Background Stable coronary artery disease (CAD) is classified into 2 types: high-risk (ie, 3-vessel disease, left main trunk lesions, or ostial lesions of the left anterior descending (LAD)) and low-risk (1- or 2-vessel disease other than ostial lesions of the LAD), which comprise the majority of CAD patients. According to ACC/AHA/ACP-ASIM guidelines for low-risk CAD, anti-anginal agents should be initially administered to control attacks, then coronary intervention should be considered when medical therapy is not effective (medical-preceding therapy: M). In Japan, however, the initial treatment is generally percutaneous coronary intervention (PCI) combined with medical therapy (PCI-preceding therapy: P). Methods and Results In the present study the long-term outcomes of 190 M patients and 192 matched P patients at 34 nationwide hospitals were surveyed over 3 years (mean: 3.4 years) starting in 2000. Age, gender, initial severity of anginal symptoms, number of lesion vessels, risk factors and prescriptions were similar between the 2 groups. During the 3.4-year follow-up, additional PCI or coronary artery bypass grafting was required in 9.4% of the M group and in 33.2% of the P group. The rates of cardiac death were similar (1.6% in M and 2.6% in P). The overall rate of cardiac death and acute coronary syndrome was 2.1% in M and 4.7% in P, but the difference was not significant. The grade of anginal symptoms 12 months later was well improved in both M (1.6±1.4 to 0.6±0.9) and P (1.7±1.4 to 0.3±0.7) and there was no significant difference. Averaged annual medical cost was lower in M than in P (4.4-fold lower in the first year and 3.1-fold by the next year). Conclusions The present study suggests that M and P for Japanese low-risk CAD may have a similar effect on long-term prognosis, but M is cheaper. (Circ J 2006; 70: 365 - 369)

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Background The present study examined how sex differences in conventional risk factors for cardiovascular disease (CVD), especially smoking, account for excess male mortality from CVD in Japan. Methods and Results In a 14-year follow-up study, causes of death were ascertained among 10,546 Japanese aged 30 years or older at the baseline. The proportion of the excess male risk of CVD explained by the differences in risk factors was estimated as (HR₀ - HR₁)/(HR₀ -1), where HR₀ is the age-adjusted hazard ratio (men vs women) and HR₁ is the age and risk factor-adjusted hazard ratio. The age-adjusted male:female ratios were 1.60 (95% confidence interval (CI), 1.32-1.94) for CVD, 1.75 (95% CI, 1.33-2.30) for stroke, and 1.55 (95% CI, 0.97-2.49) for coronary heart disease. The proportion of excess male risk of CVD explained by smoking was 46% and excess risk explained by all risk factors including smoking was 36%. In men, drinking habits decreased the excess risk of CVD. Except for the association between drinking habits and CVD, the impact of the hazard ratios of conventional risk factors had no sex difference. Conclusions Smoking contributes substantially to excess male mortality from CVD when the smoking rates vary substantially by sex. (Circ J 2006; 70: 370 - 375)

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Background Because of their favorable prognostic effects, angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB) and β blockers have become background therapy in dilated cardiomyopathy (DCM). However, there are few reports concerning the long-term prognosis of Japanese patients with DCM in relation to these treatments. Methods and Results One hundred and fifty patients with DCM were divided into 2 groups: group A (n=46) (diagnosis: 1982-1989) and group B (n=104) (diagnosis: 1990-2002). During follow-up period of 6.9±4.8 years, 62 patients died and 1 patient had a heart transplant. The survival rate at 5 and 10 years was 60.9% and 34.8%, respectively, in group A patients, and 80.9% and 65.3%, respectively, in group B patients (p=0.0079). In group A patients, ACEI/ARB or β blockers were less frequently used (p<0.0001), whereas antiarrhythmics (class Ia or Ib) were more often used (p<0.0001). The patients treated with ACEI/ARB and β blockers showed a better survival rate than those without (p<0.0001). The patients with antiarrhythmics showed a worse survival rate than those without (p<0.0001). Conclusion The prognosis of Japanese patients with DCM has significantly improved over the past 20 years. This improvement may be explained partly through the increased use of ACEI/ARB and β blockers and a declining use of antiarrhythmics. (Circ J 2006; 70: 376 - 383)

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Background C-reactive protein (CRP) independently predicts cardiovascular disease (CVD) and is considered to be part of metabolic syndrome (MS). The concentration of CRP are proposed to be <1.0 mg/L as low risk, 1.0 to 3.0 mg/L as intermediate risk, and >3.0 mg/L as high risk for CVD in Western society. Methods and Results Apparently healthy 179 men and 166 women were categorized with modified National Cholesterol Education Program Adult Treatment Panel III criteria (body mass index ≥25 in place of abdominal obesity) for defining MS. The cut-off points of CRP were evaluated for both MS defined by impaired fasting glucose criteria of ≥110 mg/dl (MS110) and ≥100 mg/dl (MS100), separately by sex. The optimal cut-off point of CRP was 0.65 mg/L in all subgroups. The sensitivity and specificity of this CRP value for male MS100, female MS100, male MS110, and female MS110 were 0.650 and 0.626, 1.000 and 0.771, 0.739 and 0.609, and 1.000 and 0.756, respectively. Conclusions The optimal cut-off point of CRP for MS might be 0.65 mg/L in Japan and this value can be useful in routine clinical practice and studies on MS. (Circ J 2006; 70: 384 - 388)

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Background The aim of the present study was to determine the predictors of depression as a complication after open heart surgery and influence of depression on the patients' prognosis. Methods and Results During the last 3 years, 97 patients (21.5%) of the 452 adult patients who had open heart surgery at our institute experienced depression after the operation. Patients who scored over 16 points using a Center for Epidemiological Studies Depression Scale were diagnosed with significant symptoms of depression. Depressed patients (group I, n=97) and non-depressed patients (group II, n=355) in terms of mortality and length of hospital stay were compared. Predictors for depression were identified by logistic regression analysis. The postoperative hospital stay was significantly longer in group I. Hospital mortality was also significantly higher in group I. Female gender (odds ratio (OR): 5.15, p<0.0001), emergency surgery (OR: 4.46, p<0.0001), and being over 70 years of age (OR: 4.67, p<0.0001) were found to be significant predictors for postoperative depression. Conclusion The prognosis for patients who had depression developed after open heart surgery was poor. It might be important to start prophylactic medication as soon as possible after the operation, particularly for patients at risk of having depression. (Circ J 2006; 70: 389 - 392)

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Background Although small dense low-density lipoprotein (sd-LDL) has an established association with diabetic dyslipidemia, previous studies have failed to show an association between sd-LDL and diabetes among coronary heart disease patients. This study investigated the prevalence of sd-LDL and abnormal glucose regulation in acute coronary syndrome (ACS). Methods and Results LDL size at the onset of ACS was measured by nondenatured gradient gel electrophoresis in 314 of 429 consecutive patients. Sd-LDL was prevalent in 54% of the patients, irrespective of the presence of previously known diabetes (50% vs 60% in nondiabetes and diabetes, respectively). Diabetes was present in 122 (28%) of the patients, and 110 patients without diabetes underwent an oral glucose tolerance test. Impaired glucose tolerance (IGT) and newly detected diabetes were found in as many as 44% and 22% of the patients tested, even though their hemoglobinA1c levels were in the normal range (5.3±0.5%). The prevalence of sd-LDL was significantly higher in patients with glucose intolerance than in those with normal glucose tolerance (61% vs 42%). Conclusion IGT and diabetes were far more common than normal glucose regulation in ACS patients, and the abnormal glycometabolism was closely associated with highly atherogenic sd-LDL. (Circ J 2006; 70: 393 - 401)

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Background Recent studies have suggested that the Rho/Rho-kinase mediated pathway (Rho-kinase pathway) regulates the vasomotion of arteries in pathological conditions. However, it remains unclear regarding whether this pathway regulates the coronary vasomotion of atherosclerotic lesions. Methods and Results The coronary diameter at the concentric stenotic site, which is considered to reflect the whole circumferential atherosclerosis, in patients with stable angina pectoris (SAP; n=11) and the control site in patients with SAP and chest pain syndrome (CPS; n=9), was measured at baseline and after the intracoronary administration of nitroglycerin (200 μg) and the subsequent intravenous infusion of fasudil (30 mg for 30 min), a Rho-kinase inhibitor, during coronary angiography. The change in the diameter with fasudil at the concentric stenotic site (22.0±10.0%) was significantly higher than that with nitroglycerin (4.7±6.0%, p<0.001) in patients with SAP. Meanwhile, the vasodilatory effect of nitroglycerin and fasudil at the control site was similar in both group of patients (25.5±17.3% and 21.9±14.9% in SAP and 34.4±20.8% and 33.2±23.6% in CPS, respectively). Conclusions The vasodilatory effect of the subsequent administration of fasudil surpassed that of nitroglycerin at the concentric coronary stenosis in patients with SAP, thus suggesting that the Rho-kinase pathway regulates the coronary vasomotion of atherosclerotic lesions. (Circ J 2006; 70: 402 -408)

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Background Coronary artery spasm plays an important role in the pathogenesis of vasospastic angina, and contributes to the development of several acute coronary syndromes. Endothelial nitric oxide synthase (ecNOS) catalyzes the synthesis of nitric oxide, which regulates vascular tone, and may be related to coronary vasospasm. The present study investigated whether coronary spasm is related to particular polymorphisms of the ecNOS gene. Methods and Results Spasm provocation by serial infusions of acetylcholine was performed on 165 patients who were clinically suspected of having angina. In both study patients and healthy controls (n=400), genomic polymorphisms of the ecNOS gene were determined by using polymerase chain reaction. Quantitative luminal diameter measurements of the 3 major coronary arteries were initially obtained before and after acetylcholine injection, and then after isosorbide dinitrate injection, by using a computer-assisted analysis system. Logistic multiple regression analysis identified the a/a or a/b genotype in intron 4 of ecNOS (NOS4a: p=0.0431, odds ratio (OR) 2.43) and diabetes mellitus (p=0.0060, OR 4.88) as significant predictors of coronary spasm. In the patients with NOS4a, both the induced and spontaneous contractions were augmented. Conclusion The present study results indicated that NOS4a could be a good marker for coronary artery spasm. (Circ J 2006; 70: 409 - 413)

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Background Plasma adiponectin is decreased in patients with coronary artery diseases, especially in patients with acute coronary syndrome (ACS). However, the correlation between plasma adiponectin and variant angina pectoris (VAP) has not been verified. Plasma adiponectin concentrations between VAP and other coronary artery diseases was compared in the present study. The association between plasma adiponectin concentration and VAP was also investigated. Methods and Results Plasma adiponectin concentrations in the VAP group (n=101) were compared with those of the ACS group (n=117), the stable angina pectoris group (n=108), and the normal coronary group (n=81). Plasma adiponectin concentrations in VAP and ACS were significantly lower than that of the normal coronary group (6.6±5.4 vs 5.2±4.0 vs 9.0 ±6.2 μg/ml, p<0.001, respectively). Multivariate analysis indicated that plasma adiponectin (odds ratio (OR) 0.735, 95% confidence interval (CI) 0.621-0.855, p=0.011), smoking (OR 2.012, 95% CI 1.210-3.880, p=0.020), and age (OR 0.976, 95% CI 0.957-0.997, p=0.022) correlated independently with the development of VAP. Conclusions Our results suggest that a decrease in plasma adiponectin concentration might be associated with the development of VAP. (Circ J 2006; 70: 414 - 418)

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Background Measurement of circulating biomarkers has enabled early diagnosis and risk assessment of acute coronary syndrome. This study sought diagnostic values of the first single-point data of biomarkers obtained soon after patient arrival by comparing with scintigraphically quantified myocardial injury in patients presenting with acute chest pain at an emergency room. Methods and Results Serial blood samples were taken soon after arrival in an emergency department in 74 patients with suspected acute coronary syndrome to quantify blood levels of troponin-T (TnT), heart-type fatty acid-binding protein (H-FABP), myocardial-bound creatine kinase (CK-MB), and myoglobin. Myocardial perfusion and metabolic defects were scintigraphically quantified. The first single-point data had high positive predictive values for detecting the defects (80-100%) but low negative predictive values (15-41%). CK-MB and TnT had higher specificities (73-100%) but significantly lower positive rates (22-27%) than the others (61-68%), resulting in greater sensitivities of H-FABP and myoglobin (75-80%) than those of CK-MB and TnT (29-35%). Among biomarkers, TnT peak concentrations most closely correlated with scintigraphic abnormalities. Conclusion H-FABP can contribute to early detection of myocardial injury and TnT is most likely to correlate with injured myocardial mass. The differential features of biomarkers are complementary in patients with acute chest pain presenting at an emergency room. (Circ J 2006; 70: 419 - 425)

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Background The involvement of interleukin (IL)-6 in restenosis of the recanalized coronary artery after the percutaneous coronary intervention (PCI) was examined. Methods and Results There were 40 patients enrolled in the study who had acute myocardial infarction and whose infarct-related coronary arteries were treated by new thrombectomy devices and stenting. Blood samples were collected from the culprit coronary artery before and immediately after the maneuver of the PCI. Restenosis was defined as residural stenosis because it accounted for more than 50% at the follow-up coronary angiography. Plasma IL-6 levels in the infarct-related coronary artery were 12.8 and 13.2 pg/ml before and after the initial maneuver of the PCI, respectively, values that were significantly greater than that of 7.2 pg/ml in the peripheral vein (p<0.0001). The levels of IL-6 in the pre- and the post-stage of PCI were significantly greater in the patients with restenosis than those without restenosis. The plasma IL-6 levels in the post-stage of PCI had significant correlations with late loss and loss index. Conclusions The present study findings indicate that plasma IL-6 levels in the culprit coronary artery at the post-stage of PCI are closely associated with the future restenosis of the revasculized coronary artery in acute myocardial infarction. (Circ J 2006; 70: 426 - 429)

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Background In animal models, granulocyte colony-stimulating factor (G-CSF) improves post-infarct cardiac function. However, in pilot studies involving patients with angina and acute myocardial infarction (AMI), G-CSF at a high dose frequently induced coronary occlusion or restenosis, but those at a low dose showed no significant beneficial effect. We hypothesized that a low dose but long duration of G-CSF will have a beneficial effect without serious complications to patients with coronary heart disease. Methods and Results Forty-six patients with angina or AMI were randomly assigned into G-CSF and non-G-CSF control groups, respectively. Recombinant G-CSF was subcutaneously injected once a day for 10 days. The leukocyte counts in the peripheral blood were controlled at approximately 30,000 /μl. One month later, a Thallium-201 single photon emission computed tomography revealed the increased percentage uptake and the reduced extent and severity scores in the G-CSF angina group. In the G-CSF AMI group, the curve between the ejection fraction and peak creatine kinase shifted significantly upward, compared with that of the non-G-CSF AMI group. Serious complications were not observed during the 6 months of observation. Conclusions A low dose but long duration of G-CSF treatment may have a beneficial effect without any serious complications in patients with coronary heart disease. (Circ J 2006; 70: 430 - 437)

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Background To evaluate the risks factors of atrial fibrillation (AF) following coronary artery bypass grafting (CABG). Methods and Results Twelve hundred patients subjected to CABG were included. Postoperative AF developed in 278 patients (23.2%). Statistical analysis identified 5 independent predictors of AF: advanced age, history of supraventricular arrhythmias, preoperative heart failure, operation with standard CABG technique and repeated revascularization. Conclusions Postoperative AF caused a significant increase in mortality and hospitalization length. There were 4 independent risk factors of postoperative AF. Administration of β-blockers and the OPCAB (off-pump CABG) operating technique were identified as protective factors. (Circ J 2006; 70: 438 - 441)

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Background Although nifekalant is a class III antiarrhythmic agent without negative inotropic activity, its effect in patients with shock-refractory ventricular fibrillation remains unclear. Methods and Results Patients who had an out-of-hospital cardiac arrest with ventricular fibrillation that persisted after 3 shocks from an external defibrillator, intravenous epinephrine, and another shock were retrospectively studied. The patients received lidocaine from January 1997 through June 2001 and nifekalant from July 2001 through December 2004. Short-term survival rates (survival to hospital admission and 24-h survival) were compared between the groups. The study group comprised 120 patients (mean age: 62±16 years): 55 received nifekalant and 65 received lidocaine. Age, sex, history of ischemic heart disease, whether arrest was witnessed or not and time to arrival at the hospital did not differ significantly between the groups. As compared with lidocaine, nifekalant was associated with significantly higher rates of survival to hospital admission (67% vs 37%, p<0.001) and 24-h survival (53% vs 31%, p=0.01). Multivariate analysis showed that treatment with nifekalant and early initiation of cardiopulmonary resuscitation were independent predictors of 24-h survival. Conclusions As compared with lidocaine, nifekalant may improve short-term survival in patients with out-of-hospital cardiac arrest due to shock-refractory ventricular fibrillation. (Circ J 2006; 70: 442 - 446)

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Background The association between plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and prognostic outcomes in patients after ischemic stroke remains unknown. The present study tested the hypothesis that NT-proBNP level is noticeably increased after ischemic stroke and that elevated NT-proBNP is associated with unfavorable clinical outcomes (UFCO). Methods and Results Blood samples for NT-proBNP levels were collected serially and examined with sandwich immunoassay after acute ischemic stroke in 86 consecutive patients. The NT-proBNP levels were also measured in 30 healthy control volunteers and 30 at-risk control subjects. The NT-proBNP levels were significantly higher at 4 intervals after ischemic stroke than in healthy and at-risk control subjects (all p<0.001). The NT-proBNP decreased to a significantly lower level on day 21 and to a substantially lower level on day 90. Additionally, the NT-proBNP level at any of the 4 intervals was significantly higher in patients with than in patients without UFCO (defined as combined congestive heart failure ≥ class 3, acute myocardial infarction, recurrent stroke or any cause of death) (all p<0.01). Multivariate analysis demonstrated that age and NIH Stroke Scale were the 2 strongest independent predictors of increased NT-proBNP levels (all p<0.01). Furthermore, increased NT-proBNP (≥150 pg/ml) was the strongest independent predictor of long-term (mean follow-up: 24 months) UFCO (26 patients) (all p<0.05). Conclusions The NT-proBNP level was markedly elevated after acute ischemic stroke and declined substantially thereafter. An increased NT-proBNP level was strongly and independently correlated with UFCO in patients after ischemic stroke. (Circ J 2006; 70: 447 - 452)

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Background The antiplatelet agent, cilostazol, is known to reduce the risk of subsequent cerebral infarction. However, the cost effectiveness of such treatment in comparison to aspirin has not been studied. Methods and Results A Markov model was developed to calculate the health outcomes and associated costs for 65-year-old patients with cerebral infarction who were treated with 200 mg/day cilostazol or 81 mg/day aspirin. Cilostazol was more effective, but also more expensive than aspirin. Cilostazol would extend quality-adjusted life years (QALY) by 0.64, while increasing life-time costs by approximately ¤1.1 million. The incremental cost-effectiveness ratio of cilostazol in comparison with aspirin was estimated to be ¤1.8 million per QALY. Conclusions The use of cilostazol to prevent recurrence of cerebral infarction appears to be cost effective. (Circ J 2006; 70: 453 - 458)

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Background As coronary flow velocity (CFV) is inversely related to the luminal size that exists for the myocardial bed, the elevated arterial tone can be assessed as the higher flow velocity in the epicardial artery. We examined the usefulness of transthoracic Doppler echocardiography (TTDE) for the assessment of coronary arterial tone. Methods and Results A total of 32 patients underwent TTDE and angiography. The luminal diameter (LD) in the left anterior descending artery (LAD) was measured by using quantitative coronary angiography before and after nitroglycerin (NTG) administration. The ratio of post NTG LD to the control (LD_NTG/Pre) was assessed as a standard parameter of coronary arterial tone. We also measured CFV and CFV reserve (CFVR) at the LAD by TTDE. We evaluated the change of CFV (CFV_NTG/Pre) and CFVR (CFVR_NTG/Pre) following NTG administration. The LD increased from 1.98±0.46 to 2.51±0.34 mm (p<0.001), while the CFV decreased from 23.9±10.0 to 16.3±5.6 cm/s (p<0.03), and the CFVR increased from 2.39±0.65 to 3.56±1.12 (p<0.001). There were significant correlations between CFV_NTG/Pre and LD_NTG/Pre (p<0.0001, R² =0.532), and between the CFVR_NTG/Pre and LD_NTG/Pre (p<0.0001, R² =0.715). Conclusion TTDE can assess the coronary arterial tone by measuring the responses of CFV and CFVR to NTG administration. (Circ J 2006; 70: 459 - 462)

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Background Nitric oxide (NO), constitutively produced by endothelial NO synthase (eNOS), plays roles in angiogenesis. Having reported that thermal therapy up-regulated the expression of arterial eNOS in hamsters, we investigated whether this therapy increased angiogenesis in mice with hindlimb ischemia. Methods and Results Unilateral hindlimb ischemia was induced in apolipoprotein E-deficient mice, which were divided into control and thermal therapy groups. The latter mice were placed in a far-infrared dry sauna at 41°C for 15 min and then at 34°C for 20 min once daily for 5 weeks. Laser Doppler perfusion imaging demonstrated that the ischemic limb/normal side blood perfusion ratio in the thermal therapy group was significantly increased beyond that in controls (0.79±0.04 vs 0.54±0.08, p<0.001). Significantly greater capillary density was seen in thermal therapy group (757±123 /mm² vs 416±20 /mm², p<0.01). Western blotting showed thermal therapy markedly increased hindlimb eNOS expression. To study possible involvement of eNOS in thermally induced angiogenesis, thermal therapy was given to mice with hindlimb ischemia with or without N^G-nitro-L-arginine methyl ester (L-NAME) administration for 5 weeks. L-NAME treatment eliminated angiogenesis induced using thermal therapy. Thermal therapy did not increase angiogenesis in eNOS-deficient mice. Conclusion Angiogenesis was induced via eNOS using thermal therapy in mice with hindlimb ischemia. (Circ J 2006; 70: 463 - 470)

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Background Basic fibroblast growth factor (bFGF) stimulates neoangiogenesis. Incorporation into biodegradable gelatin hydrogels provides the sustained release of bFGF. The effects of intramyocardial injections of slow-release bFGF on neoangiogenesis in a rat model of infarction were investigated. Methods and Results Myocardial infarction was induced in rats using coronary artery ligation. A total of 124 rats received an intramyocardial injection of 20 μg of bFGF, the same amount of bFGF incorporated into gelatin hydrogel (bFGF + gel), gelatin hydrogel (gel) or saline. Ventricular function was evaluated by echocardiography 2 or 4 weeks later. Morphometric and histological analyses were used to evaluate infarct size, vascular density and myocardial apoptosis. Capillary density in the infarct border zone was higher in the bFGF and bFGF + gel groups than in the saline and gel groups at 4 weeks (p<0.001). Arteriolar density was higher in the bFGF + gel group than in the other 3 groups (p<0.05). The bFGF and bFGF + gel groups contained fewer apoptotic cardiomyocytes in the border zone than the saline and gel groups (p<0.01). The bFGF+gel group had thicker (p<0.05) and less expanded infarcts (p<0.01) compared with the saline group at 4 weeks. Conclusions Incorporation of bFGF in gelatin hydrogels enhanced the effects of bFGF on arteriogenesis, ventricular remodeling and cardiac function. (Circ J 2006; 70: 471 - 477)

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Backgrounds Estrogen is known to dilate the coronary vascular system mainly through nitric oxide (NO) release. However, it has not been determined whether or not this effect occurs equally throughout all stages of the female life cycle. We examined the changes in coronary flow properties in adolescent, adult and ovariectomized (OVX) female rats using the endothelial NO synthetase blocker, L-N (omega) nitroarginine (L-NNA). Methods and Results Female rats were divided into 3 groups: adolescent (13 weeks, n=6), adult (19 weeks, n=8) and OVX (20 weeks, n=7, 12 weeks after oophorectomy). Coronary effluent was measured using the Langendorff non-working heart model before and 15 min after the use of L-NNA. In OVX rats, coronary effluent was significantly decreased in comparison with adolescent and adult rats (adolescent vs OVX: p<0.001; adult vs OVX: p<0.05). After treatment with L-NNA, coronary effluent was significantly higher in the adolescent group compared with the adult and OVX groups (adolescent vs adult: p<0.01; adolescent vs OVX: p<0.0005). Conclusions Oophorectomy brought about an increase in coronary vascular resistance. L-NNA exacerbated coronary vascular resistance in relation to maturation. It is suggested that the effect of estrogen on vascular dilatation in adolescents is largely dependent on a non-NO pathway, whereas adults are largely dependent on an NO pathway. (Circ J 2006; 70: 478 - 481)

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Background Diabetes mellitus is an independent risk factor for heart failure. Diabetes mellitus causes other age-related cardiovascular diseases. We assessed the hypothesis that hearts from diabetic animals are associated with accelerated aging processes. We also examined the effect of an angiotensin II receptor blocker (ARB) on the expression of senescence-associated molecules. Methods and Results We administered an ARB (candesartan 10 mg/kg per day) or saline to diabetic db/db or control db/+ mice. The treatment was started when mice were 10-weeks-old, and continued for 15 weeks. Systolic function was impaired in db/db mice and candesartan improved cardiac function. The amount of phosphorylated Akt and S6 was decreased in saline-treated db/db mice, and candesartan treatment partially preserved phosphorylation. The amount of p21, p27, p53 or Rb was increased in the heart tissue of saline treated db/db mice. Candesartan treatment completely suppressed the increases of p21, p27, p53 and Rb. Conclusions An ARB improved cardiac function of diabetic animals, and this was accompanied by decreases of senescence-associated molecules in the myocardium. ARB may be a modality for heart failure patients with diabetes mellitus. (Circ J 2006; 70: 482 - 488)

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Background We hypothesized that the negative inotropic effect of nifedipine (Nif) on cardiac ventricular muscle is partly due to the cross-bridge-dependent decrease of Ca ²⁺ sensitivity of the myofilaments as well as the decrease in Ca²⁺ influx. Method and Results We used aequorin-injected ferret papillary muscles and measured the slope of the extra-Ca²⁺-tension relation which expresses the change in the Ca²⁺ sensitivity through the feedback from the cross-bridges. Twitch tension was decreased significantly by 0.5 μmol/L Nif accompanying a significant reduction of the Ca²⁺ transient peak. When Nif (0.2-0.5 μmol/L) was added to the solution with 8 mmol/L Ca²⁺, the slope of the extra-Ca²⁺-tension relation became steeper in a concentration-dependent manner, which was similar to the change in the slope when the concentration of Ca²⁺ was decreased from 8 to 1 mmol/L in the absence of Nif. BAY-K 8644 (0.3 μmol/L), a dihydropyridine receptor agonist, showed the opposite effect on the slope of the extra-Ca²⁺-tension relation to that observed in Nif. However, 2,3-butanedione monoxime (3 mmol/L), an inhibitor of the active cross-bridges, antagonized the effect of BAY-K 8644. Conclusion Nif exerts its negative inotropic effect on cardiac muscle by suppressing Ca²⁺ binding to troponin C via the inhibition of the L-type Ca²⁺ channel, and by the cross-bridge-dependent decrease in the Ca²⁺ sensitivity, as in low extracellular Ca²⁺ concentration. (Circ J 2006; 70: 489 - 494)

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Background The defibrillation threshold (DFT) is elevated during myocardial ischemia, but the underlying mechanism remains to be elucidated. The hypothesis tested by the present study was that whole heart conductance (WHC) is a determinant of DFT. Methods and Results WHC was monitored across the longest diameter of the isolated perfused rat heart, using a 2-electrode instrument under various conditions including ischemia - reperfusion (IR). In the control study, WHC was influenced by the conductivity and flow rate of the solution. In IR, WHC decreased immediately after the onset of perfusion arrest in a single exponential manner, then declined again gradually. The second decrease was augmented and accelerated by pretreatment with 1.0 mmol/L heptanol (p<0.005) or high-[Ca²⁺]_e (p<0.001), and was attenuated and delayed by pretreatment with 1.0 μmol/L verapamil (p<0.01). WHC after reperfusion was greater than the pre ischemic level. The postischemic increase in WHC was proportional to the ischemic interval and tissue water content as assessed by desiccation method. Conclusion Although time-dependent alterations in DFT in ischemic hearts may be attributable at least in part to dynamic changes in WHC, WHC should be interpreted carefully because it reflects many physiological factors such as coronary perfusion, electrical coupling of cardiac myocytes and tissue edema. (Circ J 2006; 70: 495 - 501)

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Background This study aimed to show the mechanism how the HERG channel gating defects causes life-threatening arrhythmia in the short-QT syndrome, using a simulation model of ventricular action potentials (APs). Methods and Results To evaluate the electrophysiological consequences of the short-QT syndrome at the level of the cardiac AP, the Markov model of wild-type (WT) KCNH2 channel was modified to obtain a model of the KCNH2 channel with the N588K mutation associated with the short-QT syndrome. Two parameters (βi and ββ) were changed to reconstruct the N588K mutant Markov model, which successfully reproduced the experimental results of voltage-clamp recordings. The WT and mutant models were then integrated into the Luo-Rudy theoretical model of the cardiac ventricular AP. Unexpectedly, 1 parameter change alone, which caused gain of function, could shorten the AP duration (APD) but failed to induce early after-depolarizations (EADs). Only the condition with the combined gating defects could lead to EAD. Conclusions Although the gain of function for KCNH2 shortened APD in the short-QT syndrome, this simulation study suggested that arrhythmogenesis was associated not only with gain of function, but also with accelerated deactivation of KCNH2. (Circ J 2006; 70: 502 - 508)

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A 2-year-old Japanese girl had transient left ventricular apical ballooning on echocardiography and ST-segment elevation and T-wave inversion on electrocardiogram after withdrawal of bupirenorphine and midazolam. The findings improved within 2 weeks. There are many case reports of adults with takotsubo cardiomyopathy but none in children. Takotsubo cardiomyopathy is not well known by pediatric cardiologists, so pediatric cases may have been overlooked. Awareness of a phenomenon similar to takotsubo cardiomyopathy, even in young children, may be important. (Circ J 2006; 70: 509 - 511)

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