Effect of pulmonary vein isolation on the relationship between left atrial reverse remodeling and sympathetic nerve activity in patients with atrial fibrillation.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Significant Association Between Coronary Artery Low-Attenuation Plaque Volume and Apnea-Hypopnea Index, But Not Muscle Sympathetic Nerve Activity, in Patients With Obstructive Sleep Apnea Syndrome.

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 <30; and severe group, AHI ≥30). There were no group differences in risk factors for atherosclerosis; however, severe AHI patients showed significantly high single-unit MSNA, and low- and intermediate-attenuation plaque volumes. In regression analysis, the plaque volume of any CT value was not associated with single- or multi-unit MSNA; only AHI significantly correlated with low-attenuation plaque volume (R=0.52, P<0.05). CONCLUSIONS: Our findings provided the evidence that AHI is an independent predictor for low-attenuated, vulnerable plaque volume, but not daytime MSNA, in patients with OSAS.

Relationships between muscle sympathetic nerve activity and novel indices of arterial stiffness using single oscillometric cuff in patients with hypertension.

The arterial velocity pulse index (AVI) and arterial pressure-volume index (API) have been proposed as new arterial stiffness indices that can be measured using an oscillometric cuff. Sympathetic nerve activity (SNA) contributes to arterial stiffness via increasing vascular smooth muscle tone. However, the associations between SNA and the AVI or API are not understood. The purpose of this study was to evaluate the relationships between muscle sympathetic nerve activity (MSNA) and the AVI or API in healthy individuals and patients with hypertension (HT). Forty healthy individuals (40.1 ± 15.2 years, 8 females) (healthy group) and 40 patients with HT (60.2 ± 13.6, 18 females) (HT group) were included in this study. The AVI, API, MSNA, beat-by-beat blood pressure, and heart rate were recorded simultaneously. The AVI and API were higher in the HT group than in the healthy group (AVI, 26.1 ± 7.6 vs. 16.5 ± 4.0, p < 0.001; API, 31.2 ± 8.6 vs. 25.5 ± 7.2, p = 0.002). MSNA in the HT group was also higher than in the healthy group (p < 0.001). MSNA was correlated with the AVI, but not with the API, in both the healthy group (R = 0.52, p = 0.001) and HT group (R = 0.57, p < 0.001). MSNA was independently correlated with the AVI in multivariate analysis (ß = 0.34, p = 0.001). In conclusion, AVI, obtained by a simple and less user-dependent method, was related to the MSNA in healthy individuals and patients with HT.

Different Responses of Muscle Sympathetic Nerve Activity to Dapagliflozin Between Patients With Type 2 Diabetes With and Without Heart Failure.

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.

Different prognosis between severe and very severe obstructive sleep apnea patients; Five year outcomes.

BACKGROUND: Obstructive sleep apnea (OSA) is characterized by augmented sympathetic nerve activity. In our previous study, patients with OSA and an apnea-hyperpnea index (AHI)>55events/h showed increased single-unit muscle sympathetic nerve activity compared to patients with OSA and AHI of 30-55events/h. However, the prognostic impact in these patients remains unclear. METHODS: Ninety-one OSA patients were included. All patients who had indication for continuous positive airway pressure (CPAP) were treated with CPAP. Patients were divided into three groups: mild/moderate OSA (S), AHI<30events/h (n=44); severe OSA (SS), AHI 30-55events/h (n=29); and very severe OSA (VSS), AHI>55events/h (n=18). The primary endpoint was a composite outcome composed of death, cardiovascular events, stroke, and heart failure with hospitalization. RESULTS: In the 5-year follow-up, the primary event rate in the SS group [3 events (7%)] was the same as that in the S group [3 events (10%)]. However, the VSS group showed a significantly higher primary event rate among the three groups [6 events (33%), p<0.05]. In Cox regression analysis, the VSS group had the highest hazard ratio compared to other risk factors. CONCLUSIONS: CPAP was effective for preventing cardiovascular disease in patients with severe OSA, however patients with very severe OSA still had a high event rate, indicating that CPAP treatment might be insufficient to reduce the OSA-related risk burden in patients with very severe OSA. Additional systemic medical treatment for CPAP might be needed in patients with very severe OSA.

Altered firing pattern of single-unit muscle sympathetic nerve activity during handgrip exercise in chronic heart failure.

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 (Delta1002 +/- 50 compared with Delta636 +/- 76 units min(-1), P < 0.05) and single-unit MSNA spike incidence (Delta27 +/- 5 compared with Delta8 +/- 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 (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.

G12/13 and Gq mediate S1P2-induced inhibition of Rac and migration in vascular smooth muscle in a manner dependent on Rho but not Rho kinase.

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 S1P(2) receptor antagonist JTE-013. The C-terminal peptides of Galpha subunits (Galpha-CTs) act as specific inhibitors of respective G protein-GPCR coupling. Adenovirus-mediated expression of Galpha(12)-CT, Galpha(13)-CT, and Galpha(q)-CT, but not that of Galpha(s)-CT or LacZ or pertussis toxin treatment, abrogated S1P inhibition of PDGF-induced Rac activation and migration, indicating that both G(12/13) and G(q) classes are necessary for the S1P inhibition. The expression of Galpha(q)-CT as well as Galpha(12)-CT and Galpha(13)-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 AT(1), which robustly couples to G(q), did not mediate either Rho activation or inhibition of PDGF-induced Rac activation or migration, suggesting that activation of G(q) alone was not sufficient for Rho activation and resultant Rac inhibition. However, the AT(1) receptor fused to Galpha(12) 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 S1P(2) mediates inhibition of Rac and migration through the coordinated action of G(12/13) and G(q) for Rho activation in VSMCs.

Severity Indices for Obstructive Sleep Apnea Syndrome Reflecting Glycemic Control or Insulin Resistance.

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<90%, independent of age, gender, and body mass index (BMI). Burst incidence of MSNA was independently associated with only a 3% oxygen desaturation index. nCPAP therapy significantly lowered the OSAS severity indices and reduced the burst rate, burst incidence, and heart rate. Conclusion The OSAS severity indices reflecting apnea/hypopnea are associated with glycemic control, whereas those reflecting hypoxia, particularly % SpO2<90%, are associated with hepatic insulin resistance independent of obesity. Both types of OSAS severity indices, especially the 3% oxygen desaturation index (reflecting intermittent hypoxia), are independently associated with MSNA, which is dramatically lowered with the use of nCPAP therapy. These findings may aid in interpreting each OSAS severity index and understanding the pathophysiology of OSAS in clinical settings.

Single-Unit Muscle Sympathetic Nerve Activity Reflects Sleep Apnea Severity, Especially in Severe Obstructive Sleep Apnea Patients.

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 <30 and those with and AHI of 30-55 events/h; however, the pattern of each multiple spike firing were significantly higher in 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.

Intestinal angina in a patient with hypertrophic obstructive cardiomyopathy: a case report.

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.

Connective tissue growth factor binds vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis.

Vascular endothelial growth factor (VEGF) is a strong angiogenic mitogen and plays important roles in angiogenesis under various pathophysiological conditions. The in vivo angiogenic activity of secreted VEGF may be regulated by extracellular inhibitors, because it is also produced in avascular tissues such as the cartilage. To seek the binding inhibitors against VEGF, we screened the chondrocyte cDNA library by a yeast two-hybrid system by using VEGF165 as bait and identified connective tissue growth factor (CTGF) as a candidate. The complex formation of VEGF165 with CTGF was first established by immunoprecipitation from the cells overexpressing both binding partners. A competitive affinity-binding assay also demonstrated that CTGF binds specifically to VEGF165 with two classes of binding sites (Kd = 26 +/- 11 nM and 125 +/- 38 nM). Binding assay using deletion mutants of CTGF indicated that the thrombospondin type-1 repeat (TSP-1) domain of CTGF binds to the exon 7-coded region of VEGF165 and that the COOH-terminal domain preserves the affinity to both VEGF165 and VEGF121. The interaction of VEGF165 with CTGF inhibited the binding of VEGF165 to the endothelial cells and the immobilized KDR/IgG Fc; that is, a recombinant protein for VEGF165 receptor. By in vitro tube formation assay of endothelial cells, full-length CTGF and the deletion mutant possessing the TSP-1 domain inhibited VEGF165-induced angiogenesis significantly in the complex form. This antiangiogenic activity of CTGF was demonstrated further by in vivo angiogenesis assay by using Matrigel injection model in mice. These data demonstrate for the first time that VEGF165 binds to CTGF through a protein-to-protein interaction and suggest that the angiogenic activity of VEGF165 is regulated negatively by CTGF in the extracellular environment.

Doppler tissue analysis of atrial electromechanical coupling in paroxysmal atrial fibrillation.

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.

Effect of pimobendan on cardiopulmonary baroreflex control of sympathetic nerve activity in healthy young men.

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<0.01, respectively), but arterial pressure and heart rate unchanged after pimobendan administration. During LBNP, CVP decreased and MSNA increased significantly. CPB sensitivity was augmented from 5.53+/-0.75 to 8.59+/-0.78 burst incidence/mm Hg after pimobendan administration (p<0.01). Pimobendan did not alter the percentage increase of MSNA during handgrip exercise. In conclusion, pimobendan induces an increase in basal sympathetic nerve activity by decreasing CVP and augmenting CPB sensitivity without changing arterial pressure in healthy young men.

Ultrasonic analysis of anthracycline-induced myocardial damage using cyclic variation of integrated backscatter.

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 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.

Differential effects of azelnidipine and amlodipine on sympathetic nerve activity in patients with primary hypertension.

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 ±â€Š14.9 vs. 61.5 ±â€Š10.7  bursts per 100 beats, P < 0.05). However, no significant difference was observed in terms of the baroreflex control of HR, or MSNA, between the two groups. CONCLUSION: Our data show, first, that azelnidipine, compared with amlodipine, exerted a favorable effect on sympathetic nerve activity, without affecting baroreflex sensitivity, in hypertensive patients. These results indicate that azelnidipine might be useful for treating hypertensive patients, in whom hypertension is complicated by heart failure and ischemic heart disease.

Cigarette smoking augments sympathetic nerve activity in patients with coronary heart disease.

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.

Current status of anticoagulation therapy for elderly atrial fibrillation patients in Japan: from Hokuriku atrial fibrillation trial.

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 > or =65 years were enrolled in this study. Warfarin was used for significantly less patients in the oldest group aged > or =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. 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.

Altered interaction between plasminogen activator inhibitor type 1 activity and sympathetic nerve activity with aging.

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<0.01, respectively) in the aged group. In the young group, tPA activity tended to increase, whereas PAI-1 activity was unchanged. There was a correlation between MSNA and PAI-1 activity in the aged group (r=0.47, p<0.01). CONCLUSIONS: SNA in an aging subject leads to an increase in the activity of PAI-1, which indicates that an altered interaction between SNA and PAI-1 activity contributes to increased cardiovascular events in the elderly population.

Negative regulation of endothelial morphogenesis and angiogenesis by S1P2 receptor.

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.