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Background: A blue letter (safety advisory) for dabigatran was issued by the Japanese Ministry of Health, Labour and Welfare in August 2011. Changes in physicians' attitudes toward dabigatran use before and after the blue letter have not been previously reported., Methods and Results: Between March 2011 and July 2012, dabigatran was prescribed to 404 Japanese patients with nonvalvular atrial fibrillation at The Cardiovascular Institute (Tokyo, Japan). Patients were divided into three groups according to the first prescription date: phase I (before the blue letter, n=135); phase II (after the blue letter and before permission for longer-term prescriptions, n=112); and phase III (after permission for longer-term prescriptions, n=157). In phase II, dabigatran use tended to be avoided for patients with older age, renal dysfunction, receiving antiplatelet medication, or p-glycoprotein inhibitors. Measurement of activated partial thromboplastin time significantly increased from phase I to III. In phase III, the tendencies seen in phase II were reversed: dabigatran use in patients with older age and renal dysfunction tended to increase, but decreased or remained the same in patients receiving antiplatelet medications or p-glycoprotein inhibitors., Conclusions: We described the changes in the attitudes of attending physicians toward dabigatran prescription after the blue letter in a specialized hospital for cardiovascular care in Japan, which, we believe, involve useful information for safe use of dabigatran in a real-world clinical setting. However, a true impact or effect of the blue letter should be ascertained in a nationwide, multicenter study., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Frequent supraventricular extrasystoles (SVEs) are associated with the subsequent first-time appearance of atrial fibrillation (AF) and ischemic stroke. The aim of this study was to investigate the combined role of SVEs and an AF-related risk score for ischemic stroke, the CHADS2 score, on the occurrence of new AF in patients in sinus rhythm. The Shinken Database 2004-2010 lists 3,263 patients who underwent 24-hour Holter monitoring. A total of 2,589 patients were analyzed, after excluding 674 patients previously diagnosed with AF. Frequent SVEs were defined as ≥102 beats/day (the top quartile) and the presence of a clinical background for a CHADS2 score ≥2 points as a high CHADS2 score. During the mean follow-up period of 571.4 ± 606.4 days, new AF occurred in 38 patients (9.4 per 1,000 patient-years). The incidence of new AF was 2.7 and 37.7 per 1,000 patient-years for patients with nonfrequent SVEs (<102 beats/day) and low CHADS2 scores and those with frequent SVEs and high CHADS2 scores, respectively. Multivariate Cox regression analysis showed that the hazard ratio for frequent SVEs and a high CHADS2 score compared with nonfrequent SVEs and a low CHADS2 score was 9.49 (95% confidence interval 3.20 to 28.15, p <0.001), even after adjustment for gender, age, medications, and echocardiographic parameters. In conclusion, frequent SVEs and a high CHADS2 score independently and synergistically predict the first-time appearance of AF in patients in sinus rhythm, indicating an approximately 10-fold higher risk. Patients meeting these criteria should have more aggressive early intervention for preventing AF., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Several reports have identified that decline in renal function and presence of proteinuria are closely associated with incidence of atrial fibrillation (AF). However, it is still unclear whether these kidney-related markers are associated with the progression of AF from paroxysmal to persistent form., Methods and Results: Among the new patients who visited the Cardiovascular Institute Hospital between 2004 and 2010 (Shinken Database 2004-2010, n=15,227), both estimated glomerular filtration rate (eGFR) and proteinuria were measured in 1074 AF patients (paroxysmal/persistent 579/495, respectively), who were divided into tertiles of eGFR (the borderlines were 60.07 and 73.67 ml[min(-1)]1.73[m(-2)], respectively), and then further divided into the two categories with/without proteinuria. The average value of eGFR was lower (63.1 ml[min(-1)]1.73[m(-2)] vs. 68.8 ml[min(-1)]1.73[m(-2)], p<0.001) and the detection rate of proteinuria was higher (13.7% vs. 8.5%, p=0.006) in patients with persistent AF than in those with paroxysmal AF, respectively. In the multivariate analysis without parameters of echocardiography [left ventricular ejection fraction (LVEF) and left atrial dimension (LAD)], both eGFR and proteinuria were independently associated with persistent AF, but the association was abolished when the model included LAD and LVEF., Conclusions: In the present analysis with cross-sectional design, both eGFR and proteinuria were apparently linked to the persistent form of AF, but their role in the pathogenesis does not seem to exceed the atrial stretch and remodeling, represented by LAD and LVEF., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Tobacco smoking is a well-known risk factor for cardiovascular disease, but controversial results have been reported regarding its relationship with atrial fibrillation (AF). Moreover, no study on the relationship between smoking and AF has yet been undertaken in a Japanese context., Methods and Results: We used data from the Shinken Database 2004-2011 (men/women, n=10,714/6,803, respectively), which included all new patients attending the Cardiovascular Institute between June 2004 and March 2012. AF was diagnosed in 1,698 and 598 men and women, respectively. In men, smokers were more prevalent in the AF than in the non-AF group (54.5% vs. 44.7%), whereas in women the prevalence of smokers was similar between AF and non-AF groups (14.4% vs. 15.4%). This discrepancy between the sexes seems to derive from a characteristic distribution pattern of smoking habit in women. After adjustment for various cofactors, smoking was independently associated with AF (odds ratio 1.54; 95% confidence interval 1.35-1.75; P<0.001) without a significant interaction between sex categories (P=0.195)., Conclusions: Smoking was independently associated with AF without a significant interaction between sex categories among Japanese patients visiting a cardiovascular hospital. Further studies using a prospective cohort design are required to confirm a causal link between smoking and AF in Japanese patients.

Risk stratification for heart failure (HF) in patients with atrial fibrillation (AF) has not been well established. The aim of this study was to identify the predictors of HF events in patients with AF, consequently developing a new risk-scoring system that stratifies the risk for HF events. In this prospective, single hospital-based cohort, all patients who presented from July 2004 to March 2010 were registered (Shinken Database 2004-2009). Follow-up was maintained by being linked to the medical records or by sending study documents of prognosis. Of the 13,228 patients in the Shinken Database 2004-2009, 1,942 patients with AF were identified. Of the patients with AF, HF events (hospitalization or death from HF) occurred in 147 patients (7.6%) during a mean follow-up period of 776 ± 623 days. After identifying the parameters that were independently associated with the incidence of HF events (coexistence of organic heart diseases, anemia [hemoglobin level <11 g/dl], renal dysfunction [estimated glomerular filtration rate <60 ml/min/m(2)], diabetes mellitus, and the use of diuretics), a new scoring system was developed, the H(2)ARDD score (heart diseases = 2 points, anemia = 1 point, renal dysfunction = 1 point, diabetes = 1 point, and diuretic use = 1 point; range 0 to 6 points). This scoring system discriminated the low- and high-risk populations well (incidence in patients scoring 0 and 6 points of 0.2% and 40.8% per patient-year, respectively) and showed high predictive ability (area under the curve 0.840, 95% confidence interval 0.803 to 0.876). In conclusion, the new H(2)ARDD score may help identify the population of patients with AF at high risk for HF events., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The distribution of activated partial thromboplastin time (APTT) in nonvalvular atrial fibrillation (NVAF) patients under dabigatran therapy remains to be clarified., Methods and Results: The study population was 196 NVAF patients who were treated with dabigatran in 2011 (126 with 220 mg/day). The APTT values showed a wide distribution among the patients, especially in those with a reduced dose, who seemed to show a high value even in patients without contraindications., Conclusions: We found a wide distribution of APTT in NVAF patients under dabigatran treatment. High APTT might help screen for bleeding risks among patients under dabigatran, but requires future investigation.

Parameters obtained from cardiopulmonary exercise testing (CPX) are recognized for their high prognostic value in predicting future cardiac events in cardiac patients. Our group compared the prognostic value of CPX parameters between patients with sinus rhythm (SR) and patients with atrial fibrillation (AF).Peak O2 uptake (VO2), the ratio of the increase in VO2 to the increase in work rate (ΔVO2/ΔWR), and the slope of the increase in ventilation to the increase in CO2 output (VE-VCO2 slope) were obtained from CPX in 72 AF patients and 478 SR patients. The prognostic values of these indices were compared between the two groups.Six cardiac deaths and 25 cardiac events were observed in the AF group and 9 cardiac deaths and 96 cardiac events were observed in the SR group, over a prospective follow-up period of 1,192 days. The percentages of cardiac deaths and cardiac events were higher in the AF group than in the SR group. In a multivariate Cox proportional hazards analysis, peak VO2 was identified as a sole significant predictor of cardiac death and cardiac events in SR patients and VE-VCO2 slope was identified as a sole significant predictor of cardiac death and cardiac events in AF patients.Our results suggest that the VE-VCO2 slope is strongly predictive of future cardiac events in patients with AF and that peak VO2 is strongly predictive of future cardiac events in SR patients.

Background: The characteristics and prognosis of patients with first-detected atrial fibrillation (AF) in Japan remain unclear., Methods and Results: First-detected AF patients without structural heart disease (n=289) were reviewed with regard to 2 symptom classifications (CCS-SAF and EHRA). In both classifications, asymptomatic patients comprised ≈40% of the patients, and patients in the most symptomatic class (≈6%) had peculiar characteristics and poor prognosis. In other symptomatic classes, symptoms affected the treatment strategy without a significant difference in the patients' backgrounds and prognosis., Conclusions: This is the first report to describe the distribution, characteristics and outcomes of first-detected AF patients according to symptom classifications.

Background: Although various kinds of cardiovascular risk factors have been reported to be associated with atrial fibrillation (AF), the relationship between serum uric acid level and AF has not been fully examined., Methods and Results: Data were collected from a single hospital-based cohort in the Shinken Database 2004-2008 (n=11,123), and consisted of serum uric acid level for 7,155 patients. The association between serum uric acid level and AF prevalence was evaluated on logistic regression. Uric acid significantly increased the crude AF prevalence in both men and women (both, P<0.001). The odds ratio (OR) and 95% confidence interval (95%CI) in the highest tertile compared with the lowest one were 3.368 (2.478-4.578) and 1.408 (1.169-1.695) in women and men, respectively. Uric acid was also significantly associated with other various cardiovascular risk factors for AF. Even after the multivariate model was adjusted using these variables, the effect of uric acid on AF was independent in women (OR, 1.888; 95%CI: 1.278-2.790), but not in men., Conclusions: Reflecting the composite of various cardiovascular risk factors, serum uric acid level was apparently associated with AF prevalence. The independent association in women might imply some sex-specific mechanisms. The results should be confirmed in prospective studies.

Background: In Japan, the recent status of the mortality of atrial fibrillation (AF) patients is still unclear., Methods and Results: We used a single-hospital based cohort database in an urban city (Tokyo) in Japan, including all the new visitors from 2004 to 2009 (n=13,228). The non-adjusted death rates of AF patients for all-cause, stroke, and cardiovascular death were 1091, 97, and 727 per 100,000 patient-years, and the age-adjusted ones were 317 (95% CI, 316-318), 16 (95% CI, 16-16), and 238 (95% CI, 237-239), respectively. The age-adjusted relative risk of AF on all-cause mortality was 1.7 in the particular population., Conclusions: The present study provides the most recent data about the characteristics and the mortality of AF patients in Tokyo, thus serving as the basic information for finding problems to solve regarding Japanese AF patients., (Copyright © 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Although recent studies have suggested that height and body mass index (BMI) independently affect the prevalence of atrial fibrillation (AF), their combined effects have not been fully examined in Japanese patients., Methods and Results: Patients without organic cardiac diseases, hypertension and diabetes mellitus were screened from a prospective, single hospital-based cohort of the Shinken Database 2004-2007 (n=4,719). Both height and BMI significantly increased the crude rate of AF prevalence and the effects were significant even after adjustment by age, sex and left atrial dimension. The relative risks (RRs) for AF in the height and BMI categories were 2.07 (95% confidence interval [CI] 1.70-2.52) and 1.78 (95%CI 1.46-2.17), respectively, in the highest tertile compared with the lowest tertile. The RRs in the highest combined tertile was high to 2.98 (95%CI 2.07-4.28) compared with the lowest combined tertile, an unignorable figure for AF prevalence in the future., Conclusions: Height and BMI synergistically affected the prevalence of AF in Japanese patients. With respect to the recent increase in body size of the Japanese population, the present study predicts that there will be more occurrences of AF than previously predicted. (Circ J 2010; 74: 66 - 70).

Many large-scale randomized control trials (RCTs) have been performed regarding treatment strategy in atrial fibrillation (AF) in Western countries and also in Japan. However, limited data are available concerning real-world relationships between the treatment strategy and prognosis of AF patients. Out of a prospective cohort of The Shinken Database 2004 (n = 2 412), 286 AF patients (male 205, 64.1 +/- 12.3 years, paroxysmal form 165) were retrospectively investigated. The percentage of AF patients under the rhythm control strategy was evaluated using the Kaplan-Meier method, which showed the cumulative proportion of rhythm control strategy was approximately 30% at the 90th day after the initial visit and 40.0% at 1 year. The average time to the first rhythm control strategy was 68.3 +/- 106.7 days. Those under rhythm control strategy were associated with fewer coexisting organic cardiac diseases, a younger age, and smaller left atrial dimension. Consequently, they showed very good prognosis (cumulative incidence rate of cardiovascular events at 1 year was 0.0%). Careful induction of rhythm control strategy, which was adopted in approximately 40% of the patients in the real world, was associated with fewer comorbidities and therefore might lead to better prognosis, although this does not mean the direct effects of rhythm control strategy.

Background: Prognosis of Japanese patients with atrial fibrillation (AF) should be determined in a prospective cohort study., Methods and Results: A prospective cohort of The Shinken Database 2004 comprised details on all the new patients who visited The Cardiovascular Institute Hospital in 2004 (n=2,412), which included 286 AF patients (11.8%, 205 males, 64.1+/-12.3 years, 165 paroxysmal). In this Japanese cohort of AF patients, the prevalence of congestive heart failure (CHF) was low compared with that in Westerners. Total mortality and cardiovascular morbidity of these patients were also quite low, 1.7% and 11.2% at 1 year, respectively. However, patients with CHF exhibited higher mortality (7.3%), and hospitalization for CHF increased the rate to 22.6%. There was no significant difference in mortality between paroxysmal and persistent AF. Multiple Cox-hazard regression analysis identified hospitalization at initial visit and lack of anticoagulation as independent predictors for mortality, and existence of CHF as the only independent predictor for cardiovascular morbidity. CONCLUSIONS The present study identified the mortality (1.7%) and morbidity (11.2%) of Japanese AF patients during 1 year after initial visit. Hospitalization for CHF and lack of anticoagulation were independent predictors for mortality, suggesting important roles of co-morbidities of Japanese AF patients.

Functional mitral regurgitation (FMR) is a common and critical condition in patients with heart failure (HF); however, the prevalence and clinical outcome of FMR in Japanese real-world clinical practice remain unclear. Within a single hospital-based cohort in the Shinken Database 2004-2011, which comprised all new patients ( n = 17,517) who visited the Cardiovascular Institute, we followed symptomatic HF patients. A total of 1,701 patients were included: 104 FMR patients (who had moderate to severe FMR) and 1,597 non-FMR patients (who had none or mild FMR). FMR patients had lower rates of hypertension and dyslipidemia, but higher rates of dilated cardiomyopathy, atrial fibrillation, and New York Heart Association functional class III/IV. FMR patients had higher levels of brain natriuretic peptide and lower left ventricular function. Use of cardiovascular drugs was more common among FMR patients. Kaplan-Meier curves revealed that the incidences of all-cause death, cardiovascular death, and admission for HF were significantly higher in FMR patients. The adjusted Cox regression analysis showed that significant FMR was associated with higher incidences of all-cause death [hazard ratio (HR) 2.179, 95 % confidence interval (CI) 1.266-3.751; P = 0.005], cardiovascular death (HR 2.371, 95 % CI 1.157-4.858; P = 0.018), and admission for HF (HR 1.819, 95 % CI 1.133-2.920; P = 0.013). FMR was common in Japanese symptomatic HF patients and was associated with adverse long-term outcomes. Establishing optimal therapeutic strategies for FMR is warranted. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) is a common arrhythmia in patients with heart failure (HF); however, its impact on unselected outpatients with HF remains unclear. Methods: We followed 2024 symptomatic outpatients with HF who visited the Cardiovascular Institute Hospital (The Shinken Database: 2004–2011, N=17,517). We examined the prevalence, clinical characteristics, and outcomes of AF in these outpatients with HF. Results: AF was observed in 310 of the patients (15%). Patients with AF were older; more likely to be female; and had lower rates of hypertension, diabetes mellitus, and ischemic heart disease. However, they also had higher rates of New York Heart Association grades III/IV, lower left ventricular ejection fraction (EF), renal dysfunction, and dilated cardiomyopathy. The use of cardiovascular drugs including beta‐blockers, renin‐angiotensin‐system inhibitors, diuretics, digitalis, and antiarrhythmic drugs was more common in patients with AF. Kaplan–Meier curves revealed that the incidences of all‐cause death, cardiovascular disease death, and HF‐related admission were significantly higher in patients with AF. Kaplan–Meier curves and an unadjusted Cox regression analysis showed that AF was associated with a significantly higher risk of all‐cause death, cardiovascular death, and HF‐related admission. However, the adjusted Cox regression model showed that AF was no longer an independent risk factor for all‐cause death, cardiovascular death, and HF death but remained an independent risk factor of HF‐related admission (hazard ratio, 1.781; 95% confidence interval, 1.172–2.704; p=0.007). Conclusions: AF was frequently observed in outpatients with HF. AF was not associated with long‐term mortality but was independently associated with HF‐related admission in this outpatient population. [ABSTRACT FROM AUTHOR]

Abstract: Background: A novel risk scoring system (H2ARDD) for estimating the incidence of heart failure (HF) events in atrial fibrillation (AF) has been developed, which represents points assigned for organic heart disease (2 points), anemia (1 point), renal dysfunction (1 point), diabetes (1 point), and diuretic use (1 point). We aimed to clarify whether H2ARDD score is related to cardiopulmonary exercise testing (CPX) parameters in patients with AF. Methods: The study population included 344 consecutive patients with AF who underwent CPX as initial screening between June 2004 and March 2012. The association between 4 CPX parameters and the incidence of HF events was analyzed by using multiple linear regression models. Results: The peak O2 uptake (peak O2), anaerobic (gas exchange) threshold (AT), and ratio of the increase in O2 to the increase in work rate (Δ O2/ΔWR) were lower and the slope of the increase in ventilation to the increase in CO2 output ( E– CO2 slope) was higher in patients with than in those without each H2ARDD score component. Accordingly, the parameters significantly increased or decreased according to H2ARDD score. With the multiple linear regression models, H2ARDD score was independently associated with each CPX parameter even after adjustment for various cofactors. Conclusions: H2ARDD score was independently associated with the well-established CPX parameters in patients with AF, suggesting a potential pathophysiological basis for a risk stratification system for predicting HF events in patients with AF. [Copyright &y& Elsevier]