Chronic heart failure (HF) remains a major medical problem in the developed world, with rapidly rising prevalence, substantial morbidity, and high costs. The concept of titrating chronic HF therapies using physiologic markers, so called "biomarker guided therapy (BGT)", has become an area of substantial interest in HF given the underutilization of evidence-based medications and suboptimal outcomes with current management strategies. Several recent trials of BGT have had mixed results, with some demonstrating improved outcomes and others showing no benefit. The heterogeneity of patient populations compounded by the lack of standardized BGT algorithms and trial endpoints has complicated interpretation of these results. This article reviews the rationale, accumulated data, and unanswered questions for BGT in chronic HF. (Circ J 2011; 75: 2031-2037)

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The new classification of heart failure in the American College of Cardiology/American Heart Association guidelines includes stage D, which is refractory severe heart failure that does not respond to medical or resynchronization therapy. Among the many treatment strategies for stage D heart failure, only heart transplantation and ventricular assist devices have been established as improving prognosis. With the evolution in the mechanics of ventricular assist devices in recent years, the postoperative prognosis has improved, and less sick patients can now be candidates for these devices. In Japan, 2 continuous flow devices have been approved since April 2011, and now is the best time to consider the indications for their use. (Circ J 2011; 75: 2038-2045)

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Background: Despite mounting evidence of the benefit of intensive lowering of low-density lipoprotein-cholesterol (LDL-C) in coronary artery disease (CAD) patients, it has not been shown that intensive lowering of both LDL-C and blood pressure (BP) reduces cardiovascular events in these patients. Methods and Results: 498 patients with hypertension and hypercholesterolemia with ≥75% stenosis in at least one major coronary artery, were recruited from 17 cardiovascular centers in eastern Japan. Patients were randomly assigned to conventional therapy (CT) or intensive therapy (IT). CT aimed to reduce BP to <140/90mmHg and LDL-C to <100mg/dl, and IT aimed for <120/80mmHg and <80mg/dl, respectively. The primary endpoint was a composite of all deaths, non-fatal myocardial infarction, unstable angina pectoris, coronary artery bypass graft surgery, non-fatal stroke, non-fatal major vascular disease, and peripheral artery disease. The mean follow-up period was 3.2 years. The achieved systolic BP was 126.8mmHg for the CT group, and 121.3mmHg for the IT group (P<0.001). The achieved LDL-C was 92.1mg/dl for the CT group, and 79.6mg/dl for the IT group (P<0.001). We detected the primary endpoint in 18 (7.1%) patients in the CT group, and 26 (10.7%) in the IT group (hazard ratio 1.53, 95% confidence interval 0.84-2.80, P=0.164). Conclusions: We could not show that intensively lowering both BP and LDL-C reduced cardiovascular risks in Japanese CAD patients with hypertension and hypercholesterolemia (UMIN-CTR UMIN000000571). (Circ J 2011; 75: 2062-2070)

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Background: Embryonic cardiomyocytes undergo profound changes in their electrophysiological properties during development. However, the molecular and functional changes in Na⁺ channel during cardiogenesis are not yet fully explained. Methods and Results: To study the functional changes in the Na⁺ channel during cardiogenesis, Na⁺ currents were recorded in the early (EDS) and late (LDS) developmental stages of cardiomyocytes in embryonic mice. Compared with EDS myocytes, LDS myocytes exhibited a larger peak current density, a more negative shift in the voltage of half inactivation, a larger fast inactivation component and a smaller slow inactivation component, and smaller time constants for recovery from inactivation. Additionally, multiple Na⁺ channel α-subunits (Nav 1.1-1.6) and β-subunits (Nav β1-β3) of mouse embryos were investigated. Transcripts of Nav 1.1-1.3 were absent or present at very low levels in embryonic hearts. Transcripts encoding Nav 1.4-1.6 and Nav β1-β3 increased during embryogenesis. Data on the sensitivity of total Na⁺ currents to tetrodotoxin (TTX) showed that TTX-resistant Nav 1.5 is the predominant isoform expressed in the heart of the mouse embryo. Conclusions: The results indicate that significant changes in the functional properties of Na⁺ channels develop in the cardiomyocytes of the mouse embryo, and that different Na⁺ channel subunit genes are strongly regulated during embryogenesis, which further support a physiological role for voltage-gated Na⁺ channels during heart development. (Circ J 2011; 75: 2071-2079)

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Background: On a cellular level, Brugada syndrome has been attributed to a deep phase 1 notch and subsequent shallow and prolonged repolarization in the right ventricular outflow tract (RVOT). A sodium channel mutation that leads to early inactivation of the late sodium current has been identified in some patients. Thus, drugs that inhibit the transient outward current (I_to) responsible for the phase 1 notch and/or enhance the late sodium current might suppress arrhythmic events in patients with Brugada syndrome. The effects of quinidine gluconate, a potent inhibitor of I_to, on RVOT action potential duration (APD) restitution kinetics in patients with Brugada syndrome were evaluated. Methods and Results: Programmed ventricular stimulation was performed in 9 Brugada syndrome patients by delivering up to 3 extrastimuli from the right ventricular apex and RVOT. RVOT monophasic action potentials (MAPs) were recorded before and after intravenous administration of quinidine (n=6) or ibutilide (n=3). All patients had inducible ventricular fibrillation (VF) before drug administration. Both quinidine and ibutilide increased steady-state and minimum RVOT MAP duration during programmed stimulation. Quinidine decreased the maximum slope of the RVOT APD restitution curve and VF could not be induced after administration of quinidine in 5 of the 6 patients. Conclusions: Quinidine appears to suppress the induction of VF by increasing RVOT MAP duration and decreasing the maximum slope of the restitution curve. (Circ J 2011; 75: 2080-2086)

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Background: Time in the therapeutic range (TTR) assesses the appropriateness of international normalized ratio of prothrombin time (PT-INR) control during warfarin therapy. We examined the status of and the factors influencing TTR in Japanese patients with non-valvular atrial fibrillation (AF). Methods and Results: We enrolled 501 AF patients (mean age, 70±10 years; males 66%; mean CHADS₂ score 2.0±1.2) taking warfarin for ≥2 years from 5 prefectures. The PT-INR therapeutic range was set up according to the 2008 Japanese Guideline. TTR was 64±25% for all patients and varied from 56% to 74% with the institution. Time below and above TTR was 31±26% and 5±7%, respectively. TTR was not affected by gender or antiplatelet co-administration. TTR in patients <70 and ≥70 years old was 46±23% and 77±17%, respectively (P<0.0001). TTR in patients with CHADS₂ score ≤1 and ≥2 was 59±27% and 68±23%, respectively (P<0.0001). TTR in patients with warfarin doses <2.0, 2.0-4.9, and ≥5.0mg/day was 72±22%, 63±25% and 48±24%, respectively (all P<0.001). Multivariate analysis revealed age and warfarin dose as independent predictors of TTR. Conclusions: TTR is generally high in Japan, although it varies with institutions. Most of the time spent out of therapeutic range is below the range. TTR is influenced by age presumably because of the low range recommendation for elderly patients, and by warfarin dose presumably because of physicians' anxiety about the hemorrhage risk. (Circ J 2011; 75: 2087-2094)

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Background: Predictors of T wave oversensing with implantable cardioverter-defibrillator (ICD) systems remains to be clarified. Methods and Results: Thirteen consecutive patients who underwent ICD implantations were included. The depolarization (R) and repolarization (T) of bipolar electrograms during baseline, AAI and DDD modes, and an isoproterenol (ISO) infusion were evaluated. The R wave amplitude during DDD was significantly lower as compared to that during the other conditions in all high-pass filter settings. In contrast, there was no significant difference in the T wave amplitude during the DDD as compared to the other conditions. With the DDD, there was a significantly higher incidence of a T/R ratio of greater than 0.25 as compared to that with the other conditions. T wave amplitude in Brugada syndrome was significantly higher than that in non-Brugada syndrome. The existence of Brugada syndrome and T/R ratio during the AAI with a high-pass filter setting of 10/20Hz was an excellent predictor of T wave oversensing in the follow-up period. Conclusions: DDD had a significant impact on the R wave amplitude reduction and the T/R ratio during AAI can be predictors of T wave oversensing. These findings have important implications for inappropriate shocks due to T wave oversensing. (Circ J 2011; 75: 2095-2104)

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Background: Residual platelet reactivity (RPR) after clopidogrel loading, measured by the VerifyNow assay, has been shown to predict 12-month clinical events in patients with acute coronary syndromes. However, links between coronary angiographic findings and outcome in patients with ST-elevation myocardial infarction (STEMI), with RPR have not been reported. We investigated whether RPR is associated with the amount of intracoronary thrombus burden (TB) in patients with STEMI undergoing unexpectedly-delayed primary percutaneous coronary intervention (pPCI). Moreover, we evaluated whether RPR might influence coronary flow and myocardial perfusion immediately post-pPCI. Methods and Results: The VerifyNow assay was used to determine RPR after clopidogrel loading, expressed in P2Y12-Reaction-Units (PRU). Intracoronary-TB was angiographically estimated and stratified as TB-Grade-A, -B and -C. Thrombolysis In Myocardial Infarction (TIMI) flow and Myocardial Blush (MB) were also estimated post-PCI. A total of 74 consecutive patients who presented with STEMI were enrolled in the study. Patients with greater TB presented significantly higher PRU-levels (174.1±91.5, 196.23±113.4 and 252.8±107.8 for TB-Grade A, B and C, respectively; P=0.044). PRU-levels >251.5 were shown to predict Large-TB (LTB; TB-Grade-C) (sensitivity=57.9%; specificity=77.8%; P=0.014). Impaired TIMI-flow and MB after PCI were significantly associated with higher PRU-levels (P<0.001). Conclusions: Among the studied patients, those with a higher RPR after clopidogrel loading presented larger intracoronary TB, worse post-PCI myocardial flow and perfusion. (Circ J 2011; 75: 2105-2112)

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Background: Geographical miss (GM), representing suboptimal drug-eluting stent deployment, is associated with an increased risk of target lesion revascularization (TLR) and myocardial infarction. The impact of suboptimal stenting techniques on clinical outcomes in diabetics remains unknown. Methods and Results: Stent deployment Techniques on cLinicaL outcomes of patients treated with the cypheR^TM stent (STLLR) is the first multicenter, large trial to prospectively evaluate outcomes associated with sirolimus-eluting stent (SES) deployment techniques. Axial GM and longitudinal GM (LGM), defined as a balloon injured segment or a diseased segment not covered by a SES, were assessed by an independent core laboratory. One-year outcomes between diabetics and non-diabetics and their relationship with GM were assessed. This substudy included 1,336 patients, 28.8% with diabetes. In non-LGM patients, TLR was similarly low in both diabetics and non-diabetics (2.0% vs. 2.0%, P=NS). However, TLR increased 4.1 times in diabetics (8.0%) and 1.9 times in non-diabetics (3.8%) in the presence of LGM (P=0.03). Axial GM had no impact on outcomes. By univariate analysis, stent length, acute gain, and LGM were the predictors of TLR in the total cohort. However, by multivariate analysis, acute gain was the only predictor of TLR (P=0.03), independently of LGM or diabetes. Conclusions: Acute gain is the exclusive predictor of TLR after SES implantation. Particularly in diabetics, the negative impact of LGM on TLR seems to be amplified. Diligent SES deployment for larger acute gain is critical to improve clinical outcomes. (Circ J 2011; 75: 2113-2119)

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Background: The purpose of the present study was to compare the efficacy and safety of paclitaxel-eluting stent (PES), sirolimus-eluting stent (SES), and zotarolimus-eluting stent (ZES) in primary percutaneous coronary intervention (PCI) for acute ST-segment elevation myocardial infarction (STEMI) with metabolic syndrome (MS). Methods and Results: Using data from Korea Acute Myocardial Infarction Registry (KAMIR; November 2005-December 2007), a total of 1,768 MS patients with STEMI who underwent primary PCI were enrolled: The PES group was 634, SES group, 906, and ZES group, 228. The primary endpoint was major adverse cardiac event (all-cause death, re-myocardial infarction, target lesion revascularization) during 12 months follow-up. At 12 months, the cumulative incidence of primary endpoint in the PES, SES, and ZES groups was 10.9%, 9.1%, and 11.0%, respectively (P=0.086). Incidence of death, recurrent myocardial infarction, or target lesion revascularization did not differ among the 3 groups. There were 7 episodes of acute (0.3% in PES group, 0.4% in SES group, and 0.4% in ZES group, respectively, P=0.773) and 18 episodes of cumulative stent thrombosis including late stent thrombosis (0.9% in PES group, 1.0% in SES group, and 1.3% in ZES group, respectively, P=0.448). Conclusions: Implantation of SES, PES, and ZES in MS patients with STEMI undergoing primary PCI provided comparable clinical outcomes in patients enrolled in KAMIR. (Circ J 2011; 75: 2120-2127)

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Background: Patients with intermittent claudication (IC) could benefit from low-cost, effective rehabilitative programs. This retrospective study evaluates compliance, impact on Quality of Life (QoL) and cost-effectiveness of a hospital prescribed, at-home performed (Test-in/Train-out) rehabilitative program for patients with IC. Methods and Results: Two-hundred and eighty-nine patients with IC (71±10.1 years, M=210) were enrolled for a 2-year period. Two daily 10-min home walking sessions at maximal asymptomatic speed were prescribed, with serial check-ups at the hospital. Compliance with the program was assessed by assigning a score of 1 (lowest compliance) to 4 (highest compliance). The SF-36 questionnaire and a constant-load treadmill test were used to evaluate QoL and Initial/Absolute Claudication Distance, respectively. Both direct and indirect costs of the program were considered for cost-effectiveness analysis. Two-hundred and fifty patients (70.5±9.2 years, M=191), at Fontaine's II-B stage (86%), were included in the study. No adverse events were reported. The average compliance score was 3.1. At discharge, both SF-36 domains and walking performance significantly increased (P<0.0001). A total of 1,839 in-hospital check-ups (7.36 /patient) were performed. Direct and indirect costs represented 93% and 7% of the total costs, respectively. The average costs of a visit and of a therapy cycle were C68.93 and C507.20, respectively. The cost to walk an additional meter before stopping was C9.22. Conclusions: A Test-in/Train-out program provided favourable patient compliance, QoL impact and cost-effectiveness in patients with IC. (Circ J 2011; 75: 2128-2134)

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Background: Acute type A aortic dissection (AAAD) is rare in young people. The early- and long-term outcomes after surgery for AAAD in patients aged ≤45 years was investigated. Methods and Results: Subjects were 355 patients who had undergone emergency surgery for AAAD. The patients were grouped as those aged ≤45 years (n=30; mean age, 38.3 years; younger group) and those aged >45 years (n=325; mean age, 65.3 years; older group). Clinical and prognostic variables were compared between the groups. Male sex, Marfan syndrome, and severe aortic regurgitation were more prevalent in the younger group. In-hospital mortality (16.7% vs. 8.6%, P=0.15) and postoperative patency of the distal aorta (90.8% vs. 59.1%, P<0.01) were more frequent in the younger group. The leading causes of late death were aortic rupture in the younger group (75.0%) and malignancy in the older group (27.5%). Although actuarial survival at 10 years was similar (64.5% vs. 62.5%), freedom from aortic reoperation at 10 years was decreased in the younger group (49.4% vs. 85.0%, P=0.012). A distal aorta >45mm (P<0.001), Marfan syndrome (P<0.01), and age ≤45 years (P=0.045) were shown to be independent risk factors for reoperation. Conclusions: Early- and long-term surgical outcomes are not better for patients ≤45 years, and the risk for reoperation is high in this group. Careful follow up is important in young patients with AAAD. (Circ J 2011; 75: 2135-2143)

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Background: We studied low-dose human atrial natriuretic peptide (hANP) infusion therapy during cardiac surgery and reported the cardiac and renal protective effects. The efficacy of a bolus injection of hANP (the "hANP shot") simultaneously with induction of cardioplegia has been proven in animal experiments. In the present study the clinical effects of this "hANP shot" were examined. Methods and Results: The subjects were 67 patients undergoing Coronary artery bypass grafting. At the time of inducing cardioplegia, 1 group received a simultaneous bolus injection of 100μg of hANP (hANP group) and the other group received an injection of physiological saline (placebo group). The primary endpoints were (1) operative mortality and complications, and (2) the creatine kinase isoenzyme MB (CPK-MB), troponin-I, and human heart fatty acid binding protein (H-FABP) levels. The secondary endpoints were (1) the incidence of arrhythmia, and levels of (2) atrial and B-type natriuretic peptides, and cyclic guanosine monophosphate (cGMP), and (3) renin, angiotensin II, and aldosterone. Postoperative CPK-MB, troponin-I, and H-FABP levels were significantly lower in the hANP group than in the placebo group. Postoperative arrhythmia was significantly less frequent in the hANP group than in the placebo group. Conclusions: It is possible to achieve cardioprotective effects based on the safety of the "hANP shot", as well as from biomarkers of ischemia and results related to arrhythmia. The "hANP shot" should also be evaluated as a safer and new cardioprotective method for cardiac surgery. (Circ J 2011; 75: 2144-2150)

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Background: A natural p300-specific histone acetyltransferase (HAT) inhibitor, curcumin, may have therapeutic potential for heart failure. However, it is unclear whether curcumin exhibits beneficial additive or synergistic effects on conventional therapy with angiotensin-converting enzyme inhibitors (ACEIs). Methods and Results: Rats were subjected to a sham operation or left coronary artery ligation. One week later, 34 rats with a moderate sized myocardial infarction (MI) were randomly assigned to 4 groups: solvents as control (n=8), enalapril (an ACEI, 10mg·kg^-1·day^-1) alone (n=8), curcumin (50mg·kg^-1·day^-1) alone (n=9) and enalapril plus curcumin (n=9). Daily oral treatment was repeated and continued for 6 weeks. Echocardiographic data were similar among the 4 groups before treatment. After treatment, left ventricular (LV) fractional shortening (FS) was significantly higher in the enalapril (29.0±1.9%) and curcumin (30.8±1.7%) groups than in the vehicle group (19.7±1.6%). Notably, LVFS further increased in the enalapril/curcumin combination group (34.4±1.8%). Histologically, cardiomyocyte diameter in the non-infarct area was smaller in the enalapril/curcumin combination group than in the enalapril group. Perivascular fibrosis was significantly reduced in the enalapril/curcumin group compared with the curcumin group. Conclusions: A natural non-toxic dietary compound, curcumin, combined with an ACEI exerts beneficial effects on post-MI LV systolic function in rats. (Circ J 2011; 75: 2151-2159)

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Background: Effects of statin therapy on cardiac sympathetic nerve activity in patients with chronic heart failure (CHF) have not previously been evaluated. Methods and Results: To compare the effects of lipophilic atorvastatin and hydrophilic rosuvastatin on cardiac sympathetic nerve activity in CHF patients with dilated cardiomyopathy (DCM), 63 stable outpatients with DCM, who were already receiving standard therapy for CHF, were randomized to atorvastatin (n=32) or rosuvastatin (n=31). We evaluated cardiac sympathetic nerve activity by cardiac ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy, hemodynamic parameters and neurohumoral factors before and after 6 months of treatment. There were no differences in the baseline characteristics of the 2 groups. In the rosuvastatin group, there were no changes in MIBG parameters, left ventricular ejection fraction or plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) after 6 months of treatment. In contrast, the atorvastatin group showed a significant increase in the delayed heart/mediastinum count ratio (2.18±0.4 vs. 2.36±0.4, P<0.0001), and the washout rate was significantly decreased (34.8±5.7 vs. 32.6±6.3%, P=0.0001) after 6 months of treatment compared with the baseline values. The plasma NT-proBNP level was also significantly decreased (729±858 vs. 558±747pg/ml, P=0.0139). Conclusions: Lipophilic atorvastatin but not hydrophilic rosuvastatin improves cardiac sympathetic nerve activity in CHF patients with DCM. (Circ J 2011; 75: 2160-2166)

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Background: Time-delay indexes are limited in predicting the response to cardiac resynchronization therapy (CRT), partly because they do not reflect the residual left ventricular (LV) contractility. We computed a novel index of LV contractility loss due to dyssynchrony (the strain rate (SR) dispersion index: SRDI) by using the speckle-tracking SR and compared the efficacy of the SRDI, time-delay indexes, and strain delay index (SDI), the previously reported index of wasted energy due to dyssynchrony, for predicting the acute response to CRT. Methods and Results: Echocardiography was performed in 19 heart failure patients (LV ejection fraction (EF) 25±6%) before and 2 weeks after CRT. The standard deviation of time to peak velocity, or strain, was calculated as time-delay indexes. The SRDI was calculated as the average of segmental peak systolic SR minus global peak systolic SR. Longitudinal SDI (L-SDI), longitudinal SRDI (L-SRDI), and circumferential SRDI (C-SRDI) significantly correlated with the change in global longitudinal strain (Δglobal LSt), whereas the time-delay indexes did not. Although the time-delay indexes were comparable between responders (Δglobal LSt ≥0.3%) and nonresponders, the L-SDI, L-SRDI, and C-SRDI were greater in responders. The area under the receiver operating characteristic curve of the L-SRDI, L-SDI, and C-SRDI for predicting responders was 0.89, 0.81, and 0.78, respectively. Conclusions: The SRDI correlated fairly well with an improvement in global LV systolic function after CRT. (Circ J 2011; 75: 2167-2175)

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Background: Right ventricular (RV) systolic function has been recognized as a prognostic factor in endstage heart failure (HF) patients and in the present study we evaluated the effect of this dysfunction on prognosis in patients with newly-diagnosed systolic HF. Methods and Results: We enrolled 180 consecutive patients with newly diagnosed systolic HF (ischemic or dilated cardiomyopathy). Echocardiographic evaluation was performed to assess biventricular function. Pulse-wave tissue Doppler imaging (TDI) readings were obtained from the lateral tricuspid annulus and the peak systolic annular velocity (Stv) was recorded. Patients were followed for a 2-year period and events (death or HF hospitalization) were recorded. During the follow-up, 79 patients (44%) had an adverse event. An inverse relationship was observed between the height of Stv and the probability of an event (odds ratio (OR) 0.716, 95% confidence interval (CI) 0.583-0.880, P=0.001), after controlling for potential confounders. Furthermore, creatinine clearance (CrCl) was inversely associated with the outcome: a 1-unit increase in CrCl was associated with a 0.98-times lower likelihood of having an event. When the analysis was stratified by CrCl <60ml/min or ≥60ml/min, Stv predicted adverse events in both groups (CrCl <60ml/min: OR 0.62, 95%CI 0.39-0.98, P=0.04; CrCl ≥60ml/min: OR 0.78, 95%CI 0.61-1.01, P=0.06). Conclusions: Pulse-wave TDI readings of peak systolic velocity at the lateral tricuspid annulus, reflecting RV systolic function, has prognostic significance in newly-diagnosed systolic HF patients. (Circ J 2011; 75: 2176-2181)

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Background: A quantitative history using Calgary syncope syndrome score (CSSS) is able to define the likely cause of syncope, but there is still a lack of diagnostic screening tests for vasovagal syncope (VVS). The aim of the present study was to develop a screening test for VVS on the basis of CSSS and the relationship between polymorphic variants of the G-system signaling protein genes and tilting results. Methods and Results: From 730 syncopal patients, 307 consecutive subjects without structural and electrical abnormalities were genotyped and examined on blood pressure (BP) and tilt testing. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism in genes encoding Gsα-protein GNAS1 (rs7121), G-protein β 3 subunit (rs5443) and the cardiac regulator of G-protein signaling RGS2 (rs4606). The control group consisted of 100 healthy volunteers with a negative history of syncope. From multivariate regression analysis, being a carrier of 393T GNAS1 (odds ratio [OR], 2.29) and systolic BP (OR, 0.98) remained as independent factors associated with positive tilt results. The resultant screening test for VVS consisted of the following: carrier of 393T GNAS1; systolic BP <131mmHg (from the receiver operating characteristic [ROC] curve); and CSSS ≥-2. Using ROC curve analysis for systolic BP and CSSS, 2 final models for the screening test were constructed: highest sensitivity (89%) and highest specificity (99%). Conclusions: The novel screening test including the variation of Gsα protein gene seems to be helpful to identify tilt-induced vasovagal patients. (Circ J 2011; 75: 2182-2186)

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Background: Myocardial perfusion and fatty acid imaging have played important roles in the risk stratification of patients with coronary artery disease (CAD). However, visual image assessment requires considerable experience and training. Therefore, an automated program has been developed that can quantify perfusion and fatty acid uptake on myocardial single emission computed tomography (SPECT). The present study aimed to validate the automated quantitative program. Methods and Results: A total of 50 patients were studied with known or suspected CAD who underwent stress ²⁰¹Thallium (²⁰¹Tl) and resting ¹²³I-labelled β-methyl iodophenyl pentadecanoic acid (BMIPP) SPECT. The SPECT images were quantified in 17 segments visually and using our Heart Score View software. Values were compared with those in a normal Japanese database and calculated summed stress (SSS), summed rest (SRS), summed difference (SDS), and summed BMIPP scores for each modality. Summed scores obtained using standard visual analysis and Heart Score View significantly correlated (²⁰¹Tl: SSS: r=0.934; SRS: r=0.827; SDS: r=0.743 summed BMIPP score: r=0.913) (each P<0.001) and Bland-Altman analysis revealed good agreement between the 2 approaches. Conclusions: Correlations between scores determined using Heart Score View software and standard visual interpretation were linear for both perfusion and fatty acid images. Thus, our new automated program might be useful for the risk stratification of patients with CAD in the clinical setting. (Circ J 2011; 75: 2187-2195)

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Background: Nitrates have been widely used as anti-ischemic drugs in patients with vasospastic angina (VSA). However, the effect of long-term nitrate treatment on cardiac events in VSA patients remains unclear. Methods and Results: Two-hundred and thirty-one patients with VSA who had not been receiving any antiischemic drugs, including calcium channel blockers (CCBs), nitrates, nicorandil, or any combination of these medications were prospectively enrolled in the present study. All patients had a positive acetylcholine provocation test with normal coronary angiograms, and they received CCBs after enrollment. They were divided into 2 groups based on whether nitrates were included in the treatment: a nitrate group (n=86) and a without nitrate group (n=145). The baseline clinical characteristics and frequency of anginal attacks within 48h before enrollment were similar between the 2 groups. With a median follow-up period of 70.5 months, 29 patients developed cardiac events, including 7 sudden cardiac deaths and 22 re-admissions for acute coronary syndrome. Cardiac events occurred in 19.8% of the nitrate group and in only 8.3% of the patients who were not taking nitrates (P=0.015). In a multivariate analysis, long-term nitrate treatment (hazard ratio 5.18, 95% confidence interval: 1.69-15.89, P=0.004) was an independent predictor of cardiac events. Conclusions: These data indicate that long-term nitrate treatment in addition to CCBs might not reduce cardiac events in VSA patients. (Circ J 2011; 75: 2196-2205)

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Background: Clinical symptoms of coronary artery disease (CAD) are often atypical in women, particularly in those with diabetes mellitus. Therefore, a simple diagnostic test to identify a high-risk subset of women with diabetes who are likely to have CAD is important. Methods and Results: A total of 407 consecutive patients (319 men and 88 women, age range 68±11 years) with suspected CAD, who were not complaining of anginal pain, were evaluated. Among these patients, 170 had diabetes. Stress myocardial perfusion imaging and simultaneous brachial and ankle blood pressure measurements were performed to obtain the ischemic total perfusion deficit (TPD) and ankle-brachial pressure index (ABI), respectively. Ischemic TPD was not significantly different between men and women, whereas ischemic TPD was significantly greater in diabetic patients than in non-diabetic patients (6.9±7.7% vs. 4.9±6.1%; P=0.005). In diabetic patients, ischemic TPD was not significantly different between men and women. However, women with ABI<0.9 showed significantly greater ischemic TPD than those with ABI≥0.9 (12.1±10.8% vs. 5.1±5.9%; P=0.04), whereas no difference in ABI was observed in men. Conclusions: ABI was useful in evaluating CAD in asymptomatic women with diabetes to detect a high-risk subset showing the ischemic TPD of >10%, which is regarded as a scintigraphic indicator for coronary revascularization. (Circ J 2011; 75: 2206-2212)

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Background: Cardiac troponin I (cTnI) is currently considered to be the most sensitive and specific biochemical marker of acute coronary syndrome and acute myocardial infarction. However, few reports have described the use of cTnI assays for evaluating abnormal hemodynamic load in children with congenital heart disease (CHD). It was hypothesized that significant hemodynamic overload due to a left-to-right shunt induces myocardial injury. Methods and Results: A highly sensitive cTnI assay was used to measure the serum cTnI levels in 30 children with atrial septal defect (ASD), 32 children with ventricular septal defect (VSD), and 350 healthy children. Cardiac catheterization was performed in the children with ASD and VSD to determine the ratio of pulmonary to systemic blood flow, the ratio of pulmonary to systemic arterial pressure (Pp/Ps), the pulmonary vascular resistance index, and the right and left ventricular end-diastolic volume. Serum cTnI levels in both the ASD and VSD children were significantly higher than those in healthy children (P<0.05 and P<0.01, respectively). Furthermore, serum cTnI levels significantly correlated with Pp/Ps (r=0.745, P<0.001) in VSD children. Conclusions: Significant volume and pressure overload due to a left-to-right shunt induce myocardial injury and might eventually cause irreversible myocardial remodeling in children with CHD. The serum cTnI level is a useful biomarker for evaluating myocardial damage associated with pulmonary hypertension in VSD children. (Circ J 2011; 75: 2213-2219)

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Background: Although the prevalence of adult congenital heart disease (ACHD) in Japan continues to rise, the number and geographic distribution of facilities potentially serving as regional ACHD centers remains unknown. We examined trends in ACHD care in Japan to identify needs and to determine potential regional responses to this growing patient population. Methods and Results: A descriptive, cross-sectional, nationwide survey was conducted to assess the status and needs of cardiology specialists related to providing ACHD care. Questionnaires were mailed to 138 cardiology departments located in 8 geographical regions throughout Japan; respondents were asked to document the status and future direction of ACHD care for each facility. Of the 109 facilities that responded, approximately one-third currently treat or plan to treat all ACHD patients. Fourteen facilities (12.8%) fulfilled all criteria for becoming regional ACHD centers. Although each regional center was projected to serve a population of 9.1 million, in 2 regions, no centers possessed the necessary care structure. Conclusions: Our findings revealed a shortage of adult cardiologists dedicated to ACHD care. Moreover, basic as well as formal fellowship ACHD training was deemed necessary. In Japan, the number of potential regional ACHD centers has just reached international standards. However, based on the geographic gaps documented here, a strategy other than regional centralization might be required to deliver adequate ACHD care to rural areas. (Circ J 2011; 75: 2220-2227)

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Background: Idiopathic cardiomyopathies (CMPs) are an important heterogeneous group of diseases. With the advance of therapeutic strategies, epidemiologic data on CMP have become very important, but only a few have been reported in Asian children. We conducted a retrospective epidemiologic study of primary CMP in Korean children. Methods and Results: Using a multicenter survey, we studied primary CMP among Korean children from January 1998 to December 2006 based on classification (2006) of CMP by the American Heart Association. A total of 277 primary CMP patients were reported from 17 cardiovascular centers. The average annual occurrence of new cases of primary CMP was 0.28 per 100,000 Korean children younger than 15 years of age (95% confidence interval (CI) 0.24-0.31). Dilated CMP (DCMP) was 66.43%, hypertrophic CMP (HCMP) 23.47%, restrictive CMP (RCMP) 6.50% and others 3.61%. The point prevalence of primary CMP at the end of the study was estimated as 2.11/100,000 (95%CI 1.83-2.43), DCMP 1.39/100,000, HCMP 0.51/100,000, RCMP 0.16/100,000 and others 0.04/100,000. Survival rates over 9 years were 69.8% in DCMP, 90.3% in HCMP, and 47.2% in RCMP. Conclusions: Recent point prevalence of childhood primary CMP in Korea was estimated as 2.11/100,000. Further epidemiologic study with a nationwide survey is necessary. (Circ J 2011; 75: 2228-2234)

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Background: The purpose of the present study was to clarify the efficacy of soy at reducing visceral fat. A randomized, double-blind, controlled, comparative trial was carried out to compare formula food containing soy protein (SP) to the same food in which soy was replaced with milk protein (MP). Methods and Results: Forty-eight participants were enrolled for the treatment of visceral fat obesity (visceral fat area >100cm² on computed tomography). The SP formula contained 12g of SP, 9g of MP, and other nutrients, and was given for 20 weeks in the morning, while in the MP formula SP was replaced with MP. During the 20 weeks of the trial period, visceral fat area and subcutaneous fat area in the MP group were significantly reduced, while those in the SP group did not change as assessed on analysis of covariance. Although waist circumference was reduced in both the SP and MP groups, body weight and body mass index were significantly reduced only in the MP group. Based on a mixed-effects model, the difference in log-transformed visceral fat profiles between the 2 groups was statistically significant (P<0.05), while a negative relationship was observed between the changes in visceral fat and adiponectin in the MP group (P<0.001), but not in the SP group. Conclusions: Formula food containing MP is superior to that containing SP for reducing visceral and subcutaneous fat. (Circ J 2011; 75: 2235-2243)

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Background: Increased stiffness of the pulmonary vascular bed is known to increase mortality in patients with pulmonary arterial hypertension (PAH); and pulmonary artery (PA) stiffness is also thought to be associated with exercise capacity. The purpose of the present study was to investigate whether cardiac magnetic resonance imaging (CMRI)-derived PA distensibility index correlates with PA stiffness estimated on right heart catheterization (RHC) and predicts functional capacity (FC) in patients with PAH. Methods and Results: Thirty-five consecutive PAH patients (23% male, mean age, 44±13 years; 69% idiopathic) underwent CMRI, RHC, and 6-min walk test (6MWT). PA distensibility indices were derived from cross-sectional area change (%) in the transverse view, perpendicular to the axis of the main PA, on CMRI [(maximum area-minimum area)/minimum area during cardiac cycle]. Among the PA stiffness indices, pulmonary vascular resistance (PVR) and PA capacitance were calculated using hemodynamic dataset from RHC. CMRI-derived PA distensibility was inversely correlated with PVR (R²=0.34, P<0.001) and directly correlated with PA capacitance (R²=0.35, P<0.001), and the distance in the 6MWT (R²=0.61, P<0.001). Furthermore, PA distensibility <20% predicted poor FC (<400m in 6MWT) with a sensitivity of 82% and a specificity of 94%. Conclusions: Non-invasive CMRI-derived PA distensibility index correlates with PA stiffness and can predict FC in patients with PAH. (Circ J 2011; 75: 2244-2251)

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Background: Endothelial dysfunction is a consistent finding in uremic patients. Whether the uremic solutes, p-cresol and indoxyl sulfate, affect the cellular function of endothelial progenitor cells (EPCs) was tested. Methods and Results: EPCs were isolated from healthy adults and treated with p-cresol (10-80μg/ml) or indoxyl sulfate (25-200μg/ml) with ranges of concentration similar to those found in uremic patients. The effect of p-cresol or indoxyl sulfate on the viability of EPCs was examined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In vitro angiogenesis of EPCs was tested by a matrigel assay. Signal pathways activated by these solutes were also studied. The viability of EPCs was dose- and time- dependently inhibited by p-cresol and indoxyl sulfate, respectively (both P<0.05). The angiogenesis capacity of EPCs was suppressed significantly by p-cresol but not by indoxyl sulfate. Phosphorylated p38 and Erk1/2 was increased by p-cresol, while P38 inhibitor SB203580 reversed the effect of p-cresol in the MTT assay. Notably, a dose of 80μg/ml p-cresol decreased the Notch1 intracellular domain level in EPCs. Conclusions: This study has demonstrated that p-cresol inhibits proliferation of EPCs via activation of p38 MAPK pathways. P-cresol also attenuates angiogenesis function of EPCs and interferes with the Notch1 path-way. (Circ J 2011; 75: 2252-2259)

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Background: Mesenchymal stem cells (MSC) are multipotent and reside in bone marrow (BM), adipose tissue and many other tissues. However, the molecular foundations underlying the differences in proliferation, differentiation potential and paracrine effects between adipose tissue-derived MSC (ASC) and BM-derived MSC (BM-MSC) are not well-known. Therefore, we investigated differences in the gene and secretory protein expressions of the 2 types of MSC. Methods and Results: ASC and BM-MSC were obtained from subcutaneous adipose tissue and BM of adult Lewis rats. ASC proliferated as rapidly as BM-MSC, and had expanded 200-fold in approximately 2 weeks. On microarray analysis of 31,099 genes, 571 (1.8%) were more highly (>3-fold) expressed in ASC, and a number of these genes were associated with mitosis and immune response. On the other hand, 571 genes (1.8%) were more highly expressed in BM-MSC, and some of these genes were associated with organ development and morphogenesis. In secretory protein analysis, ASC secreted significantly larger amounts of growth factor and inflammatory cytokines, such as vascular endothelial growth factor, hepatocyte growth factor and interleukin 6, whereas BM-MSC secreted significantly larger amounts of stromal-derived factor-1α. Conclusions: There are significant differences between ASC and BM-MSC in the cytokine secretome, which may provide clues to the molecule mechanisms associated with tissue regeneration and alternative cell sources. (Circ J 2011; 75: 2260-2268)

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Background: A moderate intake of alcohol is associated with lower cardiovascular mortality, and the role of circulating progenitor cells in the beneficial effect of alcohol on atherosclerosis is unclear. The hypothesis of this study was that alcohol ameliorates atherosclerosis by modulating the circulating levels of stromal cell-derived growth factor (SDF)-1 and vascular progenitor cells. Methods and Results: Atherosclerosis was induced by infusion of angiotensin II in apolipoprotein-E deficient mice, which were treated with high and low doses of ethanol for 28 days by intraperitoneal injection. Mice treated with low-dose ethanol had significantly less dilatation and fewer atheromatous lesions than mice receiving the high-dose ethanol. The number of circulating fibrocytes was significantly lower in mice treated with high-dose ethanol compared with mice with atherosclerosis untreated with ethanol. The plasma CXCL12/SDF-1 level was significantly increased in mice treated with low-dose ethanol compared with mice treated with a high dose, and the plasma concentration of transforming growth factor-β1 was significantly increased in mice treated with high-dose ethanol compared with control mice. Ethanol regulated the secretion of SDF-1 and vascular endothelial growth factor from fibroblasts in a dose-dependent and bimodal fashion. Conclusions: The circulating level of CXCL12/SDF-1 may be involved, at least in part, in the differential effects of alcohol consumption on atherosclerosis. (Circ J 2011; 75: 2269-2279)

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