Pharmacological therapy of systolic left ventricular dysfunction has evolved over the past 3 decades. Current therapy is focused primarily on the regulation of the renin-angiotensin-aldosterone axis and sympathetic nervous system. Additional targets of pharmacotherapy include vasoconstriction, impaired nitric oxide metabolism, inflammation and improving myocardial function. As therapies in chronic systolic heart failure have evolved beyond diuretics and digoxin, so too has mortality improved. Future directions in the management of heart failure include cell-based and genetic therapy, and further refinement of current therapy through genetics. (Circ J 2012; 76: 268-277)

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Acute heart failure (AHF) is classically defined by signs and symptoms related to elevated ventricular filling pressures. Regardless of precipitant, underlying etiology or ejection fraction, the vast majority of hospital admissions are the result of worsening chronic HF. For the acutely decompensated patient, 4 hemodynamic profiles, stratified by degree of congestion ("dry" or "wet") and adequacy of perfusion ("warm" or "cold") predict prognosis and guide therapy. Relief of congestion is the primary goal of AHF management. Loop diuretics remain the mainstay of AHF treatment, but new modalities such as veno-venous ultrafiltration are promising. For patients with evidence of hypoperfusion, vasoactive agents may be needed to facilitate diuresis. The decision to use vasodilators or inotropes is complex and the need for invasive hemodynamic monitoring is often determined by the individual patient's characteristics. Routine use of inotropes should be discouraged; however when used, the short-term hemodynamic benefits conferred by these agents must be balanced against their tendency to increase adverse events. Although these strategies are effective in alleviating symptoms in most patients, management dilemmas arise from cardiorenal interactions and limitations in effective novel therapies. Epidemiological studies continue to emphasize that AHF portends a poor prognosis. Further studies are needed to improve our understanding and outcomes in this growing patient population. (Circ J 2012; 76: 278-286)

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Oral antiplatelet agents targeting the platelet P2Y12 receptor are an integral component of treating patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Clopidogrel has been the most commonly used agent in this respect worldwide. However, there are certain shortcomings of clopdiogrel, the most important of which is the wide response variability of platelet inhibition. The response to clopidogrel is affected by various clinical variables, genetic variations involved in its activation, and drug-drug interactions. Therefore, clinicians are faced with challenges in situations where high inhibition of platelets is necessary and in cases where the response to clopidogrel may be suboptimal. There are various ways of overcoming the response variability and this review will focus on the practical methods available. Namely, the data and evidence regarding increasing the dose of clopidogrel, adding cilostazol to standard dual antiplatelet therapy, and switching to more recently developed agents will be covered. (Circ J 2012; 76: 287-292)

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Background: Studies using isolated sinoatrial node (SAN) cells indicate that rhythmic spontaneous sarcoplasmic reticulum calcium release (Ca clock) plays an important role in SAN automaticity. In the intact SAN, cross-contamination of optical signals from the SAN and the right atrium (RA) prevent the definitive testing of Ca clock hypothesis. The aim of this study was to use a novel approach to selectively mapping the intact SAN to examine the Ca clock mechanism. Methods and Results: We simultaneously mapped intracellular Ca (Ca_i) and membrane potential (V_m) in 10 isolated, Langendorff-perfused normal canine RAs. The excitability of the RA was suppressed with high-potassium Tyrode's solution, allowing selective optical mapping of V_m and Ca_i of the SAN. Isoproterenol (ISO, 0.03μmol/L) decreased the cycle length of the sinus beats, and shifted the leading pacemaker site from the middle or inferior SAN to the superior SAN in all RAs. The Ca_i upstroke preceded the V_m in the leading pacemaker site by up to 18±2ms. ISO-induced changes to SAN were inhibited by ryanodine (3μmol/L), but not ZD7288 (3μmol/L), a selective I_f blocker. Conclusions: We conclude that, in the isolated canine RA, a high extracellular potassium concentration can suppress atrial excitability thus leading to SAN-RA conduction block, allowing selective optical mapping of the intact SAN. Acceleration of Ca cycling in the superior SAN underlies the mechanism of sinus tachycardia during sympathetic stimulation. (Circ J 2012; 76: 309-316)

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Background: Anticoagulation control quality affects the incidence of thromboembolic events in atrial fibrillation (AF) patients. However, the effects of anticoagulation control quality on the prothrombotic state of AF patients are unclear. Methods and Results: Ninety-five AF patients who had been treated with warfarin were prospectively followed-up for 449±92 days. We analyzed whether time in the therapeutic range (TTR) of the international normalized ratio (INR) of prothrombin time, percentage of INR values in the range (%INR), and coefficient of variation of INR values (CV-INR) were related to D-dimer levels. The mean values of TTR, %INR, and CV-INR were 62%, 59%, and 0.19, respectively, and their median values were 67%, 63%, and 0.19, respectively. TTR was significantly correlated with %INR (R²=0.917, P<0.01), but not with CV-INR (R²=0.050, P=0.26). The mean and median D-dimer levels were 0.79 and 0.60μg/ml, respectively. Low TTR, low %INR, and high CV-INR were found to contribute to high D-dimer levels (P=0.02, 0.03, and 0.02, respectively). Conclusions: In AF patients treated with warfarin, not only the duration outside the target INR range, but also the fluctuation in INR level may influence the prothrombotic state. (Circ J 2012; 76: 317-321)

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Background: Ablation of ventricular tachycardia originating from the left ventricular (LV) epicardium is often limited by the radiofrequency power delivery. We compared the effect of bipolar vs. unipolar epicardial ablation on lesion size. Methods and Results: Eleven excised pig hearts were superfused with saline (2L/min). Unipolar ablation (25 or 30W for 120s) was performed between the LV epicardial saline-irrigated electrode and an indifferent electrode (n=33 lesions). Bipolar ablation (25 or 30W for 120s) was performed between a 4-mm saline-irrigated-tip (20ml/min) electrode on the LV epicardium and an opposing 10-mm non-irrigated-tip electrode on the LV endocardium (n=38 lesions). Wall thickness did not differ between experiments (15.4±2.4 vs. 15.3±2.1mm). Impedance was lower at the beginning and end of unipolar ablation than at the beginning and end of bipolar ablation (163.2±20.3Ω and 109.9±16.0Ω vs. 194.6±23.3Ω and 127.1±16.4Ω, respectively) (P<0.001). Epicardial lesion width did not differ between unipolar and bipolar ablation (10.1±2.7 vs. 10.2±2.4mm), but lesion depth was greater with bipolar ablation (10.6±2.7 vs. 7.5±1.0mm) (P<0.001). Unipolar ablation produced no transmural lesion, but bipolar ablation produced 15 (46%) (P<0.001). Steam pop occurred in 11 (29%) and 3 (9%) cases, respectively (P=0.036). Conclusions: Bipolar ablation of the LV free wall is highly effective at creating an appropriately deep epicardial lesion. (Circ J 2012; 76: 322-327)

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Background: We explored the determinants of mortality in order to develop and validate the Kyoto model, which predicts outcomes after percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). Methods and Results: A total of 9,393 patients who underwent their first coronary revascularization without concomitant valvular, left ventricular, or major vascular surgery were followed over a median follow-up of 3.5 years in the CREDO-Kyoto Registry. We fitted separate Cox regression to mortality after PCI and CABG. The best-fitting model was internally validated by 10-fold cross-validation. The Cox regression identified the following predictors: age, sex, body mass index, ejection fraction, atrial fibrillation, diabetes mellitus, hyperlipidemia, current smoker, stroke, peripheral vascular disease, chronic obstructive pulmonary disease, malignancy, kidney disease, anemia, liver cirrhosis, diseased vessel, left main disease, proximal left anterior descending artery disease, and total occlusion. This model simulated that the 3-year mortality for a hypothetical 70-year-old man with 2-vessel disease is 2.0% after PCI and 2.6% after CABG, or 4.2% and 5.1% if he has diabetes and chronic kidney disease. The Hosmer-Lemeshow test showed no significant deviations between the observed and predicted events. The C statistics were greater than 0.78. Conclusions: The Kyoto model can assist clinicians and patients in adherence to medication and lifestyle changes after revascularization and in individualized decision making. A web application is available at http://www.biostatistics.jp/prediction/kyoto-model. (Circ J 2012; 76: 328-334)

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Background: Although infrapopliteal angioplasty may salvage the majority of limbs under threat of amputation, this procedure is still limited in diabetic patients. The purpose of the present study was to compared the outcomes of infrapopliteal angioplasty between Korean diabetic patients and non-diabetic patients with critical lower limb ischemia (CLI). Methods and Results: Between March 2002 and May 2008, infrapopliteal angioplasty was performed on 108 limbs of 93 patients (71 male; mean age, 68 years, range, 27-91 years) with CLI (Rutherford-Becker category 4, 5 or 6). Freedom from reintervention, limb salvage, and overall survival were analyzed. Median follow-up was 30 months (range, 1-93 months). The number of diabetic patients was 70 (75%). There were no significant differences between the 2 groups in technical success rate (66% vs. 84%, P=0.133) and primary clinical success rate (81% vs. 92%, P=0.234). Kaplan-Meier analysis showed that diabetic patients had a higher frequency of poor primary patency (P=0.012) during 2-year follow-up, but that there were no significant differences between the 2 groups in terms of limb salvage (P=0.930), and survival (P=0.459). Conclusions: Diabetic patients had an unfavorable 2-year primary patency compared with non-diabetic patients. There were no significant differences, however, between the 2 groups in terms of technical success rate, primary clinical success rate, 2-year limb salvage rate or overall survival. (Circ J 2012; 76: 335-341)

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Background: Scattering centers (SC) are often observed with optical coherence tomography (OCT) in some struts of bioresorbable vascular scaffolds (BVS). These SC might be caused by crazes in the polymer during crimp-deployment (more frequent at inflection points) or by other processes, such as physiological loading or hydrolysis (eventually increasing with time). The spatial distribution and temporal evolution of SC in BVS might help to understand their meaning. Methods and Results: Three patients were randomly selected from 12 imaged with Fourier-domain OCT at both baseline and 6 months in the ABSORB cohort B study (NCT00856856). Frame-by-frame analysis of the SC distribution was performed using spread-out vessel charts, and the results from baseline and 6 months were compared. A total of 4,328 struts were analyzed. At baseline and follow-up all SC appeared at inflection points. No significant difference was observed between baseline and 6 months in the number of SC struts (14.9 vs. 14.5%, P=0.754) or in the distribution of SC. The proportion and distribution of SC did not vary substantially among the patients analyzed. Conclusions: The SC observed in OCT imaging of the BVS are located exclusively at inflection points and do not increase with time. These findings strongly suggest that SC are caused by crazes in the polymer during crimp-deployment, ruling out any major role of hydrolysis or other time-dependent processes. (Circ J 2012; 76: 342-350)

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Background: Even in the drug-eluting stent era, adverse cardiac events, including restenosis after percutaneous coronary intervention (PCI), have been more frequently seen in patients on hemodialysis (HD) than in non-HD patients. The objective of this study was to compare the sirolimus-eluting stent (SES) and everolimus-eluting stent (EES) for prevention of adverse cardiac events, including restenosis, in HD patients. Methods and Results: A total of 100 consecutive patients on HD who underwent PCI were enrolled and randomly assigned to receive SES or EES. Although there was no difference between the 2 groups in baseline patient and lesion characteristics, the angiographic restenosis rate at 8-month follow-up was 21.2% in the SES group and 8.7% in the EES group (P=0.041). Significant differences were also seen in % diameter stenosis (%DS), minimal lumen diameter, and late lumen loss at 8-month follow-up (P=0.0024, P=0.0040, and P=0.033, respectively). During the 1-year follow-up, major adverse cardiac events occurred in 11 (22.0%) patients in the SES group and in 5 (10.0%) patients in the EES group (P=0.10). Conclusions: The use of EES was as safe as that of SES. Moreover, EES significantly prevented restenosis in patients on maintenance HD compared with SES. (Circ J 2012; 76: 351-355)

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Background: Successful introduction of trans-catheter aortic valve implantation for selected patients with critical aortic stenosis has raised the question of how to identify appropriate high-risk candidates. Methods and Results: To assess the risk profile of patients undergoing single aortic valve replacement (sAVR), multiple logistic regression analysis was applied for open sAVR (n=7,883) registered in the Japan Cardiovascular Surgery Database to predict surgical mortality. Three subgroup analyses stratified by age, <70 years (young), 70-79 years (middle), and ≥80 years (elderly), were also performed. Preoperative patient characteristics indicated increased prevalence of several variables in the elderly subgroup including New York Heart Association (NYHA) class III/IV, 3-vessel coronary artery disease (3VCAD), respiratory insufficiency, and stroke. The following factors, however, were decreased in the elderly subgroup: dialysis, poor heart function, reoperation, renal dysfunction, and emergency surgery. Mortality was 3.0% in all sAVR patients and 5.2% in the elderly subgroup. Multivariate analysis in all patients produced 16 variables as operative risks (P<0.05) including respiratory insufficiency, dialysis, NYHA class III/IV, and reoperation. The analysis in the elderly subgroup produced 9 variables with more pronounced relative risk (RR), which included dialysis (RR=5.4), respiratory insufficiency (RR=3.3), preoperative arrhythmia (RR=3.0), 3VCAD (RR=3.6), and emergency surgery (RR=23.1). Conclusions: sAVR has produced good surgical results in Japan. Procedure- and age-specific analyses have identified a risk profile that is unique to sAVR patients in the elderly population in Japan. (Circ J 2012; 76: 356-364)

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Background: When aortic valve replacement (AVR) is performed in patients with a small aortic annulus, prosthesis-patient mismatch (PPM) is of concern. We investigated the mid-term outcomes of AVR with a 17-mm mechanical prosthesis. Methods and Results: Seventy-eight patients with aortic stenosis underwent AVR with a 17-mm St. Jude Medical Regent prosthesis. Echocardiography was performed preoperatively, at discharge, and at follow-up (mean follow-up, 33 months). Patients were divided into 2 groups: with and without PPM at discharge. Between-group differences in postoperative variables, particularly survival, were analyzed. Overall hospital mortality was 2.6%. Actuarial 1- and 5-year survival rates were 95% and 79%, respectively. Diabetes and renal insufficiency were associated with long-term mortality. Freedom from major adverse valve-related cardiac events at 1 year and 5 years was 97.3% and 93.9%, respectively. Diabetes was shown to be an independent risk factor for major adverse valve-related cardiac events. Echocardiography 13 months after AVR showed a significant increase in mean effective orifice area index, decrease in mean left ventricular-aortic pressure gradient, and decrease in mean left ventricular mass index. PPM at discharge did not influence long-term survival or left ventricular mass regression. Conclusions: The 17-mm Regent prosthesis provided satisfactory clinical and hemodynamic results. It is a reliable choice for patients with a small aortic annulus. (Circ J 2012; 76: 365-371)

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Background: This report details experience of the conversion of the Toyobo left ventricular assist device (LVAD; Nipro, Osaka, Japan) to the DuraHeart LVAD (TerumoHeart, Ann Arbor, MI, USA) in patients awaiting heart transplantation. Methods and Results: Eight patients (4 male, 4 female) with Toyobo paracorporeal LVAD underwent conversion to the third-generation centrifugal (DuraHeart) LVAD. The apical cuff of the Toyobo was not exchanged because the size was the same as that of the DuraHeart. All conversion operations were performed safely, but 3 patients who had infection of the Toyobo LVAD cannulation site prior to conversion suffered later pocket infections and 1 patient died because of sepsis. One patient underwent heart transplantation and 6 of 8 patients were awaiting heart transplantation at home. Conclusions: Conversions from the Toyobo LVAD to the DuraHeart LVAD were performed safely. Considering that implantable LVADs provide superior long-term survival and quality of life, conversion is a reasonable decision for Toyobo LVAD users in whom there are no infections. (Circ J 2012; 76: 372-376)

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Background: Coronary perforation (CP) is a rare, but sometimes lethal, complication of percutaneous catheter intervention (PCI). We reviewed surgically-treated cases of type 3 CP during PCI. Methods and Results: From 2007 to 2010, 5 patients underwent surgical repair for type 3 CP (3 men, 2 women; mean age, 74 years). The mean number of diseased coronary branches was 2.6 and the mean SYNTAX score was 45. The target lesions were the left anterior descending artery in 4 cases and the right coronary artery in 1 case. Types of American Heart Association/American College of Cardiology classification were type B2 in only one case and type C in 4 cases. The causes of perforation were balloon inflation in 4 patients and rotational atherectomy in 1 patient. The in-hospital mortality rate was 20%. In the cases of CP associated with balloon inflation, coronary lacerations were so severe that re-bleeding occurred even if the covered stent could temporarily achieve hemostasis, and percutaneous cardiopulmonary support and emergency surgery were required. Conclusions: CP induced by balloon inflation tends to result in a serious condition compared with rotablator-induced CP. Surgery should be immediately performed even after covered stent implantation if there is any possibility of re-bleeding in the case of balloon-induced type 3 CP. (Circ J 2012; 76: 377-381)

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Background: Dyssynchrony has various detrimental effects on cardiac function, but its effect on cardiac sympathetic activity is not fully understood. Methods and Results: We studied 50 heart failure patients who underwent cardiac resynchronization therapy (CRT). Cardiac sympathetic activity was assessed by ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) scintigraphy as the delayed heart-to-mediastinum ratio (H/M ratio). Echocardiography was performed before and 7 months after CRT, and response was defined as a ≥15% decrease in end-systolic volume. Dyssynchrony was determined by the time difference between the anteroseptal-to-posterior wall using speckle-tracking radial strain (≥130ms predefined as significant). H/M ratio in patients with dyssynchrony was less than that in patients without dyssynchrony (1.62±0.31 vs. 1.82±0.36, P<0.05), even though ejection fraction was not significantly different (24±6% vs. 25±7%). Patients with dyssynchrony and H/M ratio ≥1.6 had a higher frequency of response to CRT (94%) and favorable long-term outcome over 3.0 years. In contrast, patients without dyssynchrony and H/M ratio <1.6 were more likely to show a lower frequency of response to CRT (0%) and unfavorable long-term outcome after CRT. Conclusions: Dyssynchrony is associated with cardiac sympathetic activity, and ¹²³I-MIBG scintigraphy may be valuable for predicting the response to CRT. (Circ J 2012; 76: 382-389)

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Background: Autopsy findings have suggested delayed arterial healing as a primary cause of very late stent thrombosis (VLST) after drug-eluting stent (DES) implantation. Methods and Results: Optical coherence tomography of DES-treated lesions that developed VLST (n=6) was compared with that of DES-treated lesions that developed late in-stent restenosis (L-ISR: n=32) among patients with recurrent ischemia >1 year after DES implantation (mean, 37±17 months), and with the stented segment without any evidence of VLST or L-ISR (no-event: n=20; mean, 38±19 months). The proportion of uncovered and malapposed struts in each stented segment was evaluated. A total of 961 frames, 9,763 struts were analyzed. The proportion of uncovered struts was higher in the VLST group than in the L-ISR group and the no-event group (29.2±22.8%, 7.9±9.7%, and 7.6±8.0%, respectively; P=0.0002). The proportion of malapposed struts was higher in the VLST group than in the no-event group (7.3±8.7% vs 1.1±2.4%, P=0.01). Two patients in the VLST group had lower rates of uncovered and malapposed struts, but this involved lipid-laden-like neointima with disruptions. Conclusions: Delayed neointimal coverage and incomplete stent apposition were frequently observed in the DES-treated lesions that developed very late thrombosis. Lipid-laden-like neointima with disruption within the DES may be another possible mechanism for very late thrombosis. (Circ J 2012; 76: 390-398)

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Background: Cardiac iodine-123 metaiodobenzylguanidine (¹²³I-MIBG) scintigraphy is an established method of assessment of cardiovascular sympathetic function. The aim of the present study was to investigate the long-term cardiovascular predictive value of cardiac ¹²³I-MIBG scintigraphy parameters in Japanese type 2 diabetic patients without structural heart disease. Methods and Results: Cardiac ¹²³I-MIBG scintigraphy in 108 patients with type 2 diabetes who did not have structural heart disease, was evaluated. The washout rate (WR) was considered enhanced if it was ≥40%. Accurate follow-up information for 4.6 years was obtained in 54 enhanced WR patients (27 male; mean age, 61±11 years) and in 54 sex- and age-matched preserved WR patients (27 male; mean age, 61±10 years). Major adverse cardiac and cerebrovascular events (MACCE) were investigated. During follow-up, 10 enhanced WR patients developed MACCE including cardiac death, coronary revascularization, stroke, and congestive heart failure, while MACCE occurred in only 3 male patients. The Kaplan-Meier curves indicated that enhanced WR patients had higher incidence of MACCE than those with preserved WR (P<0.05). Cox proportional hazards regression analysis showed that age and enhanced WR were independently associated with the incidence of MACCE (hazard ratio, 4.06; 95% confidence interval: 1.194-18.76, P=0.0237). Conclusions: Abnormal WR of cardiac ¹²³I-MIBG scintigraphy at baseline has long-term cardiovascular predictive value in Japanese patients with type 2 diabetes without structural heart disease. (Circ J 2012; 76: 399-404)

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Background: This study investigated the efficacy and the safety of the upstream glycoprotein (Gp) IIb/IIIa inhibitor (clotinab; ISU ABXIS, Seoul, Republic of Korea) under 600-mg clopidogrel pretreatment compared with provisional use in ST-elevation myocardial infarction (STEMI). Methods and Results: A total of 786 STEMI patients were randomized to upstream use in the emergency room (ER) (n=392) or provisional use during percutaneous coronary intervention (PCI) (n=394). All patients were prescribed 600-mg clopidogrel in the ER. The primary endpoint was the 30-day incidence of composite events including death, nonfatal myocardial infarction, target vessel revascularization, and stroke. There was no significant difference in the events that occurred in 40 patients (10.2%) in the upstream arm and 55 patients (14.0%) in the provisional arm during the 30 days (odds ratio 0.70, 95% confidence interval 0.45-1.08). Major bleeding was higher in the upstream arm (1.5% vs. 0%, P=0.02). However, there was a significant reduction in 30-day composite events in the upstream arm in the high-risk population (Killip class ≥II or GRACE score >140). Conclusions: The upstream use of clotinab under a 600-mg clopidogrel loading may not significantly reduce cardiac events following primary PCI but may improve the clinical outcome in high-risk patients. (Circ J 2012; 76: 405-413)

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Background: The effect of collaterals to occluded coronary arteries during ST-elevation myocardial infarction (STEMI) is unclear. The conventional CVP-based formula to calculate collateral flow index during STEMI yields values higher than in elective patients, which prompted derivation of a modified formula, pertinent in STEMI when left ventricular mean diastolic pressure (LVMDP) is the extravascular pressure limiting collateral flow. We aimed to evaluate this new LVMDP-based acute collateral flow index (ACFI). Methods and Results: The pressure distal to coronary artery occlusion (P_d) was measured during intervention in 111 consecutive STEMI patients, 67 (61%) of whom underwent primary intervention, followed for 58 months. ACFI (0.18±0.17, median 0.15) correlated with both P_d and collateral grade (P<0.0001). Higher creatine kinase levels and white cell counts were measured in the lowest ACFI tertile compared with the highest tertile group (P<0.012). ACFI correlated slightly with early regional but not with global left ventricular ejection fraction or with long-term coronary events and mortality. Conclusions: The ACFI is appropriate for evaluating collateral function during STEMI. Collateral flow during STEMI may marginally limit myocardial damage but had no effect on left ventricular contraction or long-term mortality, most likely because of the low flow provided by emerging collaterals and the high proportion of patients undergoing intervention before the beneficial effect of collaterals could be realized. (Circ J 2012; 76: 414-422)

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Background: The relationship between major adverse cardiac events (MACE) and serum polyunsaturated fatty acid (PUFA) parameters has not been well documented in patients who have undergone percutaneous coronary intervention (PCI). The aim of the present study was to investigate this relationship. Methods and Results: A total of 284 consecutive patients who underwent elective PCI were enrolled and stratified according to median serum levels of n-6 PUFAs (arachidonic acid [AA]), n-3 PUFAs (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]), and serum EPA/AA and DHA/AA ratios. The relationship between these PUFA parameters and the incidence of MACE including cardiac death, acute coronary syndrome, PCI for de novo lesions, and coronary artery bypass grafting, was analyzed. Multivariate analysis showed that among the PUFA parameters, only a high serum EPA/AA ratio was significantly associated with a low incidence of MACE in all the models tested (model A, without adjusted variables: hazard ratio [HR], 0.52; 95% confidence interval [CI]: 0.27-0.99, P=0.048; model B, adjusted for age and diabetes: HR, 0.51; 95%CI: 0.26-0.98, P=0.043; model C, adjusted for age, sex, diabetes, hypertension, smoking, and low-density lipoprotein cholesterol: HR, 0.49; 95%CI: 0.25-0.94, P=0.033). Conclusions: The incidence of MACE in patients who have undergone PCI is significantly associated with serum EPA/AA ratio. (Circ J 2012; 76: 423-429)

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Background: Although poststress myocardial stunning is regarded as a marker for severe coronary artery disease (CAD), no study has yet compared the diagnostic value of poststress stunning with transient ischemic dilation (TID) of the left ventricle (LV) for detecting multivessel CAD. Methods and Results: A total of 271 patients with suspected or known CAD underwent adenosine triphosphate (ATP) loading and at-rest gated single-photon emission computed tomography. We assessed myocardial perfusion with a 20-segment model, and analyzed the changes in LV volumetric analysis induced by ATP and an automatically derived TID ratio. In 147 patients with multivessel CAD, the prevalence of multi-territorial ischemia was higher, and the post-ATP increase in end-systolic volume (ESV) and TID ratio were greater, than in the 124 with insignificant or single-vessel CAD (P<0.0001, for all cases). The receiver-operating characteristic curves analysis revealed cutoff values for ESV of 5ml and a TID ratio of 1.11. Multivariate logistic regression analysis revealed that the combination of a poststress increase in ESV of ≥5ml and multi-territorial ischemia best identified multivessel CAD, with a sensitivity of 78% and a specificity of 84%, whereas the TID ratio was not shown to be an independent predictor. Conclusions: Post-ATP stress myocardial stunning is superior to the TID ratio for detecting multivessel CAD. (Circ J 2012; 76: 430-438)

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Background: It is still controversial whether intravenous administration of β-blocker in the very acute phase of acute myocardial infarction (AMI) is beneficial. Landiolol is an ultra-short-acting β-blocker that has less effect on blood pressure, but little is known about its efficacy and safety for patients with AMI undergoing primary percutaneous coronary intervention (PCI). Methods and Results: A consecutive 96 patients with AMI not manifesting cardiogenic shock were prospectively randomized to landiolol (n=47) or a control group (n=49). Continuous administration of landiolol (3μg·kg^-1·min^-1 for 24h) was done just after PCI in the landiolol group, but not in the control group. Heart rate decreased by 9.4±1.7beats/min after initiation of landiolol (P<0.01), but was unchanged in the control group. Left ventricular ejection fraction assessed 6 months later was greater than that at 2 weeks in the landiolol group (52.0±1.5 vs. 49.1±1.5%, P=0.01), but remained unchanged in the control group. Left ventricular end-diastolic volume index assessed 6 months later was increased compared with that at 2 weeks in the control group (78.0±2.7 vs. 72.5±2.8ml/m², P=0.02), whereas it was unchanged in the landiolol group. Conclusions: Early intravenous administration of landiolol in patients with AMI undergoing PCI is safe and has the potential to improve cardiac function and inhibit cardiac remodeling in the chronic phase. (Circ J 2012; 76: 439-445)

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Background: Genetic variations on chromosome 9p21 have been found to be associated with peripheral artery disease (PAD), but have not been investigated in Asians. The ankle-brachial index (ABI) is a widely-used measurement for PAD. We previously reported the BRAP gene is associated with the ABI, so the aim of the present study was to test whether the ANRIL gene on 9p21 is associated with the ABI and to test an interaction between BRAP and ANRIL in a Chinese population. Methods and Results: A total of 745 subjects with a family history of myocardial infarction or stroke were enrolled. The multiplicative and additive effects of 2 significant single-nucleotide polymorphisms (SNPs) were evaluated by multivariable regression analysis. SNP rs2383207 on ANRIL was most significantly associated with lower ABI. Similar to our previous findings, SNP rs11066001 on BRAP was associated with lower ABI. A dose-response relationship between ABI values and the number of risk alleles from the 2 significant SNPs was observed in both men and women (adjusted P=0.004 for men, 0.008 for women). The combined genetic effect on ABI was stronger in smokers than in non-smokers. Conclusions:ANRIL on 9p21 and BRAP were both associated with ABI in a Taiwanese population. An additive effect between variants of these 2 genes was found. The finding of a potential gene-gene interaction and gene-environment interaction is interesting, but needs further investigation. (Circ J 2012; 76: 446-452)

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Background: Hypertrophic cardiomyopathy (HCM), which is inherited as an autosomal dominant trait, is the most prevalent hereditary cardiac disease. Although there are several reports on the systematic screening of mutations in the disease-causing genes in European and American populations, only limited information is available for Asian populations, including Japanese. Methods and Results: Genetic screening of disease-associated mutations in 8 genes for sarcomeric proteins, MYH7, MYBPC3, MYL2, MYL3, TNNT2, TNNI3, TPM1, and ACTC, was performed by direct sequencing in 112 unrelated Japanese proband patients with familial HCM; 37 different mutations, including 13 novel ones in 5 genes, MYH7, MYBPC3, TNNT2, TNNI3, and TPM1, were identified in 49 (43.8%) patients. Among them, 3 carried compound heterozygous mutations in MYBPC3 or TNNT2. The frequency of patients carrying the MYBPC3, MYH7, and TNNT2 mutations were 19.6%, 10.7%, and 8.9%, respectively, and the most frequently affected genes in the northeastern and southwestern parts of Japan were MYBPC3 and MYH7, respectively. Several mutations were found in multiple unrelated proband patients, for which the geographic distribution suggested founder effects of the mutations. Conclusions: This study demonstrated the frequency and distribution of mutations in a large cohort of familial HCM in Japan. (Circ J 2012; 76: 453-461)

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Background: In both takotsubo cardiomyopathy (TC) and reperfused anterior acute myocardial infarction (AMI), negative T waves commonly appear on the ECG in the subacute phase. This study aimed to clarify the ECG differences between these diseases. Methods and Results: We compared the ECGs with the greatest amplitude of negative T wave from 34 patients with TC and 237 patients with a first reperfused anterior AMI who were admitted within 6h of symptom onset and who had no abnormal Q-waves on discharge ECG. Time from symptom onset to recording the ECG did not differ between TC and anterior AMI (2.4±1.5 vs. 2.1±2.0 days, P=0.48). TC was associated with a greater maximal amplitude of negative T wave (1.00±0.44 vs. 0.79±0.46mV, P=0.044), and a greater number of leads with negative T waves (9.5±1.0 vs. 6.0±2.1, P<0.001). Negative T waves were consistently observed in leads -aV_R and V_4-6, whereas negative T waves were rare in lead V₁ in TC. Negative T waves in lead -aV_R (ie, positive T waves in lead aV_R) and no negative T waves in lead V₁ identified TC with 94% sensitivity and 95% specificity, representing the highest diagnostic accuracy. Conclusions: During the subacute phase, deeper negative T waves were more frequently and broadly distributed, particularly around leads facing the apical region, in TC than in reperfused anterior AMI. (Circ J 2012; 76: 462-468)

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Background: There are few large studies of fetal congenital bradyarrhythmia. The aim of the present study was to investigate the effects and risks of transplacental treatment for this condition. Methods and Results: Using questionnaires, 128 cases of fetal bradyarrhythmia were identified at 52 Japanese institutions from 2002 to 2008. Of the 128 fetuses, 90 had structurally normal hearts. Among these 90 fetuses, 61 had complete atrioventricular block (CAVB), 16 had second-degree AVB, 8 had sinus bradycardia, and 5 had other conditions. The 61 CAVB fetuses were divided into those who did (n=38) and those who did not (n=23) receive transplacental medication. Monotherapy with β-sympathomimetics, steroid monotherapy, and combination therapy with these agents was given in 11, 5 and 22 cases, respectively. Beta-sympathomimetics improved bradycardia (P<0.001), but no medication could significantly improve the survival rate. Fetal hydrops was associated with a 14-fold increased risk of perinatal death (P=0.001), and myocardial dysfunction was a significant risk factor for poor prognosis (P=0.034). Many adverse effects were observed with steroid treatment, with fetal growth restriction increasing significantly after >10 weeks on steroids (P=0.043). Conclusions: Treatment with β-sympathomimetics improved bradycardia, but survival rate did not differ significantly in fetuses with and without transplacental medication. It is recommended that steroid use should be limited to <10 weeks to avoid maternal and fetal adverse effects, especially fetal growth restriction and oligohydramnios. (Circ J 2012; 76: 469-476)

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Background: Vascular progenitor cells (VPCs) are a heterogeneous population, containing a subpopulation co-expressing both endothelial and smooth muscle phenotypes. This study sought to determine whether the level of this subpopulation correlated with the coronary Gensini score. Methods and Results: VPCs were cultivated in 50 patients undergoing coronary angiography. A subpopulation of VPCs expressed both endothelial (VE-cadherin [VE-Cad]) and smooth-muscle phenotypes (α-smooth muscle actin [α-SMA]). Correlations of the VE-Cad^lowα-SMA⁺ VPC level and adhesion molecule expression by VPCs with the Gensini score were investigated. The association between the amount of this subpopulation and the development of intimal hyperplasia (IH) was also estimated in a vascular injury animal model. Both the number of VE-Cad^lowα-SMA⁺ VPCs (P=0.002) and the expression level of intracellular adhesion molecule (ICAM)-1 by VPCs (P=0.008) correlated with the Gensini score. However, only the number of VE-Cad^lowα-SMA⁺ VPCs (P=0.004) and the blood level of low-density lipoprotein cholesterol (P=0.016) were parameters independently associated with the Gensini score in multivariate analysis. Furthermore, in an animal model of injecting VPCs into SCID mice after femoral artery wire injury, a higher number of VE-Cad^lowα-SMA⁺ VPCs correlated with greater IH (r=0.69, P<0.0001). Conclusions: The level of VE-Cad^lowα-SMA⁺ VPCs was associated with the severity of coronary atherosclerosis as quantified by the Gensini score. Manipulating this subpopulation may provide a way of attenuating atherosclerosis in the future. (Circ J 2012; 76: 477-484)

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Background: Distal-type chronic thromboembolic pulmonary hypertension (CTEPH) is a fatal disease for which a new therapeutic strategy needs to be developed. We examined the effects of percutaneous transluminal pulmonary angioplasty (PTPA). Methods and Results: We prospectively enrolled 12 patients with distal-type CTEPH. After stabilizing their condition with pulmonary vasodilators, we then performed PTPA, which markedly improved pulmonary hemodynamics and pulmonary artery structure, as confirmed by angiography and optical coherence tomography, and also significantly improved their long-term prognosis compared with 39 historical controls. Conclusions: PTPA is a promising therapeutic option for distal-type CTEPH. (Circ J 2012; 76: 485-488)

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(Circ J 2012; 76: 221-229)

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