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Background: Atrial fibrosis is a hallmark of atrial structural remodeling leading to the persistence of atrial fibrillation. Although fibroblasts play a major role in atrial fibrosis, their source in the adult atrium is unclear. We tested the hypothesis that endothelial cells contribute to fibroblast accumulation through an endothelial-mesenchymal transition in the atrium of patients with atrial fibrillation. Methods and results: The study group consisted of patients with atrial fibrillation and valvular disease or atrial septal defect who underwent left atrial appendectomy during cardiac surgery (n =38). The amount of fibrotic depositions in the left atrium positively correlated with left atrial dimension. Furthermore, snail and S100A4, indicative of endothelial-mesenchymal transition, were quantified in the left atrium using western blot analysis, which showed statistically significant correlations with left atrial dimension. Immunofluorescence assay of the left atrial tissue identified snail and S100A4 being expressed within the endocardium which is composed of CD31+ cells. The snail-positive endocardium also showed the expression of membrane type 1-matrix metalloproteinase. Immunofluorescence multi-labeling experiments identified that heat shock protein 47, prolyl-4-hydroxylase, and procollagen type 1 co-localized with snail and S100A4 within the endothelial cells of the left atrium, indicating the mesenchymal phenotype to produce collagen. Conclusions: In this study, we showed that the endothelial-mesenchymal transition occurs in the atrium of patients with atrial fibrillation. This observation should help in constructing a novel therapeutic approach for preventing atrial structural remodeling. © 2016 Japanese College of Cardiology.

The effects of smoking on the prognosis of non-valvular atrial fibrillation (NVAF) patients are unclear.The Shinken Database 2004-11 (n = 17,517) includes all new patients visiting the Cardiovascular Institute between June 2004 and March 2012. Among these cases, 2,102 NVAF patients were identified. The effects of smoking on ischemic stroke (IS), intracranial hemorrhage (ICH), and coronary artery events including percutaneous coronary intervention (PCI) and acute coronary syndrome (ACS) were analyzed. Smokers were younger and had lower risk profiles compared with non-smokers. A similar tendency was observed between current and former smokers. In contrast, patients with high tobacco consumption were older and had higher risk profiles, including uncontrolled hypertension, compared with those with low tobacco consumption. In 8,159 patient-years, IS, ICH, PCI, and ACS occurred at rates of 7.7, 2.7, 12.4, and 3.0 per 1000 patient-years. In multivariate Cox regression analysis, smoking was not significantly associated with any adverse event. However, different effects of smoking were observed when stratified by age. In patients ≥ 65 years old, current smokers were independently associated with PCI. Moreover, current smokers and smokers with a total tobacco amount ≥ 800 were marginally and independently associated with IS. In patients < 65 years, current smokers were independently associated with ICH.Age appears to be one of the contributors to differentiation of the effects of smoking on cardiovascular events in our NVAF patients. In elderly patients who still smoke, smoking was associated with the promotion of atherosclerosis or thromboembolism, whereas in young patients it was associated with bleeding.

Background Trends of oral anticoagulant (OAC) prescription and incidence of thromboembolism (TE) and/or major bleeding (MB) in patients with non-valvular atrial fibrillation (NVAF) in Japan are still unclear. Methods and results We used data from Shinken Database 2004-2012, which included all new patients attending the Cardiovascular Institute between June 2004 and March 2013. Of them, 2,434 patients were diagnosed with NVAF. Patients were divided into 3 time periods according to the year of initial visit: 2004-2006 (n=681), 2007-2009 (n=833), and 2010-2012 (n=920). OAC prescription rate steadily increased from 2004-2006 to 2010-2012. Between 2004-2006 and 2007-2009, irrespective of increased warfarin usage, MB tended to decrease, presumably due to low-intensity therapy and avoidance of concomitant use of dual antiplatelets, but TE did not improve. In 2010-2012, direct OACs (DOAC), preferred in low-risk patients, may have contributed to not only decrease TE, but also increase MB, especially extracranial bleeds. In high-risk patients in that time period, mostly treated with warfarin, incidence of TE and MB did not improve. Conclusions The 9-year trend of stroke prevention indicated a steady increase of OAC prescription and a partial improvement of TE and MB. Even in the era of DOAC, TE prevention was insufficient in high-risk patients, and DOAC were associated with increased extracranial bleeding. (Circ J 2016; 80: 639-649).

BackgroundWe previously reported a cross-sectional analysis regarding the relationship between smoking and atrial fibrillation (AF) in a single hospital-based cohort with Japanese patients, but the effect of cessation of smoking and/or total tobacco consumption were unclear.Methods and resultsWe used data from the Shinken Database 2004–2011 (men/women, n=10,714/6803, respectively), which included all new patients attending the Cardiovascular Institute between June 2004 and March 2012. After excluding those previously diagnosed with AF (n=2296), 15,221 patients (men/women, n=9016/6205) were analyzed. During the follow-up period of 2.0±2.1 years (range 0.0–8.1), the incidence rates of new AF in smokers and non-smokers were 9.0 and 5.0 per 1000 patient-years, respectively. In adjusted models with Cox regression analysis, smokers were independently associated with new AF [hazard ratio (HR) 1.47, 95% confidence interval (CI) 1.09–2.00]. Also, current smokers (HR 1.81, 95% CI 1.17–2.79) and smokers with Brinkman index ≥800 (HR 1.69, 95% CI 1.05–2.70) were independently associated with new AF. However, in current smokers, the HRs were not different by Brinkman index (Brinkman index

Background The association between ABO blood type and the activated partial thromboplastin time (aPTT) under dabigatran therapy in nonvalvular atrial fibrillation (NVAF) patients is unclear. Methods and results Between 2011 March and 2015 May, data on ABO blood type and aPTT under dabigatran were obtained for 396 NVAF patients (baseline aPTT, 166). The prevalence of blood type O tended to increase or significantly increase according to baseline aPTT, aPTT under dabigatran, and their difference (∆aPTT) (P=0.054, 0.001, and 0.012, respectively). Conclusions In these NVAF patients, a high aPTT value under dabigatran therapy was associated with blood type O.

The effects of smoking on the prognosis of non-valvular atrial fibrillation (NVAF) patients are unclear.The Shinken Database 2004-11 (n = 17,517) includes all new patients visiting the Cardiovascular Institute between June 2004 and March 2012. Among these cases, 2,102 NVAF patients were identified. The effects of smoking on ischemic stroke (IS), intracranial hemorrhage (ICH), and coronary artery events including percutaneous coronary intervention (PCI) and acute coronary syndrome (ACS) were analyzed. Smokers were younger and had lower risk profiles compared with non-smokers. A similar tendency was observed between current and former smokers. In contrast, patients with high tobacco consumption were older and had higher risk profiles, including uncontrolled hypertension, compared with those with low tobacco consumption. In 8,159 patient-years, IS, ICH, PCI, and ACS occurred at rates of 7.7, 2.7, 12.4, and 3.0 per 1000 patient-years. In multivariate Cox regression analysis, smoking was not significantly associated with any adverse event. However, different effects of smoking were observed when stratified by age. In patients ≥ 65 years old, current smokers were independently associated with PCI. Moreover, current smokers and smokers with a total tobacco amount ≥ 800 were marginally and independently associated with IS. In patients65 years, current smokers were independently associated with ICH.Age appears to be one of the contributors to differentiation of the effects of smoking on cardiovascular events in our NVAF patients. In elderly patients who still smoke, smoking was associated with the promotion of atherosclerosis or thromboembolism, whereas in young patients it was associated with bleeding.

BACKGROUND Variability in the international normalized ratio (INR) of prothrombin time has been suggested to be related to outcome in patients with atrial fibrillation (AF) under warfarin therapy, but its determinants remain unclear.Methods and Results:The study population consisted of 626 AF patients under warfarin therapy in the Shinken Database (n=22,230). INR variability was calculated by Fihn's method. Determinants of high log INR variability (defined as over mean+standard deviation) were determined by logistic regression analyses. Symptomatic heart failure (odds ratio [OR] 3.974, 95% confidence interval [CI] 2.510-6.292), older age (≥75 years old; OR 2.984, 95% CI 1.844-4.826) and severe renal dysfunction (eGFR

Background Seasonal variations in cardiovascular disease is well recognized. However, little is known about the presentations and outcomes of Japanese heart failure (HF) patients in the winter season. Methods and results We used a single hospital-based cohort from the Shinken Database 2004–2012, comprising all new patients (n = 19,994) who visited the Cardiovascular Institute Hospital. A total of 375 patients who were admitted owing to acute decompensated HF were included in the analysis. Of these patients, 136 (36%) were admitted in winter. Winter was defined as the period between December and February. The HF patients admitted in winter were older, and had a higher prevalence of hypertension and diabetes mellitus than the patients admitted in other seasons. Patients with conditions categorized as clinical scenario 1 tended to be admitted more commonly in winter. HF with preserved left ventricular ejection fraction (LVEF) was more common in HF patients admitted in winter than in those admitted in other seasons. Beta-blocker use at hospital discharge was more common in the patients admitted in other seasons. Kaplan–Meier curves and log-rank test results indicated that the incidences of all-cause death, cardiovascular death, and HF admission were comparable between the patients admitted in winter and those admitted in other seasons. Conclusions HF admission was frequently observed in the winter season and HF patients admitted in the winter season were older, and had higher prevalence of hypertension and diabetes mellitus, and preserved LVEF suggesting that we might need to pay more attention for elderly patients with hypertension, diabetes mellitus, and HF with preserved LVEF to decrease HF admissions in the winter season.

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 O 2 uptake (peak V O 2 ), anaerobic (gas exchange) threshold (AT), and ratio of the increase in V O 2 to the increase in work rate (Δ V O 2 /ΔWR) were lower and the slope of the increase in ventilation to the increase in CO 2 output ( V E– V CO 2 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.

Background: Prothrombin time (PT) distribution in Japanese nonvalvular atrial fibrillation (NVAF) patients under rivaroxaban therapy remains to be clarified. Methods and Results: Between May 2012 and July 2013, 115 NVAF patients received rivaroxaban (PT was measured in 94; reagent: recombiplastin). In these patients, (1) PT values were distributed widely from patient to patient and from peak to trough, (2) the time-dependence was obscure with sampling at any time in the outpatient clinic, and (3) the incidence of adverse events was too low for analyzing the relation with PT. Conclusions: We report the distribution of PT for Japanese NVAF patients under rivaroxaban therapy in real-world clinical practice. (Circ J 2014; 78: 763–766)

Background Clinical data on the mortality and morbidity of unselected Japanese patients with heart failure (HF) are limited. In this study, we aimed to determine the clinical characteristics, long-term outcomes, and prognostic factors of Japanese HF patients with preserved or reduced left ventricular ejection fraction (LVEF). Methods and results We used a single hospital-based cohort from the Shinken Database 2004–2011 that comprised all new patients ( n = 17,517) visiting the Cardiovascular Institute Hospital. A total of 1,525 patients diagnosed with symptomatic HF at the initial visit were included in the analysis. Of these, 1121 patients (74%) exhibited a preserved LVEF (>50%) and 404 patients (26%) had a reduced LVEF (≤50%). HF patients with preserved LVEF (HFpEF) were older and more often female than patients with reduced LVEF (HFrEF). Kaplan–Meier curves and log-rank test results showed that HFpEF patients had a better prognosis than HFrEF patients. However, there were no significant differences in clinical outcomes between HFpEF and HFrEF patients when the analysis was limited to inpatients. Cox regression analysis showed that HFpEF patients had a significantly lower risk of all-cause death ( p = 0.027; hazard ratio, 0.547, 95% confidence interval, 0.321–0.933). Multivariate analyses performed separately showed that the independent predictors of all-cause death in HFrEF were advanced age, lower body mass index, diabetes mellitus, and the absence of statin treatment, whereas those for HFpEF were advanced age, absence of dyslipidemia, anemia, and left ventricular hypertrophy. Conclusions This prospective cohort study identified the clinical characteristics, long-term outcomes, and prognostic factors of Japanese HF patients with reduced and preserved ejection fractions in a real-world clinical setting.

Japan has become an aging society, resulting in an increased prevalence of coronary artery disease. However, clinical outcomes of elderly Japanese patients after percutaneous coronary intervention (PCI) remain unclear. Of the 15,227 patients in the Shinken Database, a single-hospital-based cohort of new patients, 1,214 patients who underwent PCI, was evaluated to determine the differences in clinical outcomes between the elderly (≥75 years) (n = 260) and the non-elderly (

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

The mortality and morbidity of patients with stable angina pectoris (SAP) after percutaneous coronary intervention (PCI) in Japan differ from those in Western countries, although Japanese data are limited. We selected from the Shinken Database a single-hospital-based cohort of Japanese patients (n = 15,227) who visited The Cardiovascular Institute between 2004 and 2010 to undergo PCI. We followed-up the patients after PCI. A major adverse cardiac event (MACE) was defined as composite endpoints including all-cause death, acute myocardial infarction (AMI), and target-lesion revascularization (TLR). This study included 747 SAP patients (median follow-up period, 1,000 ± 703 days). The all cause mortality rate in SAP was 1.3% at 1 year, 2.7% at 3 years, and 6.1% at 5 years. The AMI rate was 0.5% at 1 year, 1.1% at 3 years, and 3.0% at 5 years, and the MACE rate was 14.0% at 1 year, 17.6% at 3 years, and 25.6% at 5 years. Moreover, new lesion PCI and heart failure admission continued to occur beyond 1 year after PCI without attenuation of their annual incidences up to 5 years. Multivariate analysis showed that poor left ventricular ejection fraction, chronic kidney disease (CKD), and absence of statin treatment were independent predictors of all-cause death of SAP patients after PCI. The results of the present study revealed the characteristics and long-term outcomes of Japanese SAP patients after PCI. The results of the present study suggest cardiorenal interaction and statin treatment play important roles in the long-term outcomes of Japanese CAD patients treated by PCI.

Atrial fibrillation (AF) is associated with an increased risk of stroke and other thromboembolic events. Left atrial (LA) thrombus formation is closely related to LA dysfunction, particularly to decreased LA appendage flow velocity (LAA-FV) in patients with AF. We estimated LAA-FV using parameters noninvasively obtained by transthoracic echocardiography (TTE) in patients with paroxysmal AF.Echocardiographic and clinical parameters were assessed in 190 patients with nonvalvular paroxysmal AF showing sinus heart rhythm during transesophageal echocardiography (TEE) and TTE.LAA-FV (60 ± 22 cm/s) significantly correlated with the time interval between the initiation of the P-wave on ECG and that of the A-wave of transmitral flow on TTE (PA-TMF, correlation coefficient, -0.32; P < 0.001), LA dimension (LAD, -0.31; P < 0.001), septal a' velocity of tissue Doppler imaging (TDI, 0.35; P < 0.001), E/e' ratio (-0.28, P < 0.001), E velocity of transmitral flow (-0.20, P = 0.008), E/A ratio of transmitral flow (-0.18, P = 0.02), CHA2DS2-VASc score (-0.15, P = 0.04), and BNP plasma level (-0.32, P = 0.002). Multivariate analysis revealed that PA-TMF (standardized partial regression coefficient, -0.17; P = 0.03), a' velocity (0.24, P = 0.004), and LAD (-0.20, P = 0.01) were independent predictors of LAA-FV (multiple correlation coefficient R, 0.44; P < 0.001).Parameters of atrial remodeling, ie, decreased a' velocity, increased LAD, and PA-TMF during sinus rhythm may be useful predictors of LA blood stasis in patients with nonvalvular PAF. LAA-FV can be estimated using these TTE parameters instead of TEE.

SummaryObjectivesThis study aimed to test the hypothesis that the range of 24-h total heart beats (24h-tHB) correlates with cardiac outcomes (cardiac death and incidence of hospitalization with heart failure) in patients with permanent atrial fibrillation (AF).Methods and resultsWe divided 252 consecutive outpatients with permanent AF into 4 groups according to their 24h-tHB and examined clinical outcomes. Initial 24h-tHB at enrollment was significantly associated with patient characteristics including age, sex, presence of structural heart diseases, and left ventricular ejection fraction (EF). The cumulative incidence of heart failure was high in the lowest 24h-tHB group compared with other groups and significantly different from the highest one (23.9% vs. 7.2% at 5years, p=0.0074). Multivariate analysis showed that 24h-tHB

SummaryBackgroundThe presence of heart failure (HF) with preserved ejection fraction (HFPEF) is increasingly recognized. However, prognostic factors for HFPEF remain unclear.Methods and resultsThe data were derived from Shinken Database 2004–2010, a prospective cohort study (n=15,227). We examined 301 consecutive HFPEF patients (New York Heart Association Class II or greater) and tracked them for an average 3.5 years. Cardiopulmonary exercise testing (CPX), blood exams, and ultrasound cardiogram (UCG) were performed at the first medical examination. Acute decompensated HF (ADHF) admission was observed in 19 patients (6.3%). CPX showed that the anaerobic threshold was lower (7.3±4.8mL/min/kg vs. 9.7±4.3mL/min/kg, p=0.02) and slope of the increase in ventilation to the increase in CO2 output (VE-VCO2 slope) was higher (40.6±8.5 vs. 34.6±7.9, p

SummaryBackgroundThe effect of early statin initiation on secondary prevention remains uncertain in unselected Japanese populations with coronary artery disease (CAD).MethodsWe investigated the mortality and morbidity in CAD patients according to presence or absence of statins within 3 months after the diagnosis of CAD in the Shinken Database cohort study. The primary endpoint was all-cause mortality.ResultsData were available on 789 Japanese patients with CAD (male 78.8%). Among those, 351 patients (44.5%) received a statin. The mean (SD) baseline low-density lipoprotein (LDL)-cholesterol levels were 113.6 (35.7) mg/dL in the statin group and 113.6 (26.4) mg/dL in the non-statin group (p=0.992). Unadjusted 2-year survival in patients with or without statins was 98.4% and 92.1%, respectively (p

SummaryIt has been reported that left ventricular outflow tract (LVOT) obstruction can be provoked in patients even without significant left ventricular hypertrophy. We experienced a 74-year-old man with mild degree of left ventricular hypertrophy and latent LVOT obstruction which was successfully treated by alcohol septal ablation. LVOT was not narrow at end-diastole, but proximal septum was protruding further into LVOT during the ejection period, producing a dynamic narrowing of the LVOT. Alcohol septal ablation did not reduce the interventricular septal thickness nor enlarge LVOT. However, it limited the excursion of proximal septum. The effect of the treatment suggested the importance of the dynamic nature of LVOT in the mechanism of latent LVOT obstruction in this case.

Background— Stent thrombosis (ST) after sirolimus-eluting stent implantation has not yet been adequately characterized, mainly because of its low incidence. Methods and Results— The Registry of Stent Thrombosis for Review and Reevaluation (RESTART) is a Japanese nationwide registry of sirolimus-eluting stent–associated ST comprising 611 patients with definite ST (early [within 30 days; EST], 322 patients; late [between 31 and 365 days; LST], 105 patients; and very late [>1 year; VLST], 184 patients). Baseline demographics, clinical presentation, and long-term outcome of sirolimus-eluting stent–associated ST were compared among patients with EST, LST, and VLST. Baseline demographics were significantly different according to the timing of ST. Characteristic demographic factors for LST/VLST versus EST identified by multivariable model were hemodialysis, end-stage renal disease not on hemodialysis, absence of circumflex target, target of chronic total occlusion, prior percutaneous coronary intervention, and age P P P =0.003) or LST (23.5%; P =0.009). Conclusion— ST timing–dependent differences in baseline demographic features, Thrombolysis in Myocardial Infarction flow grade, and mortality rate suggest possible differences in the predominant pathophysiological mechanisms of ST according to timing after sirolimus-eluting stent implantation.

Summary Background We compared the efficacy of once-daily treatment with nifedipine CR 40 mg (NR) and twice-daily treatment with benidipine 4 mg (BD) in patients with coronary spastic angina (CSA) registered in 3 cardiovascular institutes in Tokyo. Methods and results CSA was diagnosed by an ischemic ST change during Holter ECG monitoring or drug-induced test. Thirty patients were randomly allocated to either NR or BD group. The number of symptomatic attacks and the total frequency of short-acting nitrates were examined based on the data in diaries written by patients. There were no significant differences in the baseline characteristics between the two groups. The median number (25–75% quartile) of attacks per week was significantly decreased in NR group, i.e., 1.0 (0.8–2.0) at baseline, 0.0 (0.0–1.0) after 4 weeks of treatment, and 0.0 (0.0–0.0) after 8 weeks of treatment ( P = 0.0093, P = 0.0002, Wilcoxon's rank-sum test). No significant decrease was observed in BD, i.e. 1.0 (0.5–2.0) at baseline, 1.3 (0.0–3.0) after 4 weeks, and 0.0 (0.0–1.0) after 8 weeks. The number of attacks was fewer in NR than in BD group ( P = 0.074, P = 0.015, U -test for difference). Conclusion Once-daily treatment with NR 40 mg was more effective than twice-daily treatment with BD in the prevention of CSA attacks.

Background: Isolated non-compaction of ventricular myocardium (INVM) is characterized by persistent embryonic myocardial morphology without other cardiac anomalies. Congestive heart failure, critical arrhythmias, and systemic thromboemboli are known as major manifestations during childhood. Recently it was reported that there are some patients who seem apparently healthy in adult INVM. Clinical characteristics including that for electrocardiograms (ECG) of adult INVM, however, are unknown for Japanese subjects. Methods and Results: From 24,082 patients who underwent echocardiography between June 2000 and June 2007, 187 patients (0.78%, 41.3±16.8 years, 122 male) were identified as having INVM according to the criteria proposed by Oechslin et al. Although fatal ventricular arrythmias and thromboembolic events occurred in 2 patients and in 1 patient, respectively, the rest had no severe cardiac complications. Normal ECG findings were found only in 24.6% of the patients. Most of the ECG abnormalities, however, were non-specific: ST-T changes in 35.2% and bundle branch block in 14.9%. Notably, Brugada-like ECG was frequently seen in the present Japanese INVM patients (3.2%). The incidence of these ECG findings was not dependent upon the extent of non-compaction. Conclusions: The prevalence and ECG findings of adult Japanese INVM patients in a hospital-based clinical practice have been identified. (Circ J 2010; 74: 1431 - 1435)

Patients with coronary artery disease (CAD) frequently have impaired renal function, but the prevalence and influence of renal dysfunction on their prognosis in Japan remain uncertain. With a prospective study comprising all the new patients who had visited our hospital between 2004 and 2007 (n=6562), we investigated the prevalence of renal dysfunction and its influence on the prognosis of CAD patients. The glomerular filtration rate (GFR) was calculated by using the GFR equation used for the Japanese population. Of those, 797 patients with CAD and blood tests available were analyzed (median follow-up periods of 693 days). Patients were further classified into four subgroups according to estimated GFR value (eGFR): normal (90or =eGFR, 12.2%), mildly impaired (60or =eGFR90, 58.3%), moderately impaired (30or =eGFR60, 23.6%) and severely impaired renal function (eGFR30, 5.9%). The 2-year survival and cardiovascular event (cardiac death, nonfatal myocardial infarction or readmission for heart failure)-free rates were significantly different among the four subgroups: 98.9, 97.7, 89.3 vs. 67.8%, respectively (P0.001 for trend), and 100, 98.8, 89.0 vs. 70.0%, respectively (P0.001 for trend). The age- and gender-adjusted mortality increased significantly in moderately impaired (hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.383-7.017) and in severely impaired subgroups (HR 10.1, 95% CI 4.244-24.178) compared with those with eGFR of 60 or more. After adjustment for baseline differences, eGFR was independently associated with death and cardiovascular events (HR 0.983 and 0.981, 95% CI 0.968-0.998 and 0.965-0.998, respectively). In conclusion, our study identified the prevalence and association of eGFR with prognosis in Japanese patients with CAD, suggesting that strict care for not only CAD but also renal dysfunction is needed for further prevention of cardiovascular events.

Vascular Ehlers-Danlos syndrome is an inherited connective-tissue disorder causing arterial and gastrointestinal fragility and spontaneous rupture of the large arteries, uterus, or bowel. Among arterial dissections and ruptures, spontaneous coronary artery dissection is extremely rare in this disorder. The specific therapeutic strategy for this disorder and its complications has not yet been established. In this report, we describe a 33-year-old woman with all three coronary artery spontaneous dissections, resulting in cardiogenic shock and therapy-resistant ventricular fibrillation. We could successfully complete revascularization of all three coronary arteries and terminate the life-threatening arrhythmia. Biochemical findings finally revealed a point mutation in the COL3A1 gene, consistent with a diagnosis of vascular Ehlers-Danlos syndrome. To the best of our knowledge, this is the first case of vascular Ehlers-Danlos syndrome causing all three coronary artery spontaneous dissections. Our case also suggests that, from vascular fragility even if it is spontaneous coronary dissection, physicians always consider connective-tissue disorders as a differential diagnosis at an early stage even though that would be a first complication, and percutaneous coronary intervention with stenting using intravascular ultrasound could be a strategic option for even repeated and fatal spontaneous coronary artery dissections in vascular Ehlers-Danlos syndrome.

Background: Inflammatory processes in the atria during systemic inflammation remain unclear, so this study tested the hypothesis that macrophages infiltrate the atrial myocardium mainly through the atrial endocardium with the contribution of fractalkine. Methods and Results: Sprague-Dawley rats were injected with lipopolysaccharide (LPS) to simulate inflammation in the atria. Inflammation was immunohistologically assessed by the presence of macrophages. Macrophage infiltration was diffuse throughout the atrial myocardium after LPS injection. At an earlier phase after LPS injection, the number of macrophages dramatically increased, mainly in the atrial endocardium, and the expression of fractalkine protein was markedly increased by treatment with LPS in the atrial endocardium. The LPS-induced increase in atrial macrophage infiltration was significantly suppressed by neutralizing the fractalkine protein (P

Background Recent investigations have demonstrated that cerebral oxyhemoglobin (O2Hb) decreases during exercise in patients with left ventricular dysfunction, reflecting a cerebral hypoxia. We sought to establish a prognostic value of decreased cerebral O2Hb during exercise in cardiac patients, and to compare it with those of indexes obtained from cardiopulmonary exercise testing (CPX). Methods and Results A total of 344 consecutive patients with coronary artery disease were enrolled in the study. All the patients performed CPX, during which cerebral O2Hb was continuously monitored using near-infrared spectroscopy. There were 13 cardiac deaths and 78 cardiovascular events during the prospective follow-up period of 1,231±538 days. The change of O2Hb measured at the forehead from rest to peak exercise (ΔO2Hb) was significantly lower in non-survivors than in survivors (-1.5±3.3 vs 1.7±3.2 μmol/L, p=0.0004). By multivariate Cox proportional hazards analysis, ΔO2Hb and left ventricular ejection fraction (LVEF) were found to be independent prognostic markers for cardiac deaths. The ΔO2Hb, LVEF and peak oxygen uptake were found to be significant prognostic markers for cardiovascular events, mainly for heart failure worsening and sudden cardiac death. Conclusion The present findings suggest that a decrease in cerebral O2Hb during exercise predicts future cardiovascular events in patients with coronary artery disease. (Circ J 2008; 72: 1852 - 1858)

Aims Oxidative damage promotes atherosclerosis. Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme localized in mitochondria. We investigated the associations of the MnSOD polymorphism (valine-to-alanine in the mitochondrial-targeting domain) with its activity in leukocytes, with macrophage apoptosis by oxidized low-density lipoprotein (oxLDL), and with coronary artery disease (CAD). Methods and results Blood samples were taken from 50 healthy subjects. The mitochondrial MnSOD activities in leukocytes were 542.4 ± 71.6 U/mg protein (alanine/alanine, n = 2), 302.0 ± 94.9 U/mg protein (alanine/valine, n = 12), and 134.0 ± 67.1 U/mg protein (valine/valine, n = 36; P < 0.0001 for non-valine/valine vs. valine/valine). Macrophages were treated with oxLDL. After incubation, the percentages of apoptotic macrophages were 48.6 ± 3.6% (alanine/alanine), 78.6 ± 9.8% (alanine/valine), and 87.5 ± 7.0% (valine/valine) ( P < 0.0001, non-valine/valine vs. valine/valine). The association of the MnSOD polymorphism with CAD was investigated using blood samples collected from 498 CAD patients and 627 healthy subjects; the alanine allele was found to reduce the risk of CAD and acute myocardial infarction (AMI). Conclusion Our data indicate that the alanine variant of signal peptide increases the mitochondrial MnSOD activity, protects macrophages against the oxLDL-induced apoptosis, and reduces the risk of CAD and AMI.

Introduction. Atrial fibrillation (AF) per se causes atrial endocardial dysfunction leading to local coagulation imbalance on the internal surface of the atrium, which contributes to thrombus formation in the fibrillating left atrium. Materials and methods. To test a hypothesis that blockade of angiotensin II type 1 receptor (AT1-receptor) prevents the endocardial dysfunction by AF, we examined the effects of olmesartan on the expression of tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), endothelial nitric oxide synthase (eNOS) and plasminogen activator inhibitor-1 (PAI-1) in the endocardium of the rapidly paced rat atria. Results. Rapid pacing induced a significant decrease in TFPI,TM and eNOS and an increase in PAI-1 protein in the left atrium. Pre-administration of low-dose olmesartan significantly prevented the down-regulation of TFPI,TM and eNOS and also attenuated the up-regulation of PAI-1. Immunohistochemistry identified these changes predominantly in the atrial endocardium. While the drug was without any effect on mRNA levels of TFPI,TM and eNOS, there was a significant decrease in its PAI-1 mRNA expression. Conclusions. AT1-receptor blocker could partially prevent the atrial endocardial dysfunction by rapid atrial pacing, which would provide one theoretical basis for beneficial effects for stroke prevention in AF.

Background It has been recently reported that cerebral oxyhemoglobin (O2Hb) decreases during exercise in nearly 50% of patients with dilated cardiomyopathy. The present study evaluated whether the inhalation of supplemental O2 diminishes the decrease in cerebral O2Hb during exercise. Methods and Results Ten patients with a left ventricular ejection fraction

Background It is well-known that both B-type natriuretic peptide (BNP) and peak oxygen uptake (VO2) are independent predictors of mortality in patients with heart failure. This study investigates the predictive power of BNP and peak VO2 for survival in cardiac patients. Methods and Results A total of 609 patients with cardiac disease participated in the study. They underwent cardiopulmonary exercise testing to determine peak VO2, with BNP being measured before exercise testing During 502.5 median follow-up days, 29 patients died of cardiovascular disease. In the univariate Cox proportional hazards analysis, peak VO2 and BNP were both found to be significant prognostic indices for survival. The time-dependent ROC curve analysis (Heagerty 2006) was applied to 3 predictors: peak VO2, BNP, and then both, with gender and age as adjusted variables. The area under the curve (AUC) compared with the follow-up period curves of peak VO2 and the 2 combined variables (ie, BNP and peak VO2) were consistently over that of BNP. The integrated AUC indices were 0.80 (peak VO2), 0.81 (peak VO2 and BNP) and 0.70 (BNP), respectively. Conclusions These results indicate that peak VO2 is more potent than BNP for predicting the mortality in patients with mixed cardiac disease. (Circ J 2008; 72: 575 - 581)

Background Percutaneous coronary interventions involving small coronary vessels represent a true challenge because of the increased risk of restenosis and adverse outcomes. We evaluated the 2-year clinical outcomes between single everolimus-eluting stents (EES) and paclitaxel-eluting stents (PES) in small coronary artery disease. Methods From the data of SACRA (SmAll CoronaRy Artery treated by TAXUS Liberte) and PLUM (PROMUS/Xience V Everolimus-ELUting Coronary Stent for sMall coronary artery disease) registries, 245 patients with 258 lesions and 264 patients with 279 lesions, respectively, were enrolled in this study. Results The 2-year clinical driven target lesion revascularization (4.5% vs. 10.6%, p = 0.01) and target vessel revascularization (8.0% vs. 13.9%, p = 0.03) rates were significantly lower in the EES group compared with the PES group. Major adverse cardiac events in the EES group tended to be lower than those in the PES group (8.7% vs. 14.3%, p = 0.05). On the other hand, all new lesions for remote target vessel revascularization were observed at the proximal site of target lesions in both groups and those rates were not different between the two groups (3.4% vs. 3.3%, p > 0.99). Conclusion EES showed better clinical results at 2-year follow-up compared with PES in small coronary artery diseases, however, new lesions at the proximal remote site of the target lesion remain problematic.

Repeated hospitalization due to acute decompensated heart failure (HF) is a pandemic health problem in Japan. However, it is difficult to predict rehospitalization after discharge for acute decompensated HF. We used a single hospital-based cohort from the Shinken Database 2004-2012, comprising all new patients (n = 19,994) who visited the Cardiovascular Institute Hospital. A total of 282 patients discharged after their first acute HF admission were included in the analysis. The median follow-up period was 908 ± 865 days. Of these patients, rehospitalization due to worsening HF occurred in 55 patients. The cumulative rate of rehospitalization was 17.5% at 1 year, 21.4% at 2 years, and 25.5% at 3 years. Patients with rehospitalization were older than those without rehospitalization. Prevalence of diabetes mellitus (DM) was more common in patients with rehospitalization. Average heart rate (HR) tended to be higher in patients with rehospitalization. Loop diuretics were more commonly used at hospital discharge in patients with rehospitalization. Multivariate Cox regression analysis revealed that age ≥ 75 years, DM, HR ≥ 75 bpm at discharge, and use of loop diuretics at discharge were independent predictors for rehospitalization. The number of these independent risk factors could be used to clearly discriminate between the HF rehospitalization low-, middle- and high-risk patients. HF rehospitalization commonly occurred in patients who were discharged after their first acute HF admission. Older age, DM, increased HR, and loop diuretics use at discharge were independently associated with HF rehospitalization. By simply counting these risk factors, we might be able to predict the risk of HF rehospitalization after discharge.

Background Many pathological conditions induce electrical remodeling, possibly through intracellular Ca2+ overload, but the currently available L-type Ca2+ channel blockers may be detrimental because of their global negative inotropic effects. Methods and results To determine whether the L-type Ca2+ channel is identical throughout the heart, the distribution of the mRNAs and proteins comprising the L-type Ca2+ channel and its electrophysiological properties were analyzed in rat atria and ventricles. The mRNA of alpha2delta-2 (Cacna2d2) was more abundantly expressed in the atrium (approximately 5-fold) than in the ventricle. In contrast, alpha1C (Cacna1c) (Cav1.2) mRNA was significantly less abundant in the atrium. The level of the alpha1C (Cacna1c) (Cav1.2) protein was decreased (approximately 0.5-fold) and that of alpha2 delta-1 (Cacna2d1) was increased (approximately 2-fold) in the atrium compared with the ventricle. Although the peak ICa,L density showed no significant differences, voltage dependence of inactivation and activation of the current showed a more depolarized shift in the atrium than in the ventricle. Conclusion These results indicate that in the rat heart the L-type Ca2+ channel differs between the atrium and ventricle with regard to gene expression and electrophysiological properties.

Antiarrhythmic drugs exert their effects by inhibiting the ion channels of cardiomyocytes. However, these effects could also modify the ionic environment around them, and thereby affect the expression of ion channels, leading to biochemical enhancement or attenuation of the antiarrhythmic effects. To test this hypothesis, the physiological and biochemical effects of cibenzoline were evaluated in a rapid atrial pacing model in rats. In rats with rapid atrial pacing, pretreatment with cibenzoline significantly inhibited the increases in Kv1.5 mRNA at 2 hours and immunoreactive protein at 4 hours by 35 +/- 15% and 30 +/- 10%, respectively. These effects were observed only in the rapid atrial pacing group, not in the sham-operated group. With cibenzoline pretreatment, 4-hour rapid atrial pacing resulted in significant prolongation of the atrial refractory period compared to the untreated group even after removal of cibenzoline. In contrast, the sham and rapid atrial pacing model with and without cibenzoline pretreatment showed similar acute physiological responses to cibenzoline. In conclusion, in addition to the acute physiological effects, pretreatment with cibenzoline exerted pleiotropic effects of inhibition of Kv1.5 channel upregulation by rapid pacing, implying differences in the cibenzoline effects when administered before and after onset of paroxysmal atrial fibrillation.

Evaluating blood pressure response during exercise rather than during rest might better detect a subtle impairment in relaxation of the resistance vessel in hypercholesterolemia. We examined the relation between serum cholesterol and blood pressure response during exercise in patients with coronary artery disease. One hundred and forty-eight consecutive patients with coronary artery disease were monitored during symptom-limited incremental exercise testing with a cycle ergometer. Cuff blood pressure was measured every minute during exercise testing with an automatic indirect manometer. Although there were no significant differences in systolic or diastolic blood pressure at rest between the patients with hypercholesterolemia (total cholesterol > or = 220 mg/dL, n = 39) and those without it (n = 109), the former reached a higher diastolic blood pressure at peak exercise (94.8+/-16.0 versus 87.8+/-12.9 mmHg, P = 0.007). The increase in diastolic blood pressure at peak exercise versus the resting value in the patients with hypercholesterolemia was 20.6+/-11.3 mmHg, and this was significantly higher than the increase in patients without hypercholesterolemia (14.8+/-11.8 mmHg, P = 0.009). However, there were no differences in the peak exercise systolic blood pressure and the magnitude of the increase in systolic blood pressure between the two groups. Among the patients with coronary artery disease in our study, we found that those with hypercholesterolemia had significantly higher diastolic blood pressure during exercise than those without hypercholesterolemia, strongly suggesting that patients with hyperlipidemia are at a higher risk of developing hypertensive complications.

Background End-tidal CO2 partial pressure (PETCO2) has been suggested as a noninvasive index reflecting cardiac output under constant ventilation. The aim of this study was to examine whether PETCO2 does reflect cardiac output, even during exercise, in patients with acute myocardial infarction (AMI) undergoing exercise training early after onset. Method and Results Patients aged 47-73 years were randomly assigned to either a training group (n=18) or a control group (n=18) 1 week after the onset of AMI. Those in the training group performed exercise training under supervision at the anaerobic threshold level for 2 weeks, while patients in the control group followed a conventional walking regimen. In the training group, but not in the control group, PETCO2 at the respiratory compensation point increased significantly from 39.1±3.5 to 41.1±3.7 mmHg (p

Background The prognostic impact of worsening renal function (WRF) in acute coronary syndrome (ACS) patients is not fully understood in Japanese clinical practice, and clinical implication of persistent versus transient WRF in ACS patients is also unclear. Methods With a single hospital-based cohort in the Shinken database 2004–2012 ( n = 19,994), we followed 604 ACS patients who underwent percutaneous coronary intervention (PCI). WRF was defined as an increase in creatinine during hospitalization of ≥0.3 mg/dl above admission value. Persistent WRF was defined as an increase in creatinine during hospitalization of ≥0.3 mg/dl above admission value and maintained until discharge, whereas transient WRF was defined as that WRF resolved at hospital discharge. Results WRF occurred in 78 patients (13%), persistent WRF 35 patients (6%) and transient WRF 43 patients (7%). WRF patients were older and had a higher prevalence of chronic kidney disease, history of myocardial infarction (MI), and ST elevation MI. WRF was associated with elevated inflammatory markers and reduced left ventricular (LV) ejection fraction in acute, chronic phase. Incidence of all-cause death and major adverse cardiac events (MACE: all-cause death, MI, and target lesion revascularization) was significantly higher in patients with WRF. Moreover, in the WRF group, incidences of all-cause death and MACE were higher in patients with persistent WRF than those with transient WRF. A multivariate analysis showed that as well as older age, female gender, and intubation, WRF was an independent determinant of the all-cause death in ACS patients who underwent PCI. Conclusions In conclusion, WRF might have a prognostic impact among Japanese ACS patients who underwent PCI in association with enhanced inflammatory response and LV remodeling. Persistent WRF might portend increased events, while transient WRF might have association with favorable outcomes compared with persistent WRF.

Background: This study investigated the progression of paroxysmal atrial fibrillation (AF) to the persistent form in Japanese asymptomatic AF patients. Methods and Results: Data were derived from a single hospital-based cohort in the Shinken Database 2004–2012 (n=19,994), in which 1,176 patients were diagnosed as having paroxysmal AF. AF progression occurred in 115 patients (6.0%/year) during the mean follow-up period (1,213±905 days). Although patients who were asymptomatic at the initial visit (n=468) had a low-risk profile compared with symptomatic patients, they had greater AF progression at follow-up (unadjusted hazard ratio, 1.611; 95% CI: 1.087–2.389; P=0.018). Absence of symptoms, male sex, and cardiomyopathy were independent predictors for AF progression in the multivariate model. It was noted that asymptomatic patients were less likely to undergo pulmonary vein isolation (PVI). In addition, the interaction term between asymptomatic AF and absence of PVI could be another independent predictor for AF progression. Prognosis was similar between asymptomatic and symptomatic patients with AF. Conclusions: Irrespective of low-risk profile, patients with asymptomatic paroxysmal AF had greater progression of AF compared with symptomatic patients. This paradoxical result appeared to be the result of less intensive clinical management, including invasive rhythm control. (Circ J 2014; 78: 1121–1126)

OBJECTIVES This study was conducted to evaluate: 1) the effect of adjunctive percutaneous transluminal coronary angioplasty (PTCA) after directional coronary atherectomy (DCA) compared with stand-alone DCA, and 2) the outcome of intravascular ultrasound (IVUS)-guided aggressive DCA. BACKGROUND It has been shown that optimal angiographic results after coronary interventions are associated with a lower incidence of restenosis. Adjunctive PTCA after DCA improves the acute angiographic outcome; however, long-term benefits of adjunctive PTCA have not been established. METHODS Out of 225 patients who underwent IVUS-guided DCA, angiographically optimal debulking was achieved in 214 patients, then they were randomized to either no further treatment or to added PTCA. RESULTS Postprocedural quantitative angiographic analysis demonstrated an improved minimum luminal diameter (2.88 ± 0.48 vs. 2.6 ± 0.51 mm; p = 0.006) and a less residual stenosis (10.8% vs.15%; p = 0.009) in the adjunctive PTCA group. Quantitative ultrasound analysis showed a larger minimum luminal diameter (3.26 ± 0.48 vs. 3.04 ± 0.5 mm; p CONCLUSIONS With IVUS guidance, aggressive DCA can safely achieve optimal angiographic results with low residual plaque mass, and this was associated with a low restenosis rate. Although adjunctive PTCA after optimal DCA improved the acute quantitative coronary angiography and quantitative coronary ultrasonography outcomes, its benefit was not maintained at six months.

Objectives. This study was designed to determine whether coronary vasospasm in patients with variant angina pectoris (VAP) may produce focal organic lesions at the site of vasospasm that would contribute to disease progression.Background. Recent clinical angiographic and experimental studies have demonstrated the potential role of vasospasm in the worsening of organic coronary stenosis.Methods. We studied histologically the coronary plaques obtained at atherectomy in 202 patients with moderate to severe coronary stenosis. This population included 22 patients with VAP, 100 patients with chronic stable angina and 80 patients with restenosis following angioplasty or atherectomy. Diagnosis of VAP was based on both the clinical feature of angina at rest associated with ST elevation and a positive response to acetylcholine provocation test.Results. The most common histological appearance in 92% of patients with stable angina was hypocellular fibroatheromatous plaques, whereas neointimal hyperplasia was the characteristic feature of the plaque observed in 90% of patients with restenosis. The coronary specimens at the site of spasm in 15 of the 22 patients (68%) with VAP demonstrated intimal injuries such as neointimal hyperplasia (15), thrombus formation (2), and intimal hemorrhage (3). Neointimal hyperplasia was significantly more common in the patients with VAP as compared with those with stable angina (68% vs. 8%; p < 0.0001). A rapid progression of organic stenosis within three years was angiographically found in 5 of the 22 patients with variant angina. In all five cases, neointimal hyperplasia was the main contributor to the worsening of the organic lesion at the site of spasm. These histological findings in patients with VAP extremely resembled those in restenosis. Except for vasospasm, no factors significantly predicted the presence of neointimal formations in primary coronary lesions.Conclusions. Coronary vasospasm may provoke vascular injury that leads to the formation of neointima in VAP patients similar to that seen with restenosis. Coronary spasm may thus play a key role in the rapid coronary stenosis progression in certain patients with VAP.

To assess the relationship between coronary artery calcification and the late success rate of percutaneous transluminal coronary angioplasty (PTCA), we performed electron beam computed tomography (EBCT) in 22 patients with ischemic heart disease who underwent PTCA. The calcification score in each coronary artery vessel was estimated and compared with the occurrence of restenosis at 3 months after PTCA. Angioplasty had been performed in 28 sites in 22 patients, and 12 sites exhibited restenosis. The mean calcium score in the unsuccessful PTCA vessels was significantly higher than in successful sites (228 vs 92). The overall late success rate of PTCA with moderate to severe calcification was extremely low at 29%. Coronary segments with diffuse and extensive calcification were not optimal target lesions for PTCA. Prediction of the late success rate after PTCA may be possible by prior evaluation of coronary artery calcification utilizing EBCT.

A 65-year-old man with Brugada-type electrocardiogram (ECG) was admitted to our hospital for chest pain, palpitation and faintness. In the cardiac electrophysiological study, no ventricular tachyarrthymia was induced either at baseline or after pilsicainide (50 mg) infusion. Intravenous administration of pilsicainide exaggerated ST-segment elevation in V(1-4) and converted it to the coved type in V(1), accompanied by severe chest pain. Coronary angiography revealed the vasospasm of the right coronary artery was induced by pilsicainide, not by ergonovine. This is the first case report of coronary vasospasm induced by a pure sodium channel blocker in a patient with Brugada-type ECG.

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.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; P0.001) without a significant interaction between sex categories (P=0.195).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.