In the past decade, both the range of indications and the efficacy and safety of interventional electrophysiology has improved considerably. This progress is attributed to both the accumulating experience of electrophysiologists and the advances in technological tools facilitating the diagnosis and treatment of cardiac arrhythmias. Real-time 3-dimensional transesophageal echocardiography (RT 3D TEE) has emerged as a new imaging tool in the clinical arena. Its ability to image in "real time" cardiac structures "en face" and the almost entire length of intracardiac catheters has made this technique a promising imaging tool to guide percutaneous catheter-based procedures. More recently it has been used in monitoring ablation procedures. In this review, the advantages and current limitations of RT 3D TEE during ablation of cavotricuspid isthmus-dependent atrial flutter and pulmonary vein isolation are described. (Circ J 2012; 76: 5-14)

View full abstract

Acute myocardial infarction (MI) and its sequelae are leading causes of morbidity and mortality worldwide. Nitroglycerin (glyceryl trinitrate [GTN]) remains a first-line treatment for angina pectoris and acute MI. Nitroglycerin achieves its benefit by giving rise to nitric oxide (NO), which causes vasodilation and increases blood flow to the myocardium. However, continuous delivery of GTN results in tolerance, limiting the use of this drug. Nitroglycerin tolerance is caused, at least in part, by inactivation of aldehyde dehydrogenase 2 (ALDH2), an enzyme that converts GTN to the vasodilator, NO. We recently found that in a MI model in animals, in addition to GTN's effect on the vasculature, sustained treatment negatively affected cardiomyocyte viability following ischemia, thus resulting in increased infarct size. Coadministration of Alda-1, an activator of ALDH2, with GTN improves metabolism of reactive aldehyde adducts and prevents the GTN-induced increase in cardiac dysfunction following MI. In this review, we describe the molecular mechanisms associated with the benefits and risks of GTN administration in MI. (Circ J 2012; 76: 15-21)

View full abstract

Right ventricular (RV) function is increasingly recognized as having prognostic significance in various disease processes. The current gold standard for noninvasive measurement of RV function is cardiac magnetic resonance imaging; however, because of practical considerations, echocardiography remains the most often used modality for evaluating the RV. In the past, because of its complex morphology, echocardiographic assessment of the RV was usually qualitative in nature. Current advances in echocardiographic techniques have been able to overcome some of the previous limitations and thus quantification of RV function is increasingly being performed. In addition, recent echocardiographic guidelines for evaluating the RV have been published to aid in standardizing practice. The evaluation of RV function almost certainly has no greater importance than in the congenital heart population, especially in those patients that have a single RV acting as the systemic ventricle. As this complex population continues to increase in number, accurate and precise evaluation of RV function will be a major issue in determining clinical care. (Circ J 2012; 76: 22-31)

View full abstract

Reperfusion therapy has become an established treatment for ST-segment elevation acute myocardial infarction (STEMI), increasing the need for early diagnosis and early treatment. Despite the development of diagnostic strategies, the electrocardiogram (ECG) plays a central role in the diagnostic pathway for STEMI because it is inexpensive, readily available, and noninvasive. Moreover, in the acute phase of STEMI, the ECG can provide useful information about the extent of area at risk, the degree of myocardial damage, reperfusion injury, and myocardial reperfusion, all of which influence infarct size. This review explores the clinical importance of the ECG for patients with anterior wall STEMI in the current interventional era. (Circ J 2012; 76: 32-40)

View full abstract

Background: The aim of the present study was to investigate the long-term outcome of sirolimus-eluting stent (SES) implantation in lesions with severe calcification that may disturb adequate stent expansion and increase the risk of restenosis and target lesion revascularization (TLR). Methods and Results: The Cypher Post-Marketing Surveillance Registry study has been conducted since August 2004 in Japan to evaluate the efficacy and safety of SES in a real-world setting. Data on 2,458 lesions in 2,050 patients were reviewed, and the angiographical outcomes at 240 days and clinical outcomes at 1,080 days after implantation compared between calcified lesions and non-calcified lesions in dialysis patients and non-dialysis patients. In non-dialysis patients, the rates of major adverse cardiac events (MACE; 16.0% vs. 12.8%; P=0.144) including TLR (4.9% vs. 6.0%; P=0.457), and restenosis (10.1% vs. 7.8%; P=0.207) were similar in calcified lesions and non-calcified lesions. In dialysis patients, the rate of MACE was similar in calcified lesions and non-calcified lesions (51.1% vs. 43.1%; P=0.544), but the rates of TLR (29.8% vs. 9.8%; P=0.020), and restenosis (39.5% vs. 17.0%; P=0.029) were significantly higher in calcified lesions than in non-calcified lesions. Conclusions: There is a differential impact of calcification on the long-term outcome of SES implantation in dialysis and non-dialysis patients. (Circ J 2012; 76: 57-64)

View full abstract

Background: The long-term safety and efficacy of drug-eluting stents for patients with acute myocardial infarction (AMI) remain controversial. Methods and Results: A total of 143 consecutive patients who presented between August 2004 and July 2006 with AMI and who underwent primary percutaneous coronary intervention (PCI) using sirolimus-eluting stents (SES), were compared with a historical control cohort of 129 consecutive patients who presented between August 2002 and July 2004 and who underwent primary PCI using bare metal stents (BMS). The rate of major adverse cardiovascular events at 3 years was significantly lower in the SES group than in the BMS group (20.3% vs. 33.1%, respectively; P=0.01). This reduction was mainly driven by a decrease in the rate of target vessel revascularization (12.3% vs. 22.4%, respectively; P=0.02). There was no significant difference in the rate of cardiovascular death (4.5% vs. 5.7%, respectively; P=0.67), non-fatal myocardial infarction (4.5% vs. 9.2%, respectively; P=0.16), coronary artery bypass grafting (2.3% vs. 2.5%, respectively; P=0.93), stroke (2.4% vs. 0.8%, respectively; P=0.35), and stent thrombosis (2.9% vs. 2.3%, respectively; P=0.80) between the 2 groups. Conclusions: SES can be used safely and effectively in patients with AMI. (Circ J 2012; 76: 65-70)

View full abstract

Background: The aim of this study was to examine the effect of proton-pump inhibitor (PPI) on clinical outcomes in Japanese patients who undergo coronary stent implantation. Methods and Results: A total of 1,270 patients (males 915, 69 years) were enrolled and dual antiplatelet therapy of aspirin and a thienopyridine derivative was prescribed (clopidogrel 630, ticlopidine 640). Patients were divided into 2 groups treated with or without PPI. PPI was administered in 331 cases (26%), and non-PPI in 939 (74%). There were no significant differences in cardiovascular death (PPI vs. non-PPI: 5 vs. 11 cases), nonfatal myocardial infarction (3 vs. 5), and stroke (3 vs. 16) between PPI and non-PPI groups, but the ratio of gastrointestinal events had a higher tendency in non-PPI group compared with PPI group (1 vs. 17, P=0.08). In subgroup analysis of patients taking clopidogrel, or patients with acute coronary syndrome, there was no significant difference in the ratio of cardiovascular events (7 vs. 16, 6 vs. 17, NS). The non-PPI group had a tendency of an increased risk of gastrointestinal events compared with the PPI group (0 vs. 9, P=0.06; 1 vs. 7, P=0.14). Conclusions: In contrast to the negative drug interaction of PPI reported elsewhere, in the present study the intake of PPI was not associated with an increased risk for adverse clinical outcomes in patients treated with stents. (Circ J 2012; 76: 71-78)

View full abstract

Background: The aim of the present study was to compare the end-tidal O₂ pressure (PETO₂) to end-tidal CO₂ pressure (PETCO₂) in cardiac patients during rest and during 2 states of exercise: at anaerobic threshold (AT) and at peak. The purpose was to see which metabolic state, PETO₂ or PETCO₂, best correlated with exercise limitation. Methods and Results: Thirty-eight patients with left ventricular (LV) ejection fraction <40% underwent cardiopulmonary exercise testing (CPX). PETO₂ and PETCO₂ were measured during CPX, along with peak O₂ uptake (VO₂), AT, slope of the increase in ventilation (VE) relative to the increase in CO₂ output (VCO₂) (VE vs. VCO₂ slope), and the ratio of the increase in VO₂ to the increase in work rate (ΔVO₂/ΔWR). Both PETO₂ and PETCO₂ measured at AT were best correlated with peakVO₂, AT, ΔVO₂/ΔWR and VE vs. VCO₂ slope. PETO₂ at AT correlated with reduced peak VO₂ (r=-0.60), reduced AT (r=-0.52), reduced ΔVO₂/ΔWR (r=-0.55) and increased VE vs. VCO₂ slope (r=0.74). PETCO₂ at AT correlated with reduced peak VO₂ (r=0.67), reduced AT (r=0.61), reduced ΔVO₂/ΔWR (r=0.58) and increased VE vs. VCO₂ slope (r=-0.80). Conclusions: PETCO₂ and PETO₂ at AT correlated with peak VO₂, AT and ΔVO₂/ΔWR, but best correlated with increased VE vs. VCO₂ slope. PETO₂ and PETCO₂ at AT can be used as a prime index of impaired cardiopulmonary function during exercise in patients with LV failure. (Circ J 2012; 76: 79-87)

View full abstract

Background: The purpose of the present study was to determine the impact of preoperative percutaneous cardiopulmonary support (PCPS) on long-term survival following implantation of a left ventricular assist device (LVAD). Methods and Results: Between 1999 and 2010, we used implantable (n=12) and paracorporeal (n=91) LVADs in 103 consecutive cardiomyopathy patients as a bridge to transplantation. Prior to LVAD implantation, all patients received inotropes, and 25 patients (24%) received PCPS because of cardiogenic shock. Postoperatively, there were no early mortalities within 30 days after surgery, and patients survived on LVAD for 560±391 days, of whom 9 patients recovered and 32 underwent heart transplantation after 711±360 days of LVAD support. More patients with preoperative PCPS required nitric oxide inhalation and prolonged inotropic support to maintain adequate LVAD flow. In addition, bilirubin level at 1 month after LVAD implantation was significantly higher in patients with preoperative PCPS. Cox regression analysis identified preoperative PCPS support as the only significant predictor for death after LVAD implantation and overall survival was significantly better in patients without preoperative PCPS. Conclusions: Despite adequate hemodynamic support after LVAD implantation, patients with preoperative PCPS had significantly worse survival. LVAD should be used for patients with end-stage heart failure, before PCPS is required for hemodynamic support. (Circ J 2012; 76: 88-95)

View full abstract

Background: Anemia is not rare in patients presenting for coronary artery bypass graft surgery (CABG) and as these patients are frequently on dual antiplatelet therapy (DAPT), the coexisting conditions could potentially increase the risk of bleeding and transfusion. The aim of this study was to evaluate the effect of tranexamic acid (TA) on blood loss and transfusion in preoperatively anemic patients who continued DAPT until within 5 days of off-pump CABG (OPCAB). Methods and Results: Seventy-six anemic patients were randomized into 2 groups: TA group receiving TA (1g bolus followed by infusion at 200mg/h) and a Control group receiving the same volume of saline. The amount of blood loss and transfusion requirement during, and at 4 and 24h after the operation were assessed. Patients' characteristics and operative data were similar between the groups. During the perioperative period, which combined the intraoperative and postoperative 24h data, the TA group received significantly smaller amounts of packed red blood cells and fresh frozen plasma. Total amount of perioperative blood loss was similar between the groups, although the blood loss during the postoperative 4h was significantly less in the TA group. Conclusions: TA infusion could reduce the amount of transfusion during the perioperative period in patients with preoperative anemia who continue DAPT until within 5 days of OPCAB. (Circ J 2012; 76: 96-101)

View full abstract

Background: When aortic valve replacement is performed in patients with a small aortic annulus, prosthesis-patient mismatch (PPM) is of concern because it can affect postoperative clinical outcomes. Although larger bioprosthetic valves have been well studied, the hemodynamics of 19-mm bioprostheses have been reported in only a small number of patients. The effectiveness as well as the impact of PPM on outcomes are thus still unclear.Methods and Results: Postoperative clinical and hemodynamic variables were compared in 67 patients with a 19-mm Carpentier Edwards Perimount Magna bioprosthesis and in 10 patients with a 19-mm Medtronic Mosaic Ultra valve. Mean follow-up time was 13 months. There was no in-hospital mortality. Echocardiography 6.5±4.0 months after surgery showed significant decreases in the mean left ventricular (LV)-aortic pressure gradient, and decreases in the mean LV mass index. Reduction in LV mass index did not differ between the valve groups, despite a higher pressure gradient in the Mosaic group. Although PPM was detected in 21 patients in the Magna group, it did not affect regression of the LV mass index during the follow-up period.Conclusions: Use of the 19-mm Magna bioprosthesis appears to provide satisfactory clinical results. LV-aortic pressure gradient was lower in the Magna group. The present data suggest that PPM is not related to reduction in the LV mass index. (Circ J 2012; 76: 102-108)

View full abstract

Background: Red cell distribution width (RDW) is a novel prognostic marker independently associated with adverse outcomes in acute decompensated heart failure (ADHF) patients. The aim of the present study was to assess whether the change in RDW after discharge had prognostic value in patients with ADHF. Methods and Results: RDW was measured in 261 patients admitted with ADHF, at admission and at discharge and 1 month after discharge. Cardiovascular (CV) events were defined as CV mortality and heart failure rehospitalization. Kaplan-Meier analysis showed that patients with positive RDW change between admission and 1 month after discharge (RDWΔ_1Mdis-adm; n=136) had a significantly higher number of CV events compared with patients with no positive RDWΔ_1Mdis-adm (n=125; 60.3% vs. 47.2%, log-rank: P=0.007). On Cox hazards analysis, a positive RDWΔ_1Mdis-adm was an independent predictor of CV events after adjusting for other CV risk factors (hazard ratio, 1.740; 95% confidence interval: 1.149-2.633, P=0.009). Conclusions: A novel relationship was noted between positive RDWΔ_1Mdis-adm and CV events in ADHF patients. Measurement of RDW at 1 month after ADHF assists in the prediction of adverse CV outcomes. Therefore, repeated measurement of RDW is a simple and inexpensive method that may facilitate assessment of CV risk stratification in patients with ADHF. (Circ J 2012; 76: 109-116)

View full abstract

Background: The authors recently reported that urinary 8-hydroxy-2'-deoxyguanosine (U8-OHdG) derived from cardiac tissue reflects clinical status and cardiac dysfunction severity in patients with chronic heart failure (CHF). The aim of the present study was to investigate whether U8-OHdG levels can accurately predict cardiac events in CHF patients and their response to β-blocker treatment. Methods and Results: Plasma brain natriuretic peptide (BNP) and U8-OHdG levels were measured in 186 consecutive CHF patients before discharge. Patients were then prospectively followed (median follow-up, 649 days) with endpoints of cardiac death or hospitalization due to progressive heart failure. From receiver operating characteristic curve analysis, cut-offs were 12.4ng/mg creatinine (Cr) for U8-OHdG and 207pg/ml for BNP. On multivariate Cox analysis, U8-OHdG and BNP were independent predictors of cardiac events. Patients were classified into 4 groups according to U8-OHdG and BNP cut-offs. The hazard ratio for cardiac events in patients with BNP ≥207pg/ml and U8-OHdG ≥12.4ng/mg Cr was 16.2 compared with approximately 4 for patients with only 1 indicator above its respective cut-off. Furthermore, carvedilol therapy was initiated in 30 CHF patients. In responders (≥10% increase in left ventricular ejection fraction [LVEF] or ≥1 class decrease in New York Heart Association [NYHA] class), U8-OHdG levels decreased significantly along with improved NYHA class, LVEF, and BNP levels after treatment. Conclusions: U8-OHdG may be a useful biomarker for predicting cardiac events and evaluating β-blocker therapy effectiveness in CHF patients. (Circ J 2012; 76: 117-126)

View full abstract

Background: Normal values and the prognostic significance of right ventricle (RV)-2D strain in chronic heart failure (CHF) patients are unknown. Methods and Results: Between 2005 and 2010, we prospectively enrolled 43 controls and 118 stable CHF patients. Standard echocardiographic variables, tricuspid annular plane systolic excursion, peak systolic velocity of tricuspid annular motion using tissue Doppler imaging, and RV and left ventricle (LV) 2D-strain were measured. The primary outcome was death or emergency transplantation or emergency ventricular assist device implantation or acute heart failure. RV-2D strain was measurable in 39 controls (58±17 years, 50% men), whose median value was 30% (95% confidence interval [95%CI], 39%; 20%); and in 104 CHF patients (80% men, mean age 57±11 years, and mean LV ejection fraction 29%±8%), whose median value was 19% (95%CI, 34%; 9%). During the mean follow-up of 37±14 months, 44 experienced the primary outcome. By Cox proportional hazards multivariate analysis, only RV-2D strain and log B-type natriuretic peptide independently predicted experiencing the primary outcome within the first year. The best RV-2D strain cut-off by receiver-operating characteristics analysis was 21%, and patients with values >21% were at greatest risk (χ²-log-rank test=14.1, P<0.0001). Conclusions: RV-2D strain is a strong independent predictor of severe adverse events in patients with CHF and may be superior to other systolic RV or LV echocardiographic variables. (Circ J 2012; 76: 127-136)

View full abstract

Background: Apelin and its cognate G protein-coupled receptor, APJ, constitute a signaling pathway with a positive inotropic effect on cardiac function. Recently, we and other investigators demonstrated that a reduction in myocardial apelin/APJ expression might play a critical role in experimental models of end-stage heart failure (HF). Therefore, we evaluated whether exogenous apelin infusion restores apelin/APJ expression and improves cardiac function in the failing heart of Dahl salt-sensitive hypertensive (DS) rats. Methods and Results: High salt-loaded DS rats were treated with vehicle and pyroglutamylated apelin-13 (Pyr-AP13; 200μg·kg^-1·day^-1, IP) from the age of 11 to 18 weeks. Decreased end-systolic elastance and percent fractional shortening in failing rats was significantly ameliorated by Pyr-AP13. Pyr-AP13 effectively inhibited vascular lesion formation and suppressed expression of inflammation factors such as tumor necrosis factor-α and interleukin-1β protein. Downregulation of apelin and APJ expression, and phosphorylation of endothelial nitric oxide synthase at Ser¹¹⁷⁷ and Akt at Ser⁴⁷³ in failing rats was significantly increased by Pyr-AP13. Upregulation of NAD(P)H oxidase p22^phox, p47^phox, and gp91^phox in DS rats was significantly suppressed by Pyr-AP13. Conclusions: Exogenous apelin-13 may ameliorate cardiac dysfunction and remodeling and restore apelin/APJ expression in DS rats with end-stage HF. Thus, apelin-13 may have significant therapeutic potential for end-stage HF. (Circ J 2012; 76: 137-144)

View full abstract

Background: Obesity has recently been shown to have a favorable effect on the prognosis of patients with congestive heart failure (CHF), but only a few such studies are available in Japan. The purpose of the present study was to investigate whether the obesity paradox is still present after adjusting for CHF characteristics. Methods and Results: A total of 219 patients hospitalized with CHF were reviewed, and the impact of body mass index (BMI) on prognosis was examined. Patients were divided into 4 groups according to BMI quartiles. The endpoint was defined as all-cause death or unplanned CHF hospitalization. According to univariate analysis, a higher BMI was associated with better outcomes. High-BMI patients were younger, likely to be male, and had a higher prevalence of hypertension and diabetes. The plasma B-type natriuretic peptide (BNP) levels and blood urea nitrogen (BUN) levels were lower, while the serum hemoglobin and sodium levels were higher in high-BMI patients. The prevalence of atrial fibrillation was lower in high-BMI patients. Predictors for all-cause death or CHF hospitalization based on univariate analysis were age, prior CHF hospitalization, estimated glomerular filtration rate, plasma BNP levels, BUN levels, and serum hemoglobin and sodium levels. According to multivariate analysis, a high BMI was still associated with better outcomes. Conclusions: High BMI was associated with better clinical outcomes in Japanese CHF patients. (Circ J 2012; 76: 145-151)

View full abstract

Background: Although α₂-adrenergic agonists have been reported to induce a vagal-dominant condition through suppression of sympathetic nerve activity, there is little direct evidence that they directly increase cardiac vagal nerve activity. Using a cardiac microdialysis technique, we investigated the effects of medetomidine, an α₂-adrenergic agonist, on norepinephrine (NE) and acetylcholine (ACh) release from cardiac nerve endings. Methods and Results: A microdialysis probe was implanted into the right atrial wall near the sinoatrial node in anesthetized rabbits and perfused with Ringer's solution containing eserine. Dialysate NE and ACh concentrations were measured using high-performance liquid chromatography. Both 10 and 100μg/kg of intravenous medetomidine significantly decreased mean blood pressure (BP) and the dialysate NE concentration, but only 100μg/kg of medetomidine enhanced ACh release. Combined administration of medetomidine and phenylephrine maintained mean BP at baseline level, and augmented the medetomidine-induced ACh release. When we varied the mean BP using intravenous administration of phenylephrine, treatment with medetomidine significantly steepened the slope of the regression line between mean BP and log ACh concentration. Conclusions: Medetomidine increased ACh release from cardiac vagal nerve endings and augmented baroreflex control of vagal nerve activity. (Circ J 2012; 76: 152-159)

View full abstract

Background: Positron emission tomography (PET) during the cold pressor test (CPT) has been used to assess endothelium-dependent coronary vasoreactivity, a surrogate marker of cardiovascular events. However, its use remains limited by cardiac PET availability. As multidetector computed tomography (MDCT) is more widely available, we aimed to develop a measurement of endothelium-dependent coronary vasoreactivity with MDCT and similar radiation burden as with PET. Methods and Results: A study group of 18 participants without known cardiovascular risk factor (9F/9M; age 60±6 years) underwent cardiac PET with ⁸²Rb and unenhanced ECG-gated MDCT within 4h, each time at rest and during CPT. The relation between absolute myocardial blood flow (MBF) response to CPT by PET (ml·min^-1·g¹) and relative changes in MDCT-measured coronary artery surface were assessed using linear regression analysis and Spearman's correlation. MDCT and PET/CT were analyzed in all participants. Hemodynamic conditions during CPT at MDCT and PET were similar (P>0.3). Relative changes in coronary artery surface because of CPT (2.0-21.2%) correlated to changes in MBF (-0.10-0.52ml·min^-1·g¹) (ρ=0.68, P=0.02). Effective dose was 1.3±0.2mSv for MDCT and 3.1mSv for PET/CT. Conclusions: Assessment of endothelium-dependent coronary vasoreactivity using MDCT CPT appears feasible. Because of its wider availability, shorter examination time and similar radiation burden, MDCT could be attractive in clinical research for coronary status assessment. (Circ J 2012; 76: 160-167)

View full abstract

Background: Cardiac event risk is estimated using quantitative gated myocardial perfusion imaging (MPI) and clinical background in patients with ischemic heart disease. The aim of the present study was to calculate major cardiac event risk and tabulate it in the Heart Risk Table for clinical use of risk stratification. Methods and Results: Multivariate logistic regression was performed based on a multicenter prognostic database (Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated Single-photon emission computed tomography [J-ACCESS investigation]) using MPI (n=2,395). The risk of major cardiac events (cardiac death, non-fatal myocardial infarction and heart failure requiring hospitalization) was estimated using age, ejection fraction (EF), estimated glomerular filtration rate (eGFR) and presence of diabetes mellitus (DM). Age-matched standard eGFR was determined in 77 subjects. Major cardiac event risk was calculated using the equation: risk (%/3 years)=1/(1+Exp(-(-4.699-0.0151×eGFR+0.7998×DM+0.0582×age+0.697×SSS-0.0359×EF))×100, where SSS refers to summed stress scores. Risk was determined without eGFR (the initial version) and using the present formula with eGFR (revised version), with consistent results. DM and chronic kidney disease were major determinants of cardiac events. Conclusions: Cardiac event risk was estimated using MPI defect score and left ventricular EF in conjunction with eGFR and the presence of DM. The risk table might be used for risk evaluation in Japanese patients undergoing MPI. (Circ J 2012; 76: 168-175)

View full abstract

Background: There is no study focusing on changes in coronary atherosclerosis during dual lipid-lowering therapy with statin and ezetimibe. Methods and Results: Eighty-nine patients with stable angina randomized in a 1:1 ratio to Group A (aggressive therapy: atorvastatin 80mg, ezetimibe 10mg) and Group S (standard therapy) were analyzed. Treatment period was 12 months. Coronary arteries were examined by intravascular ultrasound and virtual histology. We found a decrease in the percent atheroma volume (PAV) (-0.4%) in Group A compared with an increase (+1.4%) in Group S (P=0.014) and this was accompanied by an increased frequency of combined atherosclerosis regression (increased lumen volume+decreased PAV) in group A (40.5%) compared with group S (14.9%) (P=0.007). The target low-density lipoprotein cholesterol level <2mmol/L, presence of at least 4 of 5 atherosclerotic risk factors, and decreased level of vascular cellular adhesive molecule were independent predictors of plaque regression. There were no significant differences in plaque composition between the 2 groups over the study duration. However, during analysis of the 2 groups together, fibrous and fibro-fatty tissues decreased and dense calcification and necrotic core increased during follow-up. Conclusions: Dual lipid-lowering therapy starts atherosclerosis regression, but does not lead to significant changes in plaque composition. The continuous shift in plaque from fibro and fibro-fatty to necrotic with calcification was present in both groups. (Circ J 2012; 76: 176-183)

View full abstract

Background: A recent study in individuals of European ancestry demonstrated a significant association of the single nucleotide polymorphism (SNP) rs13376333 in potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3 (KCNN3) on chromosome 1q21 with lone atrial fibrillation (AF), indicating a common genetic basis for AF. The aim of the present study was to investigate whether this association between SNP rs13376333 and AF also exists in Taiwanese subjects. Methods and Results: The SNP rs13376333 was compared in 214 lone AF patients (58.3±11.4 years) vs. 214 controls (57.7±13.2 years), and in 322 structural AF patients (69.6±13.7 years) vs. 322 controls (68.4±14.2 years) in a Taiwanese population, in a case-control design. The associations between SNP rs13376333 in KCNN3 and structural or lone AF were significant. In the lone AF group, the frequency of the minor allele of SNP rs13376333 was 8.6% compared with 3.0% in the controls (P<0.001; odds ratio [OR], 3.02; 95% confidence interval [CI]: 1.54-6.29). The frequency of the minor allele of SNP rs13376333 was 6.5% in structural AF patients compared with 3.1% in controls (P=0.004; OR, 2.18; 95%CI: 1.23-3.96). Conclusions: There are significant associations between SNP rs13376333 and the risk of developing both lone and structural AF in the Taiwanese population. The minor allele frequency of SNP rs13376333 was much lower in the Taiwanese population compared to that in the Caucasian population. (Circ J 2012; 76: 184-188)

View full abstract

Background: Plakophilin2 (PKP2) is a desmosome-related protein with numerous armadillo repeats and has been linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). Fatal arrhythmias resulting in sudden death also occur in the absence of morphologic cardiac abnormalities at autopsy, and have been linked to ion channel mutations in a subset of cases, but so far not to PKP2. Methods and Results: We sequenced all 14 exons of PKP2 in DNA extracted from postmortem heart tissues of 25 patients dying from ARVC and 25 from sudden unexpected death with negative autopsy (SUDNA). The primers were designed using the Primer Express 3.0 software. Direct sequencing for both sense and antisense strands was performed with a BigDye Terminator DNA sequencing kit on a 3130XL Genetic Analyzer. Mutation damage prediction was made using Mutation Taster, Polyphen and SIFT software. In 6 of the 25 ARVC samples, 6 PKP2 mutations were identified, 4 of which were likely significant, and 3 of which were novel (p.N641del, p.L64PfsX22, p.G269R). In 6 of the 25 cases of SUDNA samples, 6 PKP2 mutations were identified, 3 of which were likely significant, and 4 of which were not previously described (p.P665S, p.Y217TfsX45, p.E540, p.S615T). Conclusions:PKP2 mutations are not specific for ARVC and may result in SUDNA. The link between ARVC and desmosomal mutations may not be causal but related to an association between defective desmosomal proteins and arrhythmias. (Circ J 2012; 76: 189-194)

View full abstract

Background: The serial hemodynamics and predictors of long-term, good Fontan survivors remain unknown. Methods and Results: Two hundred one patients who had undergone a Fontan operation before September 1998 were reviewed to compare their long-term clinical status with serial hemodynamics. During a mean follow-up of 18.7 years, 47 (30.1%) of the 156 survivors had no clinical events that required an unscheduled hospitalization. Of those, 18 survivors exhibited good serial hemodynamics and the respective mean values of central venous pressure (CVP, mmHg), cardiac index (CI, L·min^-1·m²), and ventricular ejection fraction (EF, %) before and 1, 5, 10, and 15 years after the operation were as follows: 3.8, 9.0, 11.3, 10.6, and 10.1 (CVP); 3.6, 3.1, 2.8, 2.6, and 2.6, and 69 (CI); 57, 56, 58, 54, and 53 (EF). Serial values of CVP, ventricular end-diastolic pressure (EDP) and the grade of atrioventricular valve regurgitation (AVVR) were lower and the peak oxygen uptake was greater in the good patients (P<0.05 for all). A 1-year postoperative lower CVP and no history of AVVR repair during the Fontan operation independently predicted the good patients (P<0.05). Conclusions: A lower CVP and EDP, better atrioventricular valvular function, and greater exercise capacity characterize good Fontan survivors and an early postoperative low CVP without an AVVR repair predicts good survivors. (Circ J 2012; 76: 195-203)

View full abstract

Background: The survival of stem cells upon transplantation into ischemic myocardium is a major concern in cell-based therapy. In this study, we tested the hypothesis that activation of opioid receptors would enhance the survival of mesenchymal stem cells (MSCs) upon exposure to an injury stimulus. Methods and Results: MSCs were obtained from rat bone marrow and cultured in basal DMEM cell culture medium. Delta-opioid receptor (DOR) was present in MSCs as examined by reverse transcription-polymerase chain reaction and immunochemistry. Activation of DOR with 5μmol/L SNC80 (DOR agonist) for 24h significantly enhanced MSC viability upon exposure to 5μg/ml actinomycin D as determined by TUNEL and MTT assays. The cytoprotection was abolished with 20μmol/L naltrindole hydrochloride (a DOR antagonist). Treatment of the cells with 1.5μmol/L chelerythrine (protein kinase C inhibitor) and 1.25μmol/L WP1066 (signal transducer and activator of transcription 3 (STAT3) inhibitor) blocked SNC80-induced cytoprotection. Furthermore, treatment of the cells with chelerythrine also blocked STAT3-phosphorylation and Mcl-1 gene expression. Conclusions: Taken together, the results indicate that DOR plays a critical role in MSC survival upon exposure to actinomycin D through activation of protein kinase C and its downstream signaling molecules STAT3 and Mcl-1. DOR may be a novel therapeutic target for stem cell survival during cell-based therapy. (Circ J 2012; 76: 204-212)

View full abstract

Background: Acute kidney injury (AKI) is a common complication after cardiac surgery. Urinary liver-type fatty acid-binding protein (L-FABP) reflects the presence of renal tubular injury. The aim of the present study was to evaluate the utility of urinary L-FABP compared with other urinary biomarkers for the early detection of postoperative AKI among adult patients undergoing cardiac surgery. Methods and Results: Patients were divided into the AKI (n=48) and non-AKI groups (n=37) according to whether they developed postoperative AKI within 48h after surgery. Changes in various biomarkers were evaluated. Urine and serum samples were obtained from each patient at the following time points: before the operation, immediately after the operation, and 3, 6, 18, 24, and 48h postoperatively. The urinary L-FABP level was significantly higher in the AKI group than in the non-AKI group at every time point, while other biomarkers did not show such a tendency. The biomarker with the largest area under the curve at every time point for predicting the onset of AKI was urinary L-FABP. On multiple logistic regression analysis, the urinary L-FABP level before operation and within the first 6h after cardiac surgery was significantly associated with the onset of AKI. Conclusions: Urinary L-FABP is a useful biomarker for early detection of AKI and is a good early predictor of the onset of AKI. (Circ J 2012; 76: 213-220)

View full abstract

Background: A recent trial in Western countries has shown that rosuvastatin slows progression of carotid intima-media thickness (IMT) in patients with modest carotid IMT thickening and elevated levels of low-density lipoprotein cholesterol (LDL-C). We conducted a prospective, randomized, open-label, blinded-endpoint trial to determine whether rosuvastatin is more effective than pravastatin in slowing progression of carotid IMT in Japanese patients. Methods and Results: Adult patients with hypercholesterolemia who had a maximum IMT ≥1.1mm were randomly assigned to receive rosuvastatin or pravastatin. The primary endpoint was the percent change in the mean-IMT, which was measured by a single observer who was blinded to the treatment assignments. The trial was stopped on April 2011 according to the recommendation by the data and safety monitoring committee. A total of 348 patients (173 rosuvastatin; 175 pravastatin) were enrolled and 314 (159 rosuvastatin; 155 pravastatin) were included in the primary analysis. Mean (SD) percentage changes in the mean-IMT at 12 months were 1.91% (10.9) in the rosuvastatin group and 5.8% (12.0) in the pravastatin group, with a difference of 3.89% (11.5) between the groups (P=0.004). At 12 months, 85 patients (59.4%) in the rosuvastatin group achieved a LDL-C/high-density lipoprotein cholesterol ratio ≤1.5 compared with 24 patients (16.4%) in the pravastatin group (P<0.0001). Conclusions: Rosuvastatin significantly slowed progression of carotid IMT at 12 months compared with pravastatin. (Circ J 2012; 76: 221-229)

View full abstract

Background: Vessel tension can be modulated by phosphoinositide 3-kinase (PI3K) acting on l-type calcium channel, rho kinase and phosphodiesterase (PDE) type 3 in smooth muscle cells. Inhibition of PI3K could increase the relaxation of porcine coronary arteries to nitroglycerin independent of this pathway, and the aim of the present study was therefore to determine the underlying mechanisms. Methods and Results: Isolated porcine coronary arteries were dissected from the heart and cut into rings in ice-cold modified Krebs-Ringer bicarbonate buffer. The response of these vessels was studied by using the organ chamber technique; the content of cyclic guanosine monophosphate (cGMP) was determined by using enzyme-linked immunosorbent assay kit; and PI3K and Akt activity were determined by measuring the phosphorylation level of their downstream signaling molecule on Western blot. Inhibition of PI3K with 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) potentiated the relaxation of porcine coronary arteries to nitroglycerin and nitric oxide (NO), but not to 8-bromo-guanosine 3'5'-cyclic monophosphate, isoproterenol or (R)-(+)-trans-4-(1-Aminoethyl)-N-(4-Pyridyl)cyclohexanecarboxamide dihydrochloride monohydrate (Y27632). Increased relaxation induced by LY294002 was eliminated by Akt1/2 kinase inhibitor (Akt-I: 1,3-dihydro-1-(1-((4-(6-phenyl-1H-imidazo(4,5-g)quinoxalin-7-yl)phenyl)methyl)-4-piperidinyl)-2H-benzimidazol-2-one trifluoroacetate salt hydrate) or zaprinast, but was not affected by 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one, nifedipine or milrinone. Inhibition of Akt caused similar effects as LY294002. Incubation with LY294002 or Akt-I decreased the activity of PI3K and Akt but augmented the elevation of cGMP caused by NO. Enhanced cGMP elevation induced by LY294002 or Akt-I was also eliminated by zaprinast. Conclusions: PI3K-Akt signaling may affect vascular tone through a stimulatory effect on PDE type 5. (Circ J 2012; 76: 230-237)

View full abstract