Two decades ago, a series of 8 idiopathic ventricular fibrillation patients who each had an abnormal ECG (right bundle branch block with coved-type ECG), but otherwise had normal hearts were described by Brugada and Brugada. Since then, the clinical entity has become known as Brugada syndrome (BS). Shortly thereafter, mutations of the SCN5A gene that encodes for the α-subunit of the sodium channel were found, galvanizing the field of ion channelopathies following in the footsteps of the breakthrough in long QT syndrome. Over the past 20 years, extensive research in this field has produced major progress toward better understanding of BS and the gaining of knowledge of the genetic background, pathophysiology and new management. Two consensus reports were published to help define the diagnostic criteria, risk stratification and management of BS patients. However, there are controversies. In this review, we will share our experiences of BS patients in Thailand and discuss advances in many aspects of the syndrome (ie, genetics and pathophysiology) and some of these pertinent controversies, as well as new treatment of the syndrome with catheter ablation.  (Circ J 2012; 76: 2713–2722)

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Current clinical and experimental data demonstrate that the electrocardiographic J wave plays a critical role in the pathogenesis of ventricular fibrillation (VF) in patients with Brugada syndrome (BS) and early repolarization (ER) syndrome (ERS). This has generated renewed interest in the presence of J waves and ERS in the general population, yet the identification of high-risk ECG markers and the risk stratification of subjects with ERS remain to be established. More recently, this concept has been expanded to VF mechanisms in patients with structural heart diseases. Some of the fatal arrhythmias in the setting of acute myocardial ischemia or infarction may share a similar, J wave-related electrophysiologic process. In canine arterially perfused wedge preparations, the occurrence of J wave-related arrhythmias is mediated by phase 2 reentry. The stability of the action potential (AP) dome in the ventricular epicardium is dependent on the prominence of the AP phase 1 notch. The ability to maintain the AP dome depends on a delicate balance between inward and outward ionic currents during depolarization and the early phase of repolarization. Outward shifts of the balance and inability to maintain the AP dome result in marked dispersion of repolarization and vulnerability to VF. This review describes the electrocardiographic and clinical features of the J waves in idiopathic VF and other structural heart diseases.  (Circ J 2012; 76: 2723–2731)

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Arterial calcification is the result of the same highly organized processes as seen in bone, which rely on a delicate balance between osteoblasts and osteoclasts. Although previously understood as passive precipitation, evidence has accumulated to suggest that arterial calcification is the result of organized, regulated processes bearing many similarities to osteogenesis in bone, including the presence of subpopulations of arterial wall cells that retain osteoblastic lineage potential. These cells have the potential to form mineralized nodules and express osteoblast markers, including bone morphogenetic protein-2, osteocalcin, osteopontin, and alkaline phosphatase. By contrast, osteoclast-like cells mediate the catabolic process of mineral resorption. Recent data shows that cells positive for tartrate-resistant acid phosphatase, a major marker for osteoclasts, have been histologically identified in atherosclerotic lesions and are referred to as osteoclast-like cells. Evidence has accumulated to suggest that initial arterial calcification through passive precipitation of calcium phosphate initiates balanced mineralization regulated by osteoclast-like and osteoblast-like cells. Subsequently, various pathogenic conditions may trigger an imbalance between osteoblastogenesis and osteoclastogenesis, leading to either calcification in stenotic/occlusive disease or destruction of the extracellular matrix in aneurysmal disease. Further elucidation of these newly emerging concepts could lead to a novel therapeutic approach to arterial stenotic/occlusive disease and/or abdominal aortic aneurysm.  (Circ J 2012; 76: 2732–2737)

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Background: Atrial fibrillation (AF) is associated with considerable morbidity and mortality in patients with coronary artery disease (CAD). Epicardial adipose tissue (EAT) is recognized as an important inflammatory tissue that may exert deleterious effects on the adjacent left atrial (LA) wall. Multidetector computed tomography (MDCT) can accurately assess EAT’s volume and distribution. This study used MDCT to investigate the effect of peri-atrial EAT on new-onset nonvalvular AF. Methods and Results: The study group consisted of 279 patients (176 men; age, 65±10 years) with no history of AF who underwent MDCT examination for evaluation of CAD. EAT was automatically identified on the basis of threshold attenuation values of −30 to −250 Hounsfield units. EAT volume was calculated as the sum of EAT area and subsequently divided into peri-atrial and peri-ventricular EAT. During follow-up of 3.3±1.0 years, AF occurred in 17 (6.1%) patients. Cox proportional hazards regression analysis indicated that male sex, and the LA and peri-atrial EAT volumes (P=0.03, P<0.001, and P<0.001, respectively) were independent predictors for future AF. The sensitivity and specificity for the prediction of AF using a peri-atrial EAT volume index of ≥27ml/m² were 88% and 92%, respectively. Conclusions: This is the first study demonstrating that peri-atrial EAT volume estimated by MDCT excellently predicted the development of new-onset AF in patients with CAD, independent of LA enlargement.  (Circ J 2012; 76: 2748–2754

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Background: The aim of this prospective study was to determine whether statin therapy (pitavastatin) has a beneficial effect on the prevention of new-onset atrial fibrillation (AF) in elderly patients with hypertension (HTN) and to evaluate the relationships among statin treatment, the development of AF, and left atrial (LA) and ventricular (LV) structure and function. Methods and Results: We enrolled eligible elderly patients (≥65 years old) with HTN and LV hypertrophy until the number of patients reached 110 in both groups. The 110 patients with HTN who needed statin therapy (HTN with statin group) were started on pitavastatin (1–2mg/day), and both groups continued with appropriate medication for HTN. LV and LA structure and function were examined by conventional and speckle-tracking echocardiography at baseline and after 1 year. LA volume and function in the HTN with statin group improved more than in the HTN without statin group. There was a significant difference in survival free of new-onset AF in the patients with and without statin therapy during the 2-year follow-up (hazard ratio: 0.32, P=0.027). Conclusions: Pitavastatin had a beneficial effect on LV diastolic function and LA structure and function in elderly patients with HTN. Pitavastatin treatment may be associated with a lower incidence of new-onset AF.  (Circ J 2012; 76: 2755–2762)

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Background: Brugada syndrome (BrS) is genetically heterogeneous. In Japanese BrS patients, except for SCN5A and KCNE5, mutations in the responsible genes have not yet been identified, and therefore the genetic heterogeneity remains poorly elucidated. Methods and Results: Forty consecutive patients with Brugada-pattern electrocardiogram (ECG) underwent comprehensive genetic analysis of BrS-causing genes including SCN5A, SCN1B, SCN3B, CACNA1C, CACNB2, KCNE3 and KCNE5. Besides identifying 8 SCN5A mutations in the present cohort, a KCNE3 T4A mutation was found in a 55-year-old male patient who had experienced several episodes of syncope. A head-up tilt test during passive tilt provoked both hypotension and bradycardia, followed by syncope. He was therefore diagnosed with neurally mediated syncope (NMS). To characterize the functional consequence of the mutant, electrophysiological experiments using whole-cell patch-clamp methods and computer simulations using human right ventricular wall model were carried out. It was found that KCNE3 T4A increased I_to recapitulated by heterologously coexpressing Kv4.3+KChIP2b+KCNE3-wild type or KCNE3-T4A in CHO cells. Conclusions: A KCNE3 T4A mutation was identified in a Japanese patient presenting Brugada-pattern ECG and NMS. Its functional consequence was the gain of function of I_to, which could underlie the pathogenesis of Brugada-pattern ECG. The data provide novel insights into the genetic basis of Japanese BrS.  (Circ J 2012; 76: 2763–2772)

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Background: High platelet reactivity (HPR) after clopidogrel treatment is linked to an increased risk of periprocedural myocardial infarction (PMI). The occurrence of PMI that could be associated with CYP2C19 genotype status was our hypothesis. Methods and Results: A total of 233 patients with non-ST elevation acute coronary syndromes (NSTACS) undergoing uneventful elective percutaneous coronary intervention were included. Platelet reactivity was assessed by Thrombelastograph at 24h after 300mg clopidogrel loading. HPR was defined as ≥70% adenosine diphosphate-induced platelet aggregation. The CYP2C19*2 and *3 loss-of-function (LOF) alleles were determined using DNA microarray method. Patients with PMI had significantly higher on-clopidogrel platelet reactivity compared to those without PMI (60.0±24.4% vs. 43.0±24.0%, P<0.001). HPR was more frequently observed in patients with PMI and was the strongest risk factor of PMI in multivariate analysis (OR_adj=4.348, 95% CI: 1.846–10.241, P=0.001). Furthermore, the incidence of HPR was significantly associated with the carriage of 2 CYP2C19 LOF alleles. Compared with non-carriers, patients carrying 2 CYP2C19 LOF alleles had a 3.000-fold increased risk (95% CI: 1.071–8.400, P=0.037) for PMI in multivariate analysis. However, inclusion of HPR as a covariate in the regression model changed the significant relationship between the carriage of 2 CYP2C19 LOF alleles and PMI. Conclusions: Among Chinese patients with NSTACS, carriers with 2 CYP2C19 LOF alleles are more prone to HPR, which is associated with an increased risk for PMI.  (Circ J 2012; 76: 2773–2778)

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Background: Endothelin-1 (ET-1) is a potent vasoconstrictor and an elevated plasma level is a prognostic marker in patients with cardiovascular diseases and/or malignancies. We hypothesized that an elevated plasma level might be a prognostic marker even in subjects without apparent cardiovascular disease or malignancy at baseline. Methods and Results: We measured plasma ET-1 levels in 1,440 healthy subjects over 40 years of age (580 men, 860 women) who were periodically followed for 10 years. The follow-up rate was 96.8%. Baseline plasma ET-1 levels were categorized into quartiles. Baseline plasma ET-1 levels were significantly associated with age, blood pressure, high-density lipoprotein-cholesterol, renal function, uric acid and all-cause death, but not with cardiovascular or cancer death. Kaplan-Meier curves demonstrated that all-cause mortality was significantly higher in the highest quartile of ET-1 than in the lowest quartile. Cox proportional hazards regression analysis demonstrated that ET-1 was an independent predictor of all-cause death [hazard ratio: 1.11, 95% confidence interval (CI) 1.01–1.23 per 1pg/ml difference]. The hazard ratio of all-cause death in the highest quartile of plasma ET-1 (≥5.9pg/ml) vs. the lowest quartile after adjusting for confounding factors was 1.54 (95% CI 1.09–2.20). Conclusions: The plasma ET-1 level may be a predictor of all-cause death in a healthy population.  (Circ J 2012; 76: 2779–2784)

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Background: Patients with biventricular assist device (BiVAD) placement have a poor prognosis, but preoperative risk factors for the necessity of BiVAD have not been fully elucidated. Methods and Results: Data from 79 patients who received left ventricular assist device (LVAD) between November 2002 and December 2011 were retrospectively reviewed. Overall, 9 patients (11.4%) required BiVAD, and the survival rate of BiVAD patients was significantly lower than that of LVAD patients (P<0.001). Multivariate analysis for BiVAD requirement showed left ventricular diastolic diameter (LVDd) ≤62mm (odds ratio [OR], 10.97; P=0.009) to be significantly associated with BiVAD requirement. Preoperative central venous pressure (CVP)/pulmonary capillary wedge pressure (PCWP) ratio ≥0.5 (OR, 13.09; P=0.028) was also significantly associated with BiVAD requirement. A new scoring system for predicting BiVAD requirement was created from the combination of CVP/PCWP ratio (≥0.5), body surface area (≤1.4m²), preoperative continuous hemodiafiltration use, B-type natriuretic peptide (≥1,200pg/ml) and LVDd (≤62mm), and this had a significantly larger area under the curve (0.909; P=0.003) than right ventricular stroke work index on receiver operating characteristic analysis. A score >20 using the new scoring method indicated significantly high probability of BiVAD requirement (OR, 16.00; P=0.019). Conclusions: The new scoring method, which includes CVP/PCWP ratio, is a novel risk stratification tool for BiVAD therapy.  (Circ J 2012; 76: 2785–2791)

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Background: The aim of the present study was to evaluate the mechanism of diastolic dysfunction (DD) after aortic valve replacement (AVR) in patients with aortic stenosis (AS). Methods and Results: Supine bicycle exercise Doppler echocardiography (EDE) with measurement of early diastolic peak velocities of transmitral flow (E) and mitral septal annular movement (E’) was performed in 38 patients with AS at least 24 months after AVR and in 19 sex- and age-matched normal controls. AS patients had a 27.4±32.7% decrease in the ratio of left ventricular (LV) mass index to LV end-diastolic volume index (LVMI/LVEDVI) after AVR. Pre-AVR E’ was significantly lower in AS patients (4.3±1.6cm/s vs. 7.7±1.6cm/s, P<0.005), resulting in a higher E/E’ (16.7±5.4 vs. 9.3±1.8, P<0.001). E/E’ at rest did not change significantly after AVR. Both E and E’ increased progressively with exercise, and the increase in E’ (P<0.001) but not E (P=0.675) was greater in normal controls than in AS patients (P<0.001). Peak E/E’ >13 during EDE was more common in AS patients than in controls (89.5%, 34/39 vs. 0%, 0/19, P<0.001). On multivariate analysis, LVMI/LVEDVI (Y=8.703+4.199X, r=0.433, P=0.001) was the only factor associated with peak E/E’ during EDE. Conclusions: Persistent DD is present after AVR, due primarily to failure in normal physiologic augmentation of LV relaxation during exercise, associated with incomplete or inadequate regression of LV hypertrophy.  (Circ J 2012; 76: 2792–2798)

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Background: Right atrial (RA) appendage (RAA) pacing is reported to impair hemodynamic benefits of cardiac resynchronization therapy (CRT) through a considerable delay of left atrial (LA) contraction, which compromises appropriate balance of atrioventricular (AV) and left ventricular (LV) synchrony. Potential usefulness of Bachmann’s bundle (BB) pacing to solve the problem remains to be confirmed. Methods and Results: Atrial synchrony and LV performance was investigated by echocardiography in 25 patients undergoing pacemaker implantation with preserved AV conduction and LV function (Group I), and 15 patients receiving CRT (Group II). In Group I, RAA pacing (AAI mode, n=10) increased P-wave duration (PWD) and RA-to-LA contraction delay (IAMD) compared with sinus rhythm (132±14 and 35±12ms vs. 108±16 and 13±13ms, P<0.001). The delayed LA contraction was associated with early interruption of LV filling, leading to an impairment of LV performance (Tei index: 0.43±0.12 vs. 0.34±0.09, P<0.01). BB pacing (AAI, n=15) did not cause such undesirable effects. In Group II, RA (BB)-paced biventricular pacing (DDD) reduced PWD and IAMD compared with RA-sensed biventricular pacing (VDD) (102±14 and –3±13ms vs. 117±10 and 21±18ms, P<0.001). This restoration of atrial synchrony was associated with significant improvement of LV performance (Tei index: 0.56±0.18 vs. 0.62±0.16, P<0.05). Conclusions: BB pacing preserves atrial synchrony, and might be more favorable than RAA pacing for maximizing hemodynamic efficacy of CRT.  (Circ J 2012; 76: 2799–2806)

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Background: Morphological and functional cardiac modifications attributable to neurohumoral activation and hyperdynamic circulation have been found in patients with liver cirrhosis (LC). Cardiovagal baroreflex sensitivity (BRS) has been shown to inversely correlate with left ventricular (LV) morphology. It was hypothesized that, in patients with cirrhotic cardiomyopathy, reduced BRS is associated with myocardial remodeling and increased LV mass index (LVMI). Methods and Results: Eighty-two LC patients scheduled to undergo liver transplantation were evaluated. Spectral analysis was done of beat-by-beat blood pressure and heart rate (HR) time series and BRS was derived from their cross-spectral gain. Echocardiography before liver transplantation was used to evaluate heart morphology and function. BRS was inversely correlated with LV wall thickness (P=0.038), end-diastolic interventricular septum thickness (P=0.048), LVMI (P=0.005) and HR (P<0.001). On multivariate stepwise linear analysis LVMI and HR were independently associated with BRS. On tertile analysis of LVMI, compared with the lowest tertile of LVMI (75±11g/m²), the highest tertile (118±13g/m²) showed significantly impaired BRS (4.6±2.3 vs. 6.4±3.1ms/mmHg, P=0.012). Conclusions: Reduced cardiovagal BRS is associated with increased LV mass in patients with LC, suggesting a relationship between cardiovagal BRS control of HR and cardiac end-organ damage in patients with cirrhotic cardiomyopathy.  (Circ J 2012; 76: 2807–2813)

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Background: The rostral ventrolateral medulla (RVLM) in the brainstem is responsible for regulation of the sympathetic nervous system. In the RVLM, nitric oxide (NO)-mediated γ-amino butyric acid (GABA) is a major sympathoinhibitory amino acid neurotransmitter and superoxide is a major sympathoexcitatory factor. In this study, we investigated whether or not NO-mediated GABA release is involved in superoxide-induced sympathoexcitation in the RVLM of hypertensive rats. Methods and Results: For our model hypertensive rats with sympathoexcitation, we used stroke-prone spontaneously hypertensive rats (SHRSP). GABA levels in the RVLM were measured by in vivo microdialysis. Microinjection of tempol, a superoxide scavenger, into the RVLM decreased arterial pressure (AP), heart rate (HR), and renal sympathetic nerve activity (RSNA) with an increase in GABA release in the RVLM. Microinjection of N^G-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor, into the RVLM increased AP, HR, and RSNA with a decrease in GABA release in the RVLM. Prior microinjection of L-NMMA into the RVLM attenuated the tempol-induced changes in AP, HR, RSNA, and GABA release in the RVLM. Microinjection of bicuculline, a GABA receptor blocker, into the RVLM attenuated the tempol- and L-NMMA-induced changes in AP, HR, and RSNA. Conclusions: The findings suggest that reduction of NO-mediated GABA release in the RVLM is partly involved in superoxide-induced sympathoexcitation of SHRSP.  (Circ J 2012; 76: 2814–2821)

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Background: The impact of the sampling rate (SR) of optical frequency domain imaging (OFDI) on quantitative assessment of in-stent structures (ISS) such as plaque prolapse and thrombus remains unexplored. Methods and Results: OFDI after stenting was performed in ST-segment elevation myocardial infarction (STEMI) patients using a TERUMO OFDI system (Terumo Europe, Leuven, Belgium) with 160frames/s and pullback speed of 20mm/s. A total of 126 stented segments were analyzed. ISS were classified as either attached or non-attached to stent area boundaries. The volume, mean area and largest area of ISS were assessed according to 4 frequencies of SR, corresponding to distances between the analyzed frames of 0.125, 0.25, 0.50 and 1.0mm. ISS volume was calculated by integrating cross-sectional ISS areas multiplied by each sampling distance using the disk summation method. The volume and mean area of ISS became significantly larger, while the largest area became significantly smaller as sampling distance became larger (1.11mm² for 0.125mm vs. 1.00mm² for 1.0mm, P for trend=0.036). In addition, variance of difference was positively associated with increasing width of sampling distance. Conclusions: Quantification of ISS is significantly influenced by the applied frequency of SR. This should be taken into account when designing future OFDI studies in which quantitative assessment of ISS is critical for the evaluation of STEMI patients.  (Circ J 2012; 76: 2822–2831)

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Background: For stable patients suspected of having coronary artery disease (CAD), myocardial perfusion imaging (MPI) or computed tomographic angiography (CT) is used for initial evaluation, while coronary angiography (CAG) is used for confirming the diagnosis. The choice of the initial diagnostic test might influence the treatment strategy. Methods and Results: Patients scheduled for MPI, CT, or CAG as the initial diagnostic test were enrolled. The primary and secondary end-points were a major adverse cardiac event (MACE) and revascularization, respectively. Of the 2,878 patients enrolled, 2,825 underwent initial diagnostic tests, and 2,780 were followed up for 1.42±0.49 years. After adjustment for CAD severity, Cox proportional hazard regression analysis showed that the risk of MACE in the MPI and CT groups were similar and significantly less than that in the CAG group (hazard ratio, 0.82 vs. 2.19; 95% confidence interval [CI], 0.43–1.58 vs. 1.40–3.44). Furthermore, the rate of revascularization in the MPI group was less than that of the CT (odds ratio, 1.62; 95% CI, 1.20–2.18) and CAG (odds ratio, 5.36; 95% CI, 4.07–7.05) groups. Conclusions: These data indicate that for stable patients with suspected CAD, the use of MPI or CT as the initial diagnostic test was associated with better prognosis than the use of CAG, and that initial evaluation with MPI was associated with a lower requirement of coronary intervention.  (Circ J 2012; 76: 2832–2839)

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Background: The JAPAN-ACS (Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome) trial showed that intensive statin therapy could induce significant coronary plaque regression in acute coronary syndrome (ACS). We evaluated the impact of metabolic syndrome (MetS) and its components on coronary plaque regression in the JAPAN-ACS patients. Methods and Results: Serial intravascular ultrasound measurements over 8–12 months were performed in 242 ACS patients receiving pitavastatin or atorvastatin. Patients were divided into groups according to the presence of MetS or the number of MetS components. Although the percent change in plaque volume (%PV) was not significantly different between the MetS (n=119) and non-MetS (n=123) groups (P=0.50), it was significantly associated with an increasing number of MetS components (component 0: −24.0%, n=7; components 1: −20.8%, n=31; components 2: −16.1%, n=69; components 3: −18.7%, n=83; components 4: −13.5%, n=52; P=0.037 for trend). The percent change in body mass index (%BMI) significantly correlated with %PV (r=0.15, P=0.021), especially in the MetS components 4 group (r=0.35, P=0.017). In addition, %BMI was an independent predictor of plaque regression after adjustment for the changes of low- and high-density lipoprotein cholesterol, triglycerides and HbA_1c. Conclusions: The clustering of MetS components, but not the presence of MetS itself, could attenuate coronary plaque regression during intensive statin therapy in ACS patients. Therefore, to achieve a greater degree of plaque regression, it is necessary to treat to each MetS component and use lifestyle modification.  (Circ J 2012; 76: 2840–2847)

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Background: Body fat distribution is defined as the pattern of fat deposits in different regions of the body and usually expressed as a ratio. There are few studies on the relationship between blood pressure and the ratio of central fat measured on dual-energy X-ray absorptiometry (DXA) in childhood. Methods and Results: The source population consisted of 521 fifth-grade children who attended elementary school in Hamamatsu, Japan, with 401 (77.0%) included in the study. Regional fat was determined using a DXA scanner in a mobile test room. The ratio of trunk to appendicular fat was calculated as trunk fat mass divided by appendicular (arms and legs) fat mass. In boys, the trunk-to-appendicular fat ratio was significantly related to systolic blood pressure and diastolic blood pressure after adjusting for confounding factors such as height and pubic hair appearance. In addition, an increase in trunk-to-appendicular fat ratio was related to an increase in blood pressure after adjusting for confounding factors including whole body fat volume and trunk fat volume. The relationship between fat distribution and blood pressure was not observed in girls. Conclusions: An excessive proportion of trunk fat was related to increased blood pressure in the boys in a general population of Japanese children. The relationship between fat distribution and blood pressure was independent of the relationship between fat volume and blood pressure.  (Circ J 2012; 76: 2848–2854)

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Background: Supraventricular and ventricular tachyarrhythmias (SVT, VT) are major concerns after repair of tetralogy of Fallot (TOF). This study evaluated the impact of comprehensive treatment, including hemodynamic interventions such as surgery, catheter-based intervention and pacemaker implantation (PMI), on tachyarrhythmia in repaired TOF patients. Methods and Results: Of 66 repaired TOF patients with tachyarrhythmia (age at onset, 23±11 years), 29 patients had sustained SVT, 21 had sustained or non-sustained VT, and 16 had both (SVT+VT). Successful treatment with catheter-directed ablation and/or anti-arrhythmic drugs (AADs) alone was achieved in 31 (69%) and partially achieved in 6 (13%) of 45 patients. Surgery, catheter-based intervention, and/or PMI were performed in 21 (32%) of 66 patients and resulted in complete control of the arrhythmia in 8 (38%) and partial control in 7 (33%) of these 21 patients, 20 (95%) of whom were receiving AADs. Patients with successfully controlled tachyarrhythmia in response to catheter ablation and/or AADs without hemodynamic intervention had a significantly higher probability of absence of sinus node dysfunction (odds ratio [OR], 23.2; 95% confidence interval [CI], 1.8–845.2; P=0.02) and lone intra-atrial reentrant tachycardia (OR, 12.4; 95% CI: 1.3–278.7; P=0.03). Conclusions: Hemodynamic interventions resulted in an improvement in outcomes in repaired TOF patients with tachyarrhythmia. To effectively manage intractable tachyarrhythmia with hemodynamic abnormalities, it is essential to understand hemodynamics and consider hemodynamic intervention.  (Circ J 2012; 76: 2855–2862)

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Background: Skin perfusion pressure (SPP) has been shown to be useful in the assessment of the severity of peripheral arterial disease (PAD), and ulcers can be cured when the SPP is ≥30–40mmHg. The purpose of this study was to determine the best body position for measuring SPP in patients with severe PAD. Methods and Results: We studied 24 limbs of 18 patients with PAD whose SPP was ≤40mmHg. After patients had been resting supine for 10min (Position I), their SPP was measured at the dorsum of the foot with a laser Doppler probe. Following measurement in the supine position, SPP was measured in the sitting position after the foot had been extended horizontally for 10min (Position II), and in the sitting position after the foot had been lowered vertically for 10min (Position III). SPP increased significantly from Position I to Positions II and III (25.3±10.9mmHg, 40.6±12.7mmHg, and 73.4±17.7mmHg, respectively; P<0.0001). In all patients, SPP values exceeding 30mmHg were obtained in Position III. Conclusions: The best SPP values were obtained in Position III, which is the ideal position for peripheral arterial circulation in patients with severe PAD.  (Circ J 2012; 76: 2863–2866)

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Background: The aim of the present study was to clarify the association between waist circumference and all-cause and cardiovascular disease (CVD) mortality risk in relatively lean Japanese subjects. Methods and Results: A total of 3,554 men and 4,472 women who had no history of CVD were examined and their waist circumference measured at baseline. The subjects were aged ≥40 years and were obtained from 3 prospective cohort studies during 1988–1996. Hazard ratios for all-cause and CVD mortality were analyzed over a follow-up period of 14.7 years using a Cox proportional hazards model and penalized spline method, after adjustment for study cohort, age, smoking, alcohol drinking, hypertension, dyslipidemia, and diabetes. Compared with the lowest quintile, the highest quintile of waist circumference in men was associated with a linear reduction in all-cause mortality risk (multivariate-adjusted hazard ratio, 0.73; 95% confidence interval: 0.60–0.89; P for trend=0.001). CVD mortality risk was increased in men aged ≤65 years with a higher waist circumference. This relationship was U-shaped. Waist circumference was not associated with all-cause or CVD mortality risk in women. Conclusions: Waist circumference was associated inversely with increased risk of all-cause death in men, but not in women. Middle-aged men with a greater waist circumference potentially have an increased risk of CVD mortality.  (Circ J 2012; 76: 2867–2874)

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Background: The prion protein (PrP) has been reported to serve as a surface maker for isolation of cardiomyogenic progenitors from murine embryonic stem (ES) cells. Although PrP-positive cells exhibited automaticity, their electrophysiological characteristics remain unresolved. The aim of the present study was therefore to investigate the electrophysiological properties of PrP-positive cells in comparison with those of HCN4p-or Nkx2.5-positive cells. Methods and Results: Differentiation of AB1, HCN5p-EGFP and hcgp7 ES cells into cardiac progenitors was induced by embryoid body (EB) formation. EBs were dissociated and cells expressing PrP, HCN4-EGFP and/or Nkx2.5-GFP were collected via flow cytometry. Sorted cells were subjected to reverse transcriptase-polymerase chain reaction, immunostaining and patch-clamp experiments. PrP-positive cells expressed mRNA of undifferentiation markers, first and second heart field markers, and cardiac-specific genes and ion channels, indicating their commitment to cardiomyogenic progenitors. PrP-positive cells with automaticity showed positive and negative chronotropic responses to isoproterenol and carbamylcholine, respectively. Hyperpolarization-activated cation current (I_f) was barely detectable, whereas Na⁺ and L-type Ca²⁺ channel currents were frequently observed. Their spontaneous activity was slowed by inhibition of sarcoplasmic reticulum Ca²⁺ uptake and release but not by blocking I_f. The maximum diastolic potential of their spontaneous firings was more depolarized than that of Nkx2.5-GFP-positive cells. Conclusions: PrP-positive cells contained cardiac progenitors that separated from the lineage of sinoatrial node cells. PrP can be used as a marker to enrich nascent cardiac progenitors.  (Circ J 2012; 76: 2875–2883)

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Background: Smoking is a major risk factor for cardiovascular disease. Also, inflammatory activation and metabolic disorder are the mediators of smoking-induced atherosclerotic progression. The aim of the present study was to investigate whether current smoking and smoking cessation alter inflammatory or metabolic status and affect subclinical atherosclerosis in apparently healthy men. Methods and Results: Classical risk factors and smoking habit were evaluated in 354 men who completed health examinations annually without any current medications. Carotid intima-media thickness (IMT) was followed for 27.1±4.5 months. At baseline, both maximum and mean IMT significantly changed during 2-year follow-up. They tended to increase along with progression of smoking habit, with significantly greater maximum IMT in current smokers compared with never smokers. Both maximum and mean IMT significantly changed during 2-year follow-up, and tended to increase with progression of smoking habit, with maximum IMT being greatest for current smokers. Past smokers tended to have greater IMT increase than never smokers. Among smoking habit and some atherosclerotic risk markers that showed significant correlation with maximum IMT increase, stepwise regression showed that smoking habit and serum low-density lipoprotein-cholesterol (LDL-C) level were the only independent predictors. Conclusions: Significant 2-year progression of subclinical atherosclerosis was associated with continuous smoking and LDL-C. This was only partly moderated in past smokers despite complete reversal of inflammatory activation, suggesting another crucial factor for inhibiting accelerated progression of subclinical atherosclerosis in men.  (Circ J 2012; 76: 2884–2891)

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Background: It remains unclear whether disease activity of vasospastic angina (VSA) is altered during a disaster. Methods and Results: Before and after the Great East Japan Earthquake, we examined Rho-kinase activity in circulating neutrophils of 11 VSA patients and their mental stress with the post-traumatic stress disorder (PTSD) questionnaire. Rho-kinase activity was significantly increased at 6 months after the Earthquake, and was returned to baseline level at 12 months. Importantly, percent change in Rho-kinase activity was significantly correlated with the PTSD score. Conclusions: These results indicate that the Rho-kinase activity of VSA patients was transiently enhanced associated with disaster-related mental stress.  (Circ J 2012; 76: 2892–2894)

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