Assessment of the coronary microvasculature in the clinical setting is a key issue, given that microvascular dysfunction itself has a predictive value for cardiovascular events. The index of microcirculatory resistance (IMR) is an invasive method of interrogating the microvasculature and provides further insight into the physiology of cardiovascular diseases. It is simple and readily applicable in the cardiac catheterization laboratory where many patients first present for evaluation of their coronary circulation. In contrast to other invasive and non-invasive tests, this method is known to be stable and reproducible under various hemodynamics and even in the presence of epicardial coronary artery stenosis. IMR has been shown to have prognostic value in patients with ST-segment elevation myocardial infarction; therefore it can be a surrogate marker of cardiovascular events. At the same time, it has the potential to be a therapeutic as well as an investigational tool in the physiology of cardiovascular diseases. This review summarizes the development of IMR, tips and tricks for its measurement, and its usefulness in various clinical settings.  (Circ J 2014; 78: 1021–1028)

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The mitral valve (MV) has complex 3-dimensional (3D) morphology and motion. Advance in real-time 3D echocardiography (RT3DE) has revolutionized clinical imaging of the MV by providing clinicians with realistic visualization of the valve. Thus far, RT3DE of the MV structure and dynamics has adopted an approach that depends largely on subjective and qualitative interpretation of the 3D images of the valve, rather than objective and reproducible measurement. RT3DE combined with image-processing computer techniques provides precise segmentation and reliable quantification of the complex 3D morphology and rapid motion of the MV. This new approach to imaging may provide additional quantitative descriptions that are useful in diagnostic and therapeutic decision-making. Quantitative analysis of the MV using RT3DE has increased our understanding of the pathologic mechanism of degenerative, ischemic, functional, and rheumatic MV disease. Most recently, 3D morphologic quantification has entered into clinical use to provide more accurate diagnosis of MV disease and for planning surgery and transcatheter interventions. Current limitations of this quantitative approach to MV imaging include labor-intensiveness during image segmentation and lack of a clear definition of the clinical significance of many of the morphologic parameters. This review summarizes the current development and applications of quantitative analysis of the MV morphology using RT3DE.  (Circ J 2014; 78: 1029–1037)

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With the advancement of transcriptome profiling by micro-arrays and high-throughput RNA-sequencing, transcriptome complexity and its dynamics are revealed at different levels in cardiovascular development and diseases. In this review, we will highlight the recent progress in our knowledge of cardiovascular transcriptome complexity contributed by RNA splicing, RNA editing and noncoding RNAs. The emerging importance of many of these previously under-explored aspects of gene regulation in cardiovascular development and pathology will be discussed.  (Circ J 2014; 78: 1038–1047)

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Revascularization of coronary artery stenosis should be based on objective evidence of ischemia. Fractional flow reserve (FFR) is an invasive physiologic index that can be easily measured in the cardiac catheterization laboratory to assess the functional significance of coronary stenosis. FFR-guided revascularization strategy has been proven to be better than angiography-guided strategy in patients with coronary artery disease. Recent development of more convenient ways to induce hyperemia will reduce the barrier to measuring FFR and further expand its clinical applicability. Invasive physiologic indices without hyperemia are also under active investigation. Moreover, a novel noninvasive FFR measurement based on coronary CT angiography and computational fluid dynamics has been developed and will soon be incorporated into clinical practice. Given the rapid adoption of invasive and noninvasive physiologic indices in daily practice, a review of the current status of FFR and future perspectives is presented.  (Circ J 2014; 78: 1048–1054)

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Background: YUKAWA is a 12-week, randomized, double-blind, placebocontrolled, phase 2 study evaluating the efficacy and safety of evolocumab (AMG 145) in statin-treated Japanese patients at high cardiovascular risk. Methods and Results: 310 eligible patients receiving stable statin (±ezetimibe) therapy were randomized to 1 of 6 treatments: placebo every 2 weeks (Q2W) or monthly (QM), evolocumab 70mg or 140mg Q2W, or evolocumab 280mg or 420mg QM. The primary endpoint was the percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) measured by preparative ultracentrifugation (UC). Secondary endpoints included percentage changes in other lipid parameters and the proportion of patients with LDL-C <1.8mmol/L. Mean (SD) age was 62 (10) years; 37% were female; and the mean (SD) baseline LDL-C was 3.7 (0.5) mmol/L (by UC). Mean (SE) changes vs. placebo in LDL-C were greatest in the high-dose groups: −68.6 (3.0) % and −63.9 (3.2) % with 140mg Q2W and 420mg QM dosing, respectively. Up to 96% of evolocumab-treated patients achieved LDL-C <1.8mmol/L. Adverse events (AEs) were more frequent in evolocumab (51%) vs. placebo (38%) patients; 4 patients taking evolocumab discontinued treatment because of an AE. There were no significant differences in AE rates based on dose or dose frequency. Conclusions: In Japanese patients at high cardiovascular risk with hypercholesterolemia on stable statin therapy, evolocumab significantly reduced LDL-C and was well tolerated during this 12-week study.  (Circ J 2014; 78: 1073–1082)

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Background: Transcatheter aortic valve implantation (TAVI) may be a viable solution for inoperable or high-risk patients with aortic stenosis (AS), providing the benefit of valve replacement without the associated risks of surgery. Methods and Results: The prospective, multicenter MDT-2111 Japan Trial evaluated the efficacy and safety of a self-expandable TAV in patients with severe AS. A total of 55 patients were enrolled (October 2011 to October 2012). Mean age was 82.5±5.5 years; 30.9% male, 100% NYHA III/IV, and STS 8.0±4.2%. At 6 months, 91.7% of the iliofemoral patients had met the primary endpoint (an improvement of at least 1 NYHA class and an effective orifice area >1.2cm² for iliofemoral patients). For all patients, freedom from all-cause mortality at 6 months was 90.8%. At 30 days, the Kaplan-Meier rate of major vascular complications was 10.9%, the rate of permanent pacemaker implantation was 22.2% and the rate of major stroke was 3.7%. The incidences of paravalvular regurgitation for all implanted patients at 6 months were: 38.3% (none), 25.5% (trace), 31.9% (mild), 4.3% (moderate), and 0.0% (severe). Conclusions: This is the first study to evaluate a self-expandable TAV in a Japanese patient population. The data show successful achievement of the study’s primary objective and demonstrate the functional and anatomical effectiveness of the MDT-2111 TAV system.  (Circ J 2014; 78: 1083–1090)

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Background: A nationwide survey of catheter ablation for atrial fibrillation (AF) was conducted in Japan to determine the mid-term performance of the therapy from analysis of the 1-year outcome of registered patients. Methods and Results: A total of 2,137 patients who underwent AF ablation in September 2011 and March 2012 were initially registered. In 2013, the 1-year follow-up data of 1,208 patients (56.5% of 2,137) from 119 centers were collected. Average age was 61.9±10.7 years. Patients with paroxysmal AF (PAF) constituted 64.3%. Persistent AF (pAF) and long-standing pAF (LS-pAF) were 20.4% and 15.3%, respectively. For all patients, 76.7% underwent their first AF ablation. At 1 year after AF ablation, 70.9%, 61.4%, and 56.2% of PAF, pAF, and LS-pAF patients, respectively, were free from AF or clinical/partial success (PAF vs. pAF or LS-pAF: P<0.01). Re-ablation was performed in 11.3%, 16.3%, and 17.3%, respectively. Multivariate logistic regression analysis revealed that procedure time (odds ratio [OR] 0.82, P=0.000), and results of AF induction test (OR 1.36, P<0.02) were significantly related to successful outcome. Conclusions: Approximately 70% of PAF and 60% of nonPAF patients were free from AF recurrence or had clinical/partial success status. Shorter procedure time and elimination of AF inducibility were independent predictors of mid-term success of AF ablation.  (Circ J 2014; 78: 1091–1096)

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Background: The clinical outcomes of elderly patients (≥80 years old) undergoing percutaneous coronary intervention (PCI) has not been well established, despite recent advances in both devices and techniques. Methods and Results: We recruited patients from the SHINANO Registry, a prospective, observational, multicenter, cohort study. From August 2012 to July 2013, a total of 1,923 consecutive patients with 2,250 elective/urgent PCIs (2,105 admissions) (mean age, 71±11 years; ≥80 years, 23%; men, 77%) were enrolled. The primary endpoint was procedural success. The secondary endpoints were in-hospital death and in-hospital major adverse cardiovascular events (MACE). The procedural success rate was significantly lower (83.7% vs. 89.1%, P=0.0001), and the rates of in-hospital mortality and MACE were significantly higher in elderly than in non-elderly patients (3.6% vs. 1.5%, P=0.005; 4.4% vs. 2.3%, P=0.016, respectively). For elective PCI, the rates of procedural success and in-hospital MACE were similar between groups (90.3% vs. 91.3%, P=0.65, 2.3% vs. 1.2%, P=0.2, respectively). On multivariate analysis, being elderly was not an independent predictor of procedural failure (OR, 1.15; CI, 0.81–1.61; P=0.43). Conclusions: In elderly patients, PCI is safe and feasible. The presence of comorbidities is a more important factor than age alone.  (Circ J 2014; 78: 1097–1103)

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Background: The objective of the present study was to assess the hypothesis that the introduction of endovascular aneurysm repair (EVAR) into Japan has expanded the indication of abdominal aortic aneurysm (AAA) repair without increasing surgical mortality. Methods and Results: From 10 national hospitals, we registered a total of 2,154 consecutive patients (Open surgery [OS]: n=1,577, EVAR: n=577) over 8 years, divided into 4 time periods: Group I (2005–2006: n=522), Group II (2007–2008: n=475), Group III (2009–2010: n=551), Group IV, (2011–2012: n=606). Mean age increased over the 4 time periods (P<0.0001). The incidences of COPD, smoking history, history of abdominal surgery and concomitant malignancy significantly increased as well, while the numbers of patients with preoperative shock or high ASA status reduced over time. The proportion of EVAR in AAA repair increased from: 0% in Group I, 11.6% in Group II, 41.0% in Group III, to 48.8% in Group IV (P<0.0001). Early mortality was 0.8% in the EVAR and 3.4% in the OS (P<0.001) groups. Survival rates among the 4 groups free of all-cause death and aneurysm-related death at 1 year were 92.1–96.3% (P=0.1555) and 95.5–96.8% (P=0.9891), respectively. Multiple logistic regression analysis for surgical death failed to demonstrate survival advantage of EVAR over OS. Conclusions: Introduction of EVAR expanded the indication of AAA repair without increasing mortality, while high risk for anesthesia and emergency cases reduced over time. UMIN-CTR (UMIN000008345)  (Circ J 2014; 78: 1104–1111)

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Background: The purpose of this study was to provide precise data on the current status of catheter ablation for atrial fibrillation (AF) in Japan. Methods and Results: The Japanese Heart Rhythm Society requested that members retrospectively register data for AF ablation performed in September 2011, March 2012, and September 2012. A total of 165 centers submitted data for 3,373 patients (age, 62±11 years; male, 76.1%; paroxysmal AF, 64.4%). Pulmonary vein isolation (PVI) and additional ablation were performed in 97.5% and 77.4% of patients, respectively. 3-D mapping systems and irrigated-tip catheters were used in 94.8% and 87.7% of the patients, respectively. Although the mean CHADS₂ score was 1.0±1.0, the majority received oral anticoagulant (OAC) during and following the procedure (69.8% and 97%, respectively). Vitamin K antagonist (VKA) prescription, however, decreased (1st vs. 3rd survey, during and following the procedure, 59.3% vs. 47.8% and 81.7% vs. 55.2%, respectively, P<0.0001, both) and that of new OAC (NOAC) increased drastically (9.6% vs. 24.2% and 15.8% vs. 42.1%, respectively, P<0.0001). Early complications were reported in 4.5% of the patients, but no instance of early death was reported. Conclusions: In addition to PVI, additional ablation procedures are also performed very frequently. Although the mean CHADS₂ score was low, peri-procedural OAC therapy was commonly performed, and NOAC drastically superseded VKA.  (Circ J 2014; 78: 1112–1120)

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Background: This study investigated the progression of paroxysmal atrial fibrillation (AF) to the persistent form in Japanese asymptomatic AF patients. Methods and Results: Data were derived from a single hospital-based cohort in the Shinken Database 2004–2012 (n=19,994), in which 1,176 patients were diagnosed as having paroxysmal AF. AF progression occurred in 115 patients (6.0%/year) during the mean follow-up period (1,213±905 days). Although patients who were asymptomatic at the initial visit (n=468) had a low-risk profile compared with symptomatic patients, they had greater AF progression at follow-up (unadjusted hazard ratio, 1.611; 95% CI: 1.087–2.389; P=0.018). Absence of symptoms, male sex, and cardiomyopathy were independent predictors for AF progression in the multivariate model. It was noted that asymptomatic patients were less likely to undergo pulmonary vein isolation (PVI). In addition, the interaction term between asymptomatic AF and absence of PVI could be another independent predictor for AF progression. Prognosis was similar between asymptomatic and symptomatic patients with AF. Conclusions: Irrespective of low-risk profile, patients with asymptomatic paroxysmal AF had greater progression of AF compared with symptomatic patients. This paradoxical result appeared to be the result of less intensive clinical management, including invasive rhythm control.  (Circ J 2014; 78: 1121–1126)

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Background: The strength-interval (SI) curve is an important measure of refractoriness in cardiac tissue. The anodal SI curve contains a “dip” in which the S2 threshold increases with interval. Two explanations exist for this dip: (1) electrotonic interaction between regions of depolarization and hyperpolarization; and (2) the sodium-calcium exchange (NCX) current. The goal of this study is to use mathematical modeling to determine which explanation is correct. Methods and Results: The bidomain model represents cardiac tissue and the Luo-Rudy model describes the active membrane. The SI curve is determined by applying a threshold stimulus at different time intervals after a previous action potential. During space-clamped and equal-anisotropy-ratios simulations, anodal excitation does not occur. During unequal-anisotropy-ratios simulations, electrotonic currents, not membrane currents, are present during the few milliseconds before excitation. The dip disappears with no NCX current, but is present with 50% or 75% reduction of it. The calcium-induced-calcium-release (CICR) current has little effect on the dip. Conclusions: These results indicate that neither the NCX nor the CICR current is responsible for the dip in the anodal SI curve. It is caused by the electrotonic interaction between regions of depolarization and hyperpolarization following the S2 stimulus.  (Circ J 2014; 78: 1127–1135)

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Background: Mutations in SCN5A can result in both long QT type 3 (LQT3) and Brugada syndrome (BrS), and a few mutations have been found to have an overlapping phenotype. Long QT syndrome is characterized by prolonged QT interval, and a prerequisite for a BrS diagnosis is ST elevation in the right precordial leads of the electrocardiogram. Methods and Results: In a Danish family suffering from long QT syndrome, a novel missense mutation in SCN5A, changing a leucine residue into a glutamine residue at position 1786 (L1786Q), was found to be present in heterozygous form co-segregating with prolonged QT interval. The proband presented with an aborted cardiac arrest, and his mother died suddenly and unexpectedly at the age of 65. Flecainide treatment revealed coved ST elevation in all mutation carriers. Electrophysiological investigations of the mutant in HEK293 cells indicated a reduced peak current, a negative shift in inactivation properties and a positive shift in activation properties, compatible with BrS. Furthermore, the sustained (I_Na,late) tetrodotoxin-sensitive sodium current was found to be drastically increased, explaining the association between the mutation and LQT syndrome. Conclusions: The L1786Q mutation is associated with a combined LQT3 and concealed BrS phenotype explained by gating characteristics of the mutated ion channel protein. Hence, sodium channel blockade should be considered in clinical evaluation of apparent LQT3 patients.  (Circ J 2014; 78: 1136–1143)

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Background: This study describes the surgical treatment of bicuspid aortic valve with original aortic valve reconstruction. Methods and Results: Aortic valve reconstruction was done in 102 patients with bicuspid aortic valve from April 2007 through September 2011. Thirty-four patients with ascending aortic diameter >45mm underwent hemi-arch aortic replacement concomitantly. Seventy-seven patients had aortic stenosis, and 25 had aortic regurgitation (AR). Mean age was 63.7±10.0 years old. There were 55 men and 47 women. Harvested pericardium is treated with 0.6% glutaraldehyde solution. The distance between commissures is measured with an original sizing instrument. For bicuspid valve with raphe, the raphe is considered as a commissure in order to measure the distance between each commissure. Without a raphe, we create a new annular margin and commissure using coronary ostium and the sizing instrument as a guide. Then, pericardium is trimmed with original template. Three cusps are sutured independently. The preoperative averaged peak pressure gradient of 71.1±39.0mmHg was decreased to 16.2±8.8, 13.3±6.0, and 13.9±5.6mmHg, respectively 1 week, 1 year, and 3 years after operation. AR was trivial. One reoperation was recorded. Mean follow-up was 733 days. There were 5 late mortalities. No thromboembolic event was recorded. Conclusions: Medium-term results were excellent. Tricuspidization gave good opening and closure of aortic valve with excellent hemodynamics.  (Circ J 2014; 78: 1144–1151)

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Background: Practicing healthy lifestyle behaviors is a means to prevent metabolic syndrome (MetS), but the effect of changes of various behaviors over a short period is not fully understood. The purpose of this study was to elucidate the influence of changes in 12 behaviors on the development of MetS during 1 year. Methods and Results: Of 10,442 workers who received a periodic health checkup in a health center in Tokyo in 2008, 3,137 workers aged 30–69, without MetS, who received another health checkup in 2009 were analyzed. Smoking, amounts and frequency of alcohol drinking, sleeping, exercise, walking duration and speed, late-night dinners, bedtime snacking, breakfast, eating speed, and weight control were classified into 4 groups according to change from 2008 to 2009. To examine the influence of behavioral changes on developing MetS, multiple logistic analysis was conducted after adjustment for sex, baseline age and MetS components. Changes from healthy to unhealthy behaviors in exercise, walking duration and speed, daily drinking, and weight control were significant in developing MetS compared with maintaining healthy behaviors. Those risks were higher than keeping unhealthy behaviors. Unhealthy to healthy behavior in smoking increased the risk while healthy to unhealthy behavior in eating speed decreased the risk of developing MetS. Conclusions: To prevent developing MetS during 1 year, healthy behaviors regarding physical activity, drinking, and weight management should be maintained.  (Circ J 2014; 78: 1152–1159)

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Background: Waist-to-height ratio (WHtR) has been suggested as a better screening tool than body mass index (BMI) and waist circumference (WC) for assessing cardiometabolic risk. However, most previous studies did not consider age. Methods and Results: Participants were 45,618 men and 8,092 women aged 15–84 years who received periodic health checkups in 9 companies in Japan. Clustering of cardiometabolic risk factors was defined by the existence of 2 or more of high blood pressure, hyperglycemia, and dyslipidemia. In both men and women, unadjusted area under the curve (AUC) of the receiver-operating characteristic curve for WHtR in detecting the clustering of cardiometabolic risk factors was significantly higher than that for either BMI or WC; the AUCs for WHtR, BMI, and WC, respectively, were 0.734, 0.705, and 0.717 in men and 0.782, 0.762, and 0.755 in women. After adjustment for age, however, such differences were not observed; the corresponding values were 0.702, 0.701, and 0.696 in men. In women, the age-adjusted AUC for BMI was slightly higher than for other indices (WHtR, 0.721; BMI, 0.726; WC, 0.707). Conclusions: The screening performance of WHtR for detecting the clustering cardiometabolic risk factors was not superior to that of BMI.  (Circ J 2014; 78: 1160–1168)

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Background: Myocardial perfusion SPECT (MPS) traditionally requires the patient to be in the supine position, but diaphragmatic attenuation of the inferior wall reduces test specificity. The aim of this study was to assess the feasibility of combined MPS in the supine and prone positions using a novel cadmium zinc telluride (CZT) camera. Methods and Results: A total of 276 consecutive patients with suspected/known coronary artery disease (CAD) who underwent single-day ^99mTc-tetrofosmin or ^99mTc-sestamibi stress/rest CZT SPECT, were enrolled in the study. Seventy-six underwent coronary angiography. Five-minute scan in the supine (S) position and thereafter in the prone (P) position produced images that were visually interpreted to obtain summed stress (SSS) and rest (SRS) scores. A combined stress score (C-SSS) was calculated by grouping anterior perfusion defects observed during supine imaging with inferior half segments observed during prone imaging. The SSS for the supine, prone, and combined protocols were 9±8, 7±8, and 7±8, respectively (P<0.0001). The SRS were 5±8, 4±7, and 6±7, respectively (P=0.005). The area under the ROC curve for the S-SSS, P-SSS, and C-SSS scores was 0.815 (95% CI: 0.713–0.917), 0.813 (0.711–0.914), and 0.872 (0.783–0.961), respectively. Corresponding sensitivities and specificities for detecting CAD were 87% and 50%, 80% and 77%, and 85% and 82%, respectively. C-SSS had significantly better specificity and accuracy than S-SSS (P<0.05). Conclusions: Combined imaging with a CZT camera is suitable for routine clinical MPS and provides greater diagnostic accuracy than supine imaging alone.  (Circ J 2014; 78: 1169–1175)

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Background: Augmentation index (AI) has been used as a clinical index of arterial stiffness and has been reported to be an independent predictor of cardiovascular events, but some investigators have reported that AI is not a useful marker to identify coronary artery disease (CAD) in elderly patients. The majority of CAD patients are elderly people, therefore the aim of this study was to examine whether AI is a useful marker to identify the risk of CAD. Methods and Results: A total of 120 patients (69±10 years of age; 83 male) who underwent cardiac catheterization for suspected CAD were enrolled. Invasive central blood pressure (BP) was measured using a fluid-filled catheter. Non-invasive AI was calculated by the SphygmoCor (AtCor Medical) system at the end of catheterization. Subjects consisted of 99 patients with CAD and 21 patients without CAD. There was no significant difference in AI between the CAD and the non-CAD groups (24±10 vs. 24±14%). Non-invasive systolic central BP was lower than the invasive systolic central BP (115±18 vs. 130±23mmHg, P<0.001) in all patients. Non-invasive diastolic central BP was greater than the invasive diastolic central BP (67±10 vs. 63±10mmHg, P<0.001). Conclusions: In elderly patients, AI may not be a useful marker to identify CAD.  (Circ J 2014; 78: 1176–1182)

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Background: Vasospastic angina (VSA) is known to exhibit circadian variation with an early morning peak. We examined whether Rho-kinase activity in circulating leukocytes, which is a useful biomarker for disease activity assessment of VSA, exhibits circadian variation in patients with VSA. Methods and Results: In consecutive 31 VSA patients (M/F 23/8, 57±13 [SD] years) and 18 non-VSA patients (M/F 8/10, 57±14 years), we measured Rho-kinase activity in circulating leukocytes at 6:00, 12:00 and 21:00. We also examined the relationship between the Rho-kinase activity and coronary vasomotor responses during provocation test. Rho-kinase activity was significantly higher in VSA patients than in non-VSA patients at 6:00 (1.17±0.17 vs. 0.92±0.22, P<0.001), and showed a significant circadian variation with a peak at 6:00 (1.00±0.15 at 21:00, 1.17±0.17 at 6:00 and 1.12±0.22 at 12:00, P<0.001) in VSA patients, whereas no such variation was noted in non-VSA patients. Importantly, Rho-kinase activity at spasm provocation test was significantly correlated with basal coronary tone defined by vasodilating responses to intracoronary nitrate (r=0.40, P<0.05) and coronary vasoconstricting responses to acetylcholine (r=0.44, P<0.05) in VSA patients. Furthermore, their Rho-kinase activity at 6:00 was positively correlated with nocturnal parasympathetic activity as evaluated by heart rate variability in Holter monitoring (r=0.48, P<0.05). Conclusions: Rho-kinase activity exhibits distinct circadian variation associated with alterations in coronary vasomotor responses and autonomic activity in VSA patients.  (Circ J 2014; 78: 1183–1190)

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Background: The present study investigated whether serum levels of soluble vascular endothelial growth factor receptor (sVEGFR)-1, -2 and -3 are related to poor coronary collateralization in patients with stable coronary artery disease (CAD). Methods and Results: Serum levels of sVEGFR-1, -2, -3, VEGF, and placental growth factor (PLGF) were determined in 403 consecutive patients with angiographic total or subtotal occlusion of at least 1 major coronary artery. The degree of collateralization was graded according to the Rentrop scoring system. Low (Rentrop score of 0 or 1) and high (Rentrop score of 2 or 3) coronary collateralization occurred in 161 and 242 patients, respectively. Serum levels of sVEGFR-1 and -2 were significantly elevated, in contrast, VEGF and PLGF levels were remarkably decreased in patients with low collateralization than in those with high collateralization (all P<0.05). Significant differences in sVEGFR-1, VEGF and PLGF levels was consistently detected between the low and high collateralization subgroups for patients with and without type 2 diabetes mellitus (DM) (for all comparisons, P<0.01). Multivariable regression analysis revealed that DM, dyslipidemia, elevated sVEGFR-1, and reduced VEGF and PLGF in serum were independently associated with a low degree of coronary collateralization. Conclusions: Increased serum sVEGFR-1 level is associated with poor coronary collateralization in patients with stable CAD. Type 2 DM is a predominant factor affecting collateral growth in these patients.  (Circ J 2014; 78: 1191–1196)

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Background: The Receptor for Advanced Glycation End Products (RAGE) is a pattern recognition receptor for endogenous ligands, and is associated with various inflammatory diseases. However, the role of RAGE activation in myocarditis has yet to be examined. The potential role of RAGE in the development of experimental autoimmune myocarditis (EAM) and the effect of RAGE blocking in attenuating the inflammation in the EAM was investigated. Methods and Results: EAM was evoked in Lewis rats by immunization with porcine cardiac myosin. Soluble RAGE (sRAGE) was injected to block RAGE activation. Echocardiogram, histological, and immunohistochemical examinations were conducted on days 21 and 42. In rats with EAM, RAGE expression in cardiac tissue was prominent on day 21. Rats administered sRAGE during the early antigen-priming phase showed marked attenuation in acute and chronic inflammation compared with untreated rats. RAGE expression was significantly reduced in rats treated in the early phase. However, sRAGE administration, after the initial antigen-priming phase, failed to ameliorate EAM development. Conclusions: RAGE expression was significantly increased in the heart during EAM. Blocking RAGE activation with sRAGE during the early antigen-priming phase reduced acute and chronic inflammation and improved cardiac function. In contrast, blocking RAGE after the early phase did not attenuate EAM development. These results imply that RAGE is involved in regulating innate immune responses during the early phase of myocarditis development.  (Circ J 2014; 78: 1197–1205)

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Background: Microtubule (MT) disorganization is related to cardiac disorders. To elucidate the mechanism by which disorganization of the MT network deteriorates cardiac function, the relationship between MT disorganization and mitochondrial permeability transition pore (mPTP) in cardiac myocytes was investigated. Methods and Results: The effects of MT stabilization (by paclitaxel) and MT disruption (by nocodazole) on mitochondrial membrane potential (ΔΨm) and the opening of mPTP were measured in permeabilized Sprague-Dawley rat myocytes. Both paclitaxel and nocodazole depolarized ΔΨm and opened mPTP. When isolated mitochondria were exposed to paclitaxel or nocodazole, there were no changes in ΔΨm. The effects of paclitaxel or nocodazole on ΔΨm depolarization and mPTP were inhibited by cyclosporin A. Treatment of myocytes with 0Ca+BAPTA or inhibition of sarcoplasmic reticulum (SR) Ca²⁺ uptake by thapsigargin prevented the effect of paclitaxel on mPTP, but not that of nocodazole. Inhibition of the mitochondrial Ca²⁺ uniporter by Ru360 did not alter the effect of paclitaxel on mPTP. Paclitaxel reduced the expression of the mitochondrial fusion protein, mitofusin-2, and induced mitochondrial fragmentation. Conclusions: Disruption of the MT network by nocodazole might destroy the MT-mitochondria connection and alter mitochondrial function. MT disorganization by paclitaxel could regulate mPTP through the outer mitochondrial membrane complex and the Ca²⁺-sensitive signaling pathway, which also interacts with the mitochondrial fusion protein, mitofusin-2.  (Circ J 2014; 78: 1206–1215)

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Background: Growing evidence suggests that late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) is an additive marker of disease severity, and possibly of arrhythmic risk, in hypertrophic cardiomyopathy (HCM). We investigated the possible relationship between LGE and markers of myocardial repolarization dispersion in HCM. Methods and Results: Eighty-five HCM outpatients underwent CMR and short-period electrocardiogram analysis to calculate the temporal myocardial repolarization dispersion through the QT variance normalized for QT mean (QTVN) and the QT variability index (QTVI). The QT dispersion in the spatial domain was also obtained. Patients with LGE (62%) had higher left atrial volume, maximum wall thickness, and left ventricular mass (P<0.0001), as well as a greater prevalence of non-sustained ventricular tachycardia (P<0.0001) and hypotensive blood pressure response (P=0.044). Both QTVN and QTVI were higher in the group with LGE (P<0.0001). At multivariate analysis, using QTVI as the dependent variable, %LGE (P<0.0001), age (P<0.0001), left ventricular outflow obstruction (P=0.038), and sudden cardiac death risk factor burden (P=0.020) reached statistical significance. Otherwise, only %LGE (P=0.005) and left ventricular mass index (P=0.015) remained associated with QTVN. Conclusions: Temporal myocardial repolarization dispersion correlates with LGE extent. Whether these variables could be useful in HCM clinical management warrants confirmation by larger prospective studies.  (Circ J 2014; 78: 1216–1223)

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Background: Patent ductus arteriosus (PDA) is one of the most common congenital cardiovascular defects in children. The Brown-Norway (BN) inbred rat presents a higher frequency of PDA. A previous study reported that 2 different quantitative trait loci on chromosomes 8 and 9 were significantly linked to PDA in this strain. Nevertheless, the genetic or molecular mechanisms underlying PDA phenotypes in BN rats have not been fully investigated yet. Methods and Results: It was found that the elastic fibers were abundant in the subendothelial area but scarce in the media even in the closed ductus arteriosus (DA) of full-term BN neonates. DNA microarray analysis identified 52 upregulated genes (fold difference >2.5) and 23 downregulated genes (fold difference <0.4) when compared with those of F344 control neonates. Among these genes, 8 (Tbx20, Scn3b, Stac, Sphkap, Trpm8, Rup2, Slc37a2, and RGD1561216) are located in chromosomes 8 and 9. Interestingly, it was also suggested that the significant decrease in the expression levels of the PGE₂-specfic receptor, EP4, plays a critical role in elastogenesis in the DA. Conclusions: BN rats exhibited dysregulation of elastogenesis in the DA. DNA microarray analysis identified the candidate genes including EP4 involved in the DNA phenotype. Further investigation of these newly identified genes will hopefully clarify the molecular mechanisms underlying the irregular formation of elastic fibers in PDA.  (Circ J 2014; 78: 1224–1233)

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Background: Although stent implantation is used worldwide for peripheral arterial disease, there is little data on the safety and long-term patency of stents implanted for venous disease. Methods and Results: We studied 13 patients with 14 lesions (6 males, 7 females, mean age: 63.2±10.2 years) diagnosed with venous stenosis and who underwent venous stenting. We examined the location of the stenosis, safety of venous stenting, implantation success rate, and long-term stent patency rate. All patients were suffering from venous stenosis in the left common iliac vein because of iliac vein compression syndrome. No major complications occurred during stent implantation. Acute stent occlusion occurred in 1 patient, who was given additional thrombolytic therapy. Of the 13 patients, 10 underwent venography or contrast-enhanced computed tomography (CT) during mid-term follow-up (mean: 12.9±16.1 months), and only 1 stent was occluded, resulting in a patency rate of 90.0%. The latter patient decided to stop taking warfarin soon after stent implantation. Furthermore, 5 patients underwent contrast-enhanced CT to assess the long-term patency of their stents (mean: 79.6±31.2 months), and none was occluded. Conclusions: Venous stents display a high long-term patency rate, and hence are a useful tool for treating iliac venous stenosis.  (Circ J 2014; 78: 1234–1239)

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Background: No previous study has been done on whether systemic lupus erythematosus (SLE) disease activity is related to the hemodynamics and right ventricular (RV) function in patients with SLE-associated pulmonary artery hypertension (SLE-APAH). Methods and Results: This study prospectively recruited 54 patients (mean age, 32.8±8.4 years; 92.6% female) with SLE-APAH, including 34 patients with SLE disease activity index (SLEDAI) <5 (low score) and 20 with SLEDAI ≥5 (high score). All patients underwent right heart catheterization and iloprost inhalation, and echocardiography was performed before and immediately after iloprost inhalation. There was no difference in baseline mean pulmonary artery pressure (mPAP) between the 2 groups; pulmonary vascular resistance (PVR) was significantly higher and cardiac index was significantly lower in the low-SLEDAI group. The patients with low SLEDAI had larger RV size and worse RV systolic function on echocardiography. After iloprost inhalation, the patients with low SLEDAI had a greater decrease in mPAP and PVR than those with high SLEDAI, while significantly increased RV systolic function was found only in the low-SLEDAI group. Conclusions: SLE activity is related to hemodynamics and RV function in SLE-APAH patients, and those with low SLEDAI might have better acute response to vasodilator inhalation.  (Circ J 2014; 78: 1240–1244)

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Background: Pulmonary hypertension (PH) because of left-sided heart disease carries a poor prognosis. We investigated whether non-ischemic dilated cardiomyopathy (DCM) with PH is associated with poor prognosis. Methods and Results: A total of 256 consecutive DCM patients were enrolled. We measured the ratio of the maximum first derivative of left ventricular pressure (LVdP/dt_max)/systolic blood pressure and pressure half-time (T_1/2) as cardiac function. Patients were allocated to 2 groups on the basis of mean pulmonary arterial pressure (mPAP), namely DCM without PH group (mPAP <25mmHg; n=225) and DCM with PH group (mPAP ≥25mmHg; n=31). We followed all patients for a mean of 4.3 years for the occurrence of cardiac events, defined as cardiac death or hospitalization for worsening heart failure. Cardiac events were significantly more frequent in the DCM with PH group than in the DCM without PH group (P<0.001). Multivariate Cox regression analysis revealed that mPAP ≥25mmHg and LV end-systolic volume index were significant independent risk factors for cardiac death. Incidence of cardiac death was significantly higher in patients with DCM with PH than in those without PH [hazard ratio 11.79 (3.18–43.7), P<0.0001]. Conclusions: The presence of PH was independently associated with an increased incidence of cardiac death in ambulatory patients with DCM.  (Circ J 2014; 78: 1245–1253)

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Background: Tobacco smoking is one of the most important risk factors for cardiovascular disease (CVD) and few biomarkers have been linked to the increased risk of CVD and tobacco smoking. Tobacco smoke has been shown to elevate the plasma levels of asymmetric dimethylarginine (ADMA), a metabolite of L-arginine and an endogenous inhibitor of endothelial nitric oxide synthase. The other potential biomarker that has not been studied to date is L-homoarginine, a homolog of L-arginine. The aim of this study was to evaluate the effects of cigarette smoking on L-homoarginine and other CVD biomarkers. Methods and Results: In a cross-sectional study of 231 healthy male volunteers, we measured plasma levels of L-homoarginine, L-arginine, and ADMA using the HPLC method. In smokers, we found that plasma L-homoarginine levels were 16.7% lower compared with nonsmokers after adjusting for age, body mass index, plasma creatinine, and metal blood levels (P<0.05). Plasma ADMA levels were only 6.0% higher in smokers when compared with the levels found in nonsmokers (P>0.05). Conclusions: Our results suggest that, in contrast to ADMA, there is a strong association between exposure to tobacco smoke and plasma L-homoarginine levels. Further research in this field is needed to explain the mechanisms of the relationship of low L-homoarginine levels, smoking, and cardiovascular health.  (Circ J 2014; 78: 1254–1258)

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Background: Smoking and metabolic syndrome (MetS) are major public health problems in modern society and are important risk factors of cardiovascular disease (CVD). The association of smoking, MetS, and CVD is widely reported, but reports targeted to women are few. In the present study, we evaluated risk factors, including visceral fat area (VFA), for CVD and development of subclinical atherosclerosis in female smokers especially. Methods and Results: Subjects consisted of 162 apparent healthy female and male smokers, and 315 age-matched never-smokers who underwent a health examination in the Osaka University Health Care Center. For female smokers, lifestyle and carotid intima-media thickness (IMT) were evaluated. Triglycerides were significantly higher and high-density lipoprotein-cholesterol significantly lower in smokers than in never-smokers for both men and women. However, VFA was significantly high only in smoking women when compared with never-smokers. Multivariate analysis revealed that age, body mass index, and smoking were the independent predictors of high VFA in women. In addition, annual IMT increase was significantly higher in smokers than never-smokers in women. Conclusions: VFA was notably high in female smokers, but the difference was not observed in men. Smoking habit is an important risk factor of visceral fat accumulation and progression of subclinical atherosclerosis in women.  (Circ J 2014; 78: 1259–1263)

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(Circ J 2013; 77: 667–672)

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