Hypertensive heart disease (HHD) is the leading cause of mortality and morbidity in the United States. Despite the availability of medical therapy it remains a challenge to treat. Autonomic nervous system imbalance resulting in overactivity of the sympathetic nervous system and under activity of the parasympathetic nervous system is integral in the development of hypertension and ultimately the development of HHD. Emerging data suggest that neuromodulation device therapy for treatment of HHD is promising.  (Circ J 2013; 77: 1351–1363)

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Cardiac resynchronization therapy (CRT) is an effective therapy for advanced heart failure (HF) patients. The indications are well defined in recent guidelines and broadly indicate that CRT is suitable for chronic HF patients with left ventricular ejection fraction (EF) ≤35% and in NYHA class III or IV (Class I), and those with prolonged QRS duration ≥120ms with left bundle branch block (LBBB) QRS morphology, or QRS duration ≥150ms irrespective of QRS morphology (Class IIa). For patients with NYHA class II symptoms, CRT is recommended for patients with EF ≤30% and QRS duration ≥130ms with LBBB QRS morphology (Class I, level of evidence: A), or QRS duration ≥150ms irrespective of QRS morphology (Class IIa, level of evidence: A). However, CRT may benefit additional patients outside these criteria. In this review, we summarize the role of CRT in some subgroups, including patients with mild and moderate HF, upgrading to CRT from right ventricular (RV) pacing, bradycardia patients with routine pacing indications, congenital heart disease and specific cardiomyopathies. It is possible that CRT can give symptomatic and mortality benefits in some of these subgroups in the future and further clinical trials are warranted.  (Circ J 2013; 77: 1364–1369)

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Defects in mitochondrial biogenesis are well known to contribute to cardiac dysfunction. By contrast, mechanistic details of essential homeostatic mechanisms that maintain mitochondrial health in the heart are only recently being uncovered, and the pathological potential of these processes is largely hypothetical. I will review the role of mitochondrial dynamics, focusing on cyclic organelle fission and fusion, in normal and diseased hearts. Special attention is given to recent insights into the non-canonical functioning of the mitofusin 2 (Mfn2) outer mitochondrial membrane fusion protein as a regulator of sarcoplasmic-reticular calcium crosstalk and a critical determinant of mitophagic culling of damaged mitochondria. Because mitochondrial fusion in normal adult cardiomyocytes occurs so slowly and infrequently, I postulate that the major function of Mfn2 in the heart may not be to redundantly promote mitochondrial fusion with Mfn1, but to centrally orchestrate mitochondrial quality control.  (Circ J 2013; 77: 1370–1379)

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Atrial fibrillation (AF) is a major risk factor for stroke and the prevalence increases with age. Oral anticoagulants (OACs) are effective, but underused in elderly patients, primarily because of concerns about bleeding. Clinical study data on the efficacy (stroke/systemic embolism) and safety (bleeding events) of OACs in elderly patients with AF, including studies of vitamin K antagonists and newer OACs, were evaluated to determine whether treatment effects vary in elderly vs. younger patients, and whether OACs provide a net clinical benefit for elderly patients. In general, elderly patients had greater risk of both thromboembolic and bleeding events compared with younger patients. Nevertheless, OACs were associated with significant efficacy, with most studies reporting no difference in the risk of bleeding relative to control treatments. In trials of the newer OACs, no interaction was seen between age and relative treatment effects for apixaban or rivaroxaban compared with warfarin, although the rates of extracranial bleeding events increased in older patients treated with dabigatran. In conclusion, OAC therapy is associated with a positive benefit-risk balance in elderly patients. Irrespective of age, treatment decisions regarding stroke thromboprophylaxis in all patients with AF should be based on consideration of individual potential benefits and risks of treatment and patient preferences.  (Circ J 2013; 77: 1380–1388)

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It has been appreciated for some time that cardiovascular disease involves large-scale transcriptional changes in various cell types. What has become increasingly clear only in the past few years, however, is the role of chromatin remodeling in cardiovascular phenotypes in normal physiology, as well as in development and disease. This review summarizes the state of the chromatin field in terms of distinct mechanisms to regulate chromatin structure in vivo, identifying when these modes of regulation have been demonstrated in cardiovascular tissues. We describe areas in which a better understanding of chromatin structure is leading to new insights into the fundamental biology of cardiovascular disease.  (Circ J 2013; 77: 1389–1398)

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Background: The pre-procedural prediction of atrial fibrillation (AF) termination by catheter ablation in patients with persistent AF has not been evaluated fully. The aim of this study was to evaluate the pre-procedural predictors of persistent AF termination by ablation associated with the possibility of reverse remodeling of the left atrium (LA). Methods and Results: Seventy consecutive patients (mean age, 62±8 years) with persistent or long-standing persistent AF underwent ablation. They were divided into 2 groups: those with AF terminated by ablation (n=14; group 1) and those with AF terminated by cardioversion after ablation (n=56; group 2). The left atrial appendage (LAA) contraction velocity determined on transesophageal echocardiography was significantly decreased in group 2 as compared to group 1 (P<0.001). Kaplan-Meier analysis showed that the group 1 patients had a higher AF-free survival rate than those in group 2 during 12±4.1 months of follow-up (P=0.048). The LA reverse remodeling ratio, given as the volume difference between before and 3 months after ablation in group 1, was significantly greater after ablation than that in group 2 (25.8±13% vs. 15.0±15%, P=0.015). Multivariate logistic regression analysis indicated that the LAA contraction velocity was an independent predictor of persistent AF termination by ablation (P=0.018). Conclusions: The LAA contraction velocity was the only non-invasive pre-procedural predictor of persistent AF termination by ablation, indicating the possibility of reverse remodeling of the LA.  (Circ J 2013; 77: 1416–1423)

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Background: Recent studies have suggested better outcomes from cardiac resynchronization therapy (CRT) in women. Gender differences in coronary sinus (CS) anatomy and left ventricular (LV) lead parameters in patients undergoing CRT, however, have not been well studied. Methods and Results: Two hundred and twenty-three consecutive patients, undergoing CRT at the University of California in San Diego Medical Center from 2003 to 2011 were included in this study. The location of the LV lead was assessed on coronary venography and chest X-ray recorded at the time of device implantation. Optimal LV lead position was defined as either mid-lateral or posterolateral LV wall. The relationship between LV lead position (optimal or non-optimal position) and LV lead parameters at completion of implant were compared between genders. No statistically significant gender differences were noted in baseline characteristics. LV lead implantation was successful in 217 patients (97.3%). Lateral or posterolateral CS branches were unavailable in more women than men (26.3% vs. 10.8%, P=0.011). Women had a higher LV lead pacing threshold than men (P=0.003) and gender was an independent risk factor of high LV lead pacing threshold (P=0.008). Conclusions: Women had an anatomical disadvantage for LV lead placement and had higher LV lead pacing threshold compared to men. Implanting physicians should be aware of gender differences during LV lead placement in order to maximize CRT benefits.  (Circ J 2013; 77: 1424–1429)

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Background: Although previous randomized and non-randomized studies have demonstrated the safety and efficacy of paclitaxel-eluting stents (PES), a higher revascularization rate has been reported in women than in men. A sub-analysis of the TAXUS Japan Post-market Surveillance Study (TAXUS-PMS) was done to assess the influence of gender on clinical outcome. Methods and Results: A total of 2,132 PES-treated Japanese patients (women, n=551) from this registry were analyzed. Subjects were stratified by gender to compare 1-year clinical outcome. PES-treated women were older and more likely to have insulin-treated diabetes and hypertension. In contrast, PES-treated men were more likely to be smokers, have a previous history of myocardial infarction, and lower ejection fraction. While cardiac death, myocardial infarction and stent thrombosis were similar between men and women, major cardiac events tended to be lower in women than in men (6.4% vs. 8.8%, P=0.08). Although women had significantly smaller reference vessel size (2.46±0.53mm vs. 2.59±0.60mm, P<0.0001), the restenosis rate tended to be lower in women than in men (11.5% vs. 14.8%, P=0.11). Subsequently, the target lesion revascularization rate was significantly lower in women than in men (4.2% vs. 6.5%, P<0.05). Conclusions: Despite a higher risk profile, Japanese women treated with PES did not have a higher rate of repeat revascularization or major adverse clinical outcome than PES-treated men at 1 year.  (Circ J 2013; 77: 1430–1435)

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Background: CYP2C19 loss-of-function genotype (*2 and/or *3 alleles) is related to low responsiveness to clopidogrel, which is a risk factor for ischemic cardiac events. The contribution of these genotypes to platelet reactivity in Japanese patients in a steady state receiving dual antiplatelet therapy after coronary stenting was evaluated. Methods and Results: A total of 155 Japanese patients were classified according to their CYP2C19 loss-of-function genotype. Platelet reactivity was assayed by plasma levels of soluble P-selectin and platelet-derived microparticles, light transmittance aggregometry induced by ADP (ADP-LTA), shear stress-induced platelet aggregometry, vasodilator-stimulated phosphoprotein phosphorylation (VASP) index and the VerifyNow-P2Y12 assay. Linear and logistic regression models were used to assess the associations between CYP2C19 loss-of-function genotype and high on-treatment platelet reactivity. In total, 62 patients (40.0%) were extensive metabolizers (EMs), 70 (45.2%) were intermediate metabolizers (IMs) and 23 (14.8%) were poor metabolizers (PMs). ADP-specific assays (ADP-LTA, the VASP index and VerifyNow-P2Y12) differed according to CYP2C19 genotype, with a significant gene-dose effect (PMs>IMs>EMs). CYP2C19 loss-of-function carrier status was associated with more frequent high platelet reactivity. CYP2C19 loss-of-function genotype alone could explain 12.2%, 14.3%, and 14.7% of the variability in the ADP-LTA, VASP and VerifyNow-P2Y12 assays, respectively. Conclusions: CYP2C19 loss-of-function genotype is associated with more frequent high platelet reactivity, as assessed by ADP-specific platelet function tests, in Japanese patients.  (Circ J 2013; 77: 1436–1444)

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Background: Mechanical reperfusion has proven to be an unquestionably superior treatment strategy over that of thrombolytic therapy in patients with acute coronary syndrome (ACS). Excimer laser coronary angioplasty (ELCA) is a unique revascularization device that has a lytic effect on thrombus, in addition to its debulking effect on the atherosclerotic plaque beneath the thrombus. Methods and Results: This single-center retrospective analysis consisted of consecutive ACS patients treated with ELCA (n=50) and age- and sex-matched ACS patients treated with manual aspiration (n=48) without use of a distal protection device. Success rate was judged by lesion crossability, procedure complications, and significant reduction of stenosis. Tissue-level perfusion was assessed on antegrade Thrombolysis In Myocardial Infarction (TIMI) flow grade, myocardial blush grade (MBG), and ST-segment elevation resolution (STR). Short-term outcome was evaluated according to occurrence of in-hospital major adverse cardiac events (MACE; myocardial infarction, target lesion revascularization, coronary artery bypass graft, and death). Lesion crossability was higher in the ELCA group than in the aspiration group (96.2% vs. 82.6%, P=0.04). Attainment of TIMI 3 flow (86.0% vs. 68.8%, P=0.04) and MBG 3 (76.0% vs. 54.2%, P=0.02) was also higher in the ELCA group than in the aspiration group. Complete STR was similar between the 2 groups. In-hospital MACE were significantly more frequent in the aspiration group. Conclusions: ELCA is feasible, safe, and effective for the treatment of patients with ACS and appears to be useful as an adjunctive lesion preparation device.  (Circ J 2013; 77: 1445–1452)

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Background: Limited data are available with which to compare the clinical characteristics of patients with very late stent thrombosis (VLST) after drug-eluting stent (DES) or bare-metal stent (BMS) implantation. The purpose of this study was to investigate the differences in the characteristics of VLST after DES and BMS implantation by reviewing the clinical and angiographic data. Methods and Results: A total of 28 patients (30 lesions) with VLST after DES implantation and 33 patients (33 lesions) with VLST after BMS implantation were identified. The occurrence of VLST after BMS implantation (2,647±996 days) was much later than that after DES implantation (1,194±558 days, P<0.001). The number of VLST after DES implantation increased gradually each year; however VLST after BMS implantation started to occur >50 months later, and its number increased subsequently. The prevalence of VLST related to surgical procedures involving discontinuation of antiplatelet therapy in VLST patients was higher after DES implantation (14.3%) than after BMS implantation (0%, P=0.039). Angiographic stent fracture was seen in 36.7% of VLST lesions after DES implantation at different times (464–2,102 days after procedure), while none was seen in VLST lesions after BMS implantation (P<0.001). Conclusions: The timing of VLST was different after DES and BMS implantation. Stent fracture was a specific finding of VLST after DES implantation.  (Circ J 2013; 77: 1453–1460)

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Background: Ischemic mitral regurgitation (IMR) with ischemic cardiomyopathy (ICM) was treated with surgical procedures, and mitral leaflet tethering was assessed. Twenty-two patients with both ICM (left ventricular ejection fraction <0.35) and IMR (>2) underwent coronary artery bypass grafting (CABG), mitral annuloplasty (MAP) with or without surgical ventricular restoration (SVR) and procedures targeting the subvalvular apparatus. Methods and Results: Fourteen patients (group 1) underwent CABG and MAP, and the remaining 8 (group 2) underwent CABG, MAP, SVR, papillary muscle approximation (PMA), and papillary muscle suspension (PMS). PMA joined the entire papillary muscles with 3 mattress sutures. For PMS, 2 ePTFE sutures were placed between papillary muscle tips and fibrous annuli. Anterior and posterior mitral leaflet tethering angles (ALA and PLA) relative to the line connecting annuli, posterior and apical displacement of coaptation, and IMR grade were measured on echocardiography. Although preoperative ALA and PLA in group 2 were significantly larger than in group 1, there was no significant difference between groups at 1 month after surgery. At 1 year after surgery, however, the situation reversed: ALA and PLA in group 1 were significantly larger than in group 2. Conclusions: In addition to MAP, procedures targeting the subvalvular apparatus including PMA and PMS achieved persistent reduction of mitral valve leaflet tethering, which might lead to the improvement of long-term outcome.  (Circ J 2013; 77: 1461–1465)

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Background: It has been shown that sleep-disordered breathing (SDB) is associated with adverse prognosis in patients with chronic heart failure (CHF), but little is known about the relationship between SDB and life-threatening arrhythmias. Methods and Results: Fifty patients with CHF and SDB (33 male; mean age, 61 years) underwent Holter electrocardiogram and portable sleep monitoring simultaneously. The circadian variation in positive T-wave alternans (TWA; >65μV) was determined during 6-h intervals (0–6, 6–12, 12–18, and 18–24h). In addition, power spectral analysis of heart rate variability (HRV) was evaluated across a 24-h period. The subjects were divided into 2 groups based on whether respiratory disturbance index was ≥20events/h (Group A, n=24) or not (Group B, n=26). The prevalence of positive TWA, parameters in HRV and the occurrence of ventricular tachycardia (>5 beats) were compared between the 2 groups. The prevalence of positive TWA in Group A was significantly higher than that in Group B in all 6-h intervals. Low-frequency and high-frequency powers of HRV were significantly lower in Group A than in Group B across a 24-h period. Importantly, the prevalence of ventricular tachycardia was significantly higher in Group A than in Group B (46% vs. 19%, P=0.04). Conclusions: SDB may induce cardiac electrical instability associated with life-threatening arrhythmias across a 24-h period in CHF.  (Circ J 2013; 77: 1466–1473)

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Background: Hypertensive patients with large blood pressure variability (BPV) have aggravated target organ damage. Because the aldosterone/mineralocorticoid receptor (MR) system is a possible mechanism of hypertensive organ damage, we investigated in spontaneously hypertensive rats (SHRs) whether a specific MR blocker, eplerenone, would prevent BPV-induced aggravation of hypertensive cardiac remodeling. Methods and Results: A rat model of a combination of hypertension and large BPV was created by performing bilateral sinoaortic denervation (SAD) in SHRs. SAD increased BPV without changing mean BP. SAD induced perivascular macrophage infiltration and aggravated myocardial fibrosis and cardiac hypertrophy, resulting in LV systolic dysfunction. Immunohistostaining revealed SAD-induced translocation of MRs into the nuclei (ie, MR activation) of the intramyocardial arterial medial cells and cardiac myocytes. SAD increased phosphorylation of p21-activated kinase1 (PAK1), a regulator of MR nuclear translocation. Chronic administration of a subdepressor dose of eplerenone prevented MR translocation, macrophage infiltration, myocardial fibrosis, cardiac hypertrophy, and LV dysfunction, while not affecting BPV. Circulating levels of aldosterone and cortisol were not changed by SAD. Conclusions: Eplerenone inhibited the aggravation of cardiac inflammation and hypertensive cardiac remodeling, and thereby prevented progression of LV dysfunction in SHRs with large BPV. This suggests that the PAK1-MR pathway plays a role in cardiac inflammation and remodeling induced by large BPV superimposed on hypertension, independent of circulating aldosterone.  (Circ J 2013; 77: 1474–1481)

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Background: High-density lipoprotein (HDL) plays a major role in reverse cholesterol transport. Many researchers have been working to enhance the biochemical function of HDL for use in therapy. Although HDL therapy using injections of apolipoprotein (apo)-A-I mimetics, apo A-I _Milano or full-length apo A-I is dramatically effective, it is still unclear whether apo A-I or apo A-I mimetics actually enter atherosclerotic plaque and remove cholesterol from the lipid burden. We synthesized a novel 24-amino acid apo A-I mimetic peptide (known as FAMP) that potently removes cholesterol via specific ATP-binding cassette transporter A1. We then investigated the potential of FAMP to image developing plaque lesions in vivo. Methods and Results: FAMP was modified with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with gallium-68 (⁶⁸Ga) for noninvasive positron emission tomography (PET) in an animal model (familial hypercholesterolemic myocardial infarction-prone rabbits: WHHL-MI) with atherosclerotic lesions. The ⁶⁸Ga-DOTA-FAMP was dramatically taken up by atherosclerotic tissues in the blood vessels and aorta of WHHL-MI rabbits, but not the control rabbits. Conclusions: An apo A-I mimetic peptide with ⁶⁸Ga-DOTA is a promising candidate diagnostic tracer for PET imaging of the atherosclerotic lipid burden and may contribute to the development of a tool for the diagnosis of plaque with PET.  (Circ J 2013; 77: 1482–1489)

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Background: The aim of the present study was to detect earlier the negative effect of cardiovascular risk (CVR) factors on left atrial (LA) and left ventricular (LV) function related to abdominal aortic (AAO) stiffness using 2-dimensional speckle-tracking echocardiography (2DSTE) in asymptomatic patients. Methods and Results: One hundred and twelve patients with CVR factors and 56 healthy individuals were studied. 2DSTE data were acquired for determination of LA and LV myocardial and AAO wall deformations. LA volume index, LV mass index, ratio of early diastolic transmitral flow to mitral annular velocity (E/e’)/peak systolic LA strain (S-LAs), and AAO stiffness were greater, and peak early diastolic LV longitudinal strain rate (SR-LVe) was lower in the patient group. Among the significantly correlated variables with AAO stiffness on univariate analysis, multivariate linear regression analysis identified SR-LVe and (E/e’)/S-LAs in the patient group, and only age in the healthy group, as independent predictor of AAO stiffness. Conclusions: Structural and functional changes in the LA and LV and AAO stiffening were accelerated with CVR factors, and higher AAO stiffness was associated with deteriorated LA compliance and impaired LV relaxation in asymptomatic patients with CVR factors. 2DSTE has a potential for earlier detection of abnormal LA and LV function related to increased AAO stiffness.  (Circ J 2013; 77: 1490–1498)

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Background: Contrast-enhanced ultrasound (CEUS) in the carotid artery has potential as a technique for imaging plaque neovascularization. This study examined whether CEUS could provide information on the severity and instability of coronary artery disease (CAD). Methods and Results: A total of 304 patients with CAD and carotid plaque underwent CEUS examination of the carotid artery. Intraplaque neovascularization was identified on the basis of microbubbles within the plaque and graded as: G0, not visible; G1, moderate; or G2, extensive microbubbles. The complexity and extent of the coronary lesions were assessed angiographically. A higher grade of CEUS-assessed plaque neovascularization of the carotid artery was associated significantly with greater complexity (ρ=0.48 by Spearman’s rank correlation test) and extent (ρ=0.51) of coronary lesions. G2 plaque neovascularization was a risk for acute coronary syndrome, independent of traditional risk factors (odds ratio 1.91, 95% confidence interval 1.04–3.53, P<0.01). Subgroup analysis showed that carotid CEUS-assessed neovascularization regressed in 12 (46%) of 26 plaques in patients during 6 months of statin treatment, whereas regression occurred in 2 (14%) of 14 plaques in patients not taking a statin (P=0.04, Chi-square test). Conclusions: CEUS examination of the carotid artery may provide valuable information on the severity and instability of CAD and also the efficacy of antiatherosclerotic treatment.  (Circ J 2013; 77: 1499–1507)

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Background: Limited data are available for sex-based differences in Japanese patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI). Methods and Results: The study patients comprised 1,197 women and 3,182 men who underwent primary PCI for AMI in 2005–2007. Compared with the men, the women were significantly older, and had significantly longer onset-to-balloon time and lower rate of follow-up coronary angiography. In-hospital mortality was higher among women than men (8.7% vs. 4.9%, P<0.001). Although the cumulative incidence of all-cause death at 3 years was also higher for women (17.7% vs. 10.7%, P<0.001), the adjusted risk for all-cause death was comparable [hazard ratio (HR, women vs. men)=0.94, 95% confidence interval (CI): 0.71–1.24, P=0.66]. The incidence (12.1% vs. 12.4%, P=0.77) and the adjusted risk (HR=0.99, 95% CI 0.78–1.24, P=0.92) for any clinically-driven coronary revascularization were both comparable. However, regarding any non-clinically-driven coronary revascularization, the incidence (19.6% vs. 27.8%, P<0.001) and the adjusted risk (HR=0.79, 95% CI 0.65–0.95, P=0.012) were both lower in women relative to men. Conclusions: In current Japanese clinical practice for AMI, onset-to-balloon time was significantly longer in women than in men. Female sex was associated with lower follow-up coronary angiography rate and lower incidence of any non-clinically-driven coronary revascularization, whereas the incidence of any clinically-driven coronary revascularization was comparable between the sexes.  (Circ J 2013; 77: 1508–1517)

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Background: Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is being evaluated as a therapeutic target for treatment of atherosclerosis. This is the first study to examine the effects of darapladib, a novel selective Lp-PLA₂ inhibitor, on Lp-PLA₂ activity in Japanese dyslipidemic patients with/without the Val279Phe (V279F) single-nucleotide polymorphism (SNP) of the PLA₂G7 gene. Exploratory analysis to examine the effects of V279F on Lp-PLA₂ inhibition of darapladib was also performed. Methods and Results: This was a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial of darapladib in 107 Japanese patients with dyslipidemia receiving statins. Patients were randomized to placebo (n=25), darapladib 40mg (n=28), 80mg (n=28), or 160mg (n=26). All darapladib doses produced sustained dose-dependent inhibition of Lp-PLA₂ activity of approximately 49%, 58%, and 67%, respectively (P<0.001 for all comparisons). The inhibitory effect achieved a plateau by 1 week. Patients with the V279F homogenous mutation who have no circulating levels of Lp-PLA₂, were excluded from the study. The Lp-PLA₂ activity was inhibited in both homozygous wild-type and heterozygote genotypes of the V279F polymorphism subjects to a similar extent, although the heterogeneous mutation has almost half the level of Lp-PLA₂ activity compared with that of wild-type in Japanese people. The most common adverse events were odor related. No major safety concerns were noted. Conclusions: Darapladib produced sustained inhibition of Lp-PLA₂ activity in Japanese dyslipidemic patients with/without the V279F SNP of Lp-PLA  (Circ J 2013; 77: 1518–1525)₂.

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Background: Recently, it was reported from the Justification for Atherosclerosis Regression Treatment (JART) Study that intensive therapy with rosuvastatin significantly slowed progression of carotid intima-media thickness (IMT) compared with conventional therapy with pravastatin at 12 months. To assess the long-term efficacy of intensive therapy, the present extension study was conducted. Methods and Results: Subjects in the intensive therapy group of the JART Study were asked to participate in the extension study and to continue rosuvastatin treatment. A total of 113 subjects were enrolled into the extension study and were included in the analysis. At 24 months, the mean daily dose of rosuvastatin (±SD) was 7.9±2.9mg. Mean change in mean IMT was –0.005mm (range, –0.024 to 0.015mm) at 24 months (P=0.633, compared with baseline). Rosuvastatin lowered low-density lipoprotein cholesterol (mean±SD) by 46.4±13.8% and elevated high-density lipoprotein cholesterol (mean±SD) by 8.9±24.0% at 24 months compared with baseline. Gray scale median was measured in 25 subjects. It increased by 16.93±33.12 (mean±SD) % at 12 months and by 22.50±52.83% at 24 months from baseline (P=0.017, P=0.044, respectively). Conclusions: Two-year treatment with rosuvastatin inhibited progression of carotid IMT. Rosuvastatin also improved the plaque composition, and this qualitative change occurred relatively early after starting therapy.  (Circ J 2013; 77: 1526–1533)

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Background: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heart muscle disease caused by desmosomal gene mutations, and presents as ventricular tachycardia and sudden cardiac death. Although the mean age at onset or diagnosis of ARVC/D are reported to be around the 30–40s, the age-dependent clinical and genetic differences remain unknown. Methods and Results: A total of 35 consecutive Japanese probands (23 male) who were clinically diagnosed with ARVC/D were enrolled in the present study, and genetic analysis of PKP2, DSP, DSG2, and DSC2 was done. The mean age at the first symptom and at diagnosis was 38.6±14.8 years and 40.5±17.7 years, respectively. Probands in whom the onset was cardiopulmonary arrest were significantly younger (22.3±15.3 years) than those with arrhythmia (41.1±13.2 years) or congestive heart failure (45.7±8.5 years). On genetic screening, 19 mutation carriers were identified. Although there was no age dependence for each gene mutation carrier, carriers with PKP2 premature stop codon developed the disease at a significantly younger age than other mutation carriers. Conclusions: The initial clinical manifestations in some young probands were very severe, and PKP2 mutations with a premature stop codon would be associated with disease onset at a younger age.  (Circ J 2013; 77: 1534–1542)

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Background: Previous intravascular ultrasound (IVUS) studies have reported that a tiny reference cross-sectional area (CSA), stent under-expansion, stent asymmetry, stent edge dissection, and tissue protrusion are associated with target lesion revascularization (TLR) after coronary intervention. In the lower limb, however, it has not been reported that these findings correlate with TLR after endovascular therapy (EVT). Methods and Results: A total of 236 consecutive superficial femoral artery (SFA) lesions in patients who underwent IVUS after self-expanding nitinol stent implantation, were analyzed. Stent expansion ratio was calculated as minimum stent CSA/reference lumen CSA, radial stent symmetry index as minimum/maximum stent diameter, and axial stent symmetry index as minimum/maximum stent CSA. TLR was defined as clinically driven revascularization with ≥75% restenosis of the target lesion. The mean follow-up period was 34±15 months. TLR were performed in 42 lesions (17.8%). There were no significant differences in stent expansion ratio, stent symmetry indices, and tissue protrusion between the TLR and no-TLR groups. Multivariate analysis indicated that total stent length (odds ratio [OR], 1.004; P<0.05), distal reference CSA (OR, 0.91; P<0.01), and stent edge dissection (OR, 3.51; P<0.01) were independent predictors of TLR. Conclusions: Stent implantation in tiny vessels and stent edge dissection in SFA lesions are indicators of high risk of TLR. Post-procedural stent under-expansion and stent asymmetry, however, were not associated with TLR.  (Circ J 2013; 77: 1543–1550)

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Background: The Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy (MAPPY) study has shown that losartan/hydrochlorothiazide (HCTZ) combination is superior to high-dose losartan in not only reducing morning systolic blood pressure (SBP) but also ameliorating urinary albumin excretion (UAE) after 3-month treatment. The purpose of the present study was to investigate factors associated with UAE reduction in on-treatment patients with morning hypertension. Methods and Results: A total of 95 patients registered in the MAPPY study were analyzed. Patients were treated with either a losartan/HCTZ combination regimen (n=47) or a high-dose losartan regimen (n=48). Three-month treatment significantly reduced morning SBP, evening SBP, and clinic SBP (P<0.001, P<0.05, and P<0.01, respectively). UAE and serum uric acid were significantly decreased (P<0.01 for both) without the change in estimated glomerular filtration rate. Multiple linear regression analysis indicated that %morning SBP reduction and baseline UAE were independent determinants of the UAE reduction (P=0.001 for both). After adjustments for the reduction in morning-evening SBP difference, baseline UAE, and %uric acid reduction, estimated %UAE reduction level was positively correlated with the tertiles of the increasing %morning SBP reduction level (P=0.031 for trend). Moreover, subgroup analysis showed that morning SBP reduction was an independent determinant of UAE reduction in both treatment regimens. Conclusions: Reduction in morning SBP was a key factor in UAE reduction in patients with morning hypertension, irrespective of treatment regimen.  (Circ J 2013; 77: 1551–1557)

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Background: It is important to manage a potentially fatal disease such as infective endocarditis (IE) based on evidence and guidelines for treatment published by academic societies. To clarify the current status of IE in Japan, we conducted a nationwide survey of IE (CArdiac Disease REgistration-Infective Endocarditis [CADRE-IE]). Methods and Results: We collected data on every aspect of IE using web-based survey. Only a Japanese Circulation Society-certified cardiologists who had managed a case of IE could register the patient when the outcome was known. There were 513 cases (320 men, 193 women) from 114 institutions. The median age was 61 years and more than 80% of the patients had underlying cardiac diseases. The majority was valvular heart disease, in which mitral regurgitation was a leading cause. Most of the patients had some predisposing factors, among which, decayed teeth or periodontitis was a leading factor. Streptococci were found in approximately 52% and staphylococci were found in 32% in positive-culture cases. Methicillin-resistant Staphylococcus aureus was found in 7.5%. Congestive heart failure was found in 43% and intracranial complications were found in 31%. Most of the patients were discharged (65%) but in-hospital death occurred in 11%. Conclusions: IE is still a lethal disease affecting older patients. The information obtained from the survey should be very helpful for physicians.  (Circ J 2013; 77: 1558–1564)

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Background: Periodontopathic bacteria are detected at a high rate in specimens obtained from the aortic walls of patients with abdominal aortic aneurysm (AAA) and are involved in AAA development. The purpose of this study was to clarify the role of Toll-like receptors (TLRs), which are key receptors of virulence factors of many periodontal bacteria, on periodontopathic bacteria-accelerated AAA progression. Methods and Results: AAA was produced by peri-aortic application of 0.25mol/L CaCl₂, with NaCl used as a control. The mice were inoculated with live Porphyromonas (P.) gingivalis or vehicle once weekly. At 4 weeks after the application of CaCl₂, the aortic diameter of the P. gingivalis-infected wild-type mice showed a significant increase in comparison with vehicle control mice (P<0.05). The P. gingivalis-infected TLR-2 deficient mice showed no statistical increase in aortic diameter over the same period. The aortic diameter of the P. gingivalis-infected TLR-4 deficient mice statistically increased. Immunohistochemically, the levels of matrix metalloproteinase-2 and -9 in the aneurysmal samples from wild-type mice were higher than in TLR-2 deficient mice. Conclusions: P. gingivalis accelerated the progression of experimental AAA through TLR-2 signaling.  (Circ J 2013; 77: 1565–1573)

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Background: Adipose tissue-derived stem cells (ASC) produce a variety of cytokines that potentially mediate the proangiogenic and antiapoptotic effects of the ASC. We examined whether ASC produced angiopoietin-1 (Ang1) and whether Ang1 functionally mediated ASC-induced suppression of neointimal formation. Methods and Results: Ang1 production was measured by enzyme-linked immunosorbent assay. Production of endogenous Ang1 by ASC was inhibited with small interfering RNA (siRNA) for Ang1. Overproduction of Ang1 was achieved with an adenovirus that expresses Ang1 (AdAng1). ASC expressing Ang1 siRNA, or AdAng1 were administered around the femoral artery after wire injury, and immunohistochemical analysis was performed to examine their effects on neointimal formation. ASC produced Ang1 in a time-dependent manner, especially when cultured in medium containing growth factors for vascular endothelial cells. When ASC were treated with Ang1 siRNA, the inhibitory effect of ASC on neointimal formation was significantly reduced. Knockdown of Ang1 significantly increased macrophage infiltration in the neointima, and significantly decreased endothelial regeneration. In contrast, forced expression of Ang1 using AdAng1 significantly suppressed neointimal formation and macrophage infiltration, and stimulated reendothelialization. Conclusions: Ang1 was implicated in ASC-induced suppression of neointimal formation. The results also suggested that Ang1 inhibited neointimal formation via stimulation of reendothelialization and suppression of macrophage infiltration in the neointima.  (Circ J 2013; 77: 1574–1584)

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(Circ J 2010; 74: 2666–2673)

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