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The prospective observational Nippon Storm Study aggregated clinical data from Japanese patients receiving implantable cardioverter-defibrillator (ICD) therapy. This study investigated the usefulness of prophylactic ICD therapy in patients with non-ischemic heart failure (NIHF) enrolled in the study.Methods and Results: We analyzed 540 NIHF patients with systolic dysfunction (left ventricular ejection fraction50%). Propensity score matching was used to select patient subgroups for comparison; 126 patients were analyzed in each of the primary (PP) and secondary (SP) prophylaxis groups. The incidence of appropriate ICD therapy during follow-up in the PP and SP groups was 21.4% and 31.7%, respectively (P=0.044). The incidence of electrical storm (ES) was higher in SP than PP patients (P=0.024). Cox proportional hazard analysis revealed that increased serum creatinine in SP patients (hazard ratio [HR] 1.18; 95% confidence interval [CI] 1.02-1.33; P=0.013) and anemia in PP patients (HR 0.92; 95% CI 0.86-0.98; P=0.008) increased the likelihood of appropriate ICD therapy, whereas long-lasting atrial fibrillation in PP patients (HR, 0.64 [95% CI, 0.45-0.91], P=0.013) decreased that likelihood.In propensity score-matched Japanese NIHF patients, the incidence of appropriate ICD therapy and ES was significantly higher in SP than PP patients. Impaired renal function in SP patients and anemia in PP patients increased the likelihood of appropriate ICD therapy, whereas long-lasting atrial fibrillation reduced that likelihood in PP patients.

1 Current status of non‐pharmacotherapies in Japan Pacemaker treatment for bradyarrhythmia was first approved for national health insurance coverage in Japan in 1974, and its use rapidly became widespread thereafter. Approximately 40 years later, in 2017, the number of patients treated with this technology has increased to 60 137 (41 895 new cases and approximately 18 242 replacements). 5 Capsule‐shaped leadless pacemaker also became available in 2016, and this technology is being established as a new option. Non‐pharmacological treatment of tachy‐arrhythmia began in 1969 from when Will C. Sealy performed surgery in patients with Wolff‐Parkinson‐White (WPW) syndrome (Figure 1). Since then, the application of surgical treatment has expanded to conditions such as ventricular tachycardia (VT) and atrial fibrillation (AF), and surgery has been the pioneer of radical therapy for tachyarrhythmias. At the present time, many surgical methods have been replaced by catheter ablation; however, surgical treatment still remains an indispensable option for patients with a tachycardia resistant to other medical treatments. Open in a separate window FIGURE 1 History of non‐pharmacotherapy of cardiac arrhythmia

BACKGROUND The proportion of patients with atrial fibrillation (AF) treated with anticoagulation varies from country to country. In Japan, little is known about regional differences in frequency of warfarin use or prognosis among patients with non-valvular AF (NVAF). METHODS AND RESULTS In J-RHYTHM Registry, the number of patients recruited from each of 10 geographic regions of Japan was based on region population density. A total of 7,406 NVAF patients were followed up prospectively for 2 years. At baseline, significant differences in various clinical characteristics including age, sex, type of AF, comorbidity, and CHADS2score, were detected among the regions. The highest mean CHADS2score was recorded in Shikoku. Frequency of warfarin use differed between the regions (P

Papaverine is useful for evaluating the functional status of a coronary artery, but it may provoke malignant ventricular arrhythmia (VA). The aim of this study was to investigate the incidence, and clinical and ECG characteristics of patients with papaverine-induced VAs. METHODS AND RESULTS: The 182 consecutive patients underwent fractional flow reserve (FFR) measurement of 277 lesions. FFR was determined after intracoronary papaverine administration by standard procedures. The clinical and ECG characteristics were compared between patients with and without ventricular tachycardia (VT: ≥3 successive premature ventricular beats (PVBs), or ventricular fibrillation (VF)). After papaverine administration, the QTc interval, QTUc interval, and T-peak to U-end interval were prolonged significantly. Single PVBs on the T-wave or U-wave type developed in 29 patients (15.9%). Polymorphic VT (torsade de pointes) occurred in 5 patients (2.8%), and of those, VF developed in 3 patients (1.7%). No clinical and baseline ECG parameters were predictors for VT or VF except for sex and administration of papaverine into the left coronary artery. Excessive prolongation of QT (or QTU), T-peak to U-end intervals and giant T-U waves were found immediately prior to the ventricular tachyarrhythmias (VTAs), which were unpredictable from the baseline data.Intracoronary administration of papaverine induced fatal VTAs, although the incidence is rare. Excessive prolongation of the QT (and QTU) interval appeared prior to VTAs; however, they were unpredictable.

Background: The present study was conducted to examine the association of dietary salt intake with changes in serum sodium (srNa) levels when angiotensin II receptor blocker (ARB) treatment is changed to the combination of ARB plus low-dose diuretic (hydrochlorothiazide [HCTZ]). Methods and Results: In 88 patients (age 70±12 years), ARB treatment was switched to the combination therapy (same dosage ARB+12.5mg/day HCTZ). The srNa level was measured before and 6 months after administration of the combination. The daily salt intake was estimated by the Kawasaki formula using second morning urine sample. The study subjects were divided into quintile ranges according to daily salt intake. The reduction in srNa levels by switching to the combination treatment was significant in subjects in the lowest quintile Q5 (≤8.9g/day salt intake), but not in those in Q1–4 (28.1–9.3g/day salt intake). Increases in serum creatinine and uric acid levels were significantly larger in the former group than in the latter group. Conclusions: In elderly Japanese subjects with low salt intake (

Dyslipidemia, an important risk factor for cardiovascular disease, may be associated with atrial fibrillation (AF). Cross-sectional studies that have examined this association, however, have produced controversial results, and few longitudinal studies have been conducted.Using annual health examinations in Japan, the association between lipid profile and the risk of new-onset AF was investigated in the general population. A total of 28,449 individuals who did not have AF at baseline were included in the study. During a follow-up of 4.5±2.7 years, 265 individuals (0.9%) developed AF. In multivariate models, low high-density lipoprotein (HDL) cholesterol was associated with the development of AF in women (hazard ratio [HR], 2.86; 95% confidence interval [CI]: 1.49-5.50) but not in men (HR, 1.35; 95%CI: 0.77-2.38). Women had a 28% higher risk of AF with each 10% decrease in HDL cholesterol. Neither triglycerides nor lipid ratios were associated with AF. After excluding individuals with risk factors for AF, including those who were taking anti-hypertensive drugs, had diabetes, and structural heart disease, the association between low HDL cholesterol and AF remained significant in women.Low HDL cholesterol was associated with an increased risk of new-onset AF in women, but not in men.

Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a major risk factor for stroke. For more than 60 years, warfarin has been the only approved anticoagulant for prevention of stroke in patients with AF. Although highly effective, it has many limitations that make its use difficult. Therefore, several novel anticoagulants are under development to overcome the limitations of warfarin, and some of these have entered phase III clinical trials. Dabigatran is an oral, reversible direct thrombin inhibitor approved in Europe and in several other countries for the prevention of venous thromboembolism after elective knee and hip replacement surgery. It has also been approved in the United States and Japan for the prevention of stroke and systemic embolism in patients with nonvalvular AF. In this review, the mechanism of action and pharmacological properties of new anticoagulants are described in detail, and the correct use of dabigatran in clinical practice is discussed.

Background: Bucolome, a nonsteroidal antiinflammatory drug, enhances the effects of warfarin. In the present study, the effects of combination therapy (bucolome+warfarin) vs. warfarin alone on atrial fibrillation were investigated. Methods and Results: Combined therapy resulted in a decrease in the warfarin dose to approximately one-third. The fluctuations of the international normalized ratio and the time in therapeutic range were similar in both groups. There was no adverse effect in either group. Interestingly, uric acid was lower in the bucolome group. Conclusions: Bucolome enhanced the effects of warfarin, resulting in a decreased dose of warfarin without adverse effects and it showed similar anticoagulant stability to warfarin alone. (Circ J 2011; 75: 201-203)

This study aimed to apply a software to calculate myocardial infarction (MI) volume by single-photon emission computed tomography.The cardioVol software has been developed to reconstruct 3D figures from sequential short axis images. We re-analyzed the data from the EPO/AMI-I Study. The MI volume at baseline correlated with maximum creatine kinase. The MI volume significantly decreased during the 6-month follow up in the erythropoietin (EPO) group, but not in the control group. The decrements of MI volume in the EPO group were significantly larger than those in the control group.The efficacy of EPO was further confirmed by the software.

Background: Erythropoietin (EPO) has been found to have anti-apoptotic and tissue protective effects on the myocardium. The aim of the present pilot study was to observe the safety and efficacy of EPO administration for patients with acute myocardial infarction (AMI). Methods and Results: Patients admitted with AMI had all undergone successful percutaneous coronary intervention (PCI). Patients were randomly assigned to 2 groups (control and EPO groups), and given 12,000 IU EPO iv or saline after PCI. The primary endpoints were the difference between the acute phase and chronic phase (6 months after the attack) regarding left ventricular function as measured on electrocardiogram-gated single-photon emission computed tomography. Thirty-six patients (control 16, EPO 20) were eligible for analysis. Left ventricular ejection fraction (LVEF) significantly increased in the EPO group (from 51.0±19.6% to 58.5±15.0%, P=0.0238), but not in the control group. Further analysis was separately undertaken in patients with occlusion in the left anterior descending artery (LAD) and others (non-LAD). LVEF was

Because bepridil blocks multiple myocardial ionic channels, including the muscarinic acetylcholine receptor-operated potassium current (I(KAch)), bepridil is expected to suppress atrial fibrillation (AF) mediated by vagal nerve stimulation (VNS).The therapeutic effects of bepridil were studied with a special focus on heart rate variability (HRV) in a canine model of AF. During VNS, AF was induced in 9 of 9 experiments before, vs 3 of 9 experiments after administration of bepridil (P0.01). During 350 ms atrial pacing, VNS shortened the right and left atrial monophasic action potentials at 90% repolarization (MAP90) by -31+/-8% and -22+/-12%, respectively, vs -10+/-13% and -6+/-8%, respectively, after bepridil (P0.01, N=9). Bepridil prolonged the sinus cycle length, although it had no significant effect on the conduction time measured at 300 ms pacing. Statistically insignificant change was observed in the VNS-induced slowing of the sinus cycle length and in the VNS-induced increase in high frequency amplitude of HRV before (1.2+/-0.7 to 5.3+/-4.0 ms) vs after (1.7+/-0.8 to 5.4+/-2.3 ms) bepridil administration.Bepridil prevented the VNS-induced shortening of atrial MAP90 and suppressed the inducibility of AF during VNS in two-thirds of the experiments. As far as this study shows, it may be possible that inhibition of I(KAch) played a part in this antifibrillatory effect.

The efficacy of antiarrhythmic drugs in terminating sustained monomorphic ventricular tachycardia (SMVT) was assessed in a retrospective manner to provide a basis for recommending their use.The 90 patients were included in this study to evaluate the efficacy to terminate SMVT using procainamide or lidocaine. All patients were alert and responsive. The mean systolic blood pressure was 91+/-25 mmHg (range, 40-150 mmHg). SMVT was diagnosed from ECG recordings and later in an electrophysiologic study. VTs with a cycle length of 329+/-55 and 324+/-61 ms were treated with the mean doses of 358+/-50 mg and 81+/-30 mg of procainamide and lidocaine and were terminated in 53/70 (75.7%) and in 7/20 (35.0%) respectively. The drugs were discontinued if there was no rise in blood pressure after slowing of the tachycardia rate or if there were signs of impending deterioration in consciousness. Though procainamide was effective, blood pressure was often low and DC shock should be available at all times during administration of the drug.Procainamide, the relatively older drug, was more effective than lidocaine in terminating SMVT associated with structural heart diseases. This is a retrospective analysis but can form the basis for formulating guidelines for initial management of SMVT.

Background: Lipocalin-2/neutrophil gelatinase-B associated lipocalin (Lcn2/NGAL) is involved in the transport of iron and seems to play an important role in inflammation. A recent study has reported that it is also expressed in the failing heart and may be a biomarker not only for renal failure but also for heart failure. Because Lcn2/NGAL is thought to be induced by interleukin-1, it might be strongly induced in the presence of myocarditis. Methods and Results: This study investigated the expression of Lcn2/NGAL in rat experimental autoimmune myocarditis (EAM) and in human myocarditis. In EAM hearts, the expression of Lcn2/NGAL was markedly increased (>100-fold at an early stage), and in human myocarditis it was also highly expressed compared with non-inflammatory failing hearts. Lcn2/NGAL expressing cells in hearts with EAM and human myocarditis were identified as cardiomyocytes, vascular wall cells, fibroblasts and neutrophils. Lcn2/NGAL in EAM rats was also expressed in the liver. Plasma Lcn2/NGAL levels abruptly increased at an early stage of EAM, and high levels were initially sustained during the inflammatory stage, then decreased with recovery. In contrast, levels of B-type natriuretic peptide increased only slowly as the disease progressed. Conclusions: Cardiomyocytes, vascular wall cells and fibroblasts in myocarditis strongly express Lcn2/NGAL via proinflammatory cytokines. (Circ J 2010; 74: 523 - 530)

Background: The relationship between the activation delay during programmed stimulation and the inducibility of ventricular fibrillation (VF) and filtered QRS duration on signal-averaged ECG (SAECG) were assessed in patients with Brugada syndrome (BS). Methods and Results: The activation delay was assessed using the interval between the stimulus and the QRS complex during programmed stimulation in 25 patients with BS and 10 with idiopathic ventricular tachycardia (controls). The mean increase of delay (MID) was used to characterize the conduction curves. The filtered QRS duration (fQRSd) in leads V2 (RfQRSd) and V5 (LfQRSd) were also evaluated using SAECG. Both MIDs at the right ventricular outflow tract (RVOT) were significantly greater in symptomatic and asymptomatic BS patients than in the control group (symptomatic, 7.1 ±2.7 ms vs control, 2.5 ±1.2 ms, P

A multicenter, randomized, placebo-controlled, double-blind trial was conducted with patients with persistent atrial fibrillation (AF) to determine the dose-response effects and safety of bepridil, using every-day transtelephonic monitorings.A total of 90 patients were randomized to receive placebo, 100 mg/day and 200 mg/day of bepridil treatment for 12 weeks. After the treatment, those patients who converted to sinus rhythm was 3.4% in placebo, 37.5% in those who received 100 mg/day and 69.0% in those who received 200 mg/day, thus demonstrating a linear dose-response relationship for AF conversion. The conversion rate gradually reached a maximal value at approximately 6 weeks after initiation of bepridil. However, the AF recurrence rate was high (91.7% in those receiving 100 mg/day and 75.0% in those receiving 200 mg/day). Adverse events, presumably related to the drug, were also frequent: ventricular tachycardia in 2, QT prolongation in 4 and sinus bradycardia in 2 patients. In those patients treated with 200 mg/day group, 1 patient died suddenly because of ventricular tachycardia.This study demonstrated the dose response-relationships of bepridil for AF conversion to sinus rhythm. However, the high rate of AF recurrence and substantial drug-related adverse effects, including sudden death, raised caution about using bepridil to treat persistent AF. The balance between benefits and risks of the drug should be individualized.

Background Although previous clinical trials demonstrated the non-inferiority of a rate control to rhythm control strategy for management of atrial fibrillation (AF), the optimal treatment strategy for paroxysmal AF (PAF) remains unclear. Methods and Results A randomized, multicenter comparison of rate control vs rhythm control in Japanese patients with PAF (the Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM) study) was conducted. The primary endpoint was a composite of total mortality, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for heart failure, or physical/psychological disability requiring alteration of treatment strategy. In the study, 823 patients with PAF were followed for a mean period of 578 days. The primary endpoint occurred in 64 patients (15.3%) assigned to rhythm control and in 89 patients (22.0%) to rate control (P=0.0128). No significant differences between the treatment strategies were observed in the incidences of death, stroke, bleeding and heart failure. Meanwhile, significantly fewer patients requested changes of assigned treatment strategy in the rhythm control vs the rate control group, which was accompanied by improvement in AF-specific quality of life scores. Conclusion The J-RHYTHM study showed that rhythm control was associated with fewer primary endpoints than rate control. However, mortality and cardiovascular morbidity were not affected by the treatment strategy (umin-CTR No. C000000106).

The impact of isolated diastolic dysfunction (IDD) and systolic dysfunction (SD) on health-related quality of life (HRQOL) is unknown.To evaluate HRQOL in patients with IDD and SD under treatment, information on outpatients aged 60-84 years was extracted from the records of 4,500 consecutive individuals who underwent echocardiographic examination at Sado General Hospital. The medical records of these patients were reviewed and a questionnaire, including the Medical Outcome Study Short Form 36, was mailed to 71 IDD and 99 SD patients; answers were obtained from 66 and 91 patients, respectively. The HRQOL of patients with cardiac dysfunction was impaired even when echocardiographic parameters improved with treatment. Patients with IDD showed an impairment of HRQOL similar to those with SD. Compared with males, female patients had a larger and more significant reduction in the physical and mental components of the HRQOL score. These scores correlated positively with exercise capacity in patients with IDD or SD.Impaired HRQOL, in both its mental and physical components, is a serious problem for IDD and SD patients under treatment. Because exercise intolerance may underlie the reduced HRQOL, improving exercise capacity could be an important target for managing outpatients with heart failure.

Heart failure (HF), which can be caused by left ventricular systolic dysfunction (LVSD), is a growing problem in developed countries with a large aging population. The aim of the present study was to characterize outpatients with LVSD in the adult population (45-84 years) in an urban Japanese community (Niigata City), and delineate their characteristics in comparison with those in a rural one (Sado).Over a 5-year period, 1,297 patients (67% males) with LVSD (defined as ejection fractionor =50%) were extracted from 87,953 echocardiography records available in 15 hospitals in Niigata City. The proportion of LVSD increased progressively with age (p-for-trend0.0001), reaching 1-2% in those agedor =75 years. The prevalence of comorbidities was noticeable (47% had hypertension, 41% myocardial ischemia, 34% atrial fibrillation, 33% previous hospitalization because of congestive HF, 27% cerebral stroke). In comparison with Sado, Niigata patients were younger, with a higher prevalence of comorbidities (hypertension, diabetes, dyslipidemia, and cerebral stroke).As the proportion of LVSD cases increases progressively with age, it is expected to simulate a future epidemic. The differences between patients' characteristics and disease patterns in urban and rural communities may favor individually tailoring preventive strategies for HF in these areas.

The future burden of heart failure in Japan was projected to 2055 in order to prospectively estimate of the number of these patients.The statistics are based on prevalence data of left ventricular dysfunction (LVD) in Sado City using the Sado Heart Failure Study (2003) and population estimates from the Japanese National Institute of Population and Social Security Research Report (2006). The number of Japanese outpatients with LVD was 979,000 in 2005, and is predicted to increase gradually as the population ages, reaching 1.3 million by 2030.LVD is expected to precipitate a future epidemic of heart failure in Japan.

Ventricular tachyarrhythmias (VTA), a major cause of sudden cardiac death, require meticulous management in order to prevent recurrent episodes. Recently, non-pharmacological interventions, including radiofrequency catheter ablation and implantable cardioverter defibrillators (ICD), have become important treatments of VTA. Catheter ablation is curative in a relatively high percentage of patients presenting with idiopathic monomorphic ventricular tachycardia (VT). For VT associated with structural heart disease, however, the efficacy of catheter ablation remains limited, and ICD is the first-line therapy. In a subset of patients presenting with recurrent episodes of ventricular fibrillation (VF), catheter ablation is a therapeutic option when the VF is triggered by specific premature ventricular complexes. In Japan, unlike in the United States and Europe, ICD have not yet been accepted as first-line prevention of sudden cardiac death caused by VTA. The efficacy of ICD is occasionally limited by intolerable complications, such as electrical storm, inappropriate shock delivery and infection. Catheter ablation and ICD therapy might need to be combined for problematic cases. (Circ J 2007; Suppl A: A-97 - A-105)

Background Increased cardiac insulin-like growth factor (IGF)-I production is associated with physiological cardiac hypertrophy in athletes, and IGF-I has been recognized as a cardioprotective agent in experimental animal studies. On the other hand, acromegaly which is characterized by an excess of IGF-I has been linked to impaired cardiac function. Methods and Results Both the relationship between the serum levels of IGF-I and brain natriuretic peptide (BNP), which is released from the cardiac ventricles in response to ventricular stress, and that between IGF-I and the concentrations of the plasma amino-terminal propeptide of procollagen type III (P-III-P), which is associated with myocardial fibrosis, were evaluated in 19 patients after surgical treatment for acromegaly. Echocardiography revealed that left ventricular systolic function and dimensions were within normal range in all patients. Significant inverse correlations were found between IGF-I and the BNP (r=-0.5, p=0.02) and P-III-P levels (r=-0.62, p=0.005). Conclusion We observed an inverse significant relationship between IGF-I and both the BNP and P-III-P value in surgically treated acromegaly patients. These observations suggest that appropriate levels of IGF-I have beneficial cardioprotective effects after surgery in patients with acromegaly. (Circ J 2007; 71: 1955 - 1957)

The prevalence of congestive heart failure (CHF) is increasing with the aging of the community. Management of patients with systolic dysfunction (SD) is important for prevention of CHF, but there is little information regarding the burden of SD on Japanese communities.In order to delineate the epidemiological and clinical characteristics of SD patients, the medical records of patients from Sado Island were collected and summarized in 2003. From the 5 years prior to 2003, data for 497 patients were extracted. The mortality rate was significantly higher compared with the general population; and the total number of survivors had decreased to 410 by 2003. The proportion of SD patients in the general population increased sharply after the age of 65 years in males and 70 years in females, reaching 3.3% and 1.7% for men and women, respectively, in their 80 s. In 49% of the patients, the Charlson comorbidity index wasor = 2, whereas 24% of females led a solitary life.The total count of outpatients with SD is progressively increasing with age. These patients have multiple comorbidities, making the outcome of SD a poor one. The gender difference in disease characteristics and living conditions should be taken into consideration when establishing preventive strategies for CHF in Japanese communities.

The incidence of diastolic heart failure (DHF) is increasing with the aging of the community and identifying patients with isolated diastolic dysfunction (IDD) is important for preventing DHF. However, very little information is available about such patients in the Japanese community.The medical information of all outpatients with moderate to severe IDD was extracted from the records of approximately 6,948 individuals who underwent echocardiographic (Echo) examinations during the past 5 years in Sado Island. Of the 284 patients extracted, 272 survived until 2003. In January 2003 the proportion of patients with moderate to severe IDD in the general population sector aged 45-84 years was 0.9% for males and 0.5% for females, and this proportion increased sharply after the age of 65 in both genders, reaching 1.6% for men in their 70 s and 0.8% for women in their 80 s. On Echo, 165 patients (61%) showed hypertrophic left ventricular geometry. The Charlson comorbidity index score wasor = 1 in 63% of patients. The cumulative survival of IDD patients, irrespective of a history of congestive heart failure (HF), was significantly lower than in the general population.Moderate to severe IDD is not uncommon in the elderly and has a poor prognosis. Characteristics of outpatients with IDD should be taken into consideration when establishing a preventive strategy for HF in the Japanese community.

Background The role of the angiopoietin (Ang)/Tie-2 system in coronary collateral growth is not well understood, so the purpose of this study was to investigate and elucidate the relationship of this system to coronary collateral formation in patients with coronary artery disease (CAD). Methods and Results Fifty-nine patients with CAD were recruited. Blood samples from the left ventricle (LV) and coronary sinus (CS) were obtained during cardiac catheterization, and serum concentrations of Ang-1, Ang-2, and Tie-2 were measured by enzyme-linked immunosorbent assay. Patients were then classified as mild CAD (n=30), defined as ≤90% stenosis of the coronary arterial luminal diameter, or severe CAD (n=29), which was total (or near total) coronary occlusion requiring coronary collateral growth. Ang-1, Ang-2, and Tie-2 in the LV and CS sera were not significantly different between groups. In the severe CAD group, spillover of Tie-2 (CS-LV value) from the coronary circulation was found in comparison with the mild CAD group (3.43±2.22 vs -3.29±1.54 ng/ml, p=0.01), whereas the CS-LV values of Ang-1 and Ang-2 did not differ between groups. Tie-2 production was markedly increased in patients with well-developed collaterals. A positive and significant correlation was found between coronary Ang-2 and Tie-2 levels (r=0.44, p

Mega trials of rhythm vs rate control could not demonstrate the usefulness of available antiarrhythmic drugs, so a more effective and safer therapy for atrial fibrillation (AF) is now required. One candidate is the so-called "upstream therapy", which refers to the blockade of upstream modifying elements (renin - angiotensin system, cathecholamines, oxidative stress etc) that contribute to the arrhythmogenic substrate.The Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II study) is a randomized comparative evaluation of an angiotensin II type 1 blocker (candesartan) and a dihydropiridine calcium blocker (amlodipine), both combined with antithrombotic therapy, as an antiarrhythmic therapy for the treatment of paroxysmal AF (PAF) associated with hypertension. To test the usefulness of this therapy, this study will reveal the recurrence rate of asymptomatic as well as symptomatic PAF during 1-year of treatment with candesartan or amlodipine, using daily transtelephonic monitoring.The J-RHYTHM II study will follow 400 patients with PAF and hypertension who were treated at approximately 50 sites throughout Japan, and will provide clinically important information.

Background Suppression of implantable defibrillator discharges associated with ventricular tachyarrhythmia (VTA) has been reported for sotalol. This study aimed to investigate the efficacy of intravenous nifekalant hydrochloride in predicting the effects of oral sotalol. Methods and Results The present study included 14 patients who had sustained VTA associated with structural heart disease. All patients also had inducible VTA. To compare the effects of nifekalant and sotalol, programmed electrical stimulation was performed, in the basal state, after nifekalant administration, and after sotalol administration. Nifekalant and sotalol similarly prolonged the corrected QT interval and ventricular effective refractory periods, but the heart rate was slowed by sotalol only. In 4 of 5 patients whose VTA became non-inducible by nifekalant, subsequent treatment with sotalol also suppressed the inducible VTA. In all of the 9 patients non-responding to nifekalant, VTA remained inducible during sotalol treatment. Nifekalant accurately predicted the response to sotalol during electrophysiologic study in 13 of 14 patients. Of 11 patients who remained on sotalol, VTA recurred in 3 non-responders during a follow-up of 46±11 months. Conclusions Nifekalant and sotalol had similar effects on inducible VTA. The response of inducible VTA to nifekalant may predict the clinical efficacy of sotalol. (Circ J 2006; 70: 583 - 587)

Background C-reactive protein (CRP) independently predicts cardiovascular disease (CVD) and is considered to be part of metabolic syndrome (MS). The concentration of CRP are proposed to be 3.0 mg/L as high risk for CVD in Western society. Methods and Results Apparently healthy 179 men and 166 women were categorized with modified National Cholesterol Education Program Adult Treatment Panel III criteria (body mass index ≥25 in place of abdominal obesity) for defining MS. The cut-off points of CRP were evaluated for both MS defined by impaired fasting glucose criteria of ≥110 mg/dl (MS110) and ≥100 mg/dl (MS100), separately by sex. The optimal cut-off point of CRP was 0.65 mg/L in all subgroups. The sensitivity and specificity of this CRP value for male MS100, female MS100, male MS110, and female MS110 were 0.650 and 0.626, 1.000 and 0.771, 0.739 and 0.609, and 1.000 and 0.756, respectively. Conclusions The optimal cut-off point of CRP for MS might be 0.65 mg/L in Japan and this value can be useful in routine clinical practice and studies on MS. (Circ J 2006; 70: 384 - 388)

Implantable cardioverter-defibrillators (ICDs) are the most effective therapy in reducing the mortality of patients with life-threatening ventricular tachyarrhythmias. However, the ICD cannot prevent the recurrence of tachycarida attacks and that limits the clinical usefulness of them. The Nippon ICD Plus Pharmachologic Option Necessity (NIPPON) trial was designed as the first prospective randomized study to test the hypothesis whether amiodarone could improve the patient's clinical outcome by reducing the amount of ICD therapy in the Japanese patient population.Approximately 400 patients with organic heart disease and spontaneous episode(s) of sustained ventricular tachycardia/fibrillation (VT/VF) will be randomly assigned to one of 2 groups; the amiodarone group and non-amiodarone group. Both groups of patients will be followed at least for 24 months. The end-point committee will adjudicate events in a blinded fashion. The primary end-points of this study are determination of the appropriate therapy from the ICD and alteration of the assigned treatment because of its harmful effects and/or frequent ICD therapies.The NIPPON study is expected to confirm our understanding of the prognostic and therapeutic usefulness of adjuvant amiodarone therapy for patients with an ICD and with a history of sustained VT/VF.

The purpose of this study was to assess the candidates suitable for cardiac resynchronization therapy (CRT) and to examine the significance of the QRS duration in Japanese patients with idiopathic dilated cardiomyopathy (DCM).The study population consisted of 357 patients. The selection criteria for candidates suitable for CRT were QRS duration =130 ms, left ventricular ejection fraction (LVEF) =35% and New York Heart Association (NYHA) functional class III or IV by ACC/AHA/NASPE 2002 guidelines. We divided the study population into 2 groups: group A with a QRS duration130 ms, and group B with a QRS duration =130 ms. In 25 of the 375 patients (7.0%), all the criteria were fulfilled. Group B had a significantly larger left ventricular diameter end-diastole and end-systole than group A (P0.0001). Group B had a lower LVEF (P0.0001). There was a fair inverse correlation (r=-0.58, P0.0001) between the length of the QRS duration and LVEF.Approximately 7% of the Japanese patients with DCM are CRT candidates. In the present study, we found that prolonged QRS duration was associated with poor systolic function.

The dynamics of MCP-1 and neopterin and the relation between their concentrations in coronary circulation and the severity of coronary atherosclerosis were evaluated in patients with stable coronary artery disease (CAD).Blood samples were obtained from the aortic root (Ao) and coronary sinus (CS) of 78 patients who underwent coronary angiography. Plasma MCP-1 and neopterin concentrations were measured using an enzyme-linked immunosorbent assay method and the CS-Ao differences were calculated. The severity of coronary heart disease (CHD) was evaluated in 52 patients who had no history of coronary angioplasty, using 3 coronary scoring systems: the clinical 1- to 3-vessel disease score, the American Heart Association extension score (1-15 segments), and the Gensini score. The plasma MCP-1 and neopterin concentrations increased significantly with age. The CS-Ao differences for neopterin showed weak, but significant, positive correlation with the Gensini score (r=0.347, p=0.013). There were no correlations among the MCP-1 concentrations in the Ao or CS, or in the CS-Ao difference, with the severity of CHD.The results indicate that neopterin is a useful marker of the severity of coronary atherosclerosis in patients with stable CAD, acting as an index of the activity of monocytes/macrophages.

The Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM study) is a randomized comparative evaluation of rate control and rhythm control, both combined with antithrombotic therapy, as therapeutic strategies for the treatment of atrial fibrillation (AF). This study differs from the earlier AFFIRM and RACE studies in that it has a composite primary end-point representing mortality and also physical/psychological disablement (total mortality, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for heart failure requiring intravenous administration of diuretics, and patient disablement). Patients' will to change the therapeutic strategy to the other is also considered as an end-point representing disablement under the assigned strategy. The secondary end-point includes quality of life scores and the efficacy and safety of drugs used in treating AF. The J-RHYTHM study emphasizes patient-reported experience and perception of AF-specific disablement, and the safety of antiarrhythmics available in Japan; it will follow 2600 patients treated at more than 150 sites in Japan for a 3-year period.

The basal activity of nitric oxide (NO) is reduced in spastic arteries of patients with vasospastic angina (VSA). Elevated concentrations of ADMA are associated with reduced NO production and impaired endothelium-dependent vasodilatation. The aim of this study was to elucidate the role of ADMA and its relationship to NO end-products (NOx; nitrate + nitrite) during coronary circulation in patients with VSA. The plasma ADMA and NOx concentrations during coronary circulation were evaluated in 16 VSA and 16 control patients. Blood samples were obtained from the coronary sinus (V) and the ostium of the left coronary artery (A), and the (V-A) differences of ADMA and NOx were determined. The coronary sinus plasma ADMA concentration in patients with VSA was higher than that in the control. The coronary sinus - arterial (V-A) difference of NOx was negative in the VSA group and approximately zero in the control group (VSA group =-1.4 μmol/L, control group =-0.1 μmol/L, p=0.0005). Furthermore, in the VSA patients, there was a negative correlation between the (V-A) difference of NOx and the basal coronary artery tone at the site of spasm (r=-0.60, p=0.015). A significant negative correlation between the (V-A) differences of NOx and ADMA was observed in patients with VSA (r=-0.52, p

The ventricular tachyarrhythmias associated with the LQT3 syndrome are typically bradycardia-dependent. However, some episodes can be associated with exercise or emotional stress, suggesting a different arrhythmogenic mechanism when sympathetic activity predominates. This study examined the potential arrhythmogenic mechanisms during periods of autonomically mediated transient heart rate acceleration in a canine anthopleurin-A model of LQT3 syndrome. Using plunge needle electrodes, transmural unipolar electrograms of the left ventricle were recorded from endocardial (Endo), mid-myocardial (Mid) and epicardial (Epi) sites. The activation-recovery interval (ARI) was measured to estimate local refractoriness. The cardiac cycle length was gradually shortened by cessation of vagal stimulation (vagal stimulation protocol (VSP)), and intramural electrograms and onset mode of ventricular tachyarrhythmias were analyzed in 7 experiments. The VSP was performed 8 times before and 5 times after administration of mexiletine in each experiment. Before mexiletine, vagal stimulation slowed the heart rate and created large transmural ARI dispersion because of a greater ARI prolongation at Mid rather than Epi/Endo sites. After cessation of vagal stimulation, unipolar electrograms started to show ARI alternans and ventricular premature beats developed sporadically. Sustained ventricular tachyarrhythmias were induced in 12 of the 56 trials of the VSP. Initiation of ventricular tachyarrhythmias was associated with delayed conduction at Mid/Endo sites. Mexiletine attenuated transmural ARI dispersion, and neither ARI alternans nor ventricular tachyarrhythmias was observed during all 35 trials of the VSP after mexiletine administration. Heart rate acceleration induced by an abrupt shift to a state of predominant sympathetic activity enhances arrhythmias in this LQT3 model. Mexiletine homogenizes ventricular repolarization, suppresses premature complexes and was antiarrhythmic during ventricular tachyarrhythmias induced by the VSP.

Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) is a potentially life-threatening side effect of heparin therapy, triggered by an immune response, and has been reported to be related not only to the therapeutic use of heparin but also to heparin-coated catheters. A 45-year-old woman with intrapelvic malignancy developed an acute pulmonary thromboembolism (PE) after hysterectomy despite prophylactic heparin use. Subsequent large doses of heparin for treatment of the PE exacerbated the thrombocytopenia and, moreover, a large thrombus formed around the heparin-coated central venous catheter. Anti-heparin-platelet factor 4 complex antibody and heparin-induced platelet aggregation assay were positive, so the diagnosis was HITTS, and heparin was replaced by argatroban after carrying out thrombectomy. This therapy was successful, and the patient made favorable progress.

A 73-year-old heavy drinker was admitted to hospital in a state of shock. He had been suffering from frequent angina at rest, causing him to drink more heavily in an effort to overcome his anginal chest pain. He had been drinking hard each day and had not eaten for 4 weeks. His hemodynamic state on admission showed high-output heart failure. Echocardiography revealed hyperkinesis of the left ventricle and mid-ventricular obstruction with peak intraventricular gradients of 30 mmHg. Although no improvement was seen despite administering the maximal dose in catecholamine therapy, his condition improved rapidly after vitamin B(1) was administered. Cardiac catheterization revealed mid-ventricular obstruction with an apical aneurysm. Coronary artery spasm was induced by injecting acetylcholine in the distal site of the left anterior descending artery, which perfused the area of the apical aneurysm. In the present case, both left ventricular hyperkinesis caused by shoshin beriberi and apical myocardial infarction caused by frequent coronary spasms produced mid-ventricular obstruction with an apical aneurysm.