Heart failure is a leading cause of death worldwide. Despite medical advances, the dismal prognosis of heart failure has not been improved. The heart is a high energy-demanding organ. Impairments of cardiac energy metabolism and mitochondrial function are intricately linked to cardiac dysfunction. Mitochondrial dysfunction contributes to impaired myocardial energetics and increased oxidative stress in heart failure, and the opening of mitochondrial permeability transition pore triggers cell death and myocardial remodeling. Therefore, there has been growing interest in targeting mitochondria and metabolism for heart failure therapy. Recent developments suggest that mitochondrial protein lysine acetylation modulates the sensitivity of the heart to stress and hence the propensity to heart failure. This article reviews the role of mitochondrial dysfunction in heart failure, with a special emphasis on the regulation of the nicotinamide adenine dinucleotide (NAD⁺/NADH) ratio and sirtuin-dependent lysine acetylation by mitochondrial function. Strategies for targeting NAD⁺-sensitive mechanisms in order to intervene in protein lysine acetylation and, thereby, improve stress tolerance, are described, and their usefulness in heart failure therapy is discussed. (Circ J 2015; 79: 1863–1870)

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Platelets are small blood cells that adhere to the site of vessel injury where von Willebrand factor (VWF) is expressed. Platelets bind to VWF through interaction with a membrane protein, glycoprotein (GP) Ibα. Next, the accumulated platelets are activated to change their morphological and biochemical characteristics. Various vasoactive substances, such as immune-regulatory CD40 ligand, are released locally from activated platelet cells to maintain homeostasis of the vascular system. Major roles played by platelets in the regulation of hemostasis and thrombus formation include local activation of the coagulation cascade. Translocation of negatively charged phospholipids to the surface of activated platelets helps in the formation of prothrombinase complex, which efficiently produces thrombin. Thrombin produces fibrin around the activated platelets and further activates the platelets through thrombin receptor stimulation. Of the various platelet-stimulating receptors and activation signals, cyclo-oxygenase-1, P2Y₁₂ adenosine 5’-diphosphate receptor, and thrombin receptor (protease activated receptor)-1 blockers are used clinically as antiplatelet agents. In the future, precise understanding of the quantitative contribution of platelet function in hemostasis and pathological thrombus formation should lead to the development of effective antithrombotic agents without increasing the risk of serious bleeding complications. (Circ J 2015; 79: 1871–1881)

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Atherosclerosis is considered a chronic inflammatory disease and an intervention targeting the inflammatory process could be a new therapeutic strategy for preventing atherosclerotic cardiovascular diseases (CVD). We hypothesized that the intestine, which is considered the biggest immune organ in the human body, could be a therapeutic target for preventing CVD. We demonstrated that oral administration of anti-CD3 antibody or an active form of vitamin D₃reduced atherosclerosis in mice via induction of regulatory T cells and tolerogenic dendritic cells in the gut-associated lymphoid tissues. Similar to regulatory immune responses achieved by oral tolerance, our method had systemic effects that ultimately contributed towards atherosclerosis reduction. Recently, we have been interested in the gut microbiota, which have been reported as highly associated with intestinal immunity and systemic metabolic disorders, including obesity and diabetes. Notably, the guts of obese individuals are predominantly colonized byFirmicutesoverBacteroidetes. The association between atherosclerosis and microbiota has been attracting increased attention, and gut microbiota have been shown to participate in the metabolism of a proatherogenic compound called trimethylamine-N-oxide (TMAO) and aggravate CVD. Our investigation of the relationship between susceptibility to CVD and the gut microbiota revealed a characteristic flora type. Here, we discuss the evidence for the relationship between the gut microbiota and cardiometabolic diseases, and consider the gut microbiota as new potential therapeutic targets for treating CVD. (Circ J 2015; 79: 1882–1890)

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Background:We hypothesized that a negative microvolt T-wave alternans (MTWA) test would identify patients unlikely to benefit from primary prevention implantable cardioverter defibrillator (ICD) therapy in a prospective cohort.Methods and Results:Data were pooled from 8 centers where MTWA testing was performed specifically for the purpose of guiding primary prevention ICD implantation. Cohorts were included if the ratio of ICDs implanted in patients who were MTWA “non-negative” to patients who were MTWA negative was >2:1, indicating that MTWA testing had a significant impact on the decision to implant an ICD. The pooled cohort included 651 patients: 371 MTWA non-negative and 280 MTWA negative. Among non-negative patients, 62% underwent ICD implantation whereas only 13% of MTWA-negative patients received an ICD (P<0.01). Despite a substantially lower prevalence of ICDs, long-term survival (6.9 years) was significantly better among MTWA-negative patients (68.2% non-negative vs. 87.1% negative, P=0.026).Conclusions:MTWA-negative patients had significantly better survival than MTWA non-negative patients, the majority of whom had ICDs. Despite a very low prevalence of ICDs, long-term survival among patients with left ventricular ejection fraction ≤40% and a negative MTWA test was better than in the ICD arm of any study to date that has demonstrated a benefit of ICDs. This provides further evidence that MTWA-negative patients are unlikely to benefit from primary prevention ICD therapy. (Circ J 2015; 79: 1912–1919)

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Background:Despite the benefits of implantable cardioverter-defibrillator (ICD) therapy, inappropriate shocks can lead to multiple adverse effects. The aim of this study was to clarify the predictors of inappropriate ICD shocks and their proarrhythmic consequences.Methods and Results:We retrospectively studied 316 consecutive patients who underwent ICD implantation from December 2000 to December 2011. Of them, 70 (22%) experienced inappropriate ICD shocks without proarrhythmia requiring some intervention; 2 patients (0.6%) had proarrhythmic inappropriate ICD therapy by antitachycardia pacing (ATP), thereby calculated to be 0.18% of patients per year. However, they did not have syncope from this inappropriate ATP. Multivariate analysis identified younger age (≤56 years: hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.02–2.77, P=0.043), paroxysmal atrial fibrillation (HR 3.00, 95% CI 1.64–5.31, P=0.0002), stroke (HR 2.23, 95% CI 1.11–4.47, P=0.024), and no diuretic use (HR 1.72, 95% CI 1.03–2.93, P=0.039) as independent predictors of the occurrence of inappropriate ICD shocks.Conclusions:Young age, paroxysmal atrial fibrillation, stroke, and no use of diuretics were independently associated with inappropriate ICD shocks. Proarrhythmic inappropriate ICD therapy was observed with an annual incidence of 0.18% by ATP. (Circ J 2015; 79: 1920–1927)

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Background:Few large-scale studies have examined the relationship between bleeding events not related to coronary artery bypass grafting (CABG), and the vascular access route used in acute coronary syndrome (ACS) or in elective treatment of coronary artery disease (CAD).Methods and Results:We compared the incidence of bleeding events occurring up to 3 days after percutaneous coronary intervention (PCI) or loading dose of prasugrel or clopidogrel in 2 studies of Japanese patients (PRASFIT-ACS, femoral and radial routes, n=683 and 531; PRASFIT-Elective, femoral and radial routes, n=135 and 508). Rates of periprocedural bleeding, bleeding not related to CABG, and puncture site bleeding were consistently lower in the radial access route group than in the femoral access route group in both studies. Risk factors for periprocedural bleeding included sex, body weight, age, and access route in PRASFIT-ACS (femoral access: hazard ratio [HR], 3.739; 95% confidence interval [CI]: 1.727–8.094; radial access: HR, 0.288; 95% CI: 0.128–0.65), and body weight, age, and access route in PRASFIT-Elective (femoral access: HR, 12.32; 95% CI 1.282–>100; radial access: HR, 0.125; 95% CI: 0.013–1.205).Conclusions:The incidence of periprocedural bleeding is lower with a radial access route than with a femoral access route for PCI in Japanese patients with ACS or those undergoing elective PCI for CAD. (Circ J 2015; 79: 1928–1937)

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Background:Clinical outcomes of implantation of the newer-generation drug-eluting stent (DES) following rotational atherectomy for heavily calcified lesions remain unclear in the real-world setting.Methods and Results:We enrolled 252 consecutive patients (273 lesions) treated with newer-generation DES following rotational atherectomy. The primary endpoint was the cumulative 2-year incidence of major adverse cardiovascular events (MACE), defined as cardiac death, myocardial infarction, clinically-driven target lesion revascularization, and definite stent thrombosis. Complete clinical follow-up information at 2-year was obtained for all patients. The mean age was 73.2±9.0 years and 155 patients (61.5%) were male. Cumulative 2-year incidence of MACE (cardiac death, myocardial infarction, clinically-driven target lesion revascularization and definite stent thrombosis) was 20.3% (7.0%, 2.1%, 18.1% and 2.1%, respectively). Predictors of MACE were presenting with acute coronary syndrome (hazard ratio [HR]: 3.80, 95% confidence interval [CI]: 1.29–11.2, P=0.02), hemodialysis (HR: 1.93, 95% CI: 1.04–3.56, P=0.04) and previous coronary artery bypass graft (HR: 2.26, 95% CI: 1.02–5.00, P=0.045).Conclusions:PCI for calcified lesions requiring rotational atherectomy is still challenging even in the era of newer-generation DES. (Circ J 2015; 79: 1938–1943)

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Background:Periprocedural myocardial injury (PMI) is not an uncommon complication and is related to adverse cardiac events after percutaneous coronary intervention (PCI). We investigated the predictors of PMI in patients with stable angina pectoris (SAP) on intravascular imaging.Methods and Results:We enrolled 193 SAP patients who underwent pre-PCI intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Clinical characteristics, lesion morphology, and long-term follow-up data were compared between patients with and without PMI, defined as post-PCI elevation of high-sensitivity cardiac troponin-T. PMI were observed in 79 patients (40.9%). Estimated glomerular filtration rate (odds ratio [OR], 0.973; 95% confidence interval [CI]: 0.950–0.996; P=0.020), ≥2 stents (OR, 3.100; 95% CI: 1.334–7.205; P=0.009), final myocardial blush grade 0–2 (OR, 4.077; 95% CI: 1.295–12.839; P=0.016), and IVUS-identified echo-attenuated plaque (EA; OR, 3.623; 95% CI: 1.700–7.721; P<0.001) and OCT-derived thin-cap fibroatheroma (OCT-TCFA; OR, 3.406; 95% CI: 1.307–8.872; P=0.012) were independent predictors of PMI on multivariate logistic regression analysis. A combination of EA and OCT-TCFA had an 82.4% positive predictive value for PMI. On Cox proportional hazards analysis, PMI was an independent predictor of adverse cardiac events during 1-year follow-up (hazard ratio, 2.984; 95% CI: 1.209–7.361; P=0.018).Conclusions:Plaque morphology assessment using pre-PCI IVUS and OCT may be useful for predicting PMI in SAP patients. (Circ J 2015; 79: 1944–1953)

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Background:Little is known about the clinical outcomes of patients with different types of coronary bifurcation lesions. We sought to compare long-term clinical outcomes of patients with true or non-true bifurcation lesions who underwent percutaneous coronary intervention.Methods and Results:We compared major adverse cardiac events (MACE: cardiac death, myocardial infarction [MI], or target lesion revascularization) between 1,502 patients with true bifurcation lesions (51.8%) and 1,395 with non-true bifurcation lesions (48.2%). True bifurcation lesions were defined as Medina classification (1.1.1), (1.0.1), or (0.1.1) lesions. During a median follow-up of 36 months, MACE occurred in 296 (10.2%) patients. Patients with true bifurcation lesions had a significantly higher risk of MACE than those with non-true bifurcation lesions (HR 1.39; 95% CI 1.08–1.80; P=0.01). Among true bifurcation lesions, Medina (1.1.1) and (0.1.1) were associated with a higher risk of cardiac death or MI than Medina (1.0.1) (HR 4.15; 95% CI 1.01–17.1; P=0.05). During the procedure, side branch occlusion occurred more frequently in Medina (1.1.1) and (1.0.1) than Medina (0.1.1) lesions (11.5% vs. 7.4%, P=0.03).Conclusions:Patients with true bifurcation lesions had worse clinical outcomes than those with non-true bifurcation lesions. Procedural and long-term clinical outcomes differed according to the type of bifurcation lesion. These findings should be considered in future bifurcation studies. (Circ J 2015; 79: 1954–1962)

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Background:Although intra-aortic balloon pump (IABP) is sometimes used before cardiac surgery to achieve better outcome in high-risk patients, the clinical impact of prophylactic IABP support before left ventricular assist device (LVAD) implantation in patients with worsening hemodynamics was unknown.Methods and Results:We enrolled 22 patients with worsening hemodynamics who had received IABP support before LVAD (IABP group), and also enrolled 22 patients receiving neither IABP nor extracorporeal membrane oxygenation before LVAD, who were selected on propensity score matching (non-IABP group). Although both groups had similar preoperative background, the IABP group had shorter postoperative intensive care unit (ICU) stay, and more improved hemodynamics (P<0.05 for all). Serum total bilirubin and creatinine decreased significantly in the IABP group compared with the non-IABP group during 1 month after LVAD implantation (P<0.05 for both). Medical expenses during perioperative ICU stay were significantly lower in the IABP group compared with the non-IABP group, even including the cost of preoperative IABP support (P<0.05).Conclusions:Prophylactic IABP support in heart failure patients with worsening hemodynamics improves post-LVAD clinical course and reduces perioperative medical expenses. (Circ J 2015; 79: 1963–1969)

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Background:Although survival rates have improved for patients receiving implantable continuous flow left ventricular assist devices (I-CF LVAD), postoperative exercise tolerance levels are not necessarily satisfactory.Methods and Results:We enrolled 51 patients who had received an I-CF LVAD and underwent follow-up between 2006 and 2014; all patients underwent cardiopulmonary exercise testing 3 months following surgery: 26 (51%) patients achieved peak oxygen consumption (PV̇O₂) ≥14 ml·kg⁻¹·min⁻¹and had significantly lower readmission rates for cardiovascular events than those with PV̇O₂<14 ml·kg⁻¹·min⁻¹during 2 years of LVAD treatment (17 vs. 43%, P=0.033). Uni- and multivariate logistic regression analyses showed that the preoperative serum albumin (S-ALB) level was an independent predictor for PV̇O₂≥14 ml·kg⁻¹·min⁻¹at 3 months (P=0.023, odds ratio 6.132). Patients with persistently normal S-ALB levels during the perioperative period had the lowest preoperative serum C-reactive protein level (S-CRP, 0.7±0.9 mg/dl), and the majority (77%) showed improved exercise tolerance. Conversely, patients with persistently low S-ALB levels during this period had the highest preoperative S-CRP level (2.8±1.2 mg/dl) and did not achieve the test endpoint.Conclusions:Both pre- and postoperative low S-ALB impedes recovery of exercise tolerance after I-CF LVAD surgery, and this may be attributable to inflammatory responses caused by heart failure. (Circ J 2015; 79: 1970–1975)

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Background:The most appropriate valve substitute at aortic valve replacement (AVR) for young female adult patients wanting to have children is unclear.Methods and Results:Between 1992 and 2013, 12 consecutive female patients aged >18 (median, 22.5 years; range, 18–34 years) underwent Ross operation (Ross group). Between 1984 and 2013, 9 consecutive female patients aged >18 (median, 30 years; range, 22–39 years) underwent AVR with bioprosthesis (bioprosthesis group). There was 1 late mortality in the bioprosthesis group, due to prosthetic valve endocarditis (PVE). Freedom from reoperation for aortic valve at 15 years was 90.0% in the Ross group, and 57.1% in the bioprosthesis group (log-rank, P=0.098). One in the Ross group underwent reoperation for aortic regurgitation (AR), whereas 4 in the bioprosthesis group did so for aortic stenosis (AS) in 2, combined AS and AR in 1, and PVE in 1. Five patients in the Ross group and 3 in the bioprosthesis group had 7 and 4 uneventful pregnancies, respectively. AR progressed during the perinatal period in a total of 7 of 11 pregnancies. No AS was seen at discharge, after 5 years, or during pregnancy in the Ross group.Conclusions:The long-term outcome of Ross operation for female patients wanting to have children is excellent. Although subclinical pulmonary autograft valve regurgitation during pregnancy was often observed, pulmonary autograft stenosis did not occur, therefore it would be an ideal option for patients wanting to have children. (Circ J 2015; 79: 1976–1983)

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Background:We aimed to elucidate the prognostic impact of anemia with special reference to the clinical background of patients with chronic heart failure (CHF).Methods and Results:We examined 4,646 consecutive patients with Stage C/D CHF registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (n=10,219). Among them, 1,627 (35%) had anemia and were characterized by higher age (74 vs. 66 years), lower estimated glomerular filtration rate (52.8 vs. 66.1 ml/min/1.73 m²) and higher B-type natriuretic peptide levels (154.5 vs. 81.8 pg/ml) (all P<0.001) but comparable left ventricular ejection fraction (LVEF; 57.5 vs. 56.7%). Anemic patients were more frequently treated with diuretics (55.1 vs. 42.3%) but less often treated with β-blockers (45.4 vs. 51.1%) (both P<0.001). During a median follow-up of 3.8 years, 371 and 272 patients died with and without anemia, respectively (22.8 vs. 9.0%, adjusted hazard ratio 1.40; 95% confidence interval 1.15–1.71, P=0.001). Subgroup analysis revealed that the prognostic impact of anemia was comparable in terms of age, sex, renal function and double product, but differed by LVEF level and CHF etiology (both, P for interaction <0.001). In particular, a difference in the prognostic impact of LVEF level was noted in patients with ischemic heart disease.Conclusions:These results indicate that the prognostic impact of anemia is evident in CHF patients with preserved EF and it differs by CHF etiology. (Circ J 2015; 79: 1984–1993)

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Background:A continuous flow (CF) left ventricular assist device (LVAD) has various advantages over a pulsatile flow (PF) LVAD, but the extent of preventing aortic insufficiency (AI) by each type of LVAD remains controversial.Methods and Results:Of 86 patients with non-ischemic cardiomyopathy who underwent LVAD implantation between 2006 and 2015, 20 propensity score-matched patients with PF LVADs and 20 with CF LVADs were enrolled in this study. There were no significant differences in the baseline variables of both groups. During the 6-month LVAD treatment, the LV ejection fraction of the PF group was significantly higher than that of the CF group; the PF group also had a wider pulse pressure and less enlargement of the aortic root (P<0.05 for all). Patients in the PF group experienced more frequent opening of the native aortic valve and less AI than those in the CF group (P<0.05 for both). The PF LVAD was explanted in 5 patients (25%), and a CF LVAD was explanted in 1 patient (5%).Conclusions:Compared with CF LVADs, PF LVADs seem to have an advantage in improving LV reverse remodeling and preventing AI. It may be best to incorporate pulsatility into current CF LVADs while retaining their existing benefits. (Circ J 2015; 79: 1994–1999)

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Background:It is recommended that not only door-to-balloon time but also prehospital delay for primary percutaneous coronary intervention (PCI) should be improved. We investigated the effect of prehospital transfer pathway on onset-to-balloon time and prognosis in patients with ST-segment elevation myocardial infarction (STEMI) in Japan.Methods and Results:We analyzed data from 540 consecutive patients with primary PCI for STEMI. Patient clinical data and mortality were compared between patients who visited the family physician or non-PCI-capable hospitals and were then transferred to PCI-capable centers (indirect transfer patients), and those who directly visited PCI-capable centers (direct transfer patients). Onset-to-balloon time was longer in indirect transfer patients than in direct transfer patients (mean, 270 min; range, 180–480 min vs. 180 min, 120–240 min; P<0.001). In addition, patient prognosis was evaluated on Cox proportional regression analysis. Cardiac death and all-cause death were significantly higher in indirect transfer patients (odds ratios [OR], 2.17; 95% confidence intervals [95% CI]: 1.17–4.01, P=0.01; OR, 1.71; 95% CI: 1.09–2.68, P=0.02). These results were confirmed using propensity score matching for adjusted analyses.Conclusions:Patients with indirect transfer to regional emergency departments of PCI centers had longer onset-to-balloon time and worse prognosis than those with direct transfer. (Circ J 2015; 79: 2000–2008)

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Background:In the current era of primary percutaneous coronary intervention (PCI), some patients with acute myocardial infarction (AMI) still do not undergo primary PCI.Methods and Results:To examine the clinical characteristics of AMI patients who did not undergo primary PCI, we analyzed patients enrolled between 2002 and 2010 in the MIYAGI-AMI Registry Study, in which all AMI patients in the Miyagi prefecture have been prospectively registered. Among a total of 8,640 patients, 1,879 (21.7%) did not undergo primary PCI and their in-hospital mortality was significantly worse compared with those who did (21.4% vs. 6.4%, P<0.01). Multivariate analysis demonstrated that female sex was significantly associated with non-performance of primary PCI [odds ratio (95% confidence interval): 1.40 (1.22–1.61), P<0.001], along with age [1.01 (1.01–1.02), P<0.001] and heart failure on admission [2.69 (2.29–3.16), P<0.001]. When dividing by age, the non-performance rate of primary PCI in females showed a U-shaped prevalence, whereas it simply increased with aging in males. Importantly, female patients aged <80 years had a significantly higher non-performance rate of primary PCI compared with male patients, regardless of the severity of AMI.Conclusions:These results indicate that in the current PCI era, various factors, including aging, heart failure on admission and sex differences, are associated with non-performance of primary PCI, which remain to be resolved in order to further improve critical care of AMI. (Circ J 2015; 79: 2009–2016)

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Background:Adverse effects of dietary intake of trans-fatty acids (TFA) on the incidence of coronary artery disease (CAD) are well recognized in Western countries. The risk of TFA, however, has not been well clarified in Japan. We investigated the association of serum TFA concentration with serum lipid profile, coronary risk factors, and prevalence of CAD.Methods and Results:A total of 902 patients, who were hospitalized at Kobe University Hospital from July 2008 to March 2012 and gave written informed consent, were enrolled in this study. Among them, 463 patients had CAD, and 318 patients had metabolic syndrome (MetS). Serum TFA, elaidic acid (trans-9-C18:1) and linolelaidic acid (trans-9, 12-C18:2), were measured on gas chromatography/mass spectrometry. Serum TFA level had a positive correlation with body mass index, waist circumference, low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B48, and an inverse correlation with age and high-density lipoprotein cholesterol. Fasting serum TFA, by age quartile in the young generation with CAD and/or MetS, was higher than that in patients without CAD and/or MetS. On multivariate logistic regression, TFA was identified as a CAD risk after adjustment for classical risk factors.Conclusions:Serum TFA concentration was elevated in young patients with CAD and/or MetS. Diet-derived TFA may cause a serious health problem, particularly in the young generation in Japan. (Circ J 2015; 79: 2017–2025)

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Background:Previous studies of long QT syndrome (LQTS) have revealed the presence of country-specific hot spots inKCNQ1mutations, and the purpose of this study was to evaluate the influence of a common mutation on clinical phenotypes in Japanese LQT1 patients.Methods and Results:We retrospectively studied the frequency of each mutation in 190 LQT1 Japanese probands and evaluated the clinical severity of LQT1 among carriers with a common mutation. We also compared it with that of carriers with other mutations. In the Japanese cohort, the most common mutation was p. A344spl (c.1032 G>A), comprising a substitution of a guanine for an adenine at the last base of exon 7, and it was found in 17 probands (8.9%). Regarding the clinical characteristics of A344spl carriers, the mean age-of-onset was 10±4 years, >40% were symptomatic, and the mean corrected QT interval was 461±30 ms. The prognosis for carriers of the A344spl mutation (n=31) was intermediate between that for the A341V mutation reported to be associated with severe phenotypes (n=24) and other mutations (n=290).Conclusions:The A344spl mutation was a frequent LQTS genotype in Japan, which indicates that the influence of country-specific hot spots should be considered when studying LQT1 clinical phenotypes. (Circ J 2015; 79: 2026–2030)

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Background:Less attention has been paid to evaluating subclinical cardiovascular disease (CVD) in the early stage of pediatric chronic kidney disease (CKD). Ambulatory blood pressure monitoring (ABPM) and arterial stiffness are the earliest detectable assessments of subclinical CVD. Asymmetric dimethylarginine (ADMA) is an analog of L-arginine (ARG) that inhibits nitric oxide (NO) production; thus the ARG-to-ADMA ratio (AAR) is an index of NO. Homocysteine (HCY) is a risk factor for CVD and it can be metabolized to L-cysteine (CYS). Given that HCY and ADMA/NO are closely linked and related to hypertension, we therefore investigated whether ARG and HCY metabolites, arterial stiffness parameters, ABPM profile, and left ventricular hypertrophy (LVH) are interrelated in children and adolescents with early CKD.Methods and Results:This cross-sectional study included 57 pediatric patients with CKD stages 1–3. Two-thirds of the children with CKD stages 1–3 exhibited BP abnormalities accessed by ABPM. Children with CKD stages 2–3 had higher HCY, but lower CYS levels. The plasma HCY level was increased in children with LVH and abnormal ABPM. Systolic BP positively correlated with biomarkers AAR, HCY, and CYS. LV mass positively correlated with AAR, HCY, and CYS.Conclusions:BP abnormalities were prevalent and associated with AAR, HCY, and CYS in children with early CKD. Our data highlighted the effect of NO and the HCY pathway on CKD-related hypertension. (Circ J 2015; 79: 2031–2037)

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Background:Patent foramen ovale (PFO) can cause ischemic stroke because of paradoxical embolism. Autopsy studies have shown that the prevalence of PFO is 25% in whites or blacks. However, there is a paucity of data on the prevalence of PFO in Asians. The aim of this study was to clarify the prevalence of PFO in the Japanese population.Methods and Results:We reviewed 52,717 autopsy reports, which were collected and edited by the Japanese Society of Pathology from 2009 to 2012. Next, we inspected consecutive 103 formalin-fixed specimens that had already been examined by certified pathologists from 2009 to 2013 to find PFO and atrial septal aneurysm (ASA). ASA was defined as ≥10 mm protrusion of the septum into the left or the right atrium. In the database of the Japanese Society of Pathology, the incidence of PFO was 0.08% (43/52,717). Inspection of heart specimens disclosed that the prevalence of PFO was 13.6% (14/103). None of the PFO cases was reported at the original autopsy. PFO was more frequently found in the subjects with ASA (50%) than in those without ASA (9.7%) (P=0.004).Conclusions:PFO is under-reported in autopsy reports. Re-evaluation of heart specimens disclosed that theprevalence of PFO was 13.6%. The prevalence was lower than reported in the past. (Circ J 2015; 79: 2038–2042)

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Background:Shock wave therapy (SWT) is an acoustic technology clinically used for the non-invasive treatment of ischemic heart disease (IHD). Therapeutic ultrasound (TUS) has more recently been developed for the same indication, although its effects on reperfusion and angiogenesis have yet to be directly compared to those of SWT.Methods and Results:TUS and SWT acoustic parameters were matched, and their ability to promote angiogenesis and reperfusion in a rat hindlimb ischemia model was compared. After left femoral artery excision, 3-weekly TUS, SWT or sham treatments (n=10 rats each) of the left hindlimb were performed for 2 weeks. Laser Doppler perfusion imaging demonstrated improved perfusion with TUS (66±4% L:R hindlimb perfusion, mean±SEM, P=0.02), but not with SWT (59±4%, P=0.13) compared with sham (50±4%). Immunohistochemistry of CD31 demonstrated increased microvascular density with TUS (222.6 vessels/high-power field, P=0.001) and SWT (216.9, P=0.01) compared to sham-treated rats (196.0). Tissue vascular endothelial growth factor mRNA levels were elevated in the left hindlimb of TUS-, but not SWT- or sham-treated rats.Conclusions:Direct comparison demonstrates that TUS is more effective than SWT at promoting reperfusion, whereas both therapies promote angiogenesis in ischemic gastrocnemius muscle. These results suggest that TUS may be more effective than SWT for the treatment of IHD and peripheral arterial disease. (Circ J 2015; 79: 2043–2049)

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Background:Because of ethnic difference in the risk of degenerative aortic valve disease (DAVD), risk factors should be clarified in each race to establish prophylactic strategies for severe aortic valve stenosis (AS).Methods and Results:This study prospectively followed 359 Japanese subjects with DAVD and age ≥50 years for 3 years. As both patients with peak aortic transvalvular flow velocity ≥2 m/s and <2 m/s were enrolled, subgroup analysis was also conducted. Most patients were under treatment for their comorbidities. The use of warfarin, but none of the traditional risk factors for atherosclerosis, was related to greater reduction in aortic valve area indexed to body surface area (iAVA). In patients with peak aortic transvalvular flow velocity <2 m/s, the use of an angiotensin-receptor blocker (ARB) was associated with less decrease in iAVA. In patients with peak velocity ≥2 m/s, changes in iAVA were not related to any baseline characteristics, but peak velocity was less increased under treatment with an angiotensin-converting enzyme inhibitor (ACEI).Conclusions:In Japanese, the use of warfarin may exacerbate DAVD, and augmented management of atherosclerotic risk factors beyond the recommendations in the current guidelines is unlikely to exert additional benefit. The prescription of ARB for DAVD patients before the development of AS or ACEI after the development of AS may be useful. (Circ J 2015; 79: 2050–2057)

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Background:Hypoxic pulmonary hypertension (HPH) is characterized by pulmonary vascular remodeling. Intracellular Ca²⁺concentration ([Ca²⁺]_i) is an essential signal for myocyte proliferation. Whether chronic hypoxia (CH) affects the basal [Ca²⁺]_iand Ca²⁺entry through store- and/or receptor-operated calcium channels (SOCC, ROCC), and whether canonical transient receptor potential (TRPC) proteins are involved in CH-induced Ca²⁺influx and proliferation in pulmonary venous smooth muscle cells (PVSMCs) is examined.Methods and Results:Rats were exposed to CH. PVSMCs were isolated from distal pulmonary veins. In freshly isolated PVSMCs, CH increased the basal [Ca²⁺]_i; removal of Ca²⁺or application of SKF-96365 reversed the elevated [Ca²⁺]_i, whereas nifedipine had no effect. Receptor-operated Ca²⁺entry (ROCE) was expressed in PVSMCs. In freshly isolated PVSMCs from CH rats, ROCE was enhanced, whereas store-operated Ca²⁺entry had no alteration. Furthermore, real-time polymerase chain reaction and western blotting showed that mRNA and protein expression level of TRPC6, but neither TRPC1 nor TRPC3, in pulmonary venous smooth muscle (PV) from CH rats and PVSMCs exposed to CH was greater than in normal PV and PVSMCs. The knockdown of TRPC6 in hypoxic PVSMCs with siRNA inhibited the enhanced ROCE and attenuated CH-induced PVSMCs proliferation.Conclusions:The enhanced Ca²⁺entry through ROCC, due to upregulated TRPC6, is a novel pathogenic mechanism contributing to the increased basal [Ca²⁺]_iin PVSMCs and excessive PVSMC proliferation during the development of HPH. (Circ J 2015; 79: 2058–2068)

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