[Show abstract][Hide abstract] ABSTRACT: Aim:
Malnutrition has been identified to be an independent predictor of morbidity and mortality in patients with chronic heart failure (CHF). However, the pathophysiological mechanisms underlying this pathway remain unclear.
Nutritional screening was performed using the controlling nutritional status (CONUT) score, which was calculated using the serum albumin and total cholesterol levels and lymphocyte number, in 114 CHF patients with a mean left ventricular ejection fraction of 26.6%±6.4%. The carotid intima-media thickness (CIMT) is correlated with carotid atherosclerosis and is a significant predictor of future cardiovascular events. Peripheral blood mononuclear cells (PBMCs) were isolated, and the production of monocyte tumor necrosis factor (TNF)-α was measured and expressed as mean±SD (pg/mL/10(6) PBMCs).
A multivariate linear regression analysis showed that the production of monocyte TNF-α (β coefficient=0.434, p＜0.001) and mean CIMT (β coefficient=0.204, p=0.006) were independent determinants of the CONUT score. During a median follow-up of 67.5 months, 45 patients experienced cardiac events, including 16 cardiac deaths and 29 readmissions for worsening CHF. A multivariate Cox hazard analysis demonstrated that a monocyte TNF-α level of ≥4.1 pg/mL/10(6) PBMCs (hazard ratio (HR), 14.10; 95% confidence interval (CI), 2.55-77.92; p=0.002) and CONUT score of ≥3 (HR, 11.97; 95% CI, 2.21-64.67; p=0.004) were independently associated with the incidence of cardiac events.
These data indicate that a poor nutritional status as assessed using the CONUT score and atherosclerosis as indicated by CIMT is significantly associated with inflammation and predicts poor outcomes in patients with CHF.
Preview · Article · Jan 2016 · Journal of atherosclerosis and thrombosis
[Show abstract][Hide abstract] ABSTRACT: A post-marketing surveillance (PMS) study is being conducted to investigate the safety and effectiveness of the long-term use of dabigatran etexilate (dabigatran) in Japanese patients with nonvalvular atrial fibrillation (NVAF). Results of an interim analysis of this prospective cohort study including patient characteristics and adverse drug reactions (ADRs) collected up to September 17, 2014 are reported here.
Preview · Article · Jan 2016 · Journal of Arrhythmia
[Show abstract][Hide abstract] ABSTRACT: Background:
Prior ischemic stroke or transient ischemic attack (TIA) is a high risk for thromboembolism in patients with nonvalvular atrial fibrillation (NVAF). To clarify rates of thromboembolic and hemorrhagic events, and target intensities of warfarin for secondary prevention, a subanalysis was performed using data from the J-RHYTHM Registry.
Of 7937 outpatients with atrial fibrillation, 7406 with NVAF (men 70.8%, 69.8 ± 10.0 years) were followed for 2 years or until an event occurred. Event rates and effect of warfarin were compared between patients with (secondary prevention) and without (primary prevention) prior stroke/TIA.
Prevalence of male sex, diabetes mellitus, and mean age were higher in the secondary prevention group, showing a higher CHADS2 (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and history of stroke or TIA) score than the primary prevention group (3.5 ± 1.0 versus 1.4 ± 1.0, P < .001). In the secondary prevention group, 93.4% of patients received warfarin and their time in therapeutic range was 62.8%. During follow-up, thromboembolism occurred more frequently in the secondary than in the primary prevention group (2.8% versus 1.5%, P = .004), especially in patients without warfarin. Major hemorrhage also occurred more frequently in the secondary prevention group (3.0% versus 1.7%, P = .006). Compared with patients not taking warfarin, combined rates of both events were lower at an international normalized ratio (INR) of 1.6-2.59 in patients taking warfarin in the secondary as well as in the primary prevention groups.
Both thromboembolism and major hemorrhage occurred more frequently in NVAF patients with prior ischemic stroke/TIA. Target INR should be 1.6-2.59 for secondary as well as primary prevention of thromboembolism in Japanese NVAF patients.
Preview · Article · Dec 2015 · Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association
[Show abstract][Hide abstract] ABSTRACT: Osteoprotegerin (OPG) is a soluble glycoprotein belonging to the tumor necrosis factor receptor superfamily and is linked to vascular atherosclerosis and calcification. The carotid intima-media thickness (CIMT) correlates with carotid atherosclerosis and is a significant predictor of cardiovascular events. The OPG levels are associated with the CIMT in coronary artery disease (CAD) patients. However, the pathophysiological mechanisms underlying this pathway remain unclear. We investigated 114 CAD patients (89 men, 25 women; mean age: 68.7 ± 10.3 years) and measured the Gensini score (a marker of the extent of coronary atherosclerosis), the mean CIMT and the plasma levels of OPG and asymmetric dimethylarginine (ADMA; a marker of endothelial function). Early carotid atherosclerosis was defined as a mean CIMT > 1.0 mm. Only 33 of the 114 patients (28.9%) had early carotid atherosclerosis. Patients with early carotid atherosclerosis had higher OPG levels than those without. The OPG levels were found to be significantly associated with ADMA (r = 0.191, P = 0.046) and the mean CIMT (r = 0.319, P = 0.001), but not with the Gensini score. A receiver operating curve analysis revealed the optimal cut-off value of the OPG levels for predicting early carotid atherosclerosis to be 100 pmol/L. A multivariate logistic regression analysis showed OPG ≥ 100 pmol/L to be significantly and independently associated with early carotid atherosclerosis (odds ratio: 2.98, 95% confidence interval: 1.22-7.20, P = 0.017). These data indicate that OPG is significantly associated with endothelial function and predicts early carotid atherosclerosis in patients with CAD.
Preview · Article · Nov 2015 · International Heart Journal
[Show abstract][Hide abstract] ABSTRACT: To clarify the effects of warfarin therapy in very old patients with non-valvular atrial fibrillation (NVAF), a post-hoc analysis was performed using the data of the J-RHYTHM Registry.Methods and Results:A consecutive series of AF outpatients was enrolled from 158 institutions. Of 7,937 patients, 7,406 with NVAF (men, 70.8%; 69.8±10.0 years) were followed for 2 years or until an event occurred. Patients were divided into 3 age groups (<70, 70-84, and ≥85 years) and 5 subgroups according to international normalized ratio (INR; <1.6, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0). Prevalence of female sex, permanent AF, hypertension, coronary artery disease, heart failure, and history of ischemic stroke/transient ischemic attack was higher in the older groups. In the oldest group, 79.7% of patients received warfarin and their time in therapeutic range, using the Japanese target INR of 1.6-2.6, was 67.1%. Rate of thromboembolic events was lower in the age groups <70 and 70-84 years (P=0.027 and P<0.001, respectively) for patients receiving warfarin compared with those who were not. In the oldest group, the rate of thromboembolism plus major hemorrhage was lower at INR 1.6-2.59.
Warfarin could have beneficial effects even in very old NVAF patients if INR is kept between 1.6 and 2.59.
[Show abstract][Hide abstract] ABSTRACT: Few reports are available on the characteristics of electrical storms of ventricular tachycardia (VT storm) refractory to intravenous (IV) amiodarone.Methods and Results:IV-amiodarone was administered to 60 patients with ventricular tachyarrhythmia between 2007 and 2012. VT storms, defined as 3 or more episodes of VT within 24 h, occurred in 30 patients (68±12 years, 7 female), with 12 having ischemic and 18 non-ischemic heart disease. We compared the clinical and electrocardiographic characteristics of the patients with VT storms suppressed by IV-amiodarone (Effective group) to those of patients not affected by the treatment (Refractory group). IV-amiodarone could not control recurrence of VT in 9 patients (30%). The Refractory group comprised 5 patients with acute myocardial infarctions. Although there was no difference in the VT cycle length, the QRS duration of both the VT and premature ventricular contractions (PVCs) followed by VT was narrower in the Refractory group than in the Effective group (140±30 vs. 178±25 ms, P<0.01; 121±14 vs. 179±22 ms, P<0.01). In the Refractory group, additional administration of IV-mexiletine and/or Purkinje potential-guided catheter ablation was effective.
IV-amiodarone-refractory VT exhibited a relatively narrow QRS tachycardia. The narrow triggering PVCs, suggesting a Purkinje fiber origin, may be treated by additional IV-mexiletine and endocardial catheter ablation.
[Show abstract][Hide abstract] ABSTRACT: Background: An elevated uric acid (UA) level is associated with an increased risk of adverse outcomes in patients with chronic heart failure (CHF). Febuxostat and allopurinol lower the UA levels and attenuate the expression of an inflammatory marker, monocyte chemoattractant protein (MCP)-1. However, a direct comparison of the effects of febuxostat and allopurinol on the inflammation and cardiac function in CHF patients with hyperuricemia has not yet been performed. Methods: A total of 61 CHF patients with hyperuricemia who had a mean left ventricular ejection fraction (LVEF) of 37.1 ± 6.7% were randomly assigned to receive febuxostat (n. = 31) or allopurinol (n = 30). Results: The MCP-1 levels and LVEF at baseline were comparable between the groups. However, after 12. months of treatment, the febuxostat group achieved significantly higher percent decreases in the UA and MCP-1 levels from baseline than those of the allopurinol group (p. <. 0.001). The LVEF in both groups had improved after 12. months; however, a greater percent increase in the LVEF from baseline was observed in the febuxostat group than that in the allopurinol group (p. <. 0.001). The percent increase in the LVEF from baseline was found to be significantly associated with the percent decrease in MCP-1 (r = 0.634, p. <. 0.001) in the febuxostat group. Conclusions: These data indicate that febuxostat is more effective than allopurinol in reducing the UA level and inflammation and may improve the cardiac function in CHF patients with hyperuricemia due, at least in part, to reductions in inflammation.
[Show abstract][Hide abstract] ABSTRACT: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have multiple pleiotropic effects, such as anti-inflammatory and vascular endothelium protection, that are independent of their low-density-lipoprotein (LDL) cholesterol lowering effects. However, whether different statins exert diverse effects on inflammation, insulin resistance, and the progression of carotid atherosclerosis [as indicated by the intima-media thickness (CIMT)] in patients with dyslipidemia remains unclear.
A total of 146 patients with hypercholesterolemia without known cardiovascular disease were randomly assigned to receive 5 mg/day of atorvastatin (n=73) or 1 mg/day of pitavastatin (n=73).
At baseline, age, gender, blood pressure, lipid profiles, and the serum monocyte chemoattractant protein (MCP)-1, homeostasis model assessment of insulin resistance (HOMA-IR) and CIMT values were comparable between the groups. After 12 months of treatment, atorvastatin and pitavastatin equally reduced the LDL cholesterol levels; however, atorvastatin increased the HOMA-IR by ＋26% and pitavastatin decreased this parameter by －13% (p＜0.001). The MCP-1 values were reduced by －28% in the patients treated with pitavastatin and only －11% in those treated with atorvastatin (p=0.016). A greater percent decrease in the mean CIMT from baseline was observed in the patients treated with pitavastatin than in those treated with atorvastatin (－4.9% vs. －0.5%, p=0.020).
These data indicate that, while these agents significantly and equally reduce the LDL cholesterol levels, atorvastatin and pitavastatin have different effects on inflammation, insulin resistance, and the progression of carotid atherosclerosis in patients with dyslipidemia.
Preview · Article · Jun 2015 · Journal of atherosclerosis and thrombosis
[Show abstract][Hide abstract] ABSTRACT: Because the current Japanese guideline recommends CHADS2score-based risk stratification in nonvalvular atrial fibrillation (NVAF) patients and does not list female sex as a risk for thromboembolic events, we designed the present study to compare the CHA2DS2-VASc and CHA2DS2-VA scores in the J-RHYTHM Registry.Methods and Results:We prospectively assessed the incidence of thromboembolic events for 2 years in 997 NVAF patients without warfarin treatment (age 68±12 years, 294 females). The predictive value of the CHA2DS2-VASc and CHA2DS2-VA scores for thromboembolic events was evaluated by c-statistic difference and net reclassification improvement (NRI). Thromboembolic events occurred in 7/294 females (1.2%/year) and 23/703 males (1.6%/year) (odds ratio 0.72 for female to male, 95% confidence interval (CI) 0.28-1.62, P=0.44). No sex difference was found in patient groups stratified by CHA2DS2-VASc and CHA2DS2-VA scores. There were significant c-statistic difference (0.029, Z=2.3, P=0.02) and NRI (0.11, 95% CI 0.01-0.20, P=0.02), with the CHA2DS2-VA score being superior to the CHA2DS2-VASc score. In patients with CHA2DS2-VASc scores 0 and 1 (n=374), there were markedly significant c-statistic difference (0.053, Z=6.6, P<0.0001) and NRI (0.11, 95% CI 0.07-0.14, P<0.0001), again supporting superiority of CHA2DS2-VA to CHA2DS2-VASc score.
In Japanese NVAF patients, the CHA2DS2-VA score, a risk scoring system excluding female sex from CHA2DS2-VASc, may be more useful in risk stratification for thromboembolic events than CHA2DS2-VASc score, especially in identifying truly low-risk patients.
Preview · Article · May 2015 · Circulation Journal
[Show abstract][Hide abstract] ABSTRACT: Background:
The incidence rate of ischemic stroke in Japanese non-valvular atrial fibrillation (NVAF) patients without anticoagulation therapy remains unclear.
Methods and results:
We performed a pooled analysis of 3,588 patients from the Shinken Database (n=1,099), J-RHYTHM Registry (n=1,002), and Fushimi AF Registry (n=1,487) to determine the incidence rate of ischemic stroke in Japanese NVAF patients without anticoagulation therapy. Average patient age was 68.1 years. During the follow-up period (total, 5,188 person-years; average, 1.4 years), 69 patients suffered from ischemic stroke (13.3 per 1,000 person-years; 95% confidence intervals [CI]: 10.5-16.8). The incidence rates of ischemic stroke were 5.4, 9.3, and 24.7 per 1,000 person-years and 5.3, 5.5, and 18.4 per 1,000 person-years in patients with low (0), intermediate (1), and high (≥ 2) CHADS2 and CHA2DS2-VASc scores, respectively. History of ischemic stroke or transient ischemic attack (hazard ratio [HR], 3.25; 95% CI: 1.86-5.67), age ≥ 75 years (HR, 2.31; 95% CI: 1.18-4.52), and hypertension (HR, 1.69; 95% CI: 1.01-2.86) were independent risk factors for ischemic stroke.
A low incidence rate of ischemic stroke was observed in Japanese NVAF patients except for those with CHADS2 score ≥ 2. In this pooled analysis, history of ischemic stroke or transient ischemic attack, advanced age, and hypertension were identified as independent risk factors for ischemic stroke.
Preview · Article · Dec 2014 · Circulation Journal
[Show abstract][Hide abstract] ABSTRACT: Background:
Warfarin is widely used for prevention of thromboembolism in patients with valvular atrial fibrillation (AF), and an international normalized ratio (INR) of prothrombin time between 2.0 and 3.0 is recommended. Optimal intensity of anticoagulation with warfarin in Japanese patients with valvular AF, however, has not been clarified thoroughly as yet.
Methods and results:
We evaluated the status of anti-thrombotic therapy and incidence rates of events in 410 patients with mitral stenosis and/or mechanical valve replacement (valvular AF) among 7,816 patients with AF followed in the J-RHYTHM Registry. Patients were divided into 5 groups based on INR (<1.6, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0) at the time of event or at the end of follow-up in order to determine the target INR for patients with valvular AF. Warfarin was prescribed in 407 (99.3%) of valvular AF patients. During a 2-year follow-up period, thromboembolism and major hemorrhage occurred in 12 (2.9%) and in 15 (3.7%) patients, respectively. Among patients receiving warfarin, 2-year incidence rates of thromboembolism were 10.3%, 1.6%, 0.6%, 3.0%, and 0.0% (P=0.003 for trend), and those of major hemorrhage were 1.5%, 1.6%, 3.2%, 6.1%, and 21.1% (P<0.001 for trend), respectively.
I NR between 1.6 and 2.6 could be optimal to prevent thromboembolism without increasing major hemorrhage in Japanese patients with valvular AF. INR 2.6-2.99 would also be effective, but is associated with a modestly increased risk of major hemorrhage.
Preview · Article · Dec 2014 · Circulation Journal
[Show abstract][Hide abstract] ABSTRACT: Objective:
Low serum cholesterol is associated with a poor prognosis in patients with chronic heart failure (CHF). However, the relationships between the serum cholesterol level, production of monocyte proinflammatory cytokines and long-term prognosis in CHF patients remain unclear.
A total of 95 CHF patients who had not been treated with statins and had a mean left ventricular ejection fraction of 26.0±6.0% were examined. Peripheral blood mononuclear cells (PBMCs) were isolated, and the production of monocyte tumor necrosis factor (TNF)-α and interleukin (IL)-6 was measured and expressed as the mean ± SD (pg/mL/10(6) PBMCs).
The production of monocyte TNF-α and IL-6 was found to be significantly and negatively associated with the serum low-density lipoprotein (LDL)-cholesterol level (TNF-α: r=-0.515, p<0.001, IL-6: r=-0.419, p<0.001). During a median follow-up of 66.0 months, 49 patients developed cardiac events, including 21 cardiac deaths and 28 readmissions for worsening CHF. A multivariate Cox hazard analysis showed that a monocyte TNF-α level of ≥4.9 pg/mL/10(6) PBMCs [hazard ratio (HR) 187.38, 95% confidence interval (CI) 7.92-4,434.94, p=0.001] and LDL-cholesterol level of <120 mg/dL (HR 9.41, 95% CI 1.02-86.66, p=0.048) were independently associated with the incidence of cardiac events.
Low LDL-cholesterol and the upregulation of monocyte proinflammatory cytokine production are both significantly and independently associated with poor outcomes in CHF patients.
No preview · Article · Nov 2014 · Internal Medicine
[Show abstract][Hide abstract] ABSTRACT: Background:
It is disputed whether the risk of cardiogenic embolism varies with type of atrial fibrillation (AF). Although several studies have found that the risk of cardiogenic embolism was similar among paroxysmal and persistent/permanent AF, a few studies have found that patients with paroxysmal AF had a lower rate of stroke and systemic embolism than those with persistent/permanent AF. In the present study, post-hoc analysis of the J-RHYTHM Registry was done to compare the risk of thromboembolic events among 3 types of non-valvular AF (NVAF). METHODS AND RESULTS:A total of 7,406 NVAF patients were followed up prospectively for 2 years. At baseline, warfarin was used for 78.6%, 90.0%, and 91.8% of patients with paroxysmal, persistent, and permanent AF, respectively. There were 126 thromboembolic events during the follow-up period. The crude event rate was 2-fold higher among the patients with permanent NVAF (2.29%) than among those with paroxysmal (1.16%) or persistent (1.20%) NVAF (P=0.001). After adjusting for warfarin use and CHA2DS2-VASc score components, however, the hazard ratio for thromboembolism did not differ between paroxysmal (reference) and permanent NVAF (1.007; 95% confidence interval: 0.955-1.061).
The crude rate of thromboembolic events was higher in permanent NVAF than in paroxysmal NVAF, but after adjusting for warfarin use and CHA2DS2-VASc score components, paroxysmal and permanent NVAF patients had similar risk of thromboembolism.
No preview · Article · Aug 2014 · Circulation Journal
[Show abstract][Hide abstract] ABSTRACT: Background
To maximize protection against stroke with minimal bleeding, warfarin therapy in nonvalvular atrial fibrillation (NVAF) requires tight control within a narrow therapeutic range, which might depend on racial variations.
The J-RHYTHM Registry followed 6404 NVAF patients treated with warfarin for 2 years. Using international normalized ratios (INRs) at or closest to the embolic and intracranial hemorrhagic (ICH) events, we determined odds ratios for ischemic stroke/systemic embolism (SE) and ICH according to any given INR with a reference INR range including 2.0.
Ischemic stroke and SE occurred in 97 of the patients and ICH occurred in 49. The estimated INR-risk relationships showed characteristics of Japanese NVAF patients. Compared to INR-risk relationships reported for Westerners, those observed in Japanese patients were virtually identical for ischemic stroke/SE and shifted leftward by approximately 0.5 INR for ICH.
This is the largest Japanese study providing fundamental data necessary to establish optimal anticoagulation intensities. Japanese NVAF patients may require narrower therapeutic ranges than Westerners.
No preview · Article · Aug 2014 · Journal of Cardiology
[Show abstract][Hide abstract] ABSTRACT: Causative arrhythmias of sudden cardiac arrest (SCA) are changing in this age of improved coronary care.
We examined the frequency of terminal arrhythmias and the electrical events prior to SCA.
We analyzed 24-h Holter recordings in 132 patients enrolled from 41 institutions who either died (n = 88) or had an aborted death (n = 44). The Holter recordings were performed for diagnosing and evaluating diseases and arrhythmias in those without any episodes suggestive of SCA.
In 97 (73%) patients, the SCA was associated with ventricular tachyarrhythmias and in 35 (27%) with bradyarrhythmias. The bradyarrhythmia-related SCA patients were older than those with a tachyarrhythmia-related SCA (70±13 years vs. 58±19 years, p<0.001). The most common arrhythmia for a tachyarrhythmia-related SCA was ventricular tachycardia degenerating to ventricular fibrillation (45%). The bradyarrhythmia-related SCA was caused by asystole (74%) or atrioventricular block (26%). Spontaneous conversion was observed in 37 (38%) patients with ventricular tachyarrhythmias. Of those, 62% of the patients experienced symptoms including syncope, chest pain or convulsion. A multivariate logistic analysis revealed that the independent predictors of mortality for tachyarrhythmia-related SCAs were an advanced age (odds ratio: 95% confidence interval, 1.04: 1.02-1.08) and ST elevation within the hour before the SCA (3.54: 1.07-13.5). In contrast, the presence of preceding torsades de pointes was associated with spontaneous conversion (0.20: 0.05-0.66).
The most frequent cause of an SCA remains ventricular tachyarrhythmias. Advanced age and ST elevation before the SCA are risk factors for mortality in tachyarrhythmia-related SCAs.
No preview · Article · Apr 2014 · Heart rhythm: the official journal of the Heart Rhythm Society