Heart failure remains the leading cause of mortality in the USA, despite major advances in therapy over the past several decades, including angiotensin-converting enzyme or angiotensin II inhibitors, vasodilators, calcium-channel blockers and β-adrenergic receptor blockers. New therapeutic approaches are clearly required and the conceptual origin of these new techniques will be derived from agents that protect the heart against stress and prolong longevity. The combination of stress protection and longevity has been observed in a variety of organisms, from yeast to worms to mammals, and could be the basis for a novel approach to heart failure therapy. A mouse model has been developed with genetic disruption of adenylyl cyclase type 5, which lives one-third longer than the wild-type and is protected from aging-induced, pressure overload-induced and catecholamine-induced stresses. Accordingly, inhibition of this molecule should be considered as a new therapeutic modality for heart failure.(Circ J 2009; 73: 195 - 200)

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Oxygen radicals, and other reactive oxygen species, may play an important role in the pathophysiology of atherosclerosis, stroke, and other cardiovascular diseases. Mechanisms that account for oxidative stress in different cardiovascular diseases are diverse; for example, increases in activity of NAD(P)H oxidase, "uncoupling" of nitric oxide synthase, and maladaptive changes in expression of antioxidants can all contribute to increases in oxidative stress. Very different patterns of pro-and antioxidant mechanisms that contribute to increases in oxygen radicals in atherosclerotic plaques, hemorrhagic strokes, and aortic valve stenosis have been observed. A disappointment, in relation to the hypothesis that oxygen radicals contribute to cardiovascular risk, is that many studies indicate that antioxidant vitamins fail to reduce the risk of cardiovascular disease. Better understanding of mechanisms that lead to increases in oxidative stress in different cardiovascular diseases may lead to more effective antioxidant prevention or treatment of diseases. (Circ J 2009; 73: 201 - 207)

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Not only muscle contraction, but also most cell movements depend on myosin - actin interaction using ATP. Many components of the contraction machinery are involved in the efficient coupling of energy source and force development. Among these, I have focused on myosin light chain kinase (MLCK) in this review. MLCK phosphorylates myosin regulatory light chain and controls all 3 types of muscle contraction: skeletal muscle, smooth muscle, and cardiac muscle. However, each muscle has specific MLCK and the role of MLCK in each muscle is different. This difference explains the specific role of each muscle in vivo and contributes to the activity of various force development in different ways in each tissue. Therefore, I also review the differences in the connection between each MLCK and muscle contraction in the 3 muscle types. (Circ J 2009; 73: 208 - 213)

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Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily and form heterodimers with retinoid X receptor. Three PPAR isoforms have been isolated and termed α, β (or δ) and γ. Although PPARγ is expressed predominantly in adipose tissue and associated with adipocyte differentiation and glucose homeostasis, PPARγ is also present in a variety of cell types. Synthetic antidiabetic thiazolidinediones (TZDs) are well known as ligands and activators for PPARγ. After it was reported that activation of PPARγ suppressed production of pro-inflammatory cytokines in activated macrophages, medical interest in PPARγ has grown and there has been a huge research effort. PPARγ is currently known to be implicated in various human chronic diseases such as diabetes mellitus, atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, and Alzheimer's disease. Many studies suggest that TZDs not only ameliorate insulin sensitivity, but also have pleiotropic effects on many tissues and cell types. Although activation of PPARγ seems to have beneficial effects on cardiovascular diseases, the mechanisms by which PPARγ ligands prevent their development are not fully understood. Recent data about the actions and its mechanisms of PPARγ-dependent pathway in cardiovascular diseases are discussed here. (Circ J 2009; 73: 214 - 220)

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Radiofrequency catheter ablation is widely performed as an effective treatment for recurrent, drug-resistant atrial fibrillation (AF). Recently, various types of ablation strategies, such as extensive encircling pulmonary vein (PV) isolation, linear ablation and complex fractionated electrogram-guided ablation, have been used to achieve a high efficacy for all types of AF. However, several complications (thromboembolic events, PV stenosis and atrio-esophageal fistula etc) with an incidence of 3.9-6%, have been reported. It is important to understand the incidence, prevention and management of complications in order to develop safe ablation strategies. (Circ J 2009; 73: 221 - 226)

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Background An alternative approach to complete isolation of the posterior left atrium (LA), including all pulmonary veins (PVs), for treating atrial fibrillation (AF) is the Box isolation. However, it is sometimes difficult to confirm the conduction block within the linear lesion lines, so in the present study the efficacy of the Box isolation guided by noncontact mapping (NCM) was evaluated. Methods and Results A total of 188 patients, 116 with paroxysmal, 48 with persistent and 24 with longstanding persistent AF, underwent the Box isolation using NCM system. The endpoint was defined as bi-directional conduction block in the posterior LA confirmed by an activation map using NCM during pacing inside and outside of the posterior LA. The induced atrial tachyarrhythmias and non-PV foci were also ablated using NCM. After 12±4 months of follow-up, 91% of the patients with paroxysmal AF, 73% of those with persistent AF and 46% with longstanding persistent AF were arrhythmia-free without drugs. Conclusions NCM is useful for defining complete Box isolation and detecting the conduction gaps, localizing non-PV foci, and analyzing the mechanism of atrial tachyarrhythmias. NCM-guided Box isolation is a feasible, safe and effective method of treating AF. (Circ J 2009; 73: 233 - 241)

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Background Although previous clinical trials demonstrated the non-inferiority of a rate control to rhythm control strategy for management of atrial fibrillation (AF), the optimal treatment strategy for paroxysmal AF (PAF) remains unclear. Methods and Results A randomized, multicenter comparison of rate control vs rhythm control in Japanese patients with PAF (the Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM) study) was conducted. The primary endpoint was a composite of total mortality, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for heart failure, or physical/psychological disability requiring alteration of treatment strategy. In the study, 823 patients with PAF were followed for a mean period of 578 days. The primary endpoint occurred in 64 patients (15.3%) assigned to rhythm control and in 89 patients (22.0%) to rate control (P=0.0128). No significant differences between the treatment strategies were observed in the incidences of death, stroke, bleeding and heart failure. Meanwhile, significantly fewer patients requested changes of assigned treatment strategy in the rhythm control vs the rate control group, which was accompanied by improvement in AF-specific quality of life scores. Conclusion The J-RHYTHM study showed that rhythm control was associated with fewer primary endpoints than rate control. However, mortality and cardiovascular morbidity were not affected by the treatment strategy (umin-CTR No. C000000106). (Circ J 2009; 73: 242 - 248)

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Background Obstructive sleep apnea (OSA) is closely associated with atrial fibrillation, which is provoked by electrical and structural remodeling. However, the association between OSA and atrial remodeling has not been fully elucidated. Methods and Results Atrial electromechanical activation time (EMAT) was investigated using tissue Doppler imaging (TDI) in men with severe OSA (n=24) and control subjects (n=24). The EMAT was determined as the time interval from the initiation of P-wave deflection until the peak of local lateral left atrial (LA) TDI signal. The early diastolic velocity of the mitral annulus (E_a) and the EMAT were significantly lower and longer in OSA cases than in controls (E_a: 6.1±0.9 cm/s vs 7.3±1.5 cm/s, P=0.001; EMAT: 129.7±11.5 ms vs 118.5±12.3 ms, P=0.002). Among OSA cases, the apnea - hypopnea index (AHI) was significantly correlated with EMAT (r=0.660, P<0.001), E_a (r=-0.609, P=0.002), LA dimension (r=0.486, P=0.016), and early diastolic velocity of mitral flow (E)/E_a ratio (r=0.418, P=0.042). In multivariate stepwise linear regression analysis, EMAT was independently associated with AHI (P=0.025) and E_a (P=0.028) in OSA cases. Conclusion EMAT measured by TDI could be a useful parameter for identifying atrial remodeling in patients with severe OSA. (Circ J 2009; 73: 249 - 255)

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Background Atrial arrhythmia is often encountered in chronic pulmonary disease with pulmonary hypertension (PH), but few studies have investigated the electrical remodeling of atrial Ca²⁺ channels under PH. Methods and Results Wistar rats were injected with monocrotaline (MCT), resulting in PH with right atrial and ventricular hypertrophy. The L-type Ca²⁺ channel current density was significantly decreased in right atrial cells of MCT-treated rats, accompanied by a significant reduction in mRNA expression of the CaV1.2 (α_1C) subunit and accessory β₂ subunit. Conversely, the low voltage-activated Ca²⁺ current was more marked in the right atrial cells of MCT-treated rats than in those of control rats. The current-voltage relationship and the time course of inactivation closely resembled those of T-type Ca²⁺ channels, although the current was only slightly inhibited by 10-100 μmol/L Ni²⁺. No significant differences were observed in the mRNA expression levels of CaV3.1 (α_1G) and CaV3.2 (α_1H) or the protein level of the CaV3.1 subunit. In left atrial cells, the electrophysiological molecular properties of Ca²⁺ channels were unaffected by MCT treatment. Conclusions PH causes right atrial hypertrophy, associated with alteration of the electrophysiological molecular properties of Ca²⁺ channels. (Circ J 2009; 73: 256 - 263)

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Background The traditional medical treatment for type B acute aortic dissection (AAD) is widely accepted, but the optimal clinical pathway has not been confirmed. Methods and Results From admissions over the past 12 years, 210 patients with uncomplicated type B AAD were divided into 2 groups: Conventional therapy group (CG) of 90 who were treated by 7 days of bed rest and intravenous antihypertensive agents and the Clinical pathway group (CPG) of 120 who were treated by early rehabilitation. In the CPG, patients were administered oral medication from the first day after onset and took a short walk from the third day after onset. The incidence of respiratory complications, and of delirium, was significantly decreased in the CPG. Early mortality was similar: 3.3% and 2.5%, respectively. The diameter of the aorta had not enlarged in either group 1 month later. Conclusions The clinical pathway of treatment for uncomplicated type B AAD was safer and better for preventing early complications and cost benefit. (Circ J 2009; 73: 264 - 268)

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Background The maze procedure for the treatment of atrial fibrillation (AF) is a widely used adjunctive therapy. It is necessary to define the precise indications for the procedure based on preoperative factors, but definitive parameters in terms of atrial function have not been well determined. Methods and Results In the present study, 55 consecutive patients undergoing the maze procedure for persistent AF in combination with operations for organic heart diseases were evaluated. After dividing the patients into successful (n=41) and unsuccessful procedure (n=14) groups, based on the postoperative rhythm, the preoperative left atrial (LA) emptying fraction measured by transthoracic 2-dimensional echocardiogram was compared between groups. The LA emptying fraction was calculated as [(LA maximum volume - LA minimum volume)/LA maximum volume]×100. The preoperative LA emptying fraction was higher in the successful procedure group than in the unsuccessful procedure group (31.2±8.5 vs 21.4±10.9%, P=0.0011). Based on receiver-perating characteristic curve analyses, LA emptying fraction >26% predicted successful maze procedure with 70.7% sensitivity and 78.6% specificity. Conclusions LA emptying fraction should be considered in the precise indications of the maze procedure as adjunctive therapy. (Circ J 2009; 73: 269 - 273)

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Background Diagonal earlobe crease (ELC) have been proposed as a marker of generalized atherosclerosis, so in the present study it was investigated whether individuals with ELC have a shortened telomere, which correlates with an accelerated cell turnover and premature aging, leading to atherosclerosis. Methods and Results The mean terminal restriction fragment (TRF) was determined by Southern blot hybridization in the peripheral blood cells of 34 male Japanese patients with metabolic syndrome (MetS) who were under 70 years of age with (n=17) and without (n=17) bilateral ELC, and assessed the relationship of ELC to atherosclerotic cardiovascular disease (AVD). The results showed that the TRF was shorter in the MetS patients with ELC in comparison to age- and risk-factor-matched MetS patients without ELC (7.6±1.1 kbp vs 8.6±1.2 kbp; P<0.05). ELC were present in 13 patients in the AVD group (n=18), but only 4 patients in the non-AVD group (n=16) had ELC (72.2% and 25% respectively; P<0.05). Conclusions These findings suggest that ELC is a useful dermatological indicator of an accelerated aging process, as suggested by excessive telomere loss, and might be a useful indirect marker of high-risk patients. (Circ J 2009; 73: 274 - 279)

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Background The impact of psychosocial states, such as depression or anxiety, and social support on the outcomes of stable outpatients with mild heart failure (HF) has not been evaluated in the "real world" clinical practice. Methods and Results In the present study, 139 patients with a prior history of admission for HF provided the baseline demographic, clinical, socio-environmental, and psychosocial information. Cardiac death or re-admission because of worsening of HF was monitored during the follow-up period of 1 year. The prevalence of depression and anxiety were 37% and 37%, respectively, in HF patients. Depression was independently associated with male (sβ=-0.36, P=0.01), social ties (sβ=0.22, P=0.04) and low social support (sβ=-0.39, P<0.01). Anxiety was associated with alcohol drinking (sβ=0.22, P=0.04), brain natriuretic peptide ≥200 pg/dl (sβ=0.35, P<0.01), and low social support (sβ=-0.28, P=0.01). Kaplan-Meier analysis demonstrated that patients with anxiety (log-lank test; P<0.01) and lower scores of social support (P<0.01) had a higher rate of HF-related re-admission. Conclusions Anxiety and low social support were independently associated with HF-related re-admission, which indicates the need for their inclusion in the assessment and management of HF. (Circ J 2009; 73: 280 - 287)

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Background The aim of this study was to retrospectively investigate the long-term effect of cardiac resynchronization therapy (CRT) and to clarify the useful predictors of clinical outcome. Methods and Results The study group comprised 43 patients with advanced heart failure who underwent CRT (10 females; 66±10 years): 23 were in sinus rhythm (SR group) and 20 had chronic atrial fibrillation (AF group). The clinical parameters and echocardiographic data were evaluated before and after CRT. There were no significant differences in the clinical parameters, echocardiographic data at baseline or frequency of responders between the 2 groups. In both groups, the clinical characteristics at baseline did not differ between the responders and non-responders. A prompt rise in systolic blood pressure (SBP) just after CRT was observed more often in responders than in non-responders, and SBP rise ≥5 mmHg was the only significant independent predictor of a CRT responder (P=0.0033). Furthermore, there was a significant difference in the event-free survival between patients with and without SBP rise ≥5 mmHg, demonstrated by Kaplan-Meier method, at 2 years of follow-up (P=0.045). Conclusion A prompt BP rise just after CRT may predict short- and long-term clinical improvement in CRT recipients. (Circ J 2009; 73: 288 - 294)

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Background Carvedilol may reduce the severity of central sleep apnea (CSA) in patients with chronic heart failure (CHF). Methods and Results This study prospectively examined the effect of carvedilol on the severity of CSA in patients with CHF. Polysomnographic findings, left ventricular (LV) function, and plasma brain natriuretic peptide (BNP) level were evaluated before and 6 months after induction of carvedilol in 16 patients with CHF (New York Heart Association functional class II or III and LV ejection fraction <50%) who had CSA (central apnea index [CAI] >5 with dominant central apneic events). All patients tolerated carvedilol. The 6-month treatment with carvedilol increased the LV ejection fraction (32±7.4% to 45±9.8%, P<0.001) and decreased the BNP level (159 [69-458] pg/ml to 38 [16-193] pg/ml, P=0.017). The polysomnographic findings showed that the treatment decreased the apnea-hypopnea index (34±13 to 14±13, P=0.003) and CAI (13±11 to 1.9±4.3, P<0.001), whereas it increased the obstructive apnea index (1.1±1.5 to 3.1±3.4, P=0.04). Conclusion This preliminary study shows that treatment with carvedilol reduces the severity of CSA in patients with CHF, but that episodes of obstructive sleep apnea sometimes increase after the treatment. (Circ J 2009; 73: 295 - 298)

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Background Central sleep apnea, often found in patients with chronic heart failure (CHF), has a high risk of poor prognosis. Methods and Results This study involved 20 patients with CHF (left ventricular ejection fraction (LVEF) <45%, M/F =19/1, age 65±10 years) and an apnea-hypopnea index (AHI) >5 times/h who were divided into 2 groups: 10 patients treated with nocturnal home oxygen therapy (HOT) and 10 patients without HOT (non-HOT). All patients had dilated cardiomyopathy and underwent overnight polysomnography, cardiopulmonary exercise testing, and nuclear cardiac examinations to evaluate AHI, exercise capacity according to the specific activity scale and oxygen uptake at anaerobic threshold and peak exercise (peak VO₂). Cardiac function according to ^99mTc-MIBI QGS, and the total defect score (TDS), H/M ratio and the washout rate (WR) on ¹²³I-metaiodobenzylguanidine (MIBG) imaging were calculated for all patients. As compared with the non-HOT group, the HOT group demonstrated a greater reduction in AHI (26.1±9.1 to 5.1±3.4), ¹²³I-MIBG TDS (31±8 to 25±9), and ¹²³I-MIBG WR (48±8% to 41±5%) and a greater increase in the specific activity scale (4.0±0.9 to 5.8±1.2 Mets), peak VO₂ (16.0±3.8 to 18.3±4.7 ml · min^-1 · kg^-1), and LVEF (27±9% to 37±10%). Conclusions HOT improves exercise capacity, cardiac function, and cardiac sympathetic nerve activity in patients with CHF and central sleep apnea. (Circ J 2009; 73: 299 - 304)

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Background There are few data on the differences between deep vein thrombosis (DVT) with pulmonary embolism (PE) (Group A) and without PE (Group B), and no recent data on the incidence of PE and DVT in Japan. Methods and Results The symptoms and findings of the lower extremities and risks for venous thromboembolism were compared between Groups A and B, and the numbers of new patients with PE and those with DVT in 2006 were calculated. DVT was found equally in left and right legs in Group A, but more frequently in left legs than in right legs in Group B. Proximal thrombus was more frequent in Group A than in Group B, and the number of cases of symptoms resulting from DVT was less in Group A than in Group B. Proximal DVT, DVT in the right leg, no symptoms, and younger age were related to the presence of PE. The calculated number of new patients with PE per year was 7,864 (3,492 cases in 1996), and that with DVT per year was 14,674. Conclusion DVT in patients with PE and those without PE differed in the site and symptoms. The calculated number of new patients with PE per year doubled in 1 decade in Japan. (Circ J 2009; 73: 305 - 309)

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Background Physiologic changes in the human sympathetic nervous system (SNS) may be associated with cardiovascular diseases, so the present study assessed the age and gender differences in global cardiac SNS in normal subjects. Methods and Results The 163 subjects (74 men, 89 women; age range 40-89 years) whose coronary arteriogram was normal, and who had no other cardiac or neurohormonal diseases, and no medication affecting the autonomic nervous system were included. All study subjects underwent metaiodobenzylguanidine imaging. Both initial and delayed heart-to-mediastinum (H/M) ratios had a significant gender difference and showed a progressive decrease with aging. In addition, the initial H/M ratio had a significant positive correlation with the delayed H/M ratio (r=0.89, P<0.0001). Females (50-59 years) demonstrated significantly higher delayed H/M ratio than males of the same age. After the age of 60, the delayed H/M ratio in females progressively decreased with aging, similar to males. As for the washout rate, both genders had a significantly progressive increase with aging. In addition, there was a significant decrease in the delayed H/M ratio in 10 females with surgical menopause compared with 15 age-matched females without surgical menopause. Conclusion Cardiac SNS appears to be regulated by various physiological factors. (Circ J 2009; 73: 310 - 315)

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Background Computed tomography (CT) enables detection of coronary artery stenoses, but its use is limited by deficient evaluation at elevated heart rates. The accuracy of dual-source CT (DSCT) for the detection of coronary artery disease (CAD) was assessed in 76 patients at high probability of CAD without heart rate control and compared with quantitative coronary angiography (QCA). Methods and Results The 76 patients (47 males, mean age 65.5±10 years) underwent DSCT without preceding heart rate control. Data sets were evaluated by 2 observers in consensus with respect to stenoses >50% decreased diameter. QCA served as the standard of reference. Mean heart rate during scanning was 68±9 beats per min, and the average Agatston score was 337±560. Of 1,160 coronary artery segments, all but 3 were visualized artefact-free; 58 coronary stenoses were correctly detected by CT angiography. In the segment-based analysis, sensitivity was 98.3%, specificity 99.2% and accuracy 99%; patient based analysis revealed a sensitivity of 100%, specificity of 83.3% and overall accuracy of 92.1%. Conclusions Even at elevated heart rates, DSCT can reliably detect coronary artery stenoses and the results correlate well with those for invasive coronary angiography. (Circ J 2009; 73: 316 - 322)

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Background Hemoglobin (Hb) levels may interact with inflammatory activation, but it is unknown whether the interaction has any impact on clinical outcomes in acute coronary syndromes. The aim of this study was to assess the relationship between admission Hb levels, leukocytosis and clinical outcomes of ST-elevation myocardial infarction (STEMI) treated with primary angioplasty. Methods and Results The study group comprised 1,904 (1,380 men) patients with STEMI treated with primary percutaneous coronary intervention, enrolled in a prospective registry. The primary endpoint of in-hospital death occurred in 90 (4.7%) patients. According to univariate analysis, extreme values of Hb (for 1^st and 5^th vs mid quintiles respectively: hazard ratio (HR) =7.1, P<0.001 and HR =3.2, P=0.024) and leukocytosis above median (HR =2.09, P=0.001) significantly correlated with in-hospital death. After dividing patients into high and low white blood cell (WBC) count groups, a U-shaped relationship of Hb levels and mortality was observed for patients with higher leukocytosis (1^st and 5^th vs mid quintiles respectively: HR =8.1, P=0.001 and HR =4.4, P=0.022), whereas in patients with lower WBC count higher mortality was related solely to the lowest Hb quintile (HR =6.9, P=0.010 vs mid quintile). Conclusion Higher mortality associated with higher Hb levels in STEMI patients treated with primary angioplasty is limited to patients with increased leukocytosis. (Circ J 2009; 73: 323 - 329)

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Background Experimental studies suggest that statins promote vascular fibrinolysis, so statin treatment before the onset of acute myocardial infarction (AMI) may result in a smaller infarct size. Methods and Results The study group comprised 310 patients with AMI who received fibrinolysis within 12 h after symptom onset: 39 had received statin pretreatment (statin group) and 271 had not (non-statin group). Initial Thrombolysis In Myocardial Infarction (TIMI) flow grade did not differ between groups. Among 120 patients with initial TIMI flow grade 0/1, achievement of TIMI flow grade >2 after passing the guidewire through the culprit lesion was more frequent in the statin group (70% vs 35%, P=0.03). The final rate of TIMI flow grade 3 was higher in the statin group (95% vs 86%, P=0.11). Area under the curve (AUC) for creatine kinase (CK) was lower in the statin group (55,972±45,934 vs 84,195±84,276 IU · L^-1 · h^-1, P=0.04). Multivariate analysis revealed statin pretreatment as an independent negative predictor of larger infarct size as defined by the upper tertile of AUC for CK (odds ratio 0.25, 95% confidence interval 0.07-0.91, P=0.035). Conclusion Statin pretreatment may enhance fibrinolysis and reduce infarct size in patients with AMI. (Circ J 2009; 73: 330 - 335)

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Background Dual antiplatelet therapy with acetylsalicylic acid (ASA) and a P2Y₁₂ ADP-receptor blocker is standard for prevention of coronary stent thrombosis. Clopidogrel, a 2^nd-generation P2Y₁₂ blocker, has recently become available in Japan and this study aimed to evaluate its antiplatelet effects in Japanese patients. Methods and Results Thirty Japanese patients scheduled for elective coronary stent implantation were enrolled. Under low-dose ASA therapy, 300 mg clopidogrel was loaded on the 1^st day and a daily 75-mg dose was administered on the following days. Assessed by optical aggregometer, rapid inhibition occurred at 4 h, when the inhibition of platelet aggregation rate (IPA) was 16.4±12.8% using 5 μmol/L ADP as the stimulus. The antiplatelet efficacy of clopidogrel was reasonably constant in each patient throughout the study period, although there was a broad inter-individual variation. At 48 h after clopidogrel loading, the ratios of responders (IPA ≥30%), hypo-responders (10%≤IPA<30%), and non-responders (IPA <10%) were 36%, 50%, and 14%, respectively. Conclusions The antiplatelet effectiveness of clopidogrel appeared individual-specific with wide inter-individual variation. The rate of clopidogrel non-responders was 14% among the examined Japanese patients. (Circ J 2009; 73: 336 - 342)

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Background Pioglitazone has a preventive effect on cardiovascular disease, but its ability to stabilize coronary plaque is unknown. Methods and Results A prospective, randomized trial was conducted in 54 patients with type 2 diabetes and stable angina pectoris, randomly assigned to either a pioglitazone group or control group. Non-culprit, angiographically mild-to-moderate obstructive lesions were examined with virtual histology intravascular ultrasound (VH-IVUS) at coronary intervention and 6 months later. In total, 42 lesions of 22 patients in the pioglitazone group and 44 lesions of 24 patients in the control group were analyzed. After 6 months, patients in the pioglitazone group had significantly improved blood sugar, high-sensitivity C-reactive protein, and plasma adiponectin levels. VH-IVUS analysis revealed that, although the total plaque-to-vessel volume was not changed in either group, the necrotic-core area had significantly decreased in the pioglitazone group (-4.6±5.9% vs 1.1±9.3%, P=0.001). There was a significant inverse correlation between the change in plasma adiponectin levels and the change in necrotic-core area (r=-0.46, P<0.0001). Conclusions Pioglitazone may stabilize coronary plaque by reducing the necrotic-core component, in association with enhanced plasma adiponectin levels. (Circ J 2009; 73: 343 - 351)

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Background Many clinical trials have shown that 3-hydroxy-3-methylglutaryl-conenzyme A reductase inhibitors (statins) can significantly reduce the incidence of coronary artery disease in both primary and secondary prevention. A recent study showed that aggressive lipid-lowering therapy with statins could achieve regression of coronary artery plaque evaluated with gray-scale intravascular ultrasound (IVUS). However, the actual changes in coronary artery plaque composition produced by statin therapy have not been well delineated. Methods and Results This study will be a prospective, open-label, randomized multicenter study of 160 patients with stable or unstable angina who have undergone percutaneous coronary intervention with Virtual Histology^TM IVUS (VH-IVUS). Patients will be randomly assigned to either the pitavastatin or pravastatin group. After treatment for 24-40 weeks, VH-IVUS will be performed again in the same segment of the coronary artery. The primary endpoint will be quantitative changes in each of the 4 components measured by VH-IVUS. Conclusion The treatment with statin on atheroma regression evaluated by intravascular ultrasound with Virtual Histology (TRUTH) study will be the first multicenter study using VH-IVUS to evaluate the effects of statins on changes in coronary artery plaque composition and the findings will clarify the mechanisms of coronary artery plaque stabilization. (Circ J 2009; 73: 352 - 355)

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Background Percutaneous device closure is now the widely accepted management technique for patent ductus arteriosus (PDA). In the present study, current practice of closing moderate to large PDA using the Amplatzer duct occluder (ADO) was compared with the previous experience using 0.052-inch coils. Methods and Results From August 1997 to September 2006, 76 patients were selected for either 0.052-inch coils or ADO implantation. Selection criteria were a minimal diameter of ≥2.5 mm and angiographic type A, C, D or E. In group I, 21 patients received 0.052-inch coils in a multiple coil strategy for PDA closure. In group II, 55 patients underwent ADO device implantation. The age, weight, hemodynamics, minimal PDA diameter and shunt size were insignificantly different between groups. However, group I had a higher rate of failed implantation and device embolization, and the immediate and 24-h closure rates (38.9% vs 81.8%, P<0.05; 72.3% vs 96.4%, P<0.05) favored group II. Conclusions ADO implantation is safer and more effective than the 0.052-inch coil strategy for transcatheter closure of moderate to large PDA. (Circ J 2009; 73: 356 - 360)

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Background The pleiotropic effects of HMG-CoA reductase inhibitors (statins) are thought to be mediated through inhibition of small GTP-binding proteins; however, it remains to be examined whether clinical concentrations/doses of statins actually exert them. Methods and Results In vitro studies with cultured human umbilical venous endothelial cells found that statins (atorvastatin, pitavastatin and pravastatin at 10 μmol/L) had no inhibitory effects on RhoA/Rho-kinase or Ras, but atorvastatin and pitavastatin inhibited membrane Rac1 expression. In animal studies of angiotensin II (AngII)-infused rats, atorvastatin showed only mild inhibitory effects on AngII-induced cardiovascular hypertrophy, whereas fasudil, a selective Rho-kinase inhibitor, significantly suppressed it. Statins had no inhibitory effects on RhoA/Rho-kinase, but inhibited both membrane and GTP-bound Rac1 in the heart, whereas fasudil only inhibited Rho-kinase activity. Furthermore, the combination of atorvastatin and fasudil showed more effective inhibitory effects than fasudil alone. Finally, in studies of normal healthy volunteers, clinical doses of pravastatin or atorvastatin (20 mg/day for 1 week) significantly inhibited Rac1, but not RhoA/Rho-kinase activity, in circulating leukocytes. Conclusions The pleiotropic effects of statins, if any, at their clinical doses are mediated predominantly through inhibition of the Rac1 signaling pathway. (Circ J 2009; 73: 361 - 370)

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Two similar rare cases of recurrent ampulla (takotsubo) cardiomyopathy, which was induced by physical stress of recurrent rhabdomyolysis in case 1 and aggravation of respiratory disease in case 2, are presented. At the initial admission, both patients had typical ampulla cardiomyopathy, which was indicated by transient left ventricular (LV) apical ballooning, but at the second admission, they both had atypical ampulla cardiomyopathy, as diagnosed by transient basal midventricular ballooning. Electrocardiograms at each admission showed a specific T-wave inversion, which might indicate the region of LV asynergy, and prolongation of the QT interval. In both cases, the plasma level of endogenous catecholamines was high. It is possible that excessive sympathetic stimulation induced by physical stress was the cause of this cardiomyopathy, but the cause of the differences in wall motion abnormalities between the first and second admissions was not identified. Appropriate management and treatment of the underlying disease and determining the mechanisms of recurrent ampulla cardiomyopathy might prevent its recurrence. (Circ J 2009; 73: 371 - 375)

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Danon disease is an X-linked dominant multisystem disorder that includes hypertrophic cardiomyopathy with skeletal myopathy, and results from mutations in the gene encoding the lysosome-associated membrane protein-2 (LAMP-2). To date, over 20 different mutations in LAMP2 have been identified. Three members of a family, a male proband (18 years old) and 2 sisters (15 and 20 years old) were studied. Their mother had been diagnosed with dilated cardiomyopathy at the age of 39 years, and died from advanced heart failure at the age of 43 years. The proband developed marked concentric hypertrophy at the age of 5 years and DNA analyses revealed a novel hemizygous frameshift mutation (c.573delA) in exon 5. The 2 affected sisters were also heterozygous for the same mutation. Functional analyses of this novel LAMP2 mutation are mandatory. (Circ J 2009; 73: 376 - 380)

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A 63-year-old woman was admitted to hospital with the chief complaint of new onset chest discomfort and pretibial pitting edema. Transthoracic echocardiography revealed a large invasive tumor on the heart protruding into the right atrium and right ventricle, which obstructed the outflow tract. She underwent transvenous 9Fr, 9-MHz ultra intracardiac echocardiography (ICE) (EP Technologies, Boston Scientific Corporation, San Jose, CA, USA) guided biopsy, and a diagnosis of malignant lymphoma was established from the specimen obtained. ICE-guided cardiac tumor biopsy may be one of the most useful strategies for diagnosis of cardiac tumors. (Circ J 2009; 73: 381 - 383)

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Patients with a left atrial (LA) thrombus are considered at risk of a serious thromboembolic event, and therefore endocardial radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) is contraindicated. However, RFCA of AF is inevitable in some patients with highly symptomatic AF and suspicious LA masses resembling thrombus. A patient was treated who underwent hybrid epi- and endocardial RFCA for drug resistant, highly symptomatic, paroxysmal AF with a suspicious left atrial (LA) thrombus that was a lamellated, thickened, echogenic lesion attached to the LA anterior wall and resistant to anticoagulation. During RFCA, contact with the LA endocardium was minimized using hybrid epi- and endocardial ablation guided by computed tomography merged with 3-dimensional electroanatomical mapping (NavX). The patient has been free of AF without antiarrhythmic drugs for 6 months, therefore hybrid epi- and endocardial ablation may be an effective therapy for AF patients with a LA mass. (Circ J 2009; 73: 384 - 387)

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