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Background: Although smoking is a risk factor for cardiovascular diseases, little is known about the impact of smoking on long-term outcomes in patients with atrial fibrillation (AF)., Methods: In 426 consecutive patients with nonvalvular AF (mean age, 66 years; 307 men; mean follow-up, 5.8±3.2 years), clinical variables including smoking status, CHADS2, and CHA2DS2-VASc score, incidences of cardiovascular events (stroke, myocardial infarction, or admission for heart failure), bleeding, and mortality were determined., Results: Incidences of intracranial bleeding (0.7% vs 0.1%/year, p<0.01), all-cause mortality (4.9% vs 2.6%/year, p<0.01), and death from stroke (0.8% vs 0.2%/year, p<0.05) were higher in patients with history of smoking than in those without it. Incidence of intracranial bleeding was significantly higher in persistent smokers than in non-persistent smokers (1.2% vs 0.2%/year, p<0.01). History of smoking predicted all-cause mortality [hazard ratio (HR), 2.7; 95% confidence interval (CI), 1.7-4.5; p<0.01] and death from stroke (HR 4.7; 95% CI 1.0-22.3; p<0.05) independent of age, antithrombotic treatment, CHADS2, and CHA2DS2-VASc score. Persistent smoking predicted intracranial bleeding (HR 4.4; 95% CI 1.1-17.6; p<0.05) independent of age and antithrombotic treatment., Conclusions: Smoking status, independent of age, antithrombotic treatment, and clinical risk factors, predicted long-term adverse outcomes including bleeding events in patients with nonvalvular AF. There might be an obvious impact of persistent smoking on intracranial bleeding., (Copyright © 2014. Published by Elsevier Ltd.)

Background: There is no clear consensus about antithrombotic treatment in atrial fibrillation (AF) patients at low-intermediate thromboembolic risk. Transesophageal echocardiography (TEE) is useful for prediction of thromboembolic events in AF., Methods and Results: Of 498 patients with nonvalvular AF, incidence of stroke, cardiac events, and mortality was investigated in 280 patients with CHADS(2) score 0 or 1 (mean age 64 years, mean follow-up 6.4 ± 3.1 years). Left atrial abnormality (low left atrial appendage flow, spontaneous echo contrast, or thrombi), complex aortic plaque (mobile, ulcerated, pedunculate, or thickness ≥ 4mm), or both were defined as TEE risk. The incidences of ischemic stroke, cardiovascular events, and death were higher in patients with TEE risk than in those without the risk (2.0%/year vs. 0.5%/year, p<0.05; 4.7%/year vs. 1.9%/year, p<0.01; and 4.7%/year vs. 2.0%/year, p<0.01, respectively). This was also true for patients with CHADS(2) score of 0 (1.7%/year vs. 0.3%/year, p<0.05; 4.1%/year vs. 1.6%/year, p<0.05; and 3.9%/year vs. 1.4%/year, p<0.01; respectively). On multivariate analysis, TEE risk predicted ischemic stroke, cardiovascular events, and mortality independently of clinical variables or CHADS(2) score., Conclusions: TEE could be useful for further stratification of patients with nonvalvular AF stratified at low-intermediate risk (CHADS(2) score 0 or 1) and could indicate who should receive anticoagulation treatment., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Chronic heart failure (HF) is characterized by sympathetic overactivation and periodic breathing. We examined whether adaptive servo-ventilation (ASV) exerts a sympathoinhibitory effect in patients with HF via normalizing respiratory pattern. Muscle sympathetic nerve activity (MSNA), heart rate, blood pressure, respiratory pattern and oxygen saturation were examined in 29 HF patients without obstructive sleep apnea (age, 61±15years; ejection fraction, 0.32±0.09; obstructive apnea index, <5/h) before (10 min), during (30 min) and after (10 min) the application of ASV. Periodic breathing was defined as a repeated oscillation of tidal volume with regularly recurring hyperpnea and hypopnea with a variation in tidal volume of greater than 25%. The severity of respiratory instability was determined using the coefficient of variation of tidal volume (CV-TV). Of 29 patients with HF, 11 had periodic breathing and 18 did not. There was a modest positive correlation between MSNA and CV-TV (n=29, p<0.05). ASV reduced respiratory rate, CV-TV and MSNA only in the group with periodic breathing (p<0.01). Change in MSNA significantly correlated with changes in respiratory rate, CV-TV and presence of periodic breathing. However, multivariate analyses revealed that respiratory rate and CV-TV were independent predictors of change in MSNA. ASV reduces MSNA by slowing respiratory rates and stabilizing respiratory patterns in patients with HF., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Patients with atrial fibrillation (AF) are at risk for thromboembolism. Although mitral regurgitation (MR) could be protective against left atrial (LA) blood stasis, the relationship between the severity of MR and thromboembolic risk has not been clarified in patients with AF., Methods: 271 patients with permanent AF underwent transesophageal echocardiography (TEE). The severity of MR was assessed by Doppler echocardiography. LA blood stasis on TEE and plasma D-dimer levels were used to evaluate the thromboembolic risk., Results: Patients with severe MR (n=20) had significantly higher LA appendage peak flow velocity compared to those with no MR (n=114) and those with only mild MR (n=92) (p<0.05). The grade of LA spontaneous echo contrast (SEC) was lower in patients with severe MR compared to those with no, mild or moderate MR (severe MR 0.7±0.7 grade vs moderate MR 1.7±1.0 grade, mild MR 2.2±1.3 grade, and no MR 1.9±1.3 grade, p<0.05). Multivariate analysis revealed severe MR as a negative predictor of LA blood stasis on TEE findings (odds ratio 0.27; 95% confidence interval 0.09-0.86, p<0.05). By contrast, D-dimer level was significantly higher in patients with moderate MR compared to those with any other type of severity of MR (moderate MR 1.72±1.45 µg/ml vs severe MR 0.76±0.95 µg/ml, mild MR 0.97±1.09 µg/ml, and no MR 0.82±1.15 µg/ml, p<0.05)., Conclusions: There is a protective effect of MR on LA blood stasis, but this beneficial effect on thromboembolic risk appears to be limited to patients with severe MR., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)

Cardiovascular events are characterized by circadian periodicity with a peak prevalence during the awakening period, which suggests a morning surge in sympathetic activity. We developed an experimental system to determine circadian changes in heart rate (HR), blood pressure (BP), locomotor activity (Loc), respiratory rate and autonomic function in conscious, unrestrained rats. The effects of amiodarone on circadian variation of these variables were determined in rats with myocardial infarction and subsequent congestive heart failure (CHF). We continuously recorded BP, HR and Loc for 24h in rats with CHF (n=16) or after a sham operation (Sham; n=7). To determine circadian changes in sympathovagal balance, digitized BP and HR data throughout 24h were analyzed based on maximum entropy. The study was repeated after 3 weeks of oral amiodarone (50mg/kg/day) or saline administration. Baseline HR, mean BP, and Loc were higher in the dark period than in the light period (all p<0.05) in both CHF and Sham rats, which is consistent with the circadian periodicity of nocturnal animals. Low-frequency components of diastolic BP variability (LFdp), an index of sympathetic tone, were significantly higher during the awakening period (16:00-20:00) than during the sleeping period (08:00-14:00), a finding analogous to the sympathetic morning surge in men. Amiodarone suppressed this transient increase in LFdp power during the awakening period. Our experimental system could detect sympathetic surge in conscious rats. Amiodarone suppressed the sympathetic surge, which could explain, at least in part, beneficial effects of amiodarone in patients with CHF., (Copyright © 2010 Elsevier B.V. All rights reserved.)

We investigated whether coexisting renal insufficiency (RI) is associated with elevated sympathetic activity in patients with heart failure (HF). Resting muscle sympathetic nerve activity (MSNA) was determined in 101 patients with HF (ejection fraction<0.45) and 8 patients with RI but without HF (RI group). Diagnosis of RI was made of glomerular filtration rates <60ml/min/1.73m(2) estimated using the simplified Modification of Diet in Renal Disease equation. Of 101 patients, 45 had RI (HFRI group) and 56 did not (HF group). HFRI group was older (p<0.05) and given loop diuretics more frequently (p<0.05), and had a lower specific activity scale (p<0.05) than HF group. HFRI group exhibited significantly greater MSNA indices than either HF group or RI group (burst rate, p<0.05; burst incidence, p<0.01). Univariate analysis showed that RI, age, specific activity scale level and dose of furosemide were significant predictors of increased burst incidence of MSNA in patients with HF. Notably, multivariate analysis revealed that RI was the only independent factor for increased MSNA indices. These findings suggest that coexisting RI is associated with elevated sympathetic activity in patients with HF.

Background: The present study was conducted to investigate whether an accumulation of clinical risk factors for thromboembolism would correlate with severity of blood stasis in the left atrium (LA) and aortic atherosclerosis in patients with nonvalvular atrial fibrillation (NVAF)., Methods: Risk levels of thromboembolism were assessed in 515 (mean age 67.5 years) NVAF patients using CHADS(2) score (an acronym for Congestive heart failure, Hypertension, Age >or=75, Diabetes mellitus, and prior Stroke or transient ischemic attack) to estimate the thromboembolic risk. Spontaneous echocardiographic contrast in the LA (LASEC), left atrial appendage (LAA) peak flow velocity, and severity of atherosclerosis in the descending aorta were determined with transesophageal echocardiography., Results: LASEC was significantly increased, and LAA flow velocity significantly decreased in correlation with an increase in the risk levels, as evaluated by CHADS(2) score (p<0.001). Severity of aortic atherosclerosis also increased in correlation with an increase in the risk levels (p<0.001). Even at the comparable risk level, patients with chronic atrial fibrillation (AF) (n=268) had higher LASEC (p<0.001) and lower LAA flow velocity (p<0.001) than those with paroxysmal AF (n= 52) who were in AF rhythm at the time of echocardiographic investigation., Conclusion: Severity of blood stasis in the LA and aortic atherosclerosis correlates with an accumulation of clinical risk factors for thromboembolism in NVAF patients. Additionally, the severity of blood stasis in the LA was greater in chronic AF patients than in paroxysmal AF patients at the comparable risk level.

Background: The present study was conducted to investigate the relation between the accumulation of the risk factors of thromboembolism and the levels of hemostatic markers in patients with nonvalvular atrial fibrillation (NVAF)., Methods: Five hundred ninety-one NVAF patients and 129 control subjects were categorized into low, moderate or high risk of thromboembolism, according to CHADS(2) index. One point each was given to patients with advanced age (> or =75 years), hypertension, congestive heart failure, and diabetes mellitus, and 2 points, to those with prior ischemic stroke or transient ischemic attack. Patients with CHADS(2) score of 0, 1 or 2, and > or =3 were classified as low, moderate and high risk, respectively. Levels of hemostatic markers (platelet factor 4, beta-thromboglobulin, prothrombin fragment F1+2 and D-dimer) were determined., Results: Of 591 patients with NVAF, 302 were treated with warfarin (mean international normalized ratio 1.88). D-dimer levels increased as the risk level increased irrespective of warfarin use. Particularly, NVAF patients without receiving warfarin (n=289) had significantly higher D-dimer levels than control patients (e.g., for high risk patients, 175+/-144 vs 75+/-87 ng/ml, p<0.001), while NVAF patients receiving warfarin had intermediate levels (136+/-156 ng/ml). F1+2 levels increased as the risk level increased, and were significantly suppressed by warfarin. Levels of markers of platelet activation (platelet factor 4 and beta-thromboglobulin) were increased in NVAF patients but not affected by the risk level., Conclusion: Coagulation and fibrinolytic activity is increased along with the accumulation of the risk factors of thromboembolism in NVAF patients.

Background: Elevated coagulative molecular markers could reflect the prothrombotic state in the cardiovascular system of patients with non-valvular atrial fibrillation (NVAF). A prospective, cooperative study was conducted to determine whether levels of coagulative markers alone or in combination with clinical risk factors could predict subsequent thromboembolic events in patients with NVAF., Methods: Coagulative markers of prothrombin fragment 1+2, D-dimer, platelet factor 4, and beta-thromboglobulin were determined at the enrollment in the prospective study., Results: Of 509 patients with NVAF (mean age, 66.6 +/- 10.3 years), 263 patients were treated with warfarin (mean international normalized ratio, 1.86), and 163 patients, with antiplatelet drugs. During an average follow-up period of 2.0 years, 31 thromboembolic events occurred. Event-free survival was significantly better in patients with D-dimer level < 150 ng/ml than in those with D-dimer level>or==150 ng/ml. Other coagulative markers, however, did not predict thromboembolic events. Age (>or==75 years), cardiomyopathies, and prior stroke or transient ischemic attack were independent, clinical risk factors for thromboembolism. Thromboembolic risk in patients without the clinical risk factors was quite low (0.7%/year) when D-dimer was < 150 ng/ml, but not low (3.8%/year) when D-dimer was >or==150 ng/ml. It was >5%/year in patients with the risk factors regardless of D-dimer levels. This was also true when analyses were confined to patients treated with warfarin., Conclusions: D-dimer level in combination with clinical risk factors could effectively predict subsequent thromboembolic events in patients with NVAF even when treated with warfarin.

Study Objectives: The prevalence of thromboembolism might be higher than previously recognized in patients with atrial flutter (AFL) based on findings of transesophageal echocardiography (TEE). To evaluate the potential prothrombotic state in patients with AFL, TEE findings and hemostatic markers were compared among patient groups with AFL, normal sinus rhythm (NSR) and chronic nonvalvular atrial fibrillation (AF)., Design and Settings: Cross-sectional study at a university hospital., Methods: In 28 patients (mean age, 63 years) with AFL, 58 patients (mean age, 66 years) with AF, and 27 patients (mean age, 61 years) with NSR who underwent TEE, plasma levels of markers for platelet activity (platelet factor 4 and beta-thromboglobulin [beta-TG]), thrombotic status (thrombin-antithrombin III complex and prothrombin fragments 1 and 2) and fibrinolytic status (d-dimer and plasmin-alpha(2)-plasmin inhibitor complex) were determined., Results: Left atrial appendage (LAA) blood flow velocity in patients with AFL was higher (p < 0.05) than that in patients with AF, but was lower (p < 0.05) than that in patients with NSR (AF, 25 +/- 2; AFL, 44 +/- 4; NSR, 60 +/- 4 cm/s). Dense left atrial spontaneous echo contrast (SEC) was found in 4 patients (14%) with AFL and 16 patients (28%) with AF. There was no significant difference in plasma levels of hemostatic markers between the AFL group and the NSR group. AFL patients with impaired LAA function (LAA flow < 30cm/s, dense SEC, or both), however, showed higher level of d-dimer and beta-TG than those without impaired LAA function (d-dimer, 1.9 +/- 0.6 microg/mL vs 0.4 +/- 0.1 microg/mL; beta-TG, 73 +/- 17 ng/mL vs 33 +/- 5 ng/mL, p < 0.05)., Conclusions: Patients with AFL as a whole are not in the prothrombotic state as compared with those with AF. However, patients with AFL and impaired LAA function are at potentially high risk for thromboembolism and might require anticoagulation.

Objectives: To determine the relationship between spontaneous echocardiographic contrast (SEC) in the descending thoracic aorta and plasma levels of hemostatic markers in patients with nonrheumatic atrial fibrillation (AF)., Design and Settings: A cross-sectional study at a university hospital., Patients and Measurements: In 91 consecutive patients (mean +/- SE age, 70 +/- 1 years; 68 men) with nonrheumatic AF who underwent transesophageal echocardiography, plasma levels of markers for platelet activity (platelet factor 4 [PF4] and beta-thromboglobulin [beta-TG]), thrombotic status (thrombin-antithrombin III complex [TAT]), and fibrinolytic status (D-dimer and plasmin-alpha(2)-plasmin inhibitor complex [PIC]) were determined., Results: Forty-three patients who had aortic SEC (AoSEC) were older (72 years vs 68 years; p < 0.05) and had a higher prevalence of chronic AF (88% vs 52%; p < 0.05) than 48 patients without AoSEC. TAT, PIC, and D-dimer levels were significantly higher in patients with AoSEC than in those without AoSEC, whereas PF4 and beta-TG levels were not different between the two groups. Although the prevalence of cerebral embolism did not differ between the two groups (23% vs 29%), the prevalence of peripheral embolism was higher in patients with AoSEC than in those without AoSEC (10% vs 0%; p < 0.05). Multivariate analysis revealed mitral regurgitation (odds ratio, 7.53; p < 0.02), SEC in the left atrium (odds ratio, 2.14; p < 0.02), and aortic atherosclerosis (odds ratio, 1.87; p < 0.04) emerged as independent predictors of AoSEC., Conclusions: Patients with nonrheumatic AF who have AoSEC appear to have enhanced coagulation activity but not platelet activity. Intensive anticoagulation treatment might be required for these patients.