S100A8, S100A9 and S100A12 are considered proinflammatory mediators of atherosclerosis. Known as calgranulins, they are major components of neutrophils and are upregulated in macrophages and foam cells. They influence leukocyte recruitment, and may propagate inflammation by binding TLR4 and/or receptor for advanced glycation endproducts (RAGE). However, the receptors for calgranulins remain an enigma; we have no evidence for TLR4 or RAGE activation by S100A8 or S100A12. Moreover, gene regulation studies suggest antiinflammatory functions for S100A8 and emerging reports indicate pleiotropic roles. Unlike S100A9, S100A8 effectively scavenges oxidants generated by the myeloperoxidase system in vivo, forming novel thiol modifications. S100A8 is also readily S-nitrosylated, stabilizing nitric oxide and transporting it to hemoglobin. S100A8-SNO reduces leukocyte transmigration in the vasculature. S-glutathionylation of S100A9 modifies its effects on leukocyte adhesion. Both S100A8 forms inhibit mast cell activation, at least partially by scavenging reactive oxygen species required for signaling. Conversely, S100A12 activates and sequesters mast cells. However S100A12 suppresses proinflammatory cytokine induction by SAA-activated monocytes and macrophages, and inhibits matrix metalloprotease activity. We propose that the abundance and types of cells expressing calgranulins in particular microenvironments, their relative concentrations and post-translational modifications may have distinct functional outcomes, including those that are protective, at different stages of atherogenesis.  (Circ J 2014; 78: 271–280)

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Hypercholesterolemia and hypertension are common risk factors for cardiovascular disease (CVD). Updated guidelines emphasize target reductions of overall cardiovascular risks. Experimental studies have shown reciprocal relationships between insulin resistance (IR) and endothelial dysfunction. Hypercholesterolemia and hypertension have a synergistic deleterious effect on IR and endothelial dysfunction. Unregulated renin-angiotensin system (RAS) is important in the pathogenesis of atherosclerosis and hypertension. Various strategies with different classes of antihypertensive medications to reach target goals have failed to reduce residual CVD risk further. Of interest, treating moderate cholesterol elevations with low-dose statins in hypertensive patients reduced CVD risk by 35–40% further. Therefore, statins are important in reducing CVD risk. Unfortunately, statin therapy causes IR and increases the risk of type 2 diabetes mellitus. RAS inhibitors improve both endothelial dysfunction and IR. Further, cross-talk between hypercholesterolemia and RAS exists at multiple steps of IR and endothelial dysfunction. In this regard, combined therapy with statins and RAS inhibitors demonstrates additive/synergistic effects on endothelial dysfunction and IR in addition to lowering cholesterol levels and blood pressure when compared with either monotherapy in patients. This is mediated by both distinct and interrelated mechanisms. Therefore, combined therapy with statins and RAS inhibitors may be important in developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome, or obesity to prevent CVD.  (Circ J 2014; 78: 281–287)

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The burden of advanced heart failure is reaching epidemic proportions. Generally considered for cardiac transplantation, patients often cannot receive this therapy because of their advanced age, comorbidity or the scarcity of donors. Most transplants are concentrated in North America and Europe, with the average center performing fewer than 20 annual transplants. A search for nonbiological means of cardiac support has led to the advent of mechanical circulatory support (MCS), a concept now entrenched as a bridge to transplantation or, for those ineligible for transplantation, as lifetime therapy. In this review we discuss contemporary challenges posed by the changing epidemiology of cardiac transplant and MCS and outline the basis for an understanding of the future of this important therapeutic stance.  (Circ J 2014; 78: 288–299)

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Reactive oxygen species (ROS) are the main facilitators of cardiovascular complications in diabetes mellitus (DM), and the ROS level is increased in cultured cells exposed to high glucose concentrations or in diabetic animal models. Emerging evidence shows that mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase are dominant mechanisms of ROS production in the diabetic heart. Hyperpolarization of the mitochondrial inner membrane potentials and impaired mitochondrial function promote ROS production in the mitochondria of the diabetic heart. Uncoupling proteins are upregulated and may reduce the ROS level by depolarizing the mitochondrial inner membrane potential. NADPH oxidase is another major site of ROS production and its contribution to DM-induced ROS increase has been elucidated not only in vascular smooth muscle cells and endothelial cells, but also in cardiomyocytes. Protein kinase C, angiotensin II, and advanced glycation endproducts (AGEs)/receptor for AGEs can activate NADPH oxidase. Increased intracellular calcium level mediated via the Na⁺-H⁺ exchanger and subsequent activation of Ca²⁺/calmodulin-dependent protein kinase II may also activate NADPH oxidase. This review presents the current understanding of the mechanisms of ROS production, focusing especially on the roles of mitochondria and NADPH oxidase.  (Circ J 2014; 78: 300–306)

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Background: Endovascular aortic repair (EVAR) is performed in patients with thoracic or abdominal aortic aneurysm because it is less invasive than conventional open repair. However, the effects of EVAR on vascular and cardiac function remain to be clarified. Methods and Results: We studied the effects of EVAR on several outcome variables in 40 consecutive patients undergoing EVAR for abdominal and/or thoracic aneurysm with preserved ejection fraction. Echocardiography and brachial–ankle pulse wave velocity (baPWV) data were collected before, 1 week, and 1 year after EVAR. Although no changes in blood pressure were found, baPWV, left ventricular mass index (LVMI), and left atrial volume index were significantly elevated at both post-op time periods after EVAR compared with baseline data. The changes in LVMI correlated with those in baPWV (R=0.32, P<0.05). Among the 22 patients who were successfully followed up, 13 showed deterioration in exercise tolerance 1 year after EVAR. Diastolic wall strain, an index for LV distensibility, was lower at baseline in patients with worsening exercise tolerance than in those with unchanged tolerance. Conclusions: EVAR increased vascular stiffness and induced LV hypertrophy and diastolic dysfunction without a corresponding elevation of blood pressure in the acute and chronic phases. In addition, low LV distensibility at baseline was associated with the impairment of exercise tolerance. EVAR-induced stiffness of arteries leads to limited clinical symptoms.  (Circ J 2014; 78: 322–328)

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Background: P wave ≥0.25mV in inferior leads (P pulmonale) occurs in chronic lung diseases that underlie atrial fibrillation (AF). The purpose of this study was to elucidate the prognostic value of P pulmonale for development of AF. Methods and Results: Digital analysis of 12-lead electrocardiogram (ECG) was conducted to enroll patients with P pulmonale from among a database containing 308,391 ECGs. In a total of 591 patients (382 men; 56.4±14.8 years) with P pulmonale (follow-up, 46.7±65.6 months), AF occurred in 61 patients (AF group), but did not occur in 530 patients (non-AF group). Male gender was significantly more prevalent in the AF group than in the non-AF group (80.3% vs. 62.8%, P=0.0047). P-wave duration and PQ interval were significantly longer in the AF group than in the non-AF group (115.4±17.2ms vs. 107.0±17.2ms, P=0.0003 and 166.3±23.9ms vs. 153.2±25.4ms, P=0.0001, respectively). In the total patient group, multivariate Cox proportional-hazards analysis confirmed that male gender (hazard ratio [HR], 2.24; 95% confidence interval [CI]: 1.02–5.49; P=0.045), PQ interval >150ms (HR, 6.89; 95% CI: 2.39–29.15; P<0.0001), and P-wave axis <74° (HR, 2.55; 95% CI: 1.20–5.41; P=0.016) were associated with AF development. In medication-free patients (n=400), only PQ interval >150ms (HR, 9.26; 95% CI: 1.75–170.65; P=0.0055) was independently and significantly associated with AF development. Conclusions: PQ interval is the strongest stratifier for AF development in P pulmonale.  (Circ J 2014; 78: 329–337)

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Background: Chronic atrial fibrillation (AF) is characterized by a remodeling process with prominent atrial fibrosis. Fibrocytes, a bone marrow-derived population of fibroblast-like cells, have been placed at the center of a number of fibrosing conditions. The purpose of this study was to evaluate the contribution of fibrocytes to atrial fibrosis in patients with chronic AF and the possible mechanisms. Methods and Results: We enrolled 22 consecutive valvular heart disease patients with chronic AF (>6 months: CAF group) and 15 valvular heart disease patients in sinus rhythm served as controls (SR group). Left atrial tissue samples were obtained during cardiac surgery. The infiltration of fibrocytes into the atrial interstitium was observed by confocal microscopy. The number of atrial fibrocytes was approximately three-fold higher in the CAF group compared with the SR controls, and positively correlated with both the atrial collagen volume fraction (r=0.713; P=0.0002) and the left atrial volume index (r=0.631; P=0.002). In the peripheral blood samples collected before the operation, approximately 2.5-fold higher percentage of circulating fibrocytes was identified in the CAF group. These fibrocytes showed a stronger proliferative capacity (≈2.5-fold) and higher level expression of collagen I and α-SMA (≈2-fold and 4-fold, respectively) compared with the SR controls. Conclusions: The results suggested that fibrocytes may be involved in atrial fibrosis in chronic AF through enhanced profibrotic characteristics.  (Circ J 2014; 78: 338–344)

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Background: Postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery and results in increased health-care utilization. This study identified new transthoracic echocardiographic predictors of POAF using an index of the total atrial conduction time derived on tissue Doppler imaging (PA-TDI duration) in patients undergoing off-pump coronary artery bypass grafting (OPCAB). Methods and Results: A total of 88 patients undergoing isolated OPCAB were enrolled. They were examined preoperatively on transthoracic echocardiography with tissue Doppler evaluations and monitored postoperatively with continuous electrocardiographic telemetry for 7 days. POAF occurred in 35 patients (39.8%). Patients with POAF had a significantly longer duration of hospital stay than those without (44.9±6.2 vs. 37.3±3.3 days, P=0.04). Multivariate analysis showed that PA-TDI duration (odds ratio [OR], 1.11; 95% confidence interval [CI]: 1.06–1.16; P=0.0001) and left atrial volume index (LAVI; OR, 1.11; 95% CI: 1.02–1.20; P=0.01) were independent predictors of POAF. Moreover, PA-TDI duration was more reliable, given an area under the receiver operating characteristic curve of 0.85 (sensitivity, 74.3%; specificity, 86.8%). Conclusions: PA-TDI duration was an independent predictor of POAF following OPCAB. Awareness of risk of POAF may lead to the prevention of POAF, a rapid response to POAF, shortened hospital stay, and improved prognosis.  (Circ J 2014; 78: 345–352)

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Background: In recent years, there has been a series of recalls of popular implantable cardioverter defibrillators leads, and several reports have demonstrated an increasing rate of failure of such leads over time in Caucasian patients. However, little is known about the performance of these leads in Asian patients. The aim of this study was to investigate the rate of failure of the recalled leads and the characteristics as compared with non-recalled leads in Japanese patients. Methods and Results: A retrospective chart review was conducted in 214 patients (75 Sprint Fidelis, 8 Riata, and 131 Sprint Quattro leads) who underwent implantation and follow-up at Nagoya University Hospital. During the follow-up period, 14 Sprint Fidelis leads (19%) and 1 Riata lead (13%) failed, but no abnormality was found in the Sprint Quattro, non-recalled leads. Five patients (4 Sprint Fidelis and 1 Riata, 33% of lead failure patients) received inappropriate shocks. The 3-, 4-, and 5-year lead survival rates in Sprint Fidelis leads were 95.1% (95% confidence interval [CI]: 89.6%–100%), 89.8% (95% CI: 82.1%–97.6%), and 88.0% (95% CI: 79.6%–96.4%), respectively. A previous device implantation before Sprint Fidelis lead was the only significant predictor for lead fracture (hazard ratio, 5.33; 95% CI: 1.55–18.4; P=0.008). Conclusions: The rate of Sprint Fidelis lead failure continues to increase over time in Japanese patients.  (Circ J 2014; 78: 353–359)

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Background: Electrocardiogram (ECG) recorded at the upper intercostal lead positions is recommended as an additional diagnostic clue for Brugada syndrome (BrS), but similar recording conditions to unmask ECG signs have not been explored. Methods and Results: We evaluated the diagnostic usefulness for unmasking ECG signs of BrS using recordings at the upper intercostal lead position, on deep inspiration and on standing. In 34 patients (mean age, 49±14 years; 30 male) with diagnosed and suspected BrS, ECG type and ST-elevation in leads V1–V3 recorded at a higher position by 1 rib from the standard position (3ICS), and at standard lead positions (4ICS) on deep inspiration (DI test) and on standing (Stand test) were compared with the conventional lead positions (baseline). While type 1 ECG had been documented in 17 of 34 patients on at least 1 occasion in the past, only 4 had the sign at baseline during the study. Twenty patients had type 1 on 3ICS recording, 18 on DI test, and 6 on Stand test. Among 17 patients without previous documentation of spontaneous type 1, 7 had type 1 on 3ICS recording, 6 on DI test, and 1 on Stand test. Conclusions: ECG recording on deep inspiration is useful to unmask diagnostic signs of BrS and has similar accuracy to 3ICS recording.  (Circ J 2014; 78: 360–365)

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Background: The effect of phosphodiesterase-3 (PDE-3) inhibitors on arrhythmia remains controversial, so the purpose of this study was to determine their differential effects on sympathetic hyperinnervation and the involved mechanisms in a rat model of myocardial infarction. Methods and Results: After ligating the coronary artery, male Wistar rats were randomized to cilostazol or milrinone, chemically unrelated inhibitors of PDE-3, or vehicle for 4 weeks. The postinfarction period was associated with increased myocardial norepinephrine levels and oxidant release, as measured by myocardial superoxide level and dihydroethidine fluorescence staining. Infarcted rats in the milrinone- and cilostazol-treated groups had favorable ventricular remodeling with similar potency. Compared with milrinone, cilostazol significantly increased interstitial adenosine levels and reduced the production of myocardial cAMP and superoxide. Cilostazol significantly blunted sympathetic hyperinnervation, as assessed by immunofluorescent analysis of sympathetic innervation, and western blotting and real-time quantitative RT-PCR of nerve growth factor. Furthermore, the inhibitory effect of cilostazol on nerve growth factor was reversed by 8-cyclopentyl-1,3-dipropylxanthine, a selective A₁ receptor antagonist, and enhanced by tempol administration. In spite of similar arrhythmic vulnerability during programmed stimulation in both the vehicle-and cilostazol-treated groups, cilostazol did not have proarrhythmic effects compared with milrinone. Conclusions: Unlike milrinone, cilostazol has therapeutic neutrality in arrhythmias because of adenosine uptake inhibition, which antagonizes the PDE-3-induced increase of sympathetic reinnervation via mediation of an adenosine A₁ receptor-mediated antioxidation.  (Circ J 2014; 78: 366–376)

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Background: Although there is a general fear that exercise training might deteriorate renal function in chronic kidney disease (CKD) patients, the effect of cardiac rehabilitation (CR) on renal function in acute myocardial infarction (AMI) patients with CKD remains unknown. We sought to determine whether CR is associated with amelioration or deterioration of renal function in such patients. Methods and Results: We enrolled 528 AMI patients who participated in a 3-month CR program. Clinical data before and after CR were compared according to participation in CR and comorbidities. In patients without CKD (estimated glomerular filtration rate [eGFR] ≥60ml·min⁻¹·1.73m⁻², n=348), peak oxygen uptake (VO₂) and B-type natriuretic peptide (BNP) improved without a change in eGFR. In contrast, in patients with CKD (eGFR <60ml·min⁻¹·1.73m⁻², n=180), eGFR improved (48±12 to 53±15ml·min⁻¹·1.73m⁻², P<0.001), together with improvements in peak VO₂ and BNP. When patients with CKD were divided into non-active (≤1time/week, n=70) and active participants (≥1.1time/week, n=110) according to attendance in CR, active participants showed an improvement in eGFR (50±10 to 53±13ml·min⁻¹·1.73m⁻², P<0.001), whereas eGFR did not change in non-active participants. Similar results were obtained in each subgroup of patients with hypertension, dyslipidemia, or diabetes mellitus. Conclusions: In AMI patients with CKD, active participation in CR was associated with improved peak VO₂, BNP, and eGFR.  (Circ J 2014; 78: 377–384)

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Background: Subjective clinical improvement does not always go hand-in-hand with right ventricular (RV) reverse remodeling after surgery for isolated severe tricuspid regurgitation (TR). This study aimed to evaluate the level of agreement between clinical improvement and echocardiographic RV reverse remodeling, and determine the relative prognostic powers of these 2 factors in terms of long-term prognosis for patients with isolated TR surgery. Methods and Results: Sixty-one consecutive patients (58±8 years) were included. During a median follow up of 55 months (IQR, 36.5∼71.5 months), a composite endpoint including death and admission for right heart failure was investigated. Extents of reductions in RV end-systolic area (RV-ESA) and subjective clinical improvement at 6 months were examined. There were 6 deaths and 5 admissions for right heart failure. A reduction in RV-ESA of >20% effectively predicted event-free survival, with a sensitivity of 90.9% and a specificity of 72.0% (AUC 0.81, P=0.001). With this cut-off, the agreement between a clinical and echocardiographic response was only 57.4% (35 patients). On Cox regression analysis, RV-ESA change emerged as the only independent predictor of event-free survival, whereas subjective clinical improvement did not. Conclusions: A discrepancy between subjective and echocardiographic improvement at 6 months after isolated TR surgery was observed in 42.6% of the patients. Echocardiographic RV reverse remodeling, but not subjective clinical amelioration, was a strong prognosticator after surgery.  (Circ J 2014; 78: 385–392)

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Background: Cardiac surgery performed in patients with low body weight is a challenge for surgeons. Currently, such outcomes are mainly reported from European or North American centers. In this study, we review our cardiac surgery experience with neonates and infants weighing <2,500g. Methods and Results: We included patients with a body weight <2,500g who received cardiac surgery between January 2008 and December 2012. The survival outcome was compared to that of patients with large body weight, and then the Risk Adjusted Classification for Congenital Heart Surgery (RACHS-1) categorization was used for operative risk stratification. In the 1,245 index operations, 53 patients (4.3%) were <2,500g. The mean body weight was 2,232g (range 1,320–2,500g). The hospital mortality rate was 20.7% (11/53). Most (85%) of the procedures were in RACHS-1 category ≥3. The risk ratio was significantly higher in RACHS-1 category 3 (relative risk [RR]:6.2; 95% confidence interval [CI]:1.6–23.9) and 4 (RR:4.6; 95% CI:1.4–15.0), respectively, while it was not significantly different in category 2 (RR:1.02; 95% CI:1.01–1.02) and category 6 (RR:2.9; 95% CI:0.36–13.3). Conclusions: Cardiac surgery performed on infants with low body weight is generally a complex procedure, but the results are acceptable. The risk was higher than that for patients with higher body weight in RACHS-1 category 3 and 4. Further investigation to improve the outcome of this high-risk group is needed.  (Circ J 2014; 78: 393–398)

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Background: The aim of this study was to assess the outcome of robot-assisted minimally invasive direct coronary artery bypass grafting (MIDCAB), which is also termed “ThoraCAB”. Methods and Results: From 2005 to 2013, 35 consecutive patients underwent MIDCAB via a small thoracotomy on a beating heart. Before performing MIDCAB, the internal thoracic arteries (ITAs) were endoscopically harvested through 3 ports using the da Vinci Surgical System in a completely skeletonized fashion. Distal anastomosis was hand-sewn using a vacuum stabilizer, and a coronary artery active perfusion system was used to prevent myocardial ischemia during anastomosis. Successful robot-assisted ITA harvesting was achieved in all patients. There was an average of 1.7±0.8 grafts (range, 1–3 grafts) per patient. No patient needed mechanical ventilation for more than 24h. There were no deaths, strokes or myocardial infarctions, and none of the patients required conversion to median sternotomy. Conclusions: Robot-assisted ITA harvesting is safe and feasible. ThoraCAB is a relatively simple procedure and allows multivessel bypass grafting after a small thoracotomy. Therefore, it is expected that ThoraCAB will become the standard procedure for minimally invasive coronary revascularization and will be used in totally endoscopic CABG in the future.  (Circ J 2014; 78: 399–402)

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Background: No previous population-based studies have examined secular trends in the incidence of intracerebral hemorrhage (ICH) by its location. Methods and Results: We established 3 cohorts consisting of residents of Hisayama, Japan, aged ≥40 years without a history of stroke or myocardial infarction in 1961 (the first cohort, n=1,618), in 1974 (the second cohort, n=2,038), and in 1988 (the third cohort, n=2,637). Each cohort was followed for 13 years. The age- and sex-adjusted incidence of ICH significantly declined from the first to the second cohort and showed no further change in the third cohort. With regard to the ICH location, the incidence of putaminal hemorrhage decreased steadily, mainly in subjects aged 60–69 years, whereas the incidence of thalamic hemorrhage increased, especially in those aged ≥70 years. Both hypertension and alcohol intake were strong risk factors for ICH in the first cohort, but their influence declined with time. Blood pressure levels in hypertensive subjects decreased significantly, and the proportion of current drinkers decreased slightly over the study period. Conclusions: Our findings suggest that the ICH incidence steeply declined from the 1960s to the 1970s in Japan as a result of the reduced influence of hypertension and alcohol intake, but that this decline has leveled off since then, probably because of the increased incidence of thalamic hemorrhage in the elderly in recent years.  (Circ J 2014; 78: 403–409)

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Background: Red blood cell distribution width (RDW) has been found to be an independent predictor for adverse outcome in patients with heart failure (HF), but there are no data on the association of longitudinal RDW with all-cause mortality and occurrence of anemia. Methods and Results: 1,702 patients discharged from a previous admission for acute HF (AHF) were included. RDW was measured during the available longitudinal history of the patient. Joint modeling and Multistate Markov were used for the analysis. The median RDW at baseline was 15.0% (IQR: 14.0–16.5), and 45.6% of patients had anemia. At a median follow-up of 1.5 years (IQR: 0.45–3.25), 713 patients died. The last RDW-trajectory value and cumulative RDW-trajectory mean were predictive of mortality (HR, 1.18; 95% CI: 1.12–1.24; and HR, 1.12; 95% CI: 1.08–1.16, respectively; P<0.001 for both). This effect, however, varied according the anemia status (P for interaction<0.001), being more pronounced in absence of anemia [HR=1.31 (95% CI: 1.22–1.42) and HR=1.48 (95% CI: 1.33–1.64)] compared to those with anemia [HR=1.08 (95% CI: 1.04–1.13), 1.12 (95% CI: 1.06–1.18)]. Longitudinal RDW (per 1% increasing) was also independently associated with incident anemia [HR=1.10 (95% CI: 1.03–1.18) P=0.002]. Conclusions: Following an admission for AHF, higher longitudinal RDW values over time were associated to an increased risk for both developing anemia and dying. The effect on mortality was more pronounced among non-anemic patients.  (Circ J 2014; 78: 410–418)

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Background: The aim of this study was to determine whether global strain imaging diastolic index (SIDI) obtained using 2-D speckle tracking imaging (2DSI) could predict elevation in and rapid change of LV filling pressure. Methods and Results: Patients (n=126) underwent echocardiography and 2DSI during simultaneous cardiac catheterization. There were 60 patients in whom the same measurements were repeated 5min after i.v. glyceryl trinitrate. LV pre-atrial contraction pressure (pre-A) was measured as a surrogate of LV filling pressure. SIDI was defined as the change of LV longitudinal strain measured using 2DSI during the first one-third of diastole. Then, longitudinal global SIDI (L-global SIDI) was calculated as the mean SIDI of 18 LV segments. Mitral inflow and tissue Doppler imaging were also assessed. Among 126 patients, 93 patients had LV pre-A ≥15mmHg. L-global SIDI had a better correlation with LV pre-A (P<0.001, r=−0.56) than E/e’ (P<0.01, r=0.35). On receiver operating characteristic curve analysis, L-global SIDI <0.48 was the optimum cut-off to predict LV pre-A ≥15mmHg (sensitivity, 82%; specificity, 68%). In addition, the ratio of L-global SIDI (after nitrate/before nitrate) was correlated with the ratio of LV pre-A (after nitrate/before nitrate; P=0.02, r=−0.34). Conclusions: A novel L-global SIDI derived from 2DSI may reflect elevated LV filling pressure and its rapid change better than conventional diastolic parameters.  (Circ J 2014; 78: 419–427)

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Background: The gender differences in patients with chronic heart failure (CHF) remain to be fully elucidated in the Japanese population. Methods and Results: We examined gender differences in clinical characteristics, treatment and long-term outcome in 4,736 consecutive CHF patients in stage C/D (mean age, 69 years) out of 10,219 patients registered in the CHF Registry, named CHART-2 Study (NCT 00418041). Compared with male patients (68%, n=3,234), female patients (32%, n=1,502) were 3.8 years older and had lower prevalence of ischemic heart disease, diabetes, smoking, myocardial infarction and cancer. At baseline, women had higher prevalence of preserved left ventricular function but had higher NYHA functional class and increased brain natriuretic peptide level. In women, aspirin, β-blockers and statins were less frequently used and diuretics were more frequently used. Crude mortality rate was similar between the genders during the median 3.1-year follow-up (52.4/1,000 and 47.3/1,000 person-years for women and men, respectively, P=0.225). On multivariate Cox regression analysis, women had a reduced risk of mortality (adjusted HR, 0.791; 95% CI: 0.640–0.979, P=0.031). Conclusions: Substantial gender differences exist in stage C/D CHF patients in real-world practice in Japan. Although female CHF patients had better survival than male patients after adjustment for baseline differences, crude mortality rate was similar between the genders, possibly reflecting relatively severer clinical manifestations in women.  (Circ J 2014; 78: 428–435)

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Background: Some potential biomarkers have been reported recently in patients with pulmonary arterial hypertension (PAH), but the most clinically useful among these potential biomarkers, especially in childhood PAH, has not been identified. Therefore, this study investigated which biomarker is useful in assessing severity of and patient prognosis in childhood idiopathic PAH (IPAH)/heritable PAH (HPAH). Methods and Results: Fifty-nine patients who were younger than 16 years at onset of IPAH/HPAH were selected. The following 10 biomarker candidates were quantified: high-sensitivity troponin T, human heart fatty acid-binding protein, N-terminal pro-brain natriuretic peptide (NT-proBNP), pentraxin-3, soluble ST2 (sST2), angiopoietin-2 (Ang-2), matrix metalloproteinase 2, tenascin C, endostatin (ES), and thymidine kinase. Functional characteristics and clinical outcomes were analyzed retrospectively. NT-proBNP, sST2, Ang-2, and ES correlated well with New York Heart Association class. On area under the receiver operating characteristic curve analysis, sST2 had a significantly good relationship with prognosis. On Kaplan-Meier curve and univariate Cox regression analyses, elevated sST2 and NT-proBNP level predicted poor outcome of the present patients with childhood IPAH/HPAH. Furthermore, patients with elevated sST2 had significantly worse prognosis among those with high NT-proBNP. Conclusions: The sST2 and NT-proBNP combination is a useful biomarker to predict clinical condition and outcome in patients with childhood IPAH/HPAH.  (Circ J 2014; 78: 436–442)

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Background: The number of women with congenital heart disease reaching reproductive age has increased due to therapeutic advances. The aim of this study was to examine obstetric and cardiac problems during pregnancy after Mustard/Senning repair for transposition of the great arteries. Methods and Results: Sixty pregnancies in 34 women from 3 centers were studied. The women were interviewed, and their records reviewed for clinical status and diagnostic evaluation. Age range was 16–34 years during first pregnancy, and all were in a low functional class. There were 11 miscarriages and 5 abortions. Of 44 successful pregnancies, 20 were vaginal deliveries and 24, cesarean sections. A total of 25% were delivered prematurely. Thirteen babies had birth weight <2,500g. Deterioration in functional class occurred in 7 pregnancies, without recovery in 5. Deterioration in systolic function occurred in 4 of 44 echocardiographically documented pregnancies, without recovery in 75%. In 2 women resuscitation was necessary during delivery, in 1, supraventricular tachycardia occurred during labor. Conclusions: Pregnancy is usually well-tolerated, but outcome is unforeseeable and life-threatening problems can occur. These women belong in cardiac care conducted by experienced congenital cardiologists, who systematically check for typical residua. The pregnancy should be planned and gynecologists/obstetricians with special expertise integrated into the consultations. During delivery a congenital cardiologist, and an anesthetist experienced in congenital cardiology, should be present for possible severe cardiac events.  (Circ J 2014; 78: 443–449)

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Background: Adults with transposition of the great arteries (TGA) after atrial switch repair have an increased risk for arrhythmia and sudden cardiac death. We analyzed whether a remote monitoring (RM) system as part of an implantable cardiac device contributes to timely recognition and improved treatment of critical arrhythmias in these patients. Methods and Results: All consecutive TGA patients (n=11) requiring a pacemaker or cardiac resynchronization therapy with or without implantable cardioverter defibrillator between 2008 and 2011 were included. RM-detected arrhythmia, abnormality of device integrity and reaction time from event transmission until acknowledgement via email and clinical decision making were analyzed and compared to a control group (n=21). In 10 patients (91%) 17 arrhythmias were detected, 8 patients (80%) indicated no symptoms. In the RM group time interval from transmission to acknowledgement was 2.4 days (range, 0–4.5 days). Clinical decision-making was advanced by a mean of 77.5 days (range, 10–197 days) compared with conventional follow-up and identified adaption of anti-arrhythmic medication in 8, electrical cardioversion in 2, overdrive pacing in 1 and radiofrequency ablation in 2 patients. A coronary sinus lead fracture was identified in 1 patient followed by successful replacement. Conclusions: RM enables early detection of tachyarrhythmia followed by optimization of medical treatment and potentially life-saving anti-tachycardic intervention in adults after atrial repair of TGA.  (Circ J 2014; 78: 450–456)

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Background: Although endovascular therapy (EVT) has advanced, few reports have compared EVT and bypass surgery in claudication patients with femoropopliteal disease. The present study used data from a multicenter registry in Japan to analyze outcomes of EVT and bypass surgery for claudication patients with Trans-Atlantic Inter-Society Consensus (TASC)-II C and D femoropopliteal lesions. Methods and Results: Of 1,156 patients who underwent revascularization, 696 patients were treated for intermittent claudication. A total of 263 patients with femoropopliteal lesion were classified into TASC-II C and D. The primary and secondary patency rates of the EVT and bypass surgery groups were analyzed. The overall complication rate was 14.4% in the bypass surgery group and 3.5% in the EVT group (P<0.01). The 1- and 5-year primary patency rates were 82.1% and 69.4% in the bypass surgery group and 67.8% and 45.2% in the EVT group, respectively. Although the bypass surgery group had a higher primary patency rate than the EVT group (P<0.01, log-rank test), secondary patency rates did not differ significantly between the two groups. Conclusions: Although bypass surgery is clearly feasible for claudication patients with TASC-II C and D femoropopliteal disease, EVT is also a good option because of its lower complication rate and good secondary patency rate in patients in poor condition for bypass.  (Circ J 2014; 78: 457–464)

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Background: ECG-diagnosed left ventricular hypertrophy (LVH), the Cornell voltage (CV: ≥2.8mV in males and ≥2.0mV in females) or Cornell product (CP: ≥244.0mV×ms), were selected in Western countries for their ability to diagnose anatomical LVH. Methods and Results: We aimed to elucidate the CV and CP values that were associated with a significantly increased risk of cardiovascular or stroke mortality and morbidity in a Japanese general population (n=10,172). In the receiver-operating curves analysis of CV and CP for predicting the risks, the area under the curve in females was greater than in males. In a quintile-based multivariate analysis that was performed separately for females and males, the mortality and morbidity risks of CV were significantly increased at the highest quintile of CV (>1.71mV) in females. In males, the mortality risk was significantly increased at the highest quintile of CV (>2.04mV). Additionally, in the parallel analysis of CP that included both males and females, the morbidity risk was significantly elevated in subjects with CP belonging to the 4th (158.7–193.4mV×ms; hazard ratio=1.387) or 5th quintiles (≥193.5mV×ms; hazard ratio=1.507), compared with those with CP values within the lowest quintile (<101.9mV×ms). Conclusions: Cardiovascular and stroke risks may be elevated at lower levels of CV and CP in Japanese subjects, especially females.  (Circ J 2014; 78: 465–475)

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Background: To evaluate the prognosis after pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension (CTEPH), a lung biopsy was performed in 34 patients with central CTEPH and in 7 patients with peripheral CTEPH during PTE. Methods and Results: Postoperative prognosis was classified from A to E based on the postoperative hemodynamic parameters and clinical condition, and was compared with the index of occlusion (IOCTEPH), which indicates the degree of occlusion in the small pulmonary arteries. Criteria of (A–E) were established only for central CTEPH. Category (A) corresponded to an IOCTEPH from 1.0 to 1.4, (B) from 1.5 to 1.7, (C) from 1.8 to 2.0, and (D) from 2.1 to 2.4. One patient with an index of 3.0 was rated as (E). This patient had collateral vessels around the obstructed small pulmonary arteries and died postoperatively. In all 12 patients who underwent PTE after the criteria were established, postoperative hemodynamic parameters and clinical conditions were consistent with the IOCTEPH. One patient with a high degree of medial atrophy in their small pulmonary arteries died after PTE. Conclusions: These results indicate that a lung biopsy during PTE is useful for prognostication in patients with CTEPH.  (Circ J 2014; 78: 476–482)

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Background: Patients with acute pulmonary embolism (APE) often have negative T waves (Neg T) in precordial leads at presentation, but this is also found in acute coronary syndrome (ACS) caused by left anterior descending coronary artery (LAD) disease. Methods and Results: Differences in Neg T on admission electrocardiograms were studied between 107 patients with APE and 248 patients with ACS caused by LAD disease. All patients had Neg T in leads V₁–₄ and were admitted within 7 days from symptom onset. The number of leads with Neg T (4.8±1.8 vs. 5.5±1.7, P<0.001) and maximum magnitude of Neg T (3.4±2.0 vs. 4.7±3.3mm, P<0.001) were lower in APE. The frequency of occurrence of Neg T in each of the 12 leads, and the precordial lead with the greatest Neg T (peak Neg T) differed between APE and ACS (all P<0.05, respectively). APE was strongly associated with the presence of Neg T in both leads III and V₁ and peak Neg T in leads V_1–2. The combination of these 2 findings identified APE with 98% sensitivity, 92% specificity, and 94% predictive accuracy, which represented the highest diagnostic accuracy. Conclusions: Among patients with APE and ACS who have precordial Neg T, the presence of Neg T in leads III and V₁ and/or peak Neg T in leads V_1–2 simply but accurately differentiates APE from ACS.  (Circ J 2014; 78: 483–489)

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Background: A prior phase I/IIa clinical trial provided evidence for safety, feasibility and potential efficacy of i.m. injection of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ cells in patients with critical limb ischemia (CLI). Methods and Results: A phase II trial of CD34+ cell therapy was conducted in patients with CLI to explore endpoint selection and timing. No-option CLI patients (n=11) underwent i.m. transplantation of G-CSF-mobilized CD34+ cells isolated by magnetic sorting. Ischemic rest pain scales improved from week 2 vs. baseline (P<0.05). Skin perfusion pressure (P=0.0175), transcutaneous partial oxygen pressure (P=0.0446) and pain-free walking distance (P=0.0056) improved from week 2, total walking distance from week 8 (P=0.0182) and toe brachial pressure index from week 12 (P=0.0174) vs. baseline. These parameters peaked at week 36 or 52. Rutherford’s category improved from week 24 vs. baseline (P=0.0065). CLI-free ratio serially increased and peaked (85.7%) at week 36. Serial change in Rutherford’s category correlated with that in Rest Pain Scale (P=0.0374), but not with that in any physiological parameters. Conclusions: Ischemic rest pain scales and physiological parameters improved relatively early after cell therapy, then plateaued later accompanied by recovery from the CLI state. Rutherford’s category and CLI-free ratio at week 36 or later may be suitable endpoints in cell therapy clinical trials for CLI. Functional parameters should be evaluated independently of such clinical endpoints for ischemia severity. (Clinical Trial Registration: URL: https://dbcentre3.jmacct.med.or.jp/jmactr/Default.aspx. Unique identifier: JMA-IIA00022)  (Circ J 2014; 78: 490–501)

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(Circ J 2013; 77: 2873–2874)

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