Cardiac arrhythmias are cardiac rhythm disorders that comprise an important epidemiological and public health problem. Cardiac arrhythmias are significantly associated with increased risks of cardiovascular complications and sudden death, consequently leading to decreased quality of life, disability, high mortality, and healthcare expense. Atrial fibrillation (AF) is the most common sustained arrhythmia, and has been further increasing with the aging of society. Although the prevalence is relatively lower in Asians than in Westerners, the prognostic impacts on stroke and mortality in Asians are comparable. Sudden cardiac death (SCD) occurs in approximately 40 cases per 100,000 persons annually in each country of Asia. Most cases are caused by myocardial infarction and ventricular fibrillation in out-of-hospital cardiac arrest cases, but the proportion of myocardial infarction is lower in Asia than in Western countries. The primary electrophysiological disorders related to channelopathies, such as long QT syndrome, short QT syndrome, Brugada syndrome, early repolarization syndrome, and catecholaminergic polymorphic ventricular tachycardia, are estimated to be responsible for 10% of SCDs. Implantable cardioverter-defibrillator implantation has become established as an effective secondary prevention for SCD, and numbers have been increasing annually worldwide. New insights into arrhythmic diseases have been emerging from epidemiological, clinical, and genetic research, and contribute to improvements in diagnosis and prognosis.  (Circ J 2013; 77: 2419–2431)

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary artery disease (CAD). HDL particles exert many effects in vitro and in vivo that may protect arteries from chemical or biological harm or facilitate repair of injuries. Nevertheless, HDL has not yet been successfully exploited for therapy. One potential reason for this shortfall is the structural and functional complexity of HDL particles, which carry more than 80 different proteins and more than 200 lipid species as well as several microRNAs and other potentially bioactive molecules. This physiological heterogeneity is further increased in several inflammatory conditions that increase cardiovascular risk, including CAD itself but also diabetes mellitus, chronic kidney disease, and rheumatic diseases. The quantitative and qualitative modifications of the proteome and lipidome, as well as the resulting loss of functions or gain of dysfunctions, are not recovered by the biomarker HDL-cholesterol. As yet the relative importance of the many physiological and pathological activities of normal and dysfunctional HDL, respectively, for the pathogenesis of atherosclerosis is unknown. The answer to this question, as well as detailed knowledge of structure-function-relationships of HDL-associated molecules, is a prerequisite to exploit HDL for the development of anti-atherogenic drugs as well as of diagnostic biomarkers for the identification, personalized treatment stratification, and monitoring of patients at increased cardiovascular risk.  (Circ J 2013; 77: 2432–2448)

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Efficient and functional mitochondrial networks are essential for myocardial contraction and cardiomyocyte survival. Mitochondrial autophagy (mitophagy) refers to selective sequestration of mitochondria by autophagosomes, which subsequently deliver them to lysosomes for destruction. This process is essential for myocardial homeostasis and adaptation to stress. Elimination of damaged mitochondria protects against cell death, as well as stimulates mitochondrial biogenesis. Mitophagy is a tightly controlled and highly selective process. It is modulated by mitochondrial fission and fusion proteins, BCL-2 family proteins, and the PINK1/Parkin pathway. Recent studies have provided evidence that miRNAs can regulate mitophagy by controlling the expression of essential proteins involved in the process. Disruption of autophagy leads to rapid accumulation of dysfunctional mitochondria, and diseases associated with impaired autophagy produce severe cardiomyopathies. Thus, autophagy and mitophagy pathways hold promise as new therapeutic targets for clinical cardiac care.  (Circ J 2013; 77: 2449–2454)

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Signal processing via heterotrimeric G-proteins is one of the most widely used systems for signal transfer across the cell membrane. This signaling system regulates most physiological and pathophysiological processes in mammals and is therefore the primary target of many pharmaceutical agents. The heterotrimeric G-protein signaling system includes the G-protein-coupled receptor (GPCR), heterotrimeric G-proteins, and effectors. The G-proteins are activated by the GPCR to mediate a signal to effector molecules. However, other players in this system that regulate the activation status of heterotrimeric G-proteins independently of GPCR have been identified. Such accessory proteins for heterotrimeric G-protein can provide additional signal input to the G-protein signaling system, or may act as alternative binding partners of G-protein subunits serving as yet unknown roles in cells. It has been reported that this class of proteins is expressed in the cardiovascular system and contributes to signal integration involved in the various diseases. This review provides an overview of the current understanding of accessory proteins for heterotrimeric G-proteins in their 4 functional subsets, including guanine nucleotide exchange factors (GEFs), guanine nucleotide dissociation inhibitors (GDIs), GTPase-activating proteins (GAPs), and Gβγ-interacting proteins, and discusses their roles in the development of cardiovascular diseases. Better understanding of these components may contribute new insight into the complex network of molecules governing GPCR signaling in the cardiovascular system.  (Circ J 2013; 77: 2455–2461)

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Cardiometabolic disease, a global health threat, has been linked to chronic inflammation, in which activated macrophages play a key role. Macrophages are highly heterogeneous hematopoietic cells found in nearly every tissue in the body. Various stimuli recruit monocytes into the cardiovascular system and metabolic organs, where they differentiate to macrophages, and activate these pro-inflammatory phagocytes, leading to the initiation and development of inflammation in these organs. Key regulators of macrophage activation therefore may serve as therapeutic targets for cardiometabolic disease. The Notch signaling pathway, involving 5 ligands and 4 receptors, regulates the differentiation of various cell types during development, and also contributes to the disease processes in adults. We found that the Notch ligand delta-like 4 (Dll4) activates macrophages in vitro as determined by the induction of genes and pathways associated with cardiovascular and metabolic disorders. Our recent study demonstrated in vivo that blockade of Dll4 by a neutralizing antibody attenuates key features typical of cardiovascular and metabolic diseases, such as accumulation of activated macrophages in arteries and fat; chronic atherosclerosis; arterial and valvular calcification; insulin resistance; and fatty liver. These results suggest that Dll4-mediated Notch signaling participates in the shared disease mechanisms for cardiovascular and metabolic disorders. This review summarizes the role of macrophages and Dll4/Notch signaling in the development of inflammation in both the cardiovascular system and metabolic organs.  (Circ J 2013; 77: 2462–2468)

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Background: Activation imaging with 3-dimensional speckle-tracking echocardiography (3D-STE) aims to visualize the time required for the onset of regional contraction from QRS onset. We hypothesized that the optimal setting of activation imaging was associated with electrical activation. This study was designed to determine an optimal setting of activation imaging with 3D-STE in comparison with that of a voltage mapping system and to assess the feasibility of this imaging method. Methods and Results: We enrolled 7 patients who underwent electrical voltage mapping. Regional deformation was measured by area change ratio (ACR) with 3D-STE. Activation imaging data were obtained at 10%, 25%, 50%, and 100% of maximal ACR values as the threshold for onset of regional contraction. Duration of LV electrical intraventricular activation time (IVAT_electrical) by voltage mapping and mechanical IVAT (IVAT_mechanical) by activation imaging was defined as the time difference between the first and latest endocardial activation sites. We obtained 21 data sets under various conduction patterns and pacing configurations. The strongest correlation between IVAT_mechanical and IVAT_electrical was observed at 25% of maximal ACR values (IVAT_electrical=0.47 * IVAT_mechanical+20, R=0.80, P<0.001). Concordance of the first and latest activated segments between activation imaging and voltage mapping was 90.5% at this setting (19 studies). Conclusions: Activation imaging with 3D-STE may be a feasible noninvasive method of dyssynchrony imaging based on electromechanical coupling.  (Circ J 2013; 77: 2481–2489)

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Background: The upper limit of vulnerability (ULV) closely correlates with the defibrillation threshold (DFT). The aim of this study was to establish the optimal protocol for using the ULV test to predict high DFT (>20J) without inducing ventricular fibrillation (VF). Methods and Results: The 10-J and 15-J ULV test with 3 coupling intervals (–20, 0, and +20ms to the peak of T-wave) and the DFT test were performed in 96 patients receiving implantable cardioverter defibrillator. ULV ≤10J was confirmed in 47 (49%). ULV ≤15J was confirmed in 70 (77%) of 91 patients (15-J ULV test could not be done in 5). The sensitivity and negative predictive value of both ULV >10J and >15J for predicting high DFT were 100%. The specificity and positive predictive value of ULV >15J were higher than those for ULV >10J (85% vs. 55%, 43% vs. 22%, respectively). The rate of VF inducibility for confirming ULV ≤15J was lower than that for ULV ≤10J (23% vs. 51%, P<0.0001). On analysis of single 15-J ULV test only at the peak of T-wave, VF was not induced in 79 of 91 patients, but 4 of these had high DFT. Conclusions: The 15-J ULV test with 3 coupling intervals could correctly identify high-DFT patients and reduce the necessity for VF induction at defibrillator implantation.  (Circ J 2013; 77: 2490–2496)

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Background: The superiority of drug-eluting stents (DES) over bare-metal stents (BMS) 7 years after unprotected left main coronary artery (LMCA) stenting has not been investigated. Methods and Results: From 2003 to 2005, 182 patients underwent stent implantation for unprotected LMCA disease (DES, 96 patients; BMS, 86 patients; acute coronary syndrome cases excluded), and the 7-year clinical outcomes between the DES and BMS groups were compared. The incidence of cardiac death or non-fatal myocardial infarction was similar between the DES and BMS groups (11.0% vs. 13.5%, P=0.78). The incidence of target lesion revascularization (TLR) at 7 years was significantly lower in the DES group than in the BMS group (26.4% vs. 40.5%, P=0.009); the incidence from 1 to 4 years and that beyond 4 years were similar between the DES and BMS groups (8.9% vs. 7.9%, P=0.97; 10.0% vs. 8.7%, P=0.74, respectively). Among patients with bifurcation lesions, whereas the incidence of 7-year TLR was significantly lower in the DES group than the BMS group in patients undergoing single-stent procedures (15.9% vs. 48.6%, P=0.002), it was similar between the 2 groups in patients undergoing 2-stent procedures (38.5% vs. 39.3%, P=0.49). Conclusions: With the exception of the 2-stent procedure, the 7-year outcomes after DES implantation for LMCA disease were superior to those after BMS implantation because of the lower TLR rate, when considering TLR during the late phase.  (Circ J 2013; 77: 2497–2504)

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Background: Optimal ring size in tricuspid annuloplasty (TAP) surgery to treat functional tricuspid regurgitation (TR) was investigated because optimal ring size remains undefined. Methods and Results: Sixty seven patients who underwent TAP at our institution were retrospectively studied. Tricuspid Annuloplasty Ring size Index (TARI) was defined as implanted tricuspid annuloplasty ring size divided by body surface area (BSA). Different TARI cut-off values were tested to determine which value produced the greatest difference in TR improvement (TRI=preoperative minus postoperative TR grade) between patients with TARI smaller (group S) and larger (group L) than the cut-off. Group S was also subdivided by ring type: Cosgrove rings (SC) and MC3 rings (SM). TARI and TRI were negatively correlated (r=–0.307). A TARI threshold of 18.9mm/m² produced the greatest and most significant difference (P<0.0005) in TRI. Defining groups S and L using this threshold, TRI was significantly greater for group S (1.77±0.80) than for group L (0.97±0.83); P <0.0005. There was no difference in TRI between groups SC and SM. Conclusions: A novel index TARI that normalizes tricuspid annuloplasty ring size by BSA was developed. Choosing ring size to make TARI <18.9mm/m² is likely to be better than setting an upper limit of absolute ring size in the surgical treatment of TR.  (Circ J 2013; 77: 2505–2513)

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Background: There are few investigations of the changes in tricuspid valve (TV) and right ventricular (RV) morphology following bidirectional cavopulmonary anastomosis (BCPA). Methods and Results: The 2-D echocardiograms of 35 children (male, n=23; female, n=12; median age, 6 months; range, 3–10 months) with hypoplastic left heart syndrome, 1 month before and after BCPA performed between 2005 and 2011, were retrospectively reviewed. Patients who underwent TV repair at BCPA were excluded. From the 4-chamber view, the coaptation length, vena contracta width and RV end-diastolic area before and after BCPA were measured and indexed to surface area. The severity of tricuspid regurgitation was graded qualitatively. After BCPA, RV end-diastolic area decreased from 2,951±584 to 2,580±591mm²/m² (P<0.001). The coaptation length of the anterior leaflet (8.8±5.8 vs. 11.0±6.2mm/m², P=0.0014) and of the septal leaflet (13.5±5.3 vs. 15.8±5.4mm/m², P=0.0072) increased after BCPA. The vena contracta width decreased (5.8±4.9 vs. 4.3±4.2mm/m², P=0.035), although there was no change in tricuspid regurgitation grade after BCPC (1.4±0.7 vs. 1.4±0.9, P=0.234). Conclusions: In children with hypoplastic left heart syndrome after BCPA, the coaptation length of the anterior and septal leaflets of the TV improved concomitantly with vena contracta width and RV end-diastolic area despite unchanged tricuspid regurgitation grade. This suggests that favorable RV and TV remodeling accompanies the reduction in RV volume load following BCPA.  (Circ J 2013; 77: 2514–2518)

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Background: Vagal activation by electrical stimulation has been shown to improve the long-term survival of rats with chronic heart failure (CHF) after extensive myocardial infarction (MI). Acetylcholinesterase inhibition increases synaptic acetylcholine, and can disproportionately increase vagal tone. To develop an alternative therapy for CHF using a clinically available drug, the present study investigated whether oral donepezil, an acetylcholinesterase inhitor, could reproduce the beneficial effects of electrical vagal stimulation in rats. Methods and Results: At 2 weeks after ligation of the proximal left coronary artery, resulting in extensive MI, surviving rats were randomly assigned to donepezil-treated and untreated groups. Donepezil treatment started 14 days after MI significantly decreased the heart rate (325±6 vs. 355±10beats/min, P<0.05) and improved 140-day survival (29% to 54%, P=0.03) by preventing pump failure (cardiac index: +29%, P<0.001; left ventricular+dp/dt_max: +18%, P<0.01; left ventricular end-diastolic pressue: −26%, P<0.01) and cardiac remodeling (biventricular weight: 2.73±0.04 vs. 3.06±0.08g/kg, P<0.001). In addition, donepezil treatment lowered the levels of plasma arginine vasopressin, brain natriuretic peptide, catecholamine, and tissue pro-inflammation markers. Conclusions: Oral donepezil markedly improved the long-term survival of CHF rats by preventing pump failure and cardiac remodeling, indicating that donepezil may be a new alternative therapy for CHF.  (Circ J 2013; 77: 2519–2525)

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Background:  Recent in-vitro observations suggest that left ventricular (LV) contraction is powered by ‘stretch activation’, an intrinsic mechanism by which the stretching of an activated cardiomyocyte causes delayed force redevelopment. We hypothesized that mechanical dyssynchrony is related to prolonged early systolic stretch that delays the timing of peak segmental shortening. Methods and Results: The time intervals from R wave to segmental longitudinal stretch in early systole (T_stretch) and peak shortening (T_peak) and the respective standard deviations (σT_stretch and σT_peak) were measured by speckle-tracking echocardiography in 57 patients undergoing cardiac resynchronization therapy (CRT). The percentage of time spent in shortening, normalized to T_peak duration [corrected ΔT=(T_peak–T_stretch)_/T_peak] correlated with LV reverse remodeling (reduction in end-systolic volume ≥15%). Of the 57 patients, 40 (70.2%) demonstrated LV reverse remodeling at an average follow-up of 263±125 days after CRT. At baseline, T_stretch and σT_stretch correlated with T_peak and σT_peak, respectively. Though there was no difference in T_stretch, T_peak, σT_stretch and σT_peak between responders and non-responders, corrected ΔT in the mid-lateral and mid-septal segments was shorter in the responders (P<0.05 for both) and the average of the 2 independently predicted LV reverse remodeling (area under the curve: 0.77, P=0.001). Conclusions: Mapping LV segmental shortening in relation to early systolic stretch may aid dyssynchrony assessment in patients undergoing CRT.  (Circ J 2013; 77: 2526–2534)

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Background: The implantable loop recorder (ILR) is a useful tool for diagnosing paroxysmal conditions potentially related to arrhythmias. Most investigations have focused on selected clinical studies or high-volume centers. The aim of this study was to evaluate the indications and outcomes of the ILR in real clinical practice. Methods and Results: This was a prospective, multicenter registry of patients undergoing ILR implantation for clinical indications (April 2006–December 2008). Clinical characteristics (symptoms, arrhythmias, treatments) were recorded in a database. Follow-up data at 1 year or after the occurrence of the first episode were also recorded. Total enrollment: 743 patients (male, 413, 55.6%; 64.9±16 years); 228 (30.7%) had structural heart disease (SHD), and 183 (24.6%), bundle branch block (BBB). Recurrent syncope (76.4%) was the most common indication for implantation. Complete follow-up was obtained for 680 patients (91.5%). Three hundred and twenty-five patients (48%) presented 414 events, with a final diagnosis in 230 patients (70.8% of patients with events; 33.1% of patients with follow-up). Syncope secondary to bradyarrhythmia was the most frequent diagnosis. Similar rates of final diagnoses were noted in subgroups of SHD, BBB and normal heart. Regarding the cause of implantation, higher event rates were registered among patients with recurrent syncope. Conclusions: One-third of patients obtained a final diagnosis with the ILR, independent of the baseline characteristics. Only the cause of implantation provided different rates of final diagnosis.  (Circ J 2013; 77: 2535–2541)

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Background: Heart failure (HF) is a complex clinical syndrome, resulting from structural and/or functional cardiac disease. The aim of this study was to determine whether the activity of Rho-kinase, which has been identified as an important therapeutic target of cardiovascular disease, is enhanced in HF patients. Methods and Results: Total and phosphorylated forms of myosin binding subunit (t-MBS and p-MBS), a substrate of Rho-kinase, were measured on western blotting in circulating leukocytes, and the p-MBS/t-MBS ratio was defined as an index of systemic Rho-kinase activity. First, during the time-course of acute HF (n=12), Rho-kinase activity was significantly elevated in the acute phase compared to the chronic phase (1.19±0.06 vs. 0.97±0.04, P<0.05). Next, Rho-kinase activity was examined in 30 controls and 130 chronic HF patients (cardiomyopathy, n=57; valvular heart disease, n=35; ischemic heart disease [IHD], n=33; and others, n=5). As compared with the controls, Rho-kinase activity was significantly elevated in the total HF group (1.14±0.02 vs. 0.77±0.05, P<0.0001) and in each underlying heart disease (P<0.05 each). Importantly, in the high-risk non-IHD group, Rho-kinase activity was significantly associated with plasma brain nutriuretic peptide level. Finally, p-MBS was expressed in myocardial biopsy samples (immunohistochemistry) in chronic HF patients (n=36), independent of Rho-kinase activity in leukocytes. Conclusions: Rho-kinase is activated in HF patients, suggesting that it could be a new therapeutic target of the disorder.  (Circ J 2013; 77: 2542–2550)

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Background: The pathophysiology of abnormal relaxation pattern in the transmitral flow (TMF) velocity waveform has not been fully elucidated. Methods and Results: A total of 173 patients who underwent comprehensive Doppler echocardiography and diagnostic cardiac catheterization for coronary artery disease were enrolled in the study. Peak early and late diastolic TMF velocities (E and A, respectively) were measured. Minimum left ventricular (LV) pressure; LV pre-A wave pressure (surrogate of mean left atrial [LA] pressure); time constant (τ) of LV pressure decay; and LV ejection fraction (LVEF) were calculated. Patients with E/A ratio <1.0 and LVEF ≥50% were enrolled. Patients with τ ≥48ms and those with τ <48ms were compared. The 2 groups had no significant differences in E or E/A. Minimum LV pressure (6.9±2.2mmHg vs. 3.6±2.9mmHg, P<0.0001) and LV pre-A wave pressure (9.5±2.4mmHg vs. 6.1±3.0mmHg, P<0.0001) were significantly higher in patients with τ ≥48ms compared to those with τ <48ms, but the difference between the LV pre-A and minimum LV pressures was similar between the groups (2.6±1.4mmHg vs. 2.5±1.5mmHg, P=0.89). Conclusions: Proportional elevations in minimum LV and pre-A pressures, due to deteriorated LV relaxation, resulted in no changes in the pressure gradient between the LA and LV in early diastole, E, or E/A.  (Circ J 2013; 77: 2551–2557)

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Background: Increasing evidence indicates that GABAergic neurons in the nucleus of the solitary tract (NTS) play a significant role in the arterial baroreceptor reflex and control of cardiovascular homeostasis. However, the role of these neurons in the development of hypertension is not yet fully clear. Methods and Results: In the present study, we first confirmed that GABA_B receptor (GBR) expression is enhanced in the NTS of SHR as compared with WKY rats using real-time RT-PCR and western blots. To study the functional consequence of upregulated GBR expression, GBR was overexpressed in the NTS by bilateral microinjection of the AAV2-GBR1 viral vector into the NTS of WKY rats. Immunofluorescence staining and western blots demonstrated that microinjection of AAV2-GBR1 into the NTS of WKY rats resulted in a significant increase in GBR1 expression in the NTS neurons. Overexpression of GBR in the NTS induced a chronic elevation in blood pressure and heart rate in the normotensive WKY rats. In an acute study, the pressor response to baclofen microinjected into the NTS was enhanced in SHR as compared with WKY rats. Conclusions: GBR1 expression is enhanced in the NTS of SHR vs. WKY rats and overexpression of this gene in the NTS results in chronic elevation of blood pressure and heart rate in normotensive rats.  (Circ J 2013; 77: 2558–2566)

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Background: The present study was conducted to examine the association of dietary salt intake with changes in serum sodium (srNa) levels when angiotensin II receptor blocker (ARB) treatment is changed to the combination of ARB plus low-dose diuretic (hydrochlorothiazide [HCTZ]). Methods and Results: In 88 patients (age 70±12 years), ARB treatment was switched to the combination therapy (same dosage ARB+12.5mg/day HCTZ). The srNa level was measured before and 6 months after administration of the combination. The daily salt intake was estimated by the Kawasaki formula using second morning urine sample. The study subjects were divided into quintile ranges according to daily salt intake. The reduction in srNa levels by switching to the combination treatment was significant in subjects in the lowest quintile Q5 (≤8.9g/day salt intake), but not in those in Q1–4 (28.1–9.3g/day salt intake). Increases in serum creatinine and uric acid levels were significantly larger in the former group than in the latter group. Conclusions: In elderly Japanese subjects with low salt intake (<8.9g/day), the addition of a low-dose diuretic (12.5mg HCTZ) to ARB treatment causes significant reduction in srNa levels, which might affect blood osmolarity.  (Circ J 2013; 77: 2567–2572)

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Background: Plaque disruption and its healing is thought to be the major mechanism of atherosclerosis, but the contribution of silent plaque disruption to luminal stenosis progression has not been fully clarified. The aim of this study was therefore to examine the change in luminal stenosis at the site of silent plaque disruption. Methods and Results: Consecutive patients (n=36) who received coronary angiography and angioscopy that identified silent plaque disruption (baseline) and had repeated coronary angiography later (follow-up) were included for analysis. Silent plaque disruption was defined as plaque with thrombus detected in non-culprit segments. Diameter stenosis of the site was angiographically measured at baseline and at follow-up, and their difference was defined as stenosis change. Statin was used in 89% of study patients, and serum low-density lipoprotein cholesterol level was 91±21mg/dl. The diameter stenosis decreased significantly from baseline to follow-up at 12±4 months (32±14% vs. 27±14%, P<0.001), and the stenosis change was −5.6±7.9%. High-density lipoprotein cholesterol (HDL-C) was significantly associated with stenosis change (r=−0.51, P=0.001) and was the only factor significantly associated with stenosis change. Conclusions: In the era of optimal medical therapy with statin, the site of silent plaque disruption showed significant regression of luminal stenosis. Nevertheless, serum HDL-C was inversely associated with stenosis change, and its low level remained as a potential risk of luminal stenosis progression at the site of silent plaque disruption.  (Circ J 2013; 77: 2573–2577)

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Background: Intensive lipid-lowering therapy with statins reduces cardiovascular events, but residual cardiovascular risks remain. Intake of n-3 polyunsaturated fatty acids (PUFAs) has been associated with cardiovascular events. We examined the relationships between serum n-3 PUFAs and coronary atherosclerotic findings on computed tomography angiography (CTA) in patients undergoing statin treatment. Methods and Results: We enrolled 172 subjects (mean age: 68.2 years; 64% men) prior to statin treatment for 6 months. Serum PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid, were measured. When the patients were divided into 2 groups according to the median EPA level (61.3μg/ml), the low-EPA group showed higher incidences of 3-vessel plaque involvement (62% vs. 43%, P=0.015), noncalcified plaques (NCPs) (74% vs. 52%, P=0.0016), extensive NCPs (≥2 segments) (56% vs. 34%, P=0.0036), and high-risk plaques (minimum CT density <39HU and remodeling index >1.05) (43% vs. 22%, P=0.0034). Multivariate analyses revealed that low EPA levels were an independent factor for these coronary plaque findings. The DHA levels were not independently associated with these findings. Conclusions: Low serum EPA level, but not serum DHA, is associated with the presence and extent of NCPs and high-risk plaques detected by coronary CTA in patients undergoing lipid-lowering therapy with statins.  (Circ J 2013; 77: 2578–2585)

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Background: Recent studies demonstrated that iron overload could enhance the production of arachidonic acid and prostanoid, suggesting a causal connection between these signals and iron-overload cardiomyopathy. However, information regarding the downstream signaling is limited. Because thromboxane A₂ (TXA₂) and prostacyclin are the 2 major prostanoids in the cardiovascular system, and TXA₂ plays a major role in vascular atherosclerosis and has pro-inflammatory characteristics, we intended to elucidate the role of TXA₂ in iron-overload cardiomyopathy. Methods and Results: A 4-week iron loading protocol was instituted for both TXAS gene-deleted (TXAS^−/−) mice and wild-type (WT) mice, with less severe cardiac fibrosis and preserved normal left ventricular contraction in the TXAS^−/− mice. Inflammatory profiles, including MCP-1, TNF-α, IL-6, ICAM-1, and myeloperoxidase activity were also lower in the TXAS^−/− as compared with WT littermates. TXAS supplement to the iron-injured TXAS^−/− mice re-aggravated cardiac inflammation. Using a TXA₂ analog, U46619, for NFAT reporter luciferase activity on cardiomyoctes, and intraperitonal injection of U46619 into nuclear factor of activated T cells (NFAT)-luciferase transgenic mice demonstrated that U46619 increase NFAT expression, and this expression, as well as TNF-α expression, can be blocked by TXA₂ receptor antagonist (SQ29548), NFAT-SiRNA, calcineurin inhibitor, or calcium chelator. Finally, intraperitoneal injection of the TNF-α antibody, infliximab, into iron-injured mice decreased TXAS expression and attenuated cardiac fibrosis. Conclusions: TXA₂ mediates iron-overload cardiomyopathy through the TNF-α-associated calcineurin-NFAT signaling pathway.  (Circ J 2013; 77: 2586–2595)

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Background: Although regional variation in outcome after adult out-of-hospital cardiac arrest (OHCA) is known, no clinical studies have assessed this in pediatric OHCA. Methods and Results: This nationwide, prospective, population-based observation of the whole of Japan included consecutive OHCA patients with resuscitation attempt from January 2005 through December 2009. Primary outcome was 1-month survival with neurologically favorable outcome. Japan was divided into the following 7 regions as the largest administrative units: Hokkaido-Tohoku, Kanto, Tokai-Hokuriku, Kinki, Chugoku, Shikoku, and Kyushu-Okinawa. The outcome of pediatric OHCA was then compared between the regions. Multiple logistic regression analysis was used to adjust for other factors that were considered to influence the relationship between region and outcome. A total of 8,240 pediatric OHCA patients were registered during the study period. One-month survival with neurologically favorable outcome significantly differed by region: 2.5% (24/967) in Hokkaido-Tohoku (adjusted odds ratio [AOR], 1.65; 95% confidence interval [CI]: 0.94–2.90), 2.9% (47/1614) in Tokai-Hokuriku (AOR, 2.06; 95% CI: 1.28–3.31), 2.1% (26/1239) in Kinki (AOR, 1.45; 95% CI: 0.84–2.51), 3.4% (16/465) in Chugoku (AOR, 3.11; 95% CI: 1.62–6.00), 1.5% (4/259) in Shikoku (AOR, 0.79; 95% CI: 0.26–2.43), and 2.8% (27/974) in Kyushu-Okinawa (AOR, 2.15; 95% CI: 1.24–3.74) referred to Kanto (1.4%, 37/2722). Conclusions: According to Japanese nationwide OHCA registry data there are significant regional variations in the outcome of pediatric OHCA.  (Circ J 2013; 77: 2596–2603)

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Background: Fetal hypoxia is common and in vitro evidence supports its role in the programming of adult cardiovascular dysfunction through the generation of oxidative stress. Whether fetal chronic hypoxia programmes alterations in cardiovascular control in vivo, and if these alterations can be prevented by antioxidant treatment, is unknown. This study investigated the effects of prenatal fetal hypoxia, with and without maternal supplementation with vitamin C, on basal and stimulated cardiovascular function in vivo in the adult offspring at 4 months of age in the rat. Methods and Results: From days 6 to 20 of pregnancy, Wistar rats were subjected to Normoxia, Hypoxia (13% O₂), Hypoxia+Vitamin C (5mg/ml in drinking water) or Normoxia+Vitamin C. At 4 months, male offspring were instrumented under urethane anaesthesia. Basal mean arterial blood pressure, heart rate and heart rate variability (HRV) were assessed, and stimulated baroreflex curves were generated with phenylephrine and sodium nitroprusside. Chronic fetal hypoxia increased the LF/HF HRV ratio and baroreflex gain, effects prevented by vitamin C administration during pregnancy. Conclusions: Chronic intrauterine hypoxia programmes cardiovascular dysfunction in vivo in adult rat offspring; effects ameliorated by maternal treatment with vitamin C. The data support a role for fetal chronic hypoxia programming cardiovascular dysfunction in the adult rat offspring in vivo through the generation of oxidative stress in utero.  (Circ J 2013; 77: 2604–2611)

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Background: The benefit of load expansion is controversial in acute pulmonary embolism (PE). The aim of this study was to evaluate the benefit of furosemide in cases of normotensive acute PE. Methods and Results: We retrospectively included 70 consecutive normotensive patients (systolic blood pressure ≥90mmHg) admitted for acute PE with right ventricular dilation. Overall, 40 patients were treated during the first 24h by repeated bolus of furosemide (78±42mg, range 40–160mg) and 30 patients received isotonic saline solution (1.6±0.9L). Severity of hemodynamic status was similar in both groups, but patients in the furosemide group were older and had a greater creatinine level. At 24h, only the furosemide group had a decreased shock index (0.82±0.22 vs. 0.63±0.16, P<0.0001) with improved systolic blood pressure (118±18 vs. 133±17mmHg, P<0.0001), and creatinine levels. After treatment, there were fewer patients with simplified pulmonary embolism severity index ≥1 in the diuretic group (45% vs. 55%, P=0.03) than in the fluid expansion group (47% vs. 40%, P<0.0001). Finally, oxygen requirement at 24h decreased only in the diuretic group (75% to 47%, P=0.0004), and in-hospital survival without death and PE-related shock were similar between the 2 groups. Conclusions: In normotensive PE with RV dilatation, diuretics may improve hemodynamics and oxygenation requirement.  (Circ J 2013; 77: 2612–2618)

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Background: We have previously demonstrated that long-term inhibition of Rho-kinase ameliorates pulmonary arterial hypertension (PAH) in animal models. In the present study, we examined the clinical effects of mid-term oral treatment with an extended release formulation of AT-877 (fasudil hydrochloride), a specific Rho-kinase inhibitor (AT-877ER) on PAH. Methods and Results: 23 PAH patients were treated with either placebo (10/2 females/males, 51±16 years, idiopathic PAH (IPAH) in 6, PAH associated with connective tissue disease (CTD-PAH) in 3, PAH with congenital heart disease (CHD-PAH) in 2, and portal PAH in 1) or AT-877ER (6/5 females/males, 47±14 years, IPAH in 2, CTD-PAH in 5, and CHD-PAH in 4); 3 patients were excluded. We performed a 6-min walk test and right heart catheterization in the remaining 20 patients, before and 3 months after the treatment (placebo n=11, AT-877ER n=9). Although there were no significant differences between the 2 groups for the 6-min walk distance, pulmonary hemodynamics tended to be improved in the AT-877ER group, especially the prevalence of improved cardiac index from baseline, which was significantly higher in the AT-877ER than in the placebo group. In the AT-877ER group, serum levels of hydroxyfasudil, an active metabolite of AT-877ER tended to correlate with improvements in the cardiac index and mean pulmonary artery pressure. Conclusions: Mid-term treatment with oral AT-877ER showed additional improvement in pulmonary hemodynamics in patients with PAH.  (Circ J 2013; 77: 2619–2625)

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Background: Imaging modalities to assess atherosclerotic plaque thrombogenicity have not been established, so in this study the relationship between [¹⁸F]-fluorodeoxyglucose (¹⁸F-FDG) uptake and thrombus formation was investigated in rabbit atherosclerotic arteries. Methods and Results: Atherosclerotic plaque was induced in the iliacofemoral artery by balloon injury and a 0.5% cholesterol diet. At 3 weeks after the first balloon injury, the arteries were visualized by ¹⁸F-FDG positron emission tomography (PET) imaging 2h after an ¹⁸F-FDG infusion, and then arterial thrombus was induced by a second balloon injury of both iliacofemoral arteries. Imaging with ¹⁸F-FDG-PET revealed significantly more radioactivity along the injured (0.63±0.12 SUVmax), than the contralateral non-injured artery (0.34±0.08 SUVmax, n=17, P<0.0001). Arterial radioactivity measured by autoradiography positively correlated with macrophage area, the number of nuclei that were immunopositive for nuclear factor κ B (NF-κB), and tissue factor (TF) expression. The immunopositive areas for glycoprotein IIb/IIIa and fibrin in thrombi were significantly larger in the atherosclerotic than in the contralateral arteries, and significantly correlated with radioactivity in PET (r=0.92, P<0.001, n=10) and autoradiography (r=0.73, P<0.0001, n=50) in the arteries. Inhibition of NF-κB significantly reduced TF expression in cultured atherosclerotic plaque. Conclusions: Arterial ¹⁸F-FDG uptake reflects the thrombogenicity of atherosclerotic plaque following balloon injury.  (Circ J 2013; 77: 2626–2635)

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