The distribution and burden of 5 conventional risk factors (elevated blood pressure, high total cholesterol, diabetes, obesity/overweight and smoking) for cardiovascular diseases (CVD) were reviewed in 10 selected Asian countries, in addition to the United Kingdom and the United States. Over the past 3 decades, age-standardized systolic blood pressure was on the decline in high-income countries but on the rise in low- to middle-income countries. Similar patterns were observed for total cholesterol levels, although the absolute levels remained higher in high-income countries. A pronounced increase in the prevalence of diabetes mellitus was seen in most of the Asian countries, corresponding to an increase in the levels of body mass index. The number of smokers declined markedly with time, particularly in men, in some selected Asian countries (Japan, Singapore, China, Vietnam). However, the prevalence of current smokers for all countries in 2011 remained excessive. The population-attributable risks for stroke and ischemic heart were highest for high blood pressure, followed by total cholesterol, obesity, and smoking. Evidence suggests that in both Asia and the West, no country is in sufficient control of any of these factors and that intervention programs to alter their effect on CVD are of equal importance.  (Circ J 2013; 77: 2851–2859)

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Although cardiovascular disease is widely recognized as the leading cause of death, a lesser known fact is that aortic aneurysm is the 15th leading cause of death over the age of 65 years in the USA. The golden standard of the treatments are invasive interventions either with open surgical repair (OS) or endovascular aneurysm repair (EVAR). The concept of medical treatment is to prevent abdominal aortic aneurysm (AAA) from rupture and avoid surgical treatment by preventing aneurysm enlargement or even reducing aneurysm size. Matrix metalloproteinases (MMP) are structurally related metalloendopeptidases that can degrade the extracellular matrix and is thought to play important roles in AAA. There are many proposed pharmacological treatments including: β-blockers, angiotensin-converting enzyme inhibitor (ACE inhibitors), angiotensin-receptor blocker (ARB), statins, macrolides and, doxycycline, an inhibitor of the MMP. The latter is a potential promising drug as medical treatment for AAA and the Non-invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA³CT) is currently ongoing in the USA. Here, the pathophysiology and potential medical therapy for AAA will be reviewed.  (Circ J 2013; 77: 2860–2866)

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Over the past 2 decades, a number of inherited cardiac arrhythmias, including congenital long QT syndrome (LQTS) and Brugada syndrome (BrS), have been shown to have a link to mutations in genes encoding for ion channels or other membrane components. The recent HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited arrhythmia syndromes has updated the clinical diagnosis of congenital LQTS and BrS. Genetic studies have identified 13 forms of congenital LQTS in 50–80% of clinically affected patients. Genotype-phenotype correlations have been investigated in the 3 major genotypes, LQT1, LQT2 and LQT3 syndromes, resulting in genotype-specific management and therapy. More detailed analyses of each genotype have suggested mutation location-, type-, or function-specific differences in clinical phenotype among the LQT1, LQT2, and possibly LQT3 genotypes. In BrS, only one-third of affected patients can be genotyped, mainly in the sodium channel gene, SCN5A; therefore, clinical studies of genotype-phenotype relationships have been limited. More recently, a genome-wide association study using a gene array explored the role of common genetic variants (polymorphisms) as the susceptible or modifier gene in both congenital LQTS and BrS.  (Circ J 2013; 77: 2867–2872)

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Background: Fragmented QRS (fQRS) can predict cardiac events, and inducible ventricular tachycardia/fibrillation (VT/VF) is a known high-risk factor for arrhythmic death. However, whether fQRS is a predictor of cardiac events in patients with inducible VT/VF is unknown. We aimed to evaluate whether fQRS is a predictor of cardiac events in patients with structural heart disease and inducible VT/VF. Methods and Results: We retrospectively investigated 98 patients with structural heart disease who had a defibrillator device implanted. All patients underwent electrophysiological testing prior to or after device implantation and VT/VF was induced. fQRS was present in 30 patients. Appropriate defibrillator therapies were similar between the fQRS and non-fQRS groups (47% vs. 47%). In total, 25 patients (26%) died during a mean follow-up period of 87±43 months. All-cause mortality (12 [40%] vs. 13 [19%]) and cardiovascular deaths (9 [30%] vs. 4 [6%]) were significantly higher in the fQRS group than non-fQRS group, respectively; Kaplan-Meier analysis revealed significantly lower event-free survival for all-cause mortality (P=0.012) and cardiovascular deaths (P=0.001) for fQRS patients. A multivariable Cox regression model revealed that fQRS was an independent predictor of cardiovascular death (hazard ratio, 4.58; 95% confidence interval, 1.34–15.64; P=0.015). Conclusions: fQRS is a predictor of cardiovascular death in patients with structural heart disease and inducible VT/VF.  (Circ J 2013; 77: 2889–2897)

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Background: Amiodarone-induced thyrotoxicosis (AIT) may develop long after amiodarone withdrawal. This study sought to determine the incidence and clinical characteristics of AIT after amiodarone withdrawal. Methods and Results: The incidence and clinical characteristics of AIT were examined retrospectively in 71 patients (51 males, mean age 65±13 years) whose amiodarone therapy had been discontinued after at least 1 month of administration. Five (7%) patients developed AIT late after amiodarone withdrawal (11±3 months): 2 patients exhibited exacerbation of heart failure by atrial fibrillation, 2 developed dyspnea on exertion, and 1 patient was asymptomatic. The patients who developed AIT had a high incidence of amiodarone-induced hypothyroidism during amiodarone therapy (100 vs. 24%, P=0.002), had received amiodarone therapy for longer (76±86 months vs. 16±22 months, P<0.001), with a larger cumulative dose (271.1±268.5g vs. 63.4±86.5g, P<0.001) compared with those who did not. In all 5 patients, AIT resolved spontaneously within 5 months without the use of steroids. Conclusions: Occurrence of amiodarone-induced hypothyroidism during amiodarone therapy and long duration of therapy may be cautionary markers of late AIT.  (Circ J 2013; 77: 2898–2903)

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Background: Heart rate asymmetry is caused by an unequal contribution of heart rate decelerations and accelerations to heart rate variability. This study evaluates the asymmetric properties of the variability of the AA, HH, VV, AH and HV intervals. Methods and Results: We recorded 50 1-min intracardiac ECG tracings from 10 patients (18–66 years old; 8 females) during a routine electrophysiological study. Standard descriptors of variance asymmetry were calculated for all intervals. Nonparametric tests were used for statistical comparisons. The prolongations of VV (P=0.0297), AH (P=0.0133) and HV (P=0.0004) intervals contributed significantly more than their shortenings to their short-term variance. The proportion of recordings with a larger contribution of prolongations than shortenings was significantly different from random for VV (0.66, P=0.0328), AH (0.68, P=0.0154) HV (0.74, P=0.0009). Conclusions: In addition to heart rate asymmetry (VV interval), the conduction from the atria, through the atrioventricular node, His-Purkinje system to ventricles shows asymmetric properties in 1-min tracings.  (Circ J 2013; 77: 2904–2911)

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Background: The SYNTAX score (SS) and clinical SS (cSS) can assess coronary lesion complexity and are useful indices in predicting outcomes after percutaneous coronary intervention. However, their validity has not been fully investigated in daily practice where “limus”-eluting stents are used. Methods and Results: The SS and cSS were independently assessed from the Efficacy of Xience/Promus vs. Cypher in rEducing Late Loss after stENTing (EXCELLENT) registry, together with the 1-year patient-oriented composite endpoint (POCE; all-cause death, any myocardial infarction (MI), and any revascularization) and target-lesion failure (TLF; cardiac death, target-vessel MI, and target-lesion revascularization). Among 5,102 patients, tertiles for SS were defined as low-SS <8, 8≤mid-SS≤16, high-SS >16. Both POCE (4.2% vs. 7.7% vs. 12.2%, P<0.001) and TLF (1.6% vs. 2.4% vs. 4.5%, P<0.001) increased significantly with increasing SS tertile, and SS was an independent predictor of POCE (P<0.001 for trend) and TLF (P=0.023 for trend) in multivariate analysis. The predictability of SS and cSS was similar for POCE (area under the curve (AUC): 0.635 vs. 0.629, P=0.599), whereas SS was superior in predicting restenosis-related outcomes such as revascularization (AUC: 0.624 vs. 0.577, P<0.001) and cSS was superior in other components such as death (AUC: 0.654 vs. 0.795, P<0.001). Conclusions: Both SS and cSS were applicable to unrestricted use of “limus”-eluting stents in predicting the risk of 1-year clinical outcomes.  (Circ J 2013; 77: 2912–2921)

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Background: The ideal device for percutaneous patent foramen ovale (PFO) occlusion should provide effective closure with long-term biocompatibility and it should have a low profile without interfering with adjacent cardiac structures. Long-term data regarding safety and efficacy of the GORE Septal Occluder (GSO) are lacking. The aim of this study was to investigate the short- and mid-term clinical and echocardiographic outcomes of this device. Methods and Results: Forty-five consecutive patients with clinically significant PFO were treated with GSO and their results were compared with those of 45 consecutive patients treated with Amplatzer PFO device (APO). Primary endpoint was the incidence of 6-month residual right-to-left shunting (rRLS). The procedural results and the recurrence of embolic events (REE) at 1 year were also investigated. No differences in terms of embolic risk profile and echocardiographic parameters were observed between the 2 groups. GSO was successfully implanted in all patients without device-related complication. In 2 patients for whom device position was not optimal, the GSO was easily retrieved and a new GSO was successfully repositioned. Immediate moderate–severe rRLS was similar in 2 groups. No cases of severe 6-month rRLS were registered. Two patients (4%) and 1 patient (2%) had moderate 6-month rRLS in the GSO and APO group, respectively (P=NS). No cases of REE were registered at 1-year follow-up. Conclusions: GSO appears a valuable alternative to Amplatzer device for PFO occlusion.  (Circ J 2013; 77: 2922–2927)

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Background: Edge restenosis is not an unusual finding after implantation of drug-eluting stents (DES). We hypothesized that mechanical stress imposed on the stent edge would cause vessel wall injury and inflammation, which may consequently lead to edge restenosis. Methods and Results: In total, 1,496 patients were implanted with a sirolimus-eluting stent (SES), paclitaxel-eluting stent (PES) or zotarolimus-eluting stent (ZES) in Seoul National University Hospital between 2007 and 2009. Binary restenosis occurred in 161 lesions in 119 patients. We retrospectively compared the 3 DES with regard to the percentage of edge stent restenosis among all cases of restenosis. We also evaluated the maximal, minimal, and Δ (maximal angle–minimal angle) angles. The percentage of edge restenosis was higher for SES than for ZES (37.5% vs. 16.7%, P=0.017). Maximal angle at the proximal edge was 64.82°±33.46° for 26 stents with proximal edge restenosis compared with 31.84°±31.51° for 89 stents without proximal edge restenosis (P=0.001). The Δ angle was also significantly different between the 2 groups (14.81°±15.98° vs. 7.60°±8.86°, P=0.035). Similar findings were observed for distal edge restenosis. Both the maximal angle (39.09°±21.04° vs. 22.71°±22.83°, P=0.010) and Δ angle (20.23°±15.39° vs. 9.18°±9.66°, P=0.016) at the distal edge were significantly different between the 2 groups. Conclusions: Physical stress determined by angulation at the stent edge segment and biomechanical properties of the DES can be considered as one of the plausible mechanisms for edge stent restenosis.  (Circ J 2013; 77: 2928–2935)

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Background: This study aimed to elucidate whether regional left ventricular wall thickening (LVWT) determined by quantitative gated SPECT (QGS) is useful in predicting surgical outcomes for ischemic (ICM) and nonischemic cardiomyopathy (NICM). Methods and Results: The study group comprised 53 patients with either ICM (n=30, left ventricular ejection fraction (LVEF)=24.7±7.1%) or NICM (n=23, LVEF=24.0±6.3%) scheduled for surgical repair underwent preoperative QGS to evaluate regional LV function. LVWT of 20 segments derived from QGS was normalized by being divided by the normal value of each LV level. Normalized values of the segments were summed to be representative of each area. For 16 of the 30 patients with ICM and 17 of the 23 patients with NICM, surgical ventricular restoration and papillary muscle approximation (PMA) were performed for surgical repair and, for the rest, PMA alone was done for both ICM and NICM patients. Adjunctive coronary artery bypass grafting for ICM patients was added when necessary. Mean follow-up periods were 2.5±1.8 years for ICM and 2.2±2.4 years for NICM. Posterior regional LVWT in NICM (normalized sum value <0.61 n=7, ROC: AUC=0.80) predicted cardiac events (chronic heart failure and cardiac-caused death). The one-year cardiac event-free rates were 22.2% and 85.1% and the 2 years rates were 11.1% and 48.6% for the lower posterior WT group and higher posterior WT group respectively (P=0.003). Conclusions: Posterior LVWT can be a predictor for postoperative cardiac events in patients with NICM.  (Circ J 2013; 77: 2936–2941)

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Background: Although the survival rate for repaired Tetralogy of Fallot (TOF) is dramatically improving, anatomical and functional residua and sequelae followed by arrhythmias and sudden death are still challenging issues to be resolved. Reoperation can reduce the incidence of arrhythmias and sudden death, but there is no consensus on the indications of reoperation for patients with TOF, especially in Japan. Methods and Results: A cross-sectional questionnaire survey of reoperation indications in patients with TOF was performed through a Japanese multicenter study. The questionnaire, which focused on the number of repaired TOF patients aged >15 years old, reoperation indications and management, was sent to the institutions belonging to Japanese Society for Adult Congenital Heart Disease. In total, 41.5% (78/188) of the institutions replied. The total number of repaired TOF patients was 4,010, and sudden cardiac death was observed in 45.236/4,010 (5.9%) experienced reoperation. Pulmonary stenosis (32%) and pulmonary regurgitation (29%) were the most common reasons for reoperation. There were only 2 implantable cardioverter defibrillator or resynchronization therapy defibrillator implantations. The physiological/anatomical indications of reoperation differed among the hospitals. Conclusions: Approximately 1.1% of patients suffered sudden death and 6% of repaired TOF patients had reoperation. The indications of reoperation, however, varied among the institutions. Therefore, detailed information for each case of sudden death or reoperation should be collected and analyzed in order to establish guidelines for reoperation.  (Circ J 2013; 77: 2942–2947)

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Background: Tobacco smoking is a well-known risk factor for cardiovascular disease, but controversial results have been reported regarding its relationship with atrial fibrillation (AF). Moreover, no study on the relationship between smoking and AF has yet been undertaken in a Japanese context. Methods and Results: We used data from the Shinken Database 2004–2011 (men/women, n=10,714/6,803, respectively), which included all new patients attending the Cardiovascular Institute between June 2004 and March 2012. AF was diagnosed in 1,698 and 598 men and women, respectively. In men, smokers were more prevalent in the AF than in the non-AF group (54.5% vs. 44.7%), whereas in women the prevalence of smokers was similar between AF and non-AF groups (14.4% vs. 15.4%). This discrepancy between the sexes seems to derive from a characteristic distribution pattern of smoking habit in women. After adjustment for various cofactors, smoking was independently associated with AF (odds ratio 1.54; 95% confidence interval 1.35–1.75; P<0.001) without a significant interaction between sex categories (P=0.195). Conclusions: Smoking was independently associated with AF without a significant interaction between sex categories among Japanese patients visiting a cardiovascular hospital. Further studies using a prospective cohort design are required to confirm a causal link between smoking and AF in Japanese patients.  (Circ J 2013; 77: 2948–2953)

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Background: The appropriate target ranges of heart rate (HR) and systolic blood pressure (SBP) for the management of chronic heart failure (CHF) patients remain to be elucidated in a large-scale cohort study. Methods and Results: We examined 3,029 consecutive CHF patients with sinus rhythm (SR) (mean age, 67.9 years) registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 Study (CHART-2; NCT00418041). There were 357 deaths (11.8%) during the median follow-up of 3.1 years. We first performed the classification and regression tree analysis for mortality, identifying SBP <89mmHg, HR >70beats/min and SBP <115mmHg as the primary, secondary and tertiary discriminators, respectively. According to these, we divided the patients into low- (n=1,131), middle- (n=1,624) and high-risk (n=274) groups with mortality risk <10%, 10–20% and >20%, respectively. The low-risk group was characterized by SBP >115mmHg and HR <70beats/min and the high-risk group by SBP <89mmHg regardless of HR values or SBP 89–115mmHg and HR >76beats/min. Multivariate Cox regression analysis revealed that the hazard ratio of all-cause death for low-, middle- and high-risk groups was 1.00 (reference), 1.48 (95% confidence interval (CI): 1.10–1.99, P=0.009) and 2.44 (95% CI 1.66–3.58, P<0.001), respectively. Subgroup analysis revealed that age ≥70 years, diabetes, or reduced left ventricular function had higher hazard ratios in the high-risk group. Conclusions: The results demonstrate the usefulness of combined risk stratification of HR and SBP in CHF patients with SR.  (Circ J 2013; 77: 2954–2962)

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Background: We have previously demonstrated that the prevalence of metabolic syndrome in chronic heart failure (CHF) is more than double compared with the general population in Japan. However, the impact of physical activity on cardiovascular events in CHF patients remains to be fully elucidated. Methods and Results: We performed a prospective, nationwide large-scale multicenter study of 9,178 patients with stage A/B/C/D CHF in Japan. We obtained the baseline physical activity data for 7,292 and yearly changes in physical activity data during a 3-year follow-up period for 4,353 patients. We divided the patients into high- and low-exercise groups by using the median value of physical activity in the stage A/B and C/D groups. In both groups, patients who exercised more were characterized by younger age and less advanced stage of CHF. Importantly, the baseline physical activity levels were significantly associated with all-cause death, heart failure (HF) hospitalization and other cardiovascular events (except acute myocardial infarction, stroke, HF hospitalization). Furthermore, the yearly change in physical activity level was also significantly associated with HF hospitalization and other cardiovascular events in both groups. Conclusions: The baseline level of physical activity and its yearly changes are significantly associated with all-cause death and major cardiovascular events in both stage A/B and C/D patients, suggesting that physical activity could be an important therapeutic target to improve the long-term prognosis of CHF patients.  (Circ J 2013; 77: 2963–2972)

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Background: No-reflow phenomenon is a serious complication of percutaneous coronary intervention (PCI) and associated with poor prognosis. The aim of this study was to determine whether triple anti-platelet therapy could improve clinical outcome in patients with acute myocardial infarction (AMI) who had no-reflow phenomenon during PCI compared with dual anti-platelet therapy. Methods and Results: A total of 727 eligible patients received either dual anti-platelet therapy (aspirin and clopidogrel; dual group, n=532) or triple anti-platelet therapy (aspirin, clopidogrel, and cilostazol; triple group, n=195). The triple group received additional cilostazol for at least 1 month. One-year major adverse cardiac events (MACE) including death, myocardial infarction (MI), target vessel revascularization (TVR) and coronary artery bypass graft (CABG) were evaluated. The triple group had a similar incidence of major bleeding and in-hospital mortality compared with the dual group. At 1 year, the triple group had significantly lower cardiac mortality (17.7% vs. 11.8%, log-rank P=0.039), lower all-cause mortality (19.0% vs. 12.3%, log-rank P=0.035), and lower incidence of composite MACE (25.9% vs. 16.9%, adjusted hazard ratio, 0.50; 95% confidence interval: 0.31–0.80, P=0.004) compared with the dual group with no differences in MI and TVR. Conclusions: Triple anti-platelet therapy seems to be superior to dual anti-platelet therapy in patients with AMI who had no-reflow phenomenon during PCI.  (Circ J 2013; 77: 2973–2981)

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Background: Although low high-density lipoprotein cholesterol (HDL-C) level has been reported as an independent risk factor for coronary artery disease, few studies addressed the direct relationship between the presence of thin-cap fibroatheroma (TCFA) that is considered as vulnerable plaque in pathology and HDL-C level. The aim of this study was to investigate whether lesion vulnerability is related to HDL-C level in patients with acute coronary syndrome (ACS). Methods and Results: A total of 261 patients with ACS who underwent optical coherence tomography prior to percutaneous coronary intervention, were enrolled. Patients were divided into a TCFA group (n=124) and a non-TCFA group (n=137). TCFA was defined as a lipid plaque (lipid content in ≥1 quadrant) covered with <70m-thickness fibrous caps. There were no differences in patient characteristics and clinical results between the 2 groups except for HDL-C level, low-density lipoprotein cholesterol (LDL-C) level, and high-sensitive C-reactive protein (hs-CRP) level. On multivariate regression analysis, low HDL-C level (β coefficient: 0.302, P<0.001), high LDL-C level (β coefficient: −0.172, P=0.008), hs-CRP level (β coefficient: −0.145, P=0.017), and current smoking (β coefficient: −0.124, P=0.028) were identified as independent contributors to fibrous cap thickness. Conclusions: HDL-C is correlated with fibrous cap thickness of the culprit lesion in patients with ACS. HDL-C may be considered as a therapeutic target for plaque stabilization.  (Circ J 2013; 77: 2982–2989)

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Background: Dilated cardiomyopathy (DCM) is characterized by a dilated left ventricular cavity with systolic dysfunction manifested by heart failure. It has been revealed that mutations in genes for cytoskeleton or sarcomere proteins cause DCM. However, the disease-causing mutations can be found only in far less than half of patients with a family history, indicating that there should be other disease genes for DCM. Formin homology 2 domain containing 3 (FHOD3) is a sarcomeric protein expressed in the heart that plays an essential role in sarcomere organization during myofibrillogenesis. The purpose of this study was to explore a possible novel disease gene for DCM. Methods and Results: We analyzed 48 Japanese familial DCM patients for mutations in FHOD3, and a missense variant, Tyr1249Asn, which was predicted to modify the 3D structure and damage protein function, was found in a case with adult-onset DCM. Functional studies revealed that the DCM-associated mutation significantly reduced the ability to induce actin dynamics-dependent activation of serum response factor, although no remarkable change in the cellular localization was induced in neonatal rat cardiomyocytes transfected with a mutant construct of FHOD3. Conclusions: The DCM-associated FHOD3 variant may cause DCM by interfering with actin filament assembly.  (Circ J 2013; 77: 2990–2996)

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Background: Angiotensin-converting enzyme 2 (ACE2) has been implicated in human heart failure, but the mechanism remains elusive. We hypothesized that ACE2 deficiency would exacerbate angiotensin (Ang) II-mediated myocardial injury. Methods and Results: 10-week-old ACE2 knockout (ACE2KO) and wild-type mice received by mini-osmotic pump either AngII (1.5mg·kg^–1·day^–1) or saline for 2 weeks. ACE2 deficiency triggered greater increases in the expression of connective tissue growth factor (CTGF), fractalkine (FKN) and phosphorylated ERK1/2 in AngII-treated ACE2KO hearts. These changes were associated with greater activation of matrix metalloproteinase (MMP) 2, MMP9 and MT1-MMP and exacerbation of myocardial injury and dysfunction. In cultured cardiofibroblasts, exposure to AngII (100nmol/L) for 30min resulted in marked increases in superoxide production and expression of CTGF, FKN and phosphorylated ERK1/2, which were strikingly prevented by recombinant human ACE2 (rhACE2; 1mg/ml) and the CTGF-neutralizing antibody (5μg/ml), but were aggravated by ACE2 inhibitor DX600 (0.5μmol/L). These protective effects of rhACE2 were eradicated by the Ang-(1–7) antagonist A779 (1μmol/L). More intriguingly, rhACE2 treatment significantly abolished AngII-mediated increases in MMP2, MMP9 and MT1-MMP in cardiofibroblasts. Conclusions: Loss of ACE2 exacerbates AngII-mediated inflammation, myocardial injury and dysfunction in ACE2-deficient hearts via activation of the CTGF-FKN-ERK and MMP signaling. ACE2 gene may represent a potential candidate to prevent and treat myocardial injury and heart diseases.  (Circ J 2013; 77: 2997–3006)

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Background: Compliance of the aorta is important in maintaining normal cardiovascular physiology. Pathological conditions can induce changes in elastic properties, having profound effects on their prognosis. The aim of this study was to establish age-related reference values for distensibility and wall stiffness index of the ascending aorta. Methods and Results: A total of 165 normal subjects (mean age, 11.92±4.0 years) were investigated on transthoracic echocardiography. Ascending aortic diameter was recorded in M-mode above the sinotubular junction. Blood pressure was measured simultaneously at the right arm. Aortic pulse pressure, distensibility and aortic wall stiffness index were calculated offline. Distensibility decreased significantly with age (r=−0.462, P<0.001); the regression line indicated an average decrease of 5.1 10⁻³kPa⁻¹ (95% confidence interval [CI]: 3.9–6.8 10⁻³kPa⁻¹) per year. Significant correlations could be found between distensibility and weight, height, body surface area (BSA) and body mass index (BMI) (P<0.001). Stiffness index increased significantly with age (r=0.399, P<0.001); the regression line indicated an average increase of 0.066 (95% CI: 0.047–0.085) per year; significant correlations could be found between wall stiffness index and weight, height, BSA and BMI (P<0.001). The 2.5th and 97.5th percentiles of the distribution of distensibility and stiffness index related to age, weight, height, BSA and BMI were calculated. Conclusions: Normal values of arterial elastic properties throughout childhood and adolescence have been provided, and might serve as a reference for individuals with cardiovascular and metabolic disease.  (Circ J 2013; 77: 3007–3014)

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Background: Velocity-encoded cine magnetic resonance imaging (VEC-MRI) has recently been reported as effective for assessing not only pulmonary blood flow (Qp) but also pulmonary arterial pressure (PAP) in adults. However, there have been few reports on the usefulness of VEC-MRI for assessing PAP in children with congenital heart disease (CHD). Methods and Results: We evaluated 34 children with CHD. Qp and systemic blood flows (Qs) were determined by cardiac catheterization and VEC-MRI. The right-to-left Qp ratio (R/L) was measured by pulmonary perfusion scintigraphy and VEC-MRI. The pulmonary-to-systemic blood pressure ratio (Pp/Ps) was determined by cardiac catheterization. The acceleration time (AcT), ejection time (ET), peak velocity (PV), acceleration volume (AcV), and maximal change in flow rate during ejection (MCFR) in the pulmonary arteries, which were standardized by body surface area, were determined by VEC-MRI. The children were divided into 2 groups according to Pp/Ps. The Qs, R/L ratio and Qp/Qs obtained by VEC-MRI strongly correlated with those obtained by catheterization and scintigraphy. No significant differences in AcT, ET, AcT/ET, PV, or AcV were observed between the 2 groups. However, a significant difference was observed in MCFR. Furthermore, a significant correlation was observed between the MCFR and Pp/Ps. Conclusions: This study clearly demonstrated that VEC-MRI is useful for assessing not only blood flow, but also PAP, by referring to MCFR in children.  (Circ J 2013; 77: 3015–3022)

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Background: Benefit of low-dose aspirin for primary prevention of cardiovascular events in diabetes remains controversial. The American Diabetes Association (ADA), the American Heart Association (AHA), and the American College of Cardiology Foundation (ACCF) recommend aspirin for high-risk diabetic patients: older patients with additional cardiovascular risk factors. We evaluated aspirin’s benefit in Japanese diabetic patients stratified by cardiovascular risk. Methods and Results: In the JPAD trial, we enrolled 2,539 Japanese patients with type 2 diabetes and no history of cardiovascular disease. We randomly assigned them to aspirin (81–100mg daily) or no aspirin groups. The median follow-up period was 4.4 years. We stratified the patients into high-risk or low-risk groups, according to the US recommendation: age (older; younger) and coexisting cardiovascular risk factors. The risk factors included smoking, hypertension, dyslipidemia, family history of coronary artery disease, and proteinuria. Most of the patients were classified into the high-risk group, consisting of older patients with risk factors (n=1,804). The incidence of cardiovascular events was higher in this group, but aspirin did not reduce cardiovascular events (hazard ratio [HR], 0.83; 95% confidence interval [CI]: 0.58–1.17). In the low-risk group, consisting of older patients without risk factors and younger patients (n=728), aspirin did not reduce cardiovascular events (HR, 0.55; 95% CI: 0.23–1.21). These results were unchanged after adjusting for potential confounding factors. Conclusions: Low-dose aspirin is not beneficial in Japanese diabetic patients at high risk.  (Circ J 2013; 77: 3023–3028)

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Background: Extracellular magnesium (Mg) accounts for approximately 1% of the total body Mg. Clinically, serum Mg concentration is measured, but it does not necessarily reflect total body Mg status. Although relationships have been reported between reduced Mg and cardiovascular disease in non-dialysis patients, there have been few such studies in hemodialysis patients. It was hypothesized that reduced Mg, as represented by lower Mg concentration in the hair, would be associated with echocardiographic parameters in chronic hemodialysis patients. Methods and Results: Hair Mg concentration was measured in 79 male hemodialysis patients using inductively coupled plasma mass spectrometry, and the relationships between hair Mg concentration and echocardiographic parameters were investigated. There was no significant correlation between Mg concentration in the hair and in serum. Hair Mg concentration in the patients with high-left ventricular mass index (LVMI) was significantly lower than that in the low-LVMI patients. Hair Mg concentration correlated significantly and negatively with posterior left ventricular wall thickness, interventricular septum thickness, left ventricular wall thickness (LVWT), and relative wall thickness. Serum Mg concentration, however, did not correlate with any of these echocardiographic parameters. Conclusions: In hemodialysis patients, hair Mg concentration is a biomarker, independent of serum Mg concentration. Hair Mg, but not serum Mg, was significantly and negatively associated with LVWT. Reduced tissue Mg concentration, as measured in the hair, may be associated with left ventricular hypertrophy in hemodialysis patients.  (Circ J 2013; 77: 3029–3036)

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Background: Although remote ischemic preconditioning (RIPC) is shown to preserve kidney function in patients at high risk of contrast-induced acute kidney injury (CI-AKI), the effect in patients at low-moderate risk remains unknown. The preventive effects of RIPC in patients not at high risk of CI-AKI were examined, and biomarkers with anticipated roles in renal protection via RIPC investigated. Methods and Results: Sixty patients who had moderate chronic kidney disease and who underwent angiography were randomly assigned to the control (n=30) or RIPC (intermittent arm ischemia, n=30) group. The baseline characteristics in the 2 groups did not differ significantly. CI-AKI was evaluated by measuring urinary liver-type fatty acid-binding protein (L-FABP). Biomarkers were measured before and 24 and 48h after angiography. Twenty-four hours after angiography, the percent change in urinary L-FABP level in the RIPC group was significantly smaller than in the control group (41.3±15.6 vs. 159±34.1%, P=0.003). L-FABP-based CI-AKI developed in 8 control patients (26.9%) vs. only 2 patients in the RIPC group (7.7%), suggesting that RIPC prevents CI-AKI. Factors contributing to CI-AKI were analyzed. Neither high-sensitivity C-reactive protein nor pentraxine-3 level differed significantly between the 2 groups, while the percent change in asymmetrical dimethy larginine (ADMA) level and blood derivatives of reactive oxidative metabolite levels were significantly smaller in the RIPC group. Conclusions: RIPC alleviates CI-AKI in patients at low-moderate risk. This effect might be mediated partly by decreasing oxidative stress and plasma ADMA level.  (Circ J 2013; 77: 3037–3044)

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Background: Aging-associated functional impairment of endothelial progenitor cells (EPCs) contributes to delayed re-endothelialization after vascular injury and exaggerated intimal hyperplasia (IH). This study tested if bone marrow (BM) rejuvenation accelerates post-injury re-endothelialization in aging mice. Methods and Results: Using BM transplantation (BMT^Gfp→Wild), young^Gfp to young^Wild (YTY), old^Gfp to old^Wild (OTO), young^Gfp to old^Wild (YTO), and old^Gfp to young^Wild (OTY) groups were created. After vascular injury, IH was significantly greater in the old group than the young group (P<0.001). BM rejuvenation (YTO) significantly accelerated re-endothelialization and attenuated IH. Compared with the OTO group, the YTY and YTO groups had earlier and greater EPC-derived re-endothelialization (P<0.001). The number of Sca-1⁺KDR⁺ EPCs mobilized in the circulation induced by vascular injury was higher in young, YTO, and YTY mice than in old mice (P<0.05). Sca-1⁺ BM cells from the young, YTO, and YTY groups had better migration and adhesion capacities than those from the old group (P<0.05). The increase in blood vascular endothelial growth factor (VEGF) levels after vascular injury was higher in young than in old mice. PI3K, Akt, and FAK pathways played a pivotal role in VEGF-associated EPC migration. Specifically, EPCs from young and YTO mice, compared with old mice, demonstrated stronger FAK phosphorylation after VEGF stimulation. Conclusions: EPCs play a critical role in vascular repair in aging mice. BM rejuvenation accelerates re-endothelialization by improving EPC function.  (Circ J 2013; 77: 3045–3053)

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