta27 +/- 5 compared with Delta8 +/- 2 spikes (100 heart beats)(-1)), P0.01) in the CHF patients. More importantly, the percentage of cardiac intervals that contained two or three single-unit spikes was increased (P0.05) during exercise in the CHF group only (Delta8 +/- 2% and Delta5 +/- 1% for two and three spikes, respectively). These results suggest that the larger multi-unit total MSNA response observed during HG in CHF is brought about in part by an increase in the probability of multiple firing of single-unit sympathetic neurones.

The arterial pressure (AP) response to hemodialysis was studied with echocardiography and strain gauge plethysmography in 17 patients with end-stage renal disease; mean AP was unchanged in seven (group A) and was reduced by more than 10 mm Hg in 10 patients (group B). Following dialysis, body weight decreased and heart rate increased equally in both groups. Ejection fraction did not change in the two groups. Left ventricular end-diastolic volume fell by 13 +/- 10% in group A and by 24 +/- 16% in group B. Cardiac index (CI) fell in group B, but remained unchanged in group A. Systemic vascular resistance (SVR) did not change in both groups. The change in mean AP before and after dialysis was significantly correlated with that in Cl (r = 0.49, p less than 0.05), but not with that in SVR. Calf venous pressure-volume curves were not different between the two groups before dialysis. Hemodialysis shifted the curve toward the volume axis for group B but not for group A. These results suggest that hypotension following dialysis is mainly due to the fall in cardiac output, in which increases in venous distensibility play an important role.

The number of the elderly patients with atrial fibrillation (AF) is increasing, but the current status of anticoagulation therapy for elderly patients with AF in Japan is not clear.Among the patients registered in the "Hokuriku Atrial Fibrillation Trial (HAT) 1", 365 AF patients agedor =65 years were enrolled in this study. Warfarin was used for significantly less patients in the oldest group agedor =85 years (36%) than in younger populations, but the percentage of antiplatelet use in this oldest population was largest (40%). The elderly group (or =85 years) was compared with a younger group aged between 75 and 84 years. Warfarin was given to 61% of the younger group compared with 36% in the elderly group. In the younger group, the more thromboembolic risks they had according to CHADS2 score, the more warfarin was used, whereas there was no clear trend in the usage of warfarin in the elderly group.The number of elderly Japanese patients with AF taking warfarin is currently low, but because the population of elderly AF patients will increase in the future, there is a need for safe and suitable anticoagulation therapy for elderly patients.

金沢大学医薬保健研究域医学系, Aims: The lysophospholipid mediator sphingosine-1-phosphate (S1P) activates G protein-coupled receptors (GPCRs) to induce potent inhibition of platelet-derived growth factor (PDGF)-induced Rac activation and, thereby, chemotaxis in rat vascular smooth muscle cells (VSMCs). We explored the heterotrimeric G protein and the downstream mechanism that mediated S1P inhibition of Rac and cell migration in VSMCs. Methods and results: S1P inhibition of PDGF-induced cell migration and Rac activation in VSMCs was abolished by the selective S1P2 receptor antagonist JTE-013. The C-terminal peptides of Gα subunits (Gα-CTs) act as specific inhibitors of respective G protein-GPCR coupling. Adenovirus-mediated expression of Gα12-CT, Gα13-CT, and Gα q-CT, but not that of Gαs-CT or LacZ or pertussis toxin treatment, abrogated S1P inhibition of PDGF-induced Rac activation and migration, indicating that both G12/13 and Gq classes are necessary for the S1P inhibition. The expression of Gαq-CT as well as Gα12-CT and Gα13-CT also abolished S1P-induced Rho stimulation. C3 toxin, but not a Rho kinase inhibitor or a dominant negative form of Rho kinase, abolished S1P inhibition of PDGF-induced Rac activation and cell migration. The angiotensin II receptor AT1, which robustly couples to Gq, did not mediate either Rho activation or inhibition of PDGF-induced Rac activation or migration, suggesting that activation of Gq alone was not sufficient for Rho activation and resultant Rac inhibition. However, the AT1 receptor fused to Gα12 was able to induce not only Rho stimulation but also inhibition of PDGF-induced Rac activation and migration. Phospholipase C inhibition did not affect S1P-induced Rho activation, and protein kinase C activation by a phorbol ester did not mimic S1P action, suggesting that S1P inhibition of migration or Rac was not dependent on the phospholipase C pathway. Conclusion: These observations together suggest that S1P2 mediates inhibition of Rac and migration through the coordinated action of G 12/13 and Gq for Rho activation in VSMCs. © The Author 2008..

Background Familial long-QT syndrome (LQTS) is characterized by prolonged ventricular repolarization. Clinical symptoms include recurrent syncopal attacks, and sudden death may occur due to ventricular tachyarrhythmias. Three genes responsible for this syndrome ( KVLQT1 , HERG , and SCN5A ) have been identified so far. We investigated mutations of these genes in LQTS families. Methods and Results Thirty-two Japanese families with LQTS were brought together for screening for mutations. Genomic DNA from each proband was examined by the polymerase chain reaction–single-strand conformation polymorphism technique followed by direct DNA sequencing. In four of the families, comprising 16 patients, mutations were identified in KVLQT1 ; five other families (9 patients) segregated mutant alleles of HERG . All 25 of these patients carried the specific mutations present in their respective families, and none of 80 normal individuals carried these alleles. Mutations were confirmed by endonuclease digestion or hybridization of mutant allele–specific oligonucleotides. No mutation in SCN5A was found in any family. Conclusions We identified nine different mutations among 32 families with LQTS. Eight of these were novel and account for 25% of all types of mutations reported to date. Such a variety of mutations makes it difficult to screen high-risk groups using simple methods such as endonuclease digestion or mutant allele–specific amplification.

Recording of neural firing from single-unit muscle sympathetic nerve activity (MSNA) is a new strategy offering information about the frequency of pure sympathetic firing. However, it is uncertain whether and when single-unit MSNA would be more useful than multiunit MSNA for analysis of various physiological stresses in humans. In 15 healthy subjects, we measured single-unit and multiunit MSNA before and during handgrip exercise at 30% of maximum voluntary contraction for 3 min and during the Valsalva maneuver at 40 mmHg expiratory pressure for 15 s. Shapes of individual single-unit MSNA were proved to be consistent and suitable for further evaluation. Single-unit and multiunit MSNA exhibited similar responses during handgrip exercise. However, acceleration of neural firing determined from single-unit MSNA became steeper than multiunit MSNA during the Valsalva maneuver. During the Valsalva maneuver, unlike handgrip exercise, the distribution of multiunit burst between 0, 1, 2, 3, and 4 spikes was significantly shifted toward multiple spikes within a given burst ( P < 0.05). These results indicated that evaluation of single-unit MSNA could provide more detailed and accurate information concerning the role and responses of neuronal discharges induced by various physiological stresses in humans, especially amid intense sympathetic activity.

The aim of this study was to: (1) evaluate atrial electromechanical coupling using M-mode Doppler tissue; and (2) test its clinical impact for detecting atrial abnormalities in paroxysmal atrial fibrillation (AF). Using Doppler tissue, the time intervals from the onset of P wave until the backward motions of the right and left atrioventricular rings in the apical 4-chamber view corresponding to the atrial contractions were measured. In paroxysmal AF group, these intervals were significantly longer than in the control group. Using the criteria that an abnormal time interval from the onset of P wave until the backward motion of the left atrioventricular ring is longer than 112 milliseconds, the sensitivity, the specificity, and the positive predictive values for paroxysmal AF are 73%, 93%, and 93%, respectively. This parameter is affected in patients with paroxysmal AF and should be useful for detecting atrial impairment related to paroxysmal AF.

Platelet-derived growth factors (PDGFs), potent mitogens and chemoattractants for mesenchymal cell types, play essential roles in development of several organs including blood vessels, kidney, and lung, and are also implicated in the pathogenesis of atherosclerosis and malignancies. Blood lipid mediator sphingosine 1-phosphate (S1P) regulates migration, proliferation, and apoptosis in a variety of cell types through multiple G protein-coupled receptors of the Edg family, and is necessary for vascular formation at the developmental stage. We found in the present study that S1P induced severalfold increases in the mRNA and protein levels of PDGF-A and -B chains in vascular smooth muscle cells and neointimal cells. S1P stimulation of PDGF mRNA and protein expression was abolished by the small interfering RNA duplexes targeting S1P(1)/Edg1 receptor subtype. S1P stimulated the small GTPase Ras in a G(i)-dependent manner, and activated ERK and p38 MAPK in G(i)- and Ras-dependent manners. Pertussis toxin pretreatment, adenovirus-mediated Asn(17)Ras expression, the MEK inhibitor PD98059, or the p38 MAPK inhibitor SB203580 markedly suppressed PDGF mRNA and protein up-regulation, indicating the involvement of G(i)-Ras-ERK/p38 MAPK in S1P stimulation of PDGF expression. S1P stimulated expression of the transcription factor KLF5 in manners dependent on G(i), Ras, and ERK/p38 MAPK. Down-regulation of KLF5 by small interfering RNA duplexes abolished S1P-induced PDGF-A and -B chain expression. On the other hand, overexpression of KLF5 stimulated basal and S1P-induced PDGF expression. Either S1P stimulation or KLF5 overexpression increased the PDGF-B promoter activity in a cis-element-dependent manner. These results reveal the S1P(1)-triggered, G(i)-Ras-ERK/p38 MAPK-KLF5-dependent, stimulatory regulation of PDGF gene transcription in vascular smooth muscle cells.

To test the feasibility of integrated backscatter (IB) for detecting anthracycline cardiotoxicity, we performed conventional echocardiography and IB analysis. For interindividual comparison, 32 patients with non-Hodgkin's lymphoma and 14 control subjects were selected. Of the patients, 10 had been treated with doxorubicin doses of ≤200 mg/m 2 (low dose), 15 with ≤400 mg/m 2 (moderate dose), and 7 with >400 mg/m 2 (high dose). In intraindividual comparison, 8 patients were examined before doxorubicin therapy and at a dose of 100 mg/m 2 and 8 were examined before and at a 300-mg/m 2 dose. Cyclic variation of IB (CV-IB) was obtained at the left ventricular posterior wall, using a modified, commercially available system in M-mode format. In interindividual comparison, CV-IB in high- and moderate-dose groups was smaller. In intraindividual comparison, CV-IB decreased after treatment with 300 mg/m 2 of doxorubicin. CV-IB was affected in some patients treated with a moderate dose of doxorubicin. IB analysis may be helpful for detecting early anthracycline cardiotoxicity.

Cardiovascular disease is a major cause of mortality and morbidity in patients with acromegaly. We describe the case of a 43-year-old man with acromegaly who presented with severe congestive heart failure. Treatment with the somatostatin analog octreotide improved cardiac function with an increase in left ventricular ejection fraction (LVEF) from 11% to 27%. LVEF further increased to 43% after trans-sphenoidal surgery. Recovery was uneventful. We emphasize the need for early diagnosis and effective treatment of acromegaly to prevent cardiovascular complications. Octreotide therapy or trans-sphenoidal surgery, if possible, should be considered to control cardiac function even in acromegalic patients with severe congestive heart failure.

Mutations in any of the five genes KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A can be responsible for familial long QT syndrome (LQTS), an arrhythmogenic disorder that entails a high risk of sudden death. beta-Adrenergic blocking agents are the first therapeutic choice, and 80% of patients treated with these agents show symptomatic relief; however the remaining 20% do not respond well. We previously performed a nationwide analysis of familial long QT syndrome (LQTS) in Japan and identified 32 mutations in the KCNQ1 and KCNH2 genes. In the present retrospective study, we found that patients carrying mutations in the KCNQ1 gene responded better to beta-adrenergic blocking agents than those with KCNH2 mutations (12 of 13 vs 1 of 5; P = 0.0077, Fisher's exact test). This is a good example of the power of genetic diagnosis to direct the selection of appropriate therapy for patients with diseases of heterogeneous genetic etiology.

A 38-year-old male myotonic dystrophy patient with left hemiblock, bradycardia and ventricular arrhythmias underwent electrophysiologic studies 19 months after he developed dizziness. Rapid and significant progression of binodal disease required implantation of a permanent pacemaker, which responded favorably. We suggest that careful monitoring or electrophysiologic studies are indicated in patients with these findings.

A 49-year-old woman presented with bilateral coronary fistulas with multiple sites of drainage. She had been referred to hospital for evaluation of a cardiac murmur, and a coronary arteriogram revealed multiple coronary fistulas. One fistula originated from the proximal part of the left anterior descending coronary artery and connected to the main pulmonary artery. Three coronary artery fistulas arised from a conal branch of the right coronary artery and drained into the main pulmonary artery, the right atrium and the great cardiac vein. This is the first reported case of bilateral coronary fistulas with multiple sites of drainage. (Jpn Circ J 1998; 62: 783 - 784)

The authors treated 10 patients with microvascular angina (MVA) manifesting angina pectoris, ST segment elevation suggestive of transmural myocardial ischemia, and no epicardial arterial obstruction. Since such patients frequently showed abnormal responses to oral glucose loading, the authors investigated the glucose and insulin responses to glucose loading in 10 MVA patients, 25 patients with vasospastic angina (VAP), 25 patients with effort angina (EAP), and 25 control subjects. Insulinogenic index, periph eral insulin activity [=104/(peak glucose x insulin at glucose peak)], glucose area, and insulin area were calculated. The MVA group included two patients with impaired glucose tolerance and two newly diagnosed diabetic patients. These proportions were similar to those in the VAP and EAP groups. Glucose levels at 30 to 180 min and insulin levels at 90 to 120 min in the MVA group were higher than in the control group. Peak glucose, glucose area, peak insulin, and insulin area were higher in the MVA group than in the control group (p

We investigated the frequency components of fluctuations in heart rate, arterial pressure, respiration, and muscle sympathetic nerve activity (MSNA) in 11 healthy women using an autoregressive model and examined the relation among variables using Akaike’s relative power contribution analysis with multivariate autoregressive model fitting. Power spectral analysis of MSNA revealed two peaks, with low-frequency (LF) and high-frequency (HF) components. The LF component of MSNA was a major determinant of the LF component of arterial pressure and R-R interval variability (0.70 ± 0.07 and 0.18 ± 0.05, respectively). The effect of the LF component of MSNA on arterial pressure showed no change in response to propranolol but was diminished (0.35 ± 0.08) by phentolamine ( P

Intravascular ultrasound (IVUS) frequently reveals plaque formation at sites with a normal angiographic appearance. However, whether angiographically normal coronary arteries undergo adaptive expansion in vivo remains uncertain. The authors studied 12 patients (11 men, 1 woman; mean age fifty-three ± ten years [mean ± SD]) with focal coronary stenosis. Sixty IVUS images from angiographically normal coronary segments were analyzed (14 left main, 44 left anterior descending, and 2 left circumflex coronary arteries). The mean percent area stenosis was 36 ± 5% and the circular shape factor of the lumen cross section averaged 0.97 ± 0.02. Both total arterial area and internal elastic lamina area increased as the plaque area expanded (y = 2.13x + 8.07, r = 0.87, P = 0.0001; y = 2.06x + 4.57, r = 0.87, P = 0.0001, respectively), suggesting that for every 1 mm2 increase in plaque area, the total arterial area increased by approximately 2.13 mm2 and the internal elastic lamina area increased by approximately 2.06 mm2. The lumen area also increased as the plaque area expanded ( y = 1.06x + 4.57, r = 0.68, P = 0.0001), suggesting that for every 1 mm2 increase in plaque area, the lumen area increased by approximately 1.06 mm2. The medial area did not correlate with the plaque area ( r = 0.15, P = 0.26). Thus, compensatory enlargement precedes development of angiographically detectable coronary atherosclerosis. Furthermore, in early stages of atherosclerosis, arterial enlargement may overcompensate for plaque area. The reduction of the total medial mass does not appear to contribute to the mechanism of compen satory enlargement.

The effects of insulin on vasoconstrictor response were studied in diabetics without autonomic neuropathy. Vasoconstrictor response to phenylephrine was measured before and after insulin injection in 10 diabetics. Mean blood pressure, forearm blood flow, and forearm vascular resistance remained unchanged after insulin administration. But the increase in forearm vascular resistance to phenylephrine decreased significantly and heart rate increased significantly after insulin injection. In 9 diabetics, vasoconstrictor response to tilting was measured before and after insulin injection. Mean blood pressure, cardiac index, and the total peripheral resistance index remained unchanged after insulin administration. However, the increase in the total peripheral resistance index to tilting decreased significantly and heart rate increased significantly after insulin injection. Furthermore, a significant fall in mean blood pressure following tilting was observed only after insulin administration. Although blood glucose levels decreased significantly, no hypoglycemic symptoms occurred. The present study suggests that insulin inhibits vasoconstrictor responses to both alpha agonist and tilting in diabetics.

房室結節二重伝導路を有する45例を対象とし, 心房早期刺激試験 (AEST) により房室結節回帰性頻拍 (AVNRT) の誘発されたA群 (13例) , 単発の房室結節回帰性心房エコー (Ae) の誘発されたB群 (6例) およびAeあるいはAVNRTのいずれも誘発されなかったC群 (26例) に分類した。AESTによりAeあるいはAVNRTが誘発されるためには, 良好な逆行性室房伝導を有する必要があり, A群とB群は全例最短1対1室房伝導周期は460 msec以下であった。一方, 最短1対1室房伝導周期が460 msec以下を示したC群26例中4例においては, AESTによる順行性房室伝導時間の延長が軽度であったためAeは誘発されなかった。頻拍が持続するためには, 良好な逆行性室房伝導能に加えて順行性房室伝導能も良好である必要があり, A群13例は全例最短1対1房室伝導周期は420 msec以下を示した。

A new method is presented of detecting the output current zero-point and polarity in a no-circulating cycloconverter (NCC) of the continuous current type. Reverse polarity characteristics of series thyristor-diode networks are used for this purpose. This method, which assumes an inductive load, is based on the following principles. 1) When a reverse voltage is suddenly applied to the circuit, the voltage drop at the diode terminals becomes almost equal to the impressed voltage at that instant and then decays to zero gradually. (2) When the series circuit is reverse- biased and a positive polarity trigger pulse is applied to the thyristor gate, almost all of the biasing voltage appears across the diode terminals at the triggering instant before decaying to zero.