Current pharmacological therapy for heart failure (HF) is based on improved understanding of the pathophysiological mechanisms of HF progression. In particular, inhibition of key activated neurohormonal systems (eg, the renin-angiotensin-aldosterone system) and the sympathetic nervous system has been the cornerstone of drug therapy for this condition. However, despite these major advances, many HF patients still only marginally respond to these therapies. Novel therapeutic approaches have been tested. Several recent phase III studies have failed, however, despite intriguing pathophysiological concepts and promising pilot data. In other studies, significant benefits have been observed in certain subgroups only, suggesting the need for a more tailored approach to individual risk and comorbidity. This review will focus on recent and potential future pharmacological HF therapies and where drug treatment may be in the next few years. In discussing future pharmacological therapy for HF, 3 key strategies will be considered: (1) optimization of conventional therapies, (2) a focus on new drug development within areas not yet adequately represented by major clinical data and (3) new drugs affecting novel therapeutic targets. (Circ J 2010; 74: 809 - 817)

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Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are widely used to lower serum cholesterol levels in the primary and secondary prevention of cardiovascular disease. Recent experimental and clinical evidence suggests that the beneficial effects of statins may extend beyond their cholesterol-lowering effects, to include so-called pleiotropic effects. These cholesterol-independent effects include improving endothelial function, attenuating vascular and myocardial remodeling, inhibiting vascular inflammation and oxidation, and stabilizing atherosclerotic plaques. The mechanism underlying some of these pleiotropic effects is the inhibition of isoprenoid synthesis by statins, which leads to the inhibition of intracellular signaling molecules Rho, Rac and Cdc42. In particular, inhibition of Rho and one of its downstream targets, Rho kinase, may be a predominant mechanism contributing to the pleiotropic effects of statins. The aim of the present review is to provide an update on the non-cholesterol-dependent statin effects in the cardiovascular system and highlight some of the recent findings from bench to bedside to support the concept of statin pleiotropy. (Circ J 2010; 74: 818 - 826)

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Oxidative stress is a key factor in the pathogenesis of hypertension and target organ damage, beginning in the earliest stages. Extensive evidence indicates that the pivotal role of oxidative stress in the pathogenesis of hypertension is due to its effects on the vasculature in relation to the development of atherosclerotic processes. It remains unclear, however, whether oxidative stress in the brain, particularly the autonomic nuclei (including the vasomotor center), has an important role in the occurrence and maintenance of hypertension via activation of the sympathetic nervous system. The aim of the present review is to describe the contribution of oxidative stress in the brain to the neural mechanisms that underlie hypertension, and discuss evidence that brain oxidative stress is a potential therapeutic target. (Circ J 2010; 74: 827 - 835)

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Prostacyclin (PGI₂) is one of the important vascular prostanoids, the effects of which counteract those of thromboxane (TXA₂), and these 2 prostanoids provide an important balance in cardiovascular homeostasis. The clinical experience of COX-2 selective inhibitors having unexpected adverse effects in patients with cardiovascular risk has opened up a debate about the role of COX-2-derived prostanoids in vascular pathophysiology. PGI₂ is a major anti-atherogenic prostanoid produced by COX-2 in vascular cells, including endothelial and vascular smooth muscle cells. The balance between COX-2-derived PGI₂, COX-1-derived TXA₂, and other COX-2-mediated atherogenic prostanoids is a crucial factor in determining pathophysiological outcomes. Recent studies using stable PGI₂ analogs and genetically deficient mice have revealed novel effects of PGI₂ on its target cells, such as endothelial and endothelial progenitor cells. The role PGI₂ in the physiology and pathophysiology of vascular diseases is reviewed and the recent findings linking PGI₂, COX-2 and atherothrombosis are summarized. (Circ J 2010; 74: 836 - 843)

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Background: Occasionally it is difficult to inhibit electrical storm (ES) with standard pharmacological treatment. In the present study the effect of landiolol, an ultra-short-acting β₁-selective blocker, on ES refractory to class III antiarrhythmic drugs was evaluated. Methods and Results: The study group comprised 42 consecutive patients who developed ES for which intravenous class III antiarrhythmic drugs, such as amiodarone and nifekalant, were ineffective. Landiolol was administered intravenously with an initial dose of 2.5 μg · kg^–1 · min^–1, which was doubled if it was ineffective, up to a maximum dose of 80 μg · kg^–1 · min^–1. Landiolol inhibited ES in 33 patients (79%) at a mean dose of 7.5±12.2 μg · kg^–1 · min^–1. All patients in whom landiolol was ineffective died of arrhythmia. Of the 33 patients in whom landiolol was effective, 25 survived and were discharged (60% of all patients). Landiolol significantly decreased heart rate (P<0.0001), but did not affect blood pressure. Landiolol was not discontinued for adverse effects in any of the responders. Age, APACHE II score, and pH of arterial blood gas differed significantly between the responders and nonresponders. Conclusions: Landiolol is useful as a life-saving drug for class III antiarrhythmic drug-resistant ES. The main mechanism of ES refractory to class III antiarrhythmic drugs could be abnormal automaticity but not reentry. (Circ J 2010; 74: 856 - 863)

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Background: 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. Methods and Results: 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. Conclusions: 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. (Circ J 2010; 74: 864 - 869)

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Background: The Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM) study showed rhythm control was associated with fewer changes in the assigned treatment strategy compared to rate control in atrial fibrillation (AF). The aim was to describe how antiarrhythmics (AAs) were altered in the rhythm control arm and whether altering AAs would impact long-term outcomes. Methods and Results: Of 390 enrolled patients, 23.5% altered their AAs (drug alteration [DA] group). The hard endpoint (HE) was defined as a composite of death, stroke, embolism, major bleeding or heart failure hospitalization; soft endpoint (SE) was defined physical/psychological disability requiring alteration of treatment strategy. The patients were followed for 1.7 years. No significant difference was noted in the occurrence of HE (4.0% vs 6.5%, P=0.31), but DA-group patients had higher rates of SE (9.3% vs 18.4%, P=0.017) compared to single AA patients. The DA group was also associated with the occurrence of SE after adjustment (HR 1.90, P=0.042). When the DA group was subdivided according to the use of class III drugs or change of drugs between classes, there were no differences in outcomes. Conclusions: The need to change AA was associated with physical/psychological disabilities that seemed not to be relieved simply by changing AAs, and this should be considered as a marker for refractory paroxysmal AF requiring other strategies. (Circ J 2010; 74: 870 - 875)

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Background: Although bepridil is a useful anti-arrhythmic agent for atrial fibrillation, the appearance of serious ventricular arrhythmia, such as torsades de pointes, might be a problem. In this study, T-U wave morphology was evaluated during bepridil therapy and was examined as a predictor of ventricular arrhythmic events. Methods and Results: The study population consisted of 113 patients on bepridil therapy. They were divided into 2 groups with and without ventricular arrhythmic events. Morphological changes in T-U waves were analyzed in leads V_2-5. During bepridil treatment, the QTc interval was prolonged from 0.45±0.01 to 0.49±0.01 s^1/2 in all patients (P<0.0001) and any type of T-U wave change (fused U, slurred, bifid, biphasic or negative) appeared in 73% of event-free and 100% of event groups. In univariate analysis, QTc interval before bepridil (P=0.028), a wide QRS complex (P=0.042) before bepridil, biphasic (P=0.027) or negative (P=0.002) T-U waves in the stable phase, and the new appearance of biphasic (P=0.004) or negative (P<0.0001) T-U waves exhibited significant differences. In multivariate analysis, only newly appeared negative T-U wave exhibited a significant difference (odds ratio 10.13, 95% confidence interval = 0.031-2.302, P=0.041). Conclusions: In patients with stable bepridil treatment, a change in T-U wave morphology might be a useful predictor of ventricular arrhythmia assisting the QT interval. (Circ J 2010; 74: 876 - 884)

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Background: Atrial electrical remodeling (AER) is the underlying mechanism of atrial fibrillation (AF). The present study investigated the impact of epicardial fat pad (FP) ablation on acute AER (AAER) and inducibility of AF. Methods and Results: AAER was performed in 28 mongrel dogs through 4-h rapid atrial pacing (RAP). Before RAP, 14 dogs (ablation group) underwent FP ablation, and the other 14 (control group) underwent a sham procedure. The atrial effective refractory period (ERP) and vulnerability window (VW) of AF were measured with and without bilateral cervical vagosympathetic nerve stimulation (VNS) at the high right atrium, ostium of the coronary sinus (CS) and distal CS before and after every hour of RAP. In the control group, ERP was markedly shortened in the first 2 h of RAP and then stabilized. AF was only slightly induced. After RAP, the time course of ERP with and without VNS was similar. VNS significantly shortened ERP and increased VW before and after RAP. In the ablation group, ERP was significantly prolonged after FP ablation. Moreover, neither VNS nor RAP shortened the ERP or increased the VW. AF could not be induced (VW=0). Conclusions: RAP resulted in AAER, which may be mediated and aggravated by autonomic activity. Epicardial FP ablation generated denervation, which not only abolishes AF inducibility but also prevents RAP-mediated AAER. (Circ J 2010; 74: 885 - 894)

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Background: 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). Methods and Results: 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 (P<0.01). 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 (P<0.01, 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. Conclusions: 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. (Circ J 2010; 74: 895 - 902)

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Background: Differences between paclitaxel-eluting stents (PES) and sirolimus-eluting stent (SES) in neointimal proliferation under strictly matched conditions remain to be clarified by optical coherence tomography (OCT). Methods and Results: Between May and December 2007, 27 patients were implanted with a PES and a SES, randomized to either the proximal or distal site in a single coronary artery, and underwent follow-up angiography and OCT examination at 6 months. The frequency of vessel wall apposition with neointima was greater for PES than for SES (92.6% vs 85.8%, P<0.01). The median (25th, 75th percentiles) neointimal thickness (NIT) in PES was significantly greater than that in SES (90 μm [25th: 40 μm; 75th: 200 μm] vs 50 μm [25th: 20 μm; 75th: 140 μm]; P<0.01). Both the average difference between the maximum and minimum NIT in each cross-section and the average difference between the maximum and minimum NIT in the longitudinal axis were larger in PES than in SES (206±88 vs 131±57 μm; P<0.001, 607±243 vs 400±185 μm; P<0.001). Low-density spots were significantly more frequently observed in PES than in SES (30.9% vs 17.0%, P=0.001). Conclusions: Compared with SES, PES had a non-uniform and larger neointimal thickness with fewer uncovered struts, and more peri-strut low-density areas. (Circ J 2010; 74: 903 - 908)

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Background: Although microvascular dysfunction following percutaneous coronary intervention (PCI) can be evaluated with the index of microcirculatory resistance (IMR), no method of treatment has been established. We hypothesized that intracoronary administration of nicorandil can improve IMR after successful primary PCI in patients with ST-segment elevation myocardial infarction (STEMI). Methods and Results: In 40 patients with first STEMI after successful primary PCI, IMR was measured using PressureWire^TM Certus (St. Jude Medical, MN, USA). In 20 of the patients (Group N), IMR was measured at baseline and after intracoronary nicorandil (2 mg/10 ml). In the other 20 patients (Control), IMR was measured at baseline, after intracoronary saline (10 ml) and after intracoronary nicorandil (2 mg/10 ml). In Group N, IMR significantly decreased after intracoronary nicorandil (median IMR, 27.7-18.7 U, P<0.0001). In the Control group, IMR did not change after saline administration (median IMR, 24.3-23.8 U, P=0.8193), but was significantly decreased after intracoronary nicorandil (median IMR, 23.8-14.9 U, P<0.0001). Next, all 40 patients were divided into subgroups by tertile of baseline IMR. In those with intermediate to high IMR (baseline IMR ≥21), intracoronary nicorandil significantly decreased IMR, although it did not change IMR in those with low IMR (baseline IMR <21). Conclusions: High IMR levels in patients with STEMI after successful primary PCI can be improved by intracoronary administration of nicorandil. (Circ J 2010; 74: 909 - 915)

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Background: Increasing numbers of patients with advanced coronary artery disease have limited options for percutaneous and/or surgical revascularization. A prospective, randomized, phase I clinical multicenter trial was performed to assess the feasibility and safety of delivering a pro-angiogenic transcription factor termed "hypoxia inducible factor-1α", delivered to ischemic cardiac muscle via a type 2 adenoviral (Ad2HIF) vector. Methods and Results: The 13 patients were included under the following criteria: 1 hypoperfused area of viable ventricular muscle without options for revascularization and left ventricular ejection fraction ≥30%. After coronary artery bypass grafting was completed, 10 injections of the study drug (n=10), in 3 escalating doses up to 1×10¹¹ viral particles or saline (n=3) as a placebo control, were injected intramyocardially. After completion of the 1-year follow-up, all patients had uncomplicated postoperative courses, are alive and feeling well; 1 patient had a self-limited run of tachycardia postoperatively and at 6 months, 1 patient developed recurrent angina. Positron emission tomography perfusion analysis revealed improvement in the Ad2HIF injected areas in selected patients. Conclusions: These data support the feasibility and preliminary safety of adenoviral transfection with Ad2HIF in regions of viable myocardium. Additional studies will be required to determine the efficacy and safety of Ad2HIF. (Circ J 2010; 74: 916 - 924)

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Background: Tricuspid valve (TV) repair using ring annuloplasty is reportedly to be superior to suture annuloplasty for treating tricuspid regurgitation (TR). The Duran ring TV annuloplasty technique was modified in order to reduce the risk of complete atrioventricular block and aortic valve injury and the outcomes are reported here. The modification involved not suturing half of the septal annulus. Methods and Results: Between January 1998 and July 2007, 219 patients diagnosed with secondary TR underwent TV repair using a modified Duran ring procedure. The mean patient age was 54.2±12.7 years, and 65 (29.7%) patients were male. The median follow-up duration was 35.8 months (range, 0.03–122.6 months). The mean ring size was 27.4±2.0 mm. The prevalence of 3+ or 4+ regurgitation was 9.5% (21/218) at 1 week postoperatively, and 9.4% at more than 2 years postoperatively (mean, 57 months; 96 patients assessed). The in-hospital mortality rate was 1.4% (3/219). The overall survival rate was 95±1.5% at 1 year, 86.2±3.0% at 5 years, and 79.9±4.2% at 8 years. Multivariate analysis showed that atrial fibrillation at the last follow-up (P<0.001) and cardiopulmonary bypass time (P=0.016) were risk factors for recurrent or persistent significant TR. Conclusions: The modified Duran ring TV repair procedure for secondary TR patients was safe and durable. Notably, postoperative atrial fibrillation was found to be a significant risk factor for recurrent TR. (Circ J 2010; 74: 925 - 930)

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Background: Several reports have raised the possibility that newly addressed lipid measures might be superior to the traditional ones for cardiovascular risk prediction. However, data on the associations between these lipid measures with metabolic syndrome (MetS) is limited. Methods and Results: A cross-sectional study of participants in routine health examinations was performed. The associations between lipid measure variables (total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), TC/HDL-C, LDL-C/HDL-C, TG/HDL-C ratio and non-HDL-C) and MetS, insulin resistance (IR) by homeostatic model assessment (HOMA) and adiponectin were analyzed in 6,546 participants (3,820 men; mean age 46.0±9.2 years in men, 44.6±9.5 years in women). In multivariable adjusted regression analysis, the 3 lipid ratios of TC/HDL-C, LDL-C/HDL-C and TG/HDL-C showed significant association with the number of MetS components, HOMA and log adiponectin level in both men and women without MetS (P<0.001, respectively), though these relations were weaker in participants with MetS. The mean levels of the lipid ratios also associated with increasing numbers of the MetS components, quartiles of HOMA and adiponectin. Conclusions: Lipid ratios of TC/HDL-C, LDL-C/HDL-C and TG/HDL-C, as well as TG and HDL, were consistently associated with MetS and IR in participants without MetS. Lipid ratios might be used as integrated and simple lipid measures. (Circ J 2010; 74: 931 - 937)

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Background: Electrocardiographic (ECG) left ventricular hypertrophy (LVH) is a risk factor for cardiovascular events and the incidence of LVH increases with age. However, few studies have assessed risks associated with LVH in elderly hypertensive patients. Methods and Results: The Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients (JATOS) was conducted to determine optimal blood pressure in elderly patients. At study entry, the sum of the S-wave in lead V₁ and the R-wave in lead V₅ (SV1+ RV5) could be determined in 3,230 patients, among whom 164 (5.1%) had cardiovascular events. On univariate analysis, the hazard ratio for cardiovascular events was 1.51 for each 10 mm (=1 mV) (95% confidence interval (CI): 1.34–1.69, P<0.0001) when SV1+ RV5 was considered a continuous variable, and 2.17 (95%CI: 1.54–3.05, P<0.0001) and 2.83 (95%CI: 1.91–4.19, P<0.0001) when SV1+ RV5 was classified into 2 groups at threshold values of either 35 mm or 40 mm, respectively. Multivariate Cox analysis showed that gender, age, current smoking, diabetes mellitus, history of renal disease, history of stroke, and SV1+ RV5 were significantly related to the occurrence of cardiovascular events. Kaplan – Meier curves showed that increasing SV1+ RV5 values were associated with higher incidences of cardiovascular events. Conclusions: ECG LVH is strongly related to cardiovascular events in elderly hypertensive patients. (Circ J 2010; 74: 938 - 945)

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Background: Cardiac allograft vasculopathy (CAV) is a major complication that limits the long-term survival of recipients of heart transplants. In the present study the feasibility of 2 noninvasive approaches for detecting CAV (multidetector computed tomography (MDCT) and whole-heart magnetic resonance coronary angiography (MRCA)) was compared with conventional coronary angiography (CCAG). Methods and Results: Of 22 heart transplant recipients who underwent CCAG screening, 13 had only MDCT, 16 had only MRCA, and 7 had both noninvasive modalities. The coronary arterial tree was divided into 9 segments. Detection of vasculopathy by coronary segments was compared between 16-/64-detector computed tomography (CT) or MRCA and CCAG. The sensitivity of both 16- and 64-detector CT for diagnosing CAV was 69.6%, and specificity was 96.8%. The sensitivity and specificity by 64-detector CT alone were 90.0% and 97.5%, respectively; its positive and negative predictive values were 81.8% and 98.7% respectively. For MRCA, sensitivity was 60%, specificity, 100%, positive predictive value, 100% and negative predictive value, 92.2%. MRCA showed no false positives. Conclusions: MDCT, especially 64-detector CT, is feasible for detecting CAV, whereas MRCA currently shows limited sensitivity. (Circ J 2010; 74: 946 - 953)

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Background: The purpose of this study was to explore the effect of lifestyle modification, mainly daily aerobic exercise, on coronary atherosclerosis in patients with coronary artery disease (CAD). Methods and Results: A 6-month prospective observational study was conducted with 84 CAD patients receiving pravastatin treatment in order to evaluate the relationship between lifestyle modification, in particular aerobic exercise, and plaque volume as assessed by intravascular ultrasound (IVUS). Lifestyle during the study period was assessed by the-lifestyle modification score. A significant decrease in plaque volume by 12.9% was observed after 6 months of pravastatin therapy (P<0.0001 vs baseline). The change in plaque volume correlated with the change in the serum level of high-density lipoprotein cholesterol (HDL-C) (r=-0.549, P<0.0001), non-HDL-C (r=0.248, P=0.03), low-density lipoprotein cholesterol/HDL-C (r=0.505, P<0.0001), apolipoprotein (apo) A-1 (r=-0.335, P=0.007) and apoB/apoA-1 (r=0.335, P=0.007), and lifestyle modification score (r=-0.616, P<0.0001). There was a clear positive correlation between a change in the serum HDL-C level and lifestyle modification score. Multivariate regression analysis revealed that the increase in serum HDL-C level and lifestyle modification score were independent predictors of coronary plaque regression. Conclusions: An appropriate combination of statin therapy and lifestyle modification, in particular, physical activity, may result in coronary plaque regression. This combined treatment strategy, inducing an increase of the serum HDL-C, may contribute to coronary plaque regression. (Circ J 2010; 74: 954 - 961)

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Background: Beta-blockers are underprescribed for coronary artery disease (CAD) patients in Japan. Considering the vast amount of evidence showing their benefits in this group of patients, the aim of the present study was to investigate the use of β-blockers in a large cohort of CAD patients. Methods and Results: The 13,812 patients with angiographically confirmed CAD were followed up for 2.7 years. From this group, 4,160 (30.1%) patients were prescribed β-blockers at the time of discharge. These patients were significantly more likely to have hypertension, hyperlipidemia, obesity, a family history of ischemic diseases and a higher number of diseased arteries. The rate of continuation for β-blockers was 90.8%. A propensity score matching analysis showed no additional benefits of β-blockers in reducing all-cause mortality, cardiac events and cerebrovascular events. Lipophilic β-blockers were significantly more effective than hydrophilic ones in reducing all-cause mortality (hazard ratio 0.467, 95% confidence interval 0.247-0.880, P=0.019). Conclusions: Despite the low prescription rate of β-blockers for CAD patients among Japanese physicians, the continuation rate was relatively high. Lipophilic β-blockers may be a better choice than hydrophilic β-blockers in terms of mortality risk, although a randomized control study would need to be conducted to verify this assertion. (Circ J 2010; 74: 962 - 969)

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Background: The characteristics of the periodic variation in acute myocardial infarction (AMI) and the subsequent effect on management and prognosis have not been fully investigated in a large number of Asian populations. Methods and Results: From a prospective, observational multicenter online registry, 4,573 patients diagnosed as AMI in Korea from January to December 2006 were included. The highest incidence of AMI was between 8 a.m. and noon. The number of cases was highest in the winter and lowest in the autumn (13.6 vs 11.4 patients per day, P<0.001). Patients with symptom onset during working hours had a shorter time to first medical contact (203±288 min) compared with out-of-hours onset (230±288 min, P=0.003). In patients who underwent primary angioplasty, out-of hours symptom onset was associated with a greater time delay in both the patient's and the medical facility's response (door-to-balloon time out-of hours vs working hours: 101±54 min vs 84±44 min, P<0.001). In patients with ST-segment elevation myocardial infarction, symptoms to first medical contact showed a significant relationship to in-hospital mortality (for every 10 min of symptoms to first medical contact, odds ratio 1.006, 95% confidence interval 1.001-1.012, P=0.018) Conclusions: Circadian and periodic variation in AMI exists in Korean patients, which resulted in different patient behavior, hospital management and outcomes. (Circ J 2010; 74: 970 - 976)

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Background: Warfarin dosing is difficult to establish because of considerable interindividual variation. Thus, warfarin pharmacogenetics have attracted particular interest in relation to appropriate control of anticoagulation. Methods and Results: The 200 eligible subjects were chosen from participants in a hospital cohort. Performance of a pharmacogenetic algorithm recently developed by the International Warfarin Pharmacogenetics Consortium (IWPC) was tested and compared with a clinical algorithm (without genotype data) by calculating the percentage of patients for whom the predicted dose deviated by less than 7 mg/week (1 mg/day) from the actual dose. The pharmacogenetic algorithm accurately identified a significantly (P<0.05) larger proportion of patients to achieve the target international normalized ratio than did the clinical algorithm (68% vs 36% for a low-dose group; and 21% vs 0% for a high-dose group). Also, an increase in warfarin dosage was found to be appropriate for the current status of alcohol drinking (4 mg/week, as against non-drinking) and smoking (3.3 mg/week, as against non-smoking). Conclusions: The IWPC pharmacogenetic algorithm has clinical application, particularly in identifying Japanese patients who require a low dosage of warfarin and are at greater risk of excessive anticoagulation. (Circ J 2010; 74: 977 - 982)

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Background: The literature regarding interleukin (IL)-10 polymorphisms and coronary artery lesions (CALs) in Kawasaki disease (KD) is limited. We investigated whether 3 IL-10 genetic polymorphisms (-1082 A/G, -819 T/C, and -592 A/C) are associated with development of CALs in KD. Methods and Results: The genotyping of IL-10 polymorphisms was conducted for 279 KD children (172 without and 107 with CALs in acute stage). Thirty-three patients had CALs in chronic stage and 74 only with transient CALs. The homozygous variant genotype CC of IL-10-819 and IL-10-592 was associated with 80% (P=0.006) and 79% (P=0.008) reduction in risk of CALs in acute stage, respectively. The C allele of IL-10-819 and IL-10-592 was associated with 34% (P=0.034) and 33% (P=0.044) reduction in risk of CALs in acute stage, respectively. Compared with ATA haplotype (adjusted odds ratio (AOR) 0.63, P=0.029) or non-ACC haplotype (AOR 0.64, P=0.033), ACC haplotype was associated with a significantly reduced risk for CALs in acute stage, but not for CALs in chronic stage. Compared with non-ATA haplotype (AOR 1.53, P=0.034), ATA haplotype was associated with a significantly increased risk of CALs, except for CALs in the chronic stage. Conclusions: The effects of IL-10 gene polymorphism on CALs in acute KD are important. The persistence of CALs in chronic stage depends much more on other factors such as the times of intravenous immunoglobulin treatment. (Circ J 2010; 74: 983 - 989)

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Background: Although the existence of the young patients with aortic disease not fulfilling the diagnostic criteria for Marfan syndrome (MFS) has been known, the etiology of their disease has not yet been elucidated. The purpose of the present study was to elucidate the genetic and clinical features of the young patients with aortic disease not having MFS. Methods and Results: Eighty young adult patients with aortic disease were examined. They were divided into a definite MFS (n=51) and a non-definite MFS group (n=29) according to the Ghent nosology. Clinical and genetic characteristics were compared between the 2 groups. Among 29 non-definite MFS probands, 1 (3%) FBN1, 2 (7%) TGFBR1, and 3 (10%) TGFBR2 mutations were found, and 4 ACTA2 mutations were found in the 23 probands examined without FBN1, TGFBR1, or TGFBR2 mutations. In total, more than 10 out of 29 (34%) probands in the non-definite MFS group were associated with genetic mutations. Skeletal involvement was less frequent in the non-definite than in the definite MFS group (7% vs 82%, P<0.01). Conclusions: In the probands with aortic diseases in young who cannot be diagnosed with MFS, mutations other than FBN1 mutations accounted for at least one-third of all causes of aortic disease. (Circ J 2010; 74: 990 - 997)

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Background: Both B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are useful biomarkers for the assessment of congestive heart failure (CHF) in adults. The purpose of this study was to determine whether BNP and NT-proBNP levels could be used to stratify the severity of CHF in children. Methods and Results: The study comprised 181 children with CHF and 232 healthy children aged from 4 months to 14 years who were categorized into CHF grades I, II, III and IV according to the modified Ross scoring system. The plasma BNP and serum NT-proBNP levels were significantly correlated with increasing CHF grades. The NT-proBNP levels were significantly different among the 4 CHF grades. However, only 2 significant differences were observed in the BNP levels between each CHF grade. NT-proBNP testing with cut-off points of >438 pg/ml (≥grade II), >1,678 pg/ml (≥grade III) and >7,734 pg/ml (grade IV) in the patients below 3 years of age, and >295 pg/ml (≥grade II), >1,545 pg/ml (≥grade III) and >3,617 pg/ml (grade IV) in those above 3 years of age was determined to be highly sensitive and specific by receiver operating characteristic analysis. Conclusions: The blood levels of BNP and NT-proBNP therefore reflect the severity of CHF in children. In particular, NT-proBNP is a useful biomarker for evaluating CHF in children. (Circ J 2010; 74: 998 - 1005)

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Background: Transplantation of endothelial progenitor cell (EPC) augments angiogenesis in animal models of tissue ischemia. Although it is desirable to use expanded autologous EPCs for therapeutic angiogenesis in the clinical arena, a major obstacle is the limitation of the EPC expansion technique without using animal-derived serum such as fetal bovine serum (FBS). To overcome this issue, the possibility of human EPC (hEPCs) expansion using autologous serum (AS) culture was investigated. Methods and Results: Peripheral blood mononuclear cells were isolated from healthy volunteers by density-gradient centrifugation and culture-expanded in medium containing either FBS or AS. In vitro angiogenic functions, such as differentiation, migration and tube formation, were not significantly different between hEPCs cultured with FBS and AS. Next, we investigated whether transplantation of hEPCs would augment angiogenesis in unilateral hind limb ischemia using nude mice. The ratio of ischemic/normal limb blood flow and tissue capillary density in mice receiving hEPCs cultured with either FBS or AS significantly increased as compared with control mice receiving PBS alone. The ischemic/normal limb blood flow ratio and histological capillary density were not significantly different between hEPCs cultured with FBS and AS. Conclusions: hEPCs can be culture-expanded in medium containing AS. Moreover, the angiogenic functions of such hEPCs are almost identical to those of hEPCs cultured with FBS. Ex vivo expanded hEPCs using AS seems to be useful for future clinical therapeutic angiogenesis. (Circ J 2010; 74: 1006 - 1013)

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Background: The aims were to characterize in muscular arteries (a) the passive and active effects of the adventitia on vessel biomechanical properties and conduit function (CF), and (b) potential differences between the adventitial role in elastic and muscular arteries. Methods and Results: Ovine femoral arteries were studied in vivo and in vitro (reduced smooth muscle-tone) in a circulation mock-up during hemodynamic conditions similar to those found in vivo. Pressure and diameter were assessed before and after removing the adventitia. The arterial compliance, distensibility, stiffness β-index and CF were quantified. Results were compared with those obtained in brachiocephalic trunks. In vivo, after removing the adventitia there was a nonsignificant diameter reduction and an increase in stiffness (P<0.05). The CF decreased in the early recordings (P<0.02). In vitro, there were no biomechanical changes but vascular dilatation after the adventitia removal. Biomechanical changes associated with the adventitia removal were higher in muscular arteries, whereas diameter changes were major in elastic vessels. Conclusions: After removing the adventitia, (a) the arterial stiffness and CF were modified in vivo only, suggesting the changes could be ascribed to variations in smooth muscle tone, and (b) changes in elastic and muscular arteries were quantitatively different. (Circ J 2010; 74: 1014 - 1022)

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Background: Overlapping drug-eluting stents might be associated with an adverse vessel response because of increased drug/polymer toxicity and lesion rigidity. Methods and Results: Lesions treated with overlapping everolimus- (EES=36) or paclitaxel-eluting stents (PES=38) were analyzed for 8-9-months by 3-dimensional intravascular ultrasound. EES were associated with significantly greater neointimal suppression in the single-strut regions than PES, with a similar trend in the overlap region. PES had significant vessel expansion in all regions, whereas there were no changes with EES. Neither stent fracture nor late incomplete stent apposition (LISA) in the overlap region was observed. Conclusions: Overlapping EES appears to be effective without vessel expansion, stent fracture or LISA for up to 8-9 months. (Circ J 2010; 74: 1023 - 1025)

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