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Background: Appropriate indications and protocols for induction therapy using basiliximab have not been fully established in heart transplant (HTx) recipients. This study elucidated the influence of induction therapy using basiliximab along with delayed tacrolimus (Tac) initiation on the outcomes of high-risk HTx recipients., Methods and results: A total of 86 HTx recipients treated with Tac-based immunosuppression were retrospectively reviewed. Induction therapy was administered to 46 recipients (53.5%) with impaired renal function, pre-transplant sensitization, and recipient- and donor-related risk factors (Induction group). Tac administration was delayed in the Induction group. Induction group subjects showed a lower cumulative incidence of acute cellular rejection grade ≥1R after propensity score adjustment, but this was not significantly different (hazard ratio [HR]: 0.63, 95% confidence interval [CI]: 0.37-1.08, P=0.093). Renal dysfunction in the Induction group significantly improved 6 months post-transplantation (P=0.029). The cumulative incidence of bacterial or fungal infections was significantly higher in the Induction group (HR: 10.6, 95% CI: 1.28-88.2, P=0.029)., Conclusions: These results suggest that basiliximab-based induction therapy with delayed Tac initiation may suppress mild acute cellular rejection and improve renal function in recipients with renal dysfunction, resulting in its non-inferior outcome, even in high-risk patients, when applied to the appropriate recipients. However, it should be carefully considered in recipients at a high risk of bacterial and fungal infections.

Background: Coronary artery disease (CAD) after heart transplantation (HTx) develops as a combination of donor-transmitted coronary atherosclerosis (DTCA) and cardiac allograft vasculopathy. Assessing donor CAD before procurement is important. Because coronary artery calcification (CAC) is a predictor for CAD, donor-heart CAC is usually evaluated to estimate the risk of donor CAD. The usefulness of CAC for predicting DTCA, however, is not known. Methods and Results: Sixty-four HTx recipients whose donor underwent chest computed tomography before procurement or ≤2 weeks after HTx and who underwent coronary angiography and intravascular ultrasound (IVUS) ≤3 months after HTx were enrolled. Eight patients had CAC (CAC group) and 56 patients did not have CAC (no-CAC group). Patients in the CAC group were significantly older and had a higher prevalence of maximum intimal thickness (MIT) of the coronary artery ≥0.5 mm at initial IVUS than patients in the no-CAC group (100% vs. 55%, P=0.02). Adverse cardiac events and death were not significantly different. Everolimus tended to be used more often in the CAC group., Conclusions: Donor-heart CAC is a significant predictor for MIT of the coronary artery ≥0.5 mm after HTx. The presence of CAC, however, is not associated with future cardiac events. The higher prevalence of everolimus use in the CAC group may have affected the results.

Background: Cardiac allograft vasculopathy (CAV) limits long-term success after heart transplant. We assessed the post-transplant risk factors for CAV development., Methods and results: Patients who underwent heart transplant between May 1999 and December 2013 were included in this study. Patients (n=54) were divided into 2 groups according to the presence or absence of CAV progression after transplant. Coronary angiogram and intravascular ultrasound were conducted within 5-11 weeks after transplant, at 12 months, and annually thereafter. Scheduled endomyocardial biopsies were performed after transplant or whenever acute cellular rejection (ACR) or antibody-mediated rejection was suspected. Twenty-five of 54 patients (46.2%) had CAV progression. ACR ≥ International Society for Heart and Lung Transplantation grade 2 (ACR ≥ 2) and donor age >50 years were significantly associated with CAV development compared with ACR <2 and donor age <50 years. Patients with no history of ACR ≥ 2 and donor age ≤50 years had a significantly low risk of developing CAV compared with the other groups., Conclusions: Donor age and history of ACR ≥ 2 are independent risk factors for CAV development. Identifying patients at risk of developing CAV is important for appropriate direction of resources and intensity of follow-up.

Background: Although coronary vasospasm (CVS) would be one of the major causes of out-of-hospital cardiac arrest (OHCA), the characteristics of patients with cardiac arrest caused by CVS have not been clarified., Methods and Results: In study 1, 1,000 consecutive patients with OHCA were retrospectively categorized based on the cause of OHCA, and the prevalence of CVS OHCA was elucidated. In study 2, 138 consecutive CVS patients were divided into 2 groups: CVS with cardiac arrest (arrest-CVS, n=12) and CVS without cardiac arrest (non-arrest-CVS, n=126). In study 1, 589 patients had OHCA caused by cardiovascular disease and 121 patients were successfully resuscitated. Among the 121 resuscitated patients, 9 had CVS OHCA. In study 2, the incidence of cardiac events (ie, cardiac arrest or chest pain) occurring on vigorous exertion, in the daytime and without prodromal chest symptoms was higher in the arrest-CVS group than in the non-arrest-CVS group., Conclusions: CVS is an important cause of OHCA. Because significantly different characteristics are observed between CVS patients with cardiac arrest and those without, care should be taken to diagnose CVS as the cause of cardiac arrest.

Background: The predictive factors for survival after percutaneous cardiopulmonary support (PCPS) are unknown., Methods and Results: Data for 105 patients with cardiovascular disease requiring PCPS were analyzed. The patients were divided into a survivor (n=21) or a non-survivor group (n=84). The age was significantly lower, and there were more patients with fulminant myocarditis and PCPS attempted before cardiac arrest (CA) in the survivor group. Additionally, there were fewer cases of out-of-hospital CA, and the mean time from CA to PCPS was shorter in the survivor group. On multivariate logistic regression it was found that the age and the time from CA to PCPS were independently associated with survival. A predictive scoring system was constructed that included the following: (1) age <50 years; (2) diagnosis of fulminant myocarditis; (3) no out-of-hospital CA; (4) PCPS attempted before CA; and (5) time from CA to PCPS <45 min. The predictive score was significantly higher in the survivor than in the non-survivor group (2.33 ± 1.32 vs. 1.06 ± 1.02). The sensitivity and specificity for survival were 85.7% and 66.7% when the score was ≥ 2. Kaplan-Meier survival analysis showed that any-cause death was significantly higher in patients with PCPS survival score ≤ 1 than in those with a score ≥ 2., Conclusions: PCPS survival score is suitable for clinically predicting survival in patients with cardiovascular disease undergoing PCPS.

Background: Hospitalized heart failure (HHF) is a critical issue in Japan. To improve its management and outcomes, the clinical features, in-hospital management, and outcomes should be analyzed to improve the guidelines for HHF., Methods and Results: The acute decompensated heart failure syndromes (ATTEND) registry is the largest study of HHF in Japan. The present report covers the clinical features and in-hospital management of HHF patients. The data from 4,842 enrolled patients have demonstrated that most Japanese HHF patients are elderly, with new onset, and a history of hypertension and orthopnea on admission. During hospitalization, furosemide and carperitide were commonly used and the length of stay was extremely long (mean 30 days), with 6.4% in-hospital mortality., Conclusions: The findings of the present study suggest the following: (1) the focus for hypertensive elderly and diabetic patients should be on primary prevention of HHF,(2) more intensive management with noninvasive positive pressure ventilation should be performed at the urgent stage, (3) it is necessary to clarify the clinical benefit of carperitide and angiotensin-receptor blockers, because they are commonly used in Japan, and (4) it is necessary to clarify the relationship between in-hospital mortality and length of stay from the viewpoint of both outcome and cost of patient care.

Background: The relationship between acute kidney injury (AKI) in the acute phase of acute decompensated heart failure (ADHF) and patient outcome has not yet been reported., Methods and Results: Data for 625 patients with ADHF admitted to the intensive care unit were analyzed. No AKI occurred in 281 patients (no AKI) during the first 5 days. The AKI patients were assigned to 3 groups based on the timing: AKI present on admission and stable risk, injury, failure, loss, and endstage (RIFLE) class (stable early AKI; n=125), stepped-up RIFLE class (worsening early AKI; n=49), or AKI that occurred after admission (late AKI; n=170). The AKI patients were grouped into another 3 groups based on severity: class R (risk; n=214), class I (injury; n=73), or class F (failure; n=57). A multivariate logistic regression model found class I, class F, late AKI and worsening early AKI to be independently associated with in-hospital mortality. Kaplan-Meier survival curves showed that the survival rate in any-cause death during 2 years was significantly lower in class I, class F and the worsening early-AKI group, and there were significantly more HF events in class F and the worsening early-AKI group. There were significantly more class I and class F patients in the worsening early-AKI group., Conclusions: The presence of AKI on admission, worsening of AKI, and severe AKI (class I or class F) are associated with a poorer prognosis for ADHF patients.

Background: Because it remains unclear whether noninvasive ventilation (NIV) is an effective therapy for cardiogenic pulmonary edema secondary to acute myocardial infarction (AMI), we retrospectively evaluated our experience with NIV in the treatment of pulmonary edema secondary to AMI and other cardiac conditions., Methods and Results: The study group included 206 patients with cardiogenic pulmonary edema, divided into an AMI group (53 patients) and a non-AMI group (153 patients). The weaning rate from NIV was similar in the AMI and non-AMI groups (90.6% vs. 90.8%, P=0.950). Heart rate, blood pressure, and respiratory rate decreased significantly 1h after initiation of NIV in both groups, and were maintained until weaning from NIV. The frequency of endotracheal intubation after weaning from NIV was higher in the AMI group than in the non-AMI group (7.5% vs. 0.7%, P=0.016), although the overall frequency of intubation was similar in both groups. The in-hospital mortality rate was similar in the AMI and non-AMI groups (13.1% vs. 9.8%, P=0.489)., Conclusions: NIV effectively improved vital signs and oxygenation and lowered the intubation rate in patients with cardiogenic pulmonary edema of all etiologies, including AMI. The outcome in patients with AMI treated with NIV depends primarily on the severity of the course of AMI and not on the severity of acute respiratory failure.

Background: The association between elevated malondialdehyde-modified low-density lipoprotein (MDA-LDL) and plaque instability in patients with coronary artery disease (CAD) is suspected but not established. The aim of the present study was therefore to investigate the association between serum MDA-LDL and plaque characteristics on angioscopy., Methods and Results: A total of 37 consecutive patients with CAD and single-vessel disease who underwent pre-interventional angioscopy, were studied. Using angioscopy at the target lesions, the presence of yellow plaque and complex plaque was examined. Moreover, we evaluated the yellow intensity, which has been shown to have an inverse correlation with the fibrous-cap thickness of the plaques, with quantitative colorimetry to identify a thin-cap atheroma. Serum MDA-LDL in patients with thin-cap atheroma diagnosed on quantitative colorimetry was significantly higher than in patients without thin-cap atheroma (P<0.0009). Univariate logistic regression indicated that serum MDA-LDL was a predictor for thin-cap atheroma (odds ratio [OR], 1.48; 95% confidence interval [CI]: 1.10-1.97; P=0.003) and for complex plaque (OR, 1.22; 95% CI: 1.00-1.48; P=0.046). On multivariate logistic regression serum MDA-LDL was the only independent predictor for thin-cap atheroma (OR, 1.48; 95% CI: 1.10-1.97; P=0.011)., Conclusions: Using angioscopy and quantitative colorimetry, elevated MDA-LDL was confirmed to be associated with thin-cap atheroma in CAD patients.

Background: The effects of statin therapy on the production of monocyte pro-inflammatory cytokines, cardiac function and the long-term prognosis in chronic heart failure (CHF) patients with dyslipidemia remain unclear., Methods and Results: A total of 146 CHF patients with a mean left ventricular ejection fraction (LVEF) of 26.9 ± 6.6% were divided into 2 groups based on whether or not statins were included in their treatment: a statin group (n=63) and a no statin group (n=83). Only patients with dyslipidemia were treated with statins. Peripheral blood mononuclear cells (PBMCs) were isolated, and the production of monocyte tumor necrosis factor (TNF)-α and interleukin (IL)-6 were measured at baseline and after 6 months of treatment, and the data expressed as mean ± SD (pg·ml(-1)·10(-6) PBMCs). The LVEF in the statin group improved, and the monocyte TNF-α and IL-6 production decreased (respectively, P<0.001), but the LVEF and cytokine production remained unchanged in the no statin group. Multivariate Cox hazard analysis showed that statin therapy (hazard ratio, 0.14; 95% confidence interval: 0.02-0.97, P=0.046) was an independent predictor of cardiac events., Conclusions: Statin therapy attenuates the production of monocyte pro-inflammatory cytokines, and ameliorates the cardiac function and may improve long-term prognosis in CHF patients with dyslipidemia.

Background: The aim of this study was to determine the relationship between the morphological and physiological information of coronary CT angiography (CCTA) and stress myocardial perfusion imaging (S-MPI) from the standpoint of risk stratification of patients with intermediate to high probability of coronary artery disease (CAD)., Methods and Results: In total, 51 patients underwent both CCTA and S-MPI as sequential examinations. In each patient, the severity of coronary plaque and stenosis (>50%) and the presence of myocardial perfusion abnormalities were assessed and the prognostic information from the CCTA and S-MPI results was compared. In 30 patients with normal S-MPI, 3 (10%) had only completely normal coronaries and another 3 (10%) had non-obstructive CAD as observed on CCTA. The remaining 24 patients (80%) with normal S-MPI and all 21 patients with abnormal S-MPI study had obstructive CAD. High-risk CAD (defined as obstructive left main trunk (LMT) lesion or 3-vessel disease) was seen in 10 (33%) of 30 patients with normal S-MPI, although it was less frequent than in the 14 (67%) of 21 patients with abnormal S-MPI., Conclusions: A normal S-MPI result can reflect a wide range of coronary atherosclerosis types and severities and, to some extent, involves severe coronary atherosclerosis such as LMT lesion and 3-vessel disease in patients with an intermediate to high probability of CAD.

Background: Matrix metalloproteinase-9 (MMP-9) is regarded as a biomarker of plaque rupture or vulnerability and is elevated in patients with acute coronary syndrome (ACS). The aim of the present study was to evaluate the diagnostic value of MMP-9 for early ACS (≤4h of onset) and late ACS (>4h after onset), compared with high-sensitivity troponin T (hs-TnT)., Methods and Results: MMP-9 and hs-TnT were measured in 200 patients with ST elevation ACS (STEACS; 115 early STEACS and 85 late STEACS patients), and 66 patients with non-ST elevation ACS (NSTEACS; 25 early NSTEACS and 41 late NSTEACS patients). Forty patients with stable angina pectoris (SAP) were enrolled as a control group. MMP-9 levels were significantly higher in patients with early STEACS (P<0.001), early NSTEACS (P<0.001), late STEACS (P<0.001) and late NSTEACS (P=0.025) than SAP. MMP-9 levels were significantly higher in patients with early STEACS (P=0.017) and early NSTEACS (P=0.034) than late STEACS and late NSTEACS, respectively. Levels of hs-TnT were significantly lower in patients with early STEACS (P<0.001) and early NSTEACS (P=0.007) than late STEACS and late NSTEACS, respectively. On receiver operating characteristic curve analysis, area under the curve of early STEACS, early NSTEACS, late STEACS and late NSTEACS was 0.880, 0.782, 0.790 and 0.648 for MMP-9, and 0.707, 0.725, 0.993 and 0.920 for hs-TnT, respectively., Conclusions: MMP-9 levels were elevated earlier than hs-TnT and had a higher diagnostic value for early ACS, but not for late ACS, reflecting plaque rupture or vulnerability.

Background: Although highly sensitive assays for troponin T (hs-TnT) have been developed, the sensitivity and specificity of hs-TnT for diagnosing acute coronary syndrome (ACS) remains imperfect. We evaluated the diagnostic value of a new biomarker of plaque vulnerability (soluble lectin-like oxidized low-density lipoprotein receptor-1, sLOX-1) as compared with hs-TnT in the emergency room (ER)., Methods and Results: Plasma sLOX-1 and serum hs-TnT levels were measured in 200 consecutive patients presenting with chest symptoms and ECG abnormalities in the ER (116 ST elevation ACS [STEACS], 44 non-ST elevation ACS [NSTEACS], 40 non-ACS). The non-ACS group consisted of patients with cardiovascular diseases such as coronary spastic angina pectoris, pulmonary thromboembolism, perimyocarditis and takotsubo cardiomyopathy. Levels of sLOX-1 and hs-TnT were significantly higher in STEACS and NSTEACS than in non-ACS patients. The receiver-operating characteristic (ROC) curves of sLOX-1 and hs-TnT for detecting ACS, using the non-ACS patients as negative references, showed that the area under the curve (AUC) values of sLOX-1 and hs-TnT were 0.769 and 0.739, respectively. In the lower hs-TnT (<0.0205ng/ml) subgroup, the AUC value of the ROC curve of sLOX-1 for detecting ACS was 0.869., Conclusions: The diagnostic value for ACS was comparable between sLOX-1 and hs-TnT, and the accuracy of ACS diagnosis appeared to improve when sLOX-1 and hs-TnT were measured in combination.

Background: Beta-blockers (BB) have been widely used in the management of hypertension and acute myocardial infarction (AMI), and both national and international guidelines have recommended them as first-line agents. Calcium channel antagonists (CCA) are also effective in the treatment of hypertension and angina pectoris. However, the efficacy of CCA in the prevention of cardiovascular events in post-myocardial infarction (MI) patients in comparison to that of BB remains unclear., Methods and Results: A total of 120 post-MI patients (71 patients who were at least 1 month after the onset AMI and 49 stable coronary artery disease patients with a history of MI) were randomly assigned to receive a BB (atenolol, 25-50mg/day, n=60) or a CCA (benidipine, 4-8 mg/day, n=60). All patients with AMI within the previous 1 month or with vasospastic angina were excluded from the present study. The baseline clinical characteristics were generally similar in the BB and CCA groups. The rate of primary composite outcome was 26.3% in the BB group in comparison to 13.3% in the CCA group, with no significant between-group differences (hazard ratio with the CCA group 0.640, P=0.276). Both treatments were well tolerated with few severe adverse events., Conclusions: CCA treatment was found to be as effective as BB in reducing cardiovascular events in post-MI patients.

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.

Background: The diagnostic sensitivity of myocardial necrosis markers, such as creatine kinase-MB (CK-MB), cardiac troponins, myoglobin and heart-type fatty acid-binding protein (H-FABP) for the earliest stage of ST-elevation myocardial infarction (STEMI), remains insufficient. We compared a new biomarker of plaque vulnerability (soluble lectin-like oxidized low-density lipoprotein receptor-1, sLOX-1) with other biomarkers at the earliest stage of STEMI., Methods and Results: Plasma sLOX-1 levels were measured in 125 STEMI, 44 non-STEMI (NSTEMI) and 125 non-acute myocardial infarction (non-AMI) patients and were significantly (P < 0.0001) higher in the STEMI and NSTEMI than in the non-AMI patients (median, 25th and 75th percentiles: 241.0, 132.3 and 472.2 vs. 147.3, 92.9 and 262.4 vs. 64.3, 54.4 and 84.3 pg/ml, respectively). At the optimal cut-off value of 91.0 pg/ml, sLOX-1 discriminated STEMI from non-AMI with 89.6% sensitivity and 82.4% specificity. Time-dependent changes in sLOX-1, H-FABP, myoglobin, troponin T and CK-MB were analyzed in 27 STEMI patients. Elevated plasma sLOX-1 levels persisted for 24h after admission, whereas other markers were not elevated at the time of admission and peaked at ≥ 2h thereafter. The diagnostic sensitivity of sLOX-1, H-FABP, myoglobin, troponin T and CK-MB for STEMI upon admission (89 min after onset) was 93%, 78%, 70%, 56% and 33%, respectively., Conclusions: Plasma sLOX-1 diagnosed the early stages of STEMI more accurately than H-FABP, myoglobin, troponin T and CK-MB.

Background: The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors closely linked to inflammation and insulin resistance (IR). Tissue factor (TF) is an initiator of the extrinsic coagulation cascade and is expressed on peripheral blood monocytes and macrophages in atherosclerotic plaques. Monocytes are the principle cells capable of TF synthesis. Therefore, TF plays an important role in both thrombosis and atherosclerosis. Elevated levels of lipopolysaccharide (LPS), a strong stimulator of TF, have been observed in patients with MetS. No study has investigated the relationship between monocyte TF activity and inflammation, and IR in MetS., Methods and Results: Peripheral blood mononuclear cells (PBMCs) were collected from 40 normal subjects and 77 patients with MetS. Mononuclear cell TF procoagulant activity (MPCA) was measured with and without 100 pg/ml LPS stimulation using a 1-stage clotting assay and expressed as the mean +/- SD (mU TF/10(6) PBMCs). MPCA in MetS was significantly greater than in normal subjects (without LPS: 88.0+/-74.8 vs 52.6+/-9.8 mU TF/10(6) PBMCs, P<0.001; with LPS: 269.6+/-165.6 vs 158.6+/-42.8 mU TF/10(6) PBMCs, P<0.001). The LPS-stimulated log MPCA in MetS patients was significantly associated with homeostasis model assessment of IR (r=0.256, P=0.024) and log high-sensitivity C-reactive protein (r=0.332, P=0.003)., Conclusions: Upregulation of monocyte TF is significantly associated with low-grade inflammation and IR in MetS.

Although preventive pharmacological therapies effectually reduce the risk of cardiovascular events, acute coronary syndrome (ACS) remains a leading cause of morbidity and mortality in our country, Japan. Disruption of atherosclerotic vulnerable plaques and flow-limiting thrombus formation in non-stent segments of native coronary arteries are considered a main mechanism of ACS. In addition, stent thrombosis originating from implanted metallic coronary stents, so-called vulnerable stents, occasionally appears as ACS in the clinical settings. Coronary angioscopy is a unique imaging modality permitting direct visualization of luminal structures, such as atherosclerotic plaque, thrombus, stent struts, and proliferating neointima. On the basis of accumulated angioscopic findings, intense yellow plaques and stents without neointimal coverage are considered vulnerable plaques and vulnerable stents, respectively. In contrast, morphological disappearance of vulnerable plaques or vulnerable stents by pharmacological and trans-catheter therapies imply stabilization of the plaques or stents. Hence, angioscopic assessment for vulnerability (or stability) of atherosclerotic plaques and implanted stents might be useful for risk classification in the future events of ACS. To evaluate serial changes of coronary lumen after pharmacological and catheter interventions using angioscopy might also provide important information on potential benefits and surrogate endpoints of the therapies and on patients' management.

Background: It is unclear how much the sympathetic nervous system is involved in the development of pulmonary arterial hypertension (PAH). The present study examined whether or not a pure alpha/beta-adrenergic receptor blocker (arotinolol) could prevent the development of PAH and right ventricular hypertrophy (RVH) in a rat model of monocrotaline (MCT)-induced PAH., Methods and Results: The heart rate, arterial blood pressure (BP), left ventricular pressure, pulmonary artery pressure (PAP), and right ventricular pressure (RVP) were measured after administration of arotinolol or saline for 2 weeks. Ventricular weight and myocyte size were also measured. Mean PAP was increased less in the arotinolol group (n=6), (53 +/-9 vs 21 +/-2 mmHg in the control (n=6); P<0.01). Systolic RVP was also less in the arotinolol group (41 +/-3 vs 91 +/-14 mmHg in the control, P<0.05) without differences in BP. It also significantly reduced the RV/body weight ratio (0.58 +/-0.01 vs 0.77 +/-0.04 mg/g; P<0.01). Furthermore, the myocyte width was significantly decreased in the arotinolol group., Conclusions: The pure alpha/beta-blocker arotinolol prevented the progression of MCT-induced PAH and RVH in rats, suggesting that sympathetic nervous activation might play a role in the development of PAH.

Background: To prevent a future shortage of cardiologists, it is important for female cardiologists to continue working. Gender differences in the professional and private lives of cardiologists, as well as the barriers to work for female cardiologists, were surveyed., Methods and Results: In August 2007, a questionnaire was mailed to all 195 faculty members/fellows and 155 alumni of the Department of Cardiovascular Medicine at Nippon Medical School. More female cardiologists were dissatisfied with their job than male cardiologists (34% vs 17%, P<0.005). Women reported greater career limitation by family responsibilities and housework. Men and women both reported that long working hours was the most problematic issue, but significantly more women reported this than men (76% vs 94%, P<0.05). Female cardiologists were more concerned about occupational radiation exposure (88% vs 59%, P<0.01) and wanted opportunities for retraining after childcare leave (100% vs 76%, P<0.01)., Conclusions: The following measures should be taken: (1)establishment of more family-friendly working conditions in hospitals, (2)provision of various work positions that allow more flexibility and predictability for women, (3)establishment of a retraining system, and (4)development of work and research opportunities that are attractive to women. The Japanese Circulation Society is expected to establish a retraining system at certified institutions.

Background: There is a hypothesis that advanced neointimal stent coverage may protect against stent thrombosis. In the present study, differences in neointimal growth and prevalence of in-stent thrombus between paclitaxel- and sirolimus-eluting stent (PES and SES) were evaluated by optical coherence tomography (OCT)., Methods and Results: Follow-up angiographic and OCT examinations at approximately 6 months were performed for 40 patients (20 PES, 20 SES). Late loss was measured by quantitative coronary angiography. Neointimal hyperplasia (NIH) thickness on stent struts was measured by cross-sectional OCT images at 1 mm intervals. After measuring the NIH area in each cross-section, NIH volume was calculated as integral of NIH area within the stent. Late loss, NIH thickness, and NIH volume were greater for PES than for SES (0.42 +/-0.44 vs 0.13 +/-0.12 mm, 118 +/-141 vs 31 +/-39 mum, 53.2 +/-30.5 vs 24.3 +/-14.0 mm(3); P<0.05, respectively). In-stent thrombus was found more frequently in PES than in SES (50 vs 15%; P=0.02)., Conclusions: Although the degree of neointimal growth in PES was generally greater, in-stent thrombus was more common compared with SES. Presence of thrombus in first-generation drug-eluting stents was not related to advanced neointimal growth.

Background: Increased expression of cytokines and chemokines has been observed in chronic heart failure (CHF). Amiodarone reduces circulating cytokine levels, so it may attenuate the production of monocyte cytokines and chemokines by C-reactive protein (CRP) and thus improve the left ventricular ejection fraction (LVEF) in dilated cardiomyopathy (DCM) patients with ventricular tachycardia (VT)., Methods and Results: Peripheral blood mononuclear cells (PBMCs) were stimulated by 25 microg/ml CRP in 23 patients with DCM, who were divided into 2 groups based on whether or not amiodarone was included in their treatment (Amiodarone group n=8; No amiodarone group n=15). Tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein (MCP)-1 on monocytes at baseline and after 4 weeks of treatment was measured by ELISA and expressed as mean+/-SD (pg.ml(-1)x10(-6) PBMCs). The LVEF and the CRP-induced monocyte cytokine and chemokine production were unchanged in the No amiodarone group after 4 weeks; however, LVEF in the Amiodarone group was increased (32.7+/-6.9 to 39.2+/-6.9%; P=0.005), and TNF-alpha and MCP-1 production in the Amiodarone group were decreased (P=0.012, respectively)., Conclusions: Amiodarone attenuates the production of monocyte cytokines and chemokines by CRP, and improves LVEF in CHF patients with VT.

Transient receptor potential (TRP) channels are expressed in almost every human tissue, including the heart and vasculature. Most are permeable to Ca(2+) and play unique roles as multifunctional cellular sensors. Their involvement in many fundamental cell functions (eg, contraction, proliferation, and cell death) has made investigating their roles in human disease an urgent priority for medical science. This review presents an overview of current knowledge about the pathological role of TRP channels in heart disease and highlights some TRP channels with anticipated roles in disease. Evidence suggests that (a) upregulation of TRPC channels is involved in the development of cardiac hypertrophy and heart failure; (b) TRPC1, TRPC6, and TRPV2 play a role in the pathogenesis of cardiomyopathy associated with muscular dystrophy; (c) TRPC6 or TRPM4 is involved in the delayed after-depolarization; (d) TRPP2 is involved in the normal development of the interventricular and interatrial septa; and (e) neuronal TRPV1 acts as a detector of pain-producing stimuli. Ultimately, TRP channels might become novel pharmacological targets in the treatment of human heart disease.

Background: Thin cap fibroatheroma (TCFA) is considered to be a vulnerable plaque. Virtual Histology-intravascular ultrasound (VH-IVUS) can precisely identify TCFA in vivo. Intense yellow plaque on angioscopy determined by quantitative colorimetry with L a b color space corresponds with histological TCFA; in particular, a plaque of color b value >23 indicates an atheroma with a fibrous cap thickness <100 mum. In the present study, the relationship between VH-TCFA and angioscopic plaque color determined by colorimetry was investigated., Methods and Results: Fifty-seven culprit plaques in 57 patients were evaluated by VH-IVUS and angioscopy. VH-TCFA was defined as a plaque with a necrotic core >10% of plaque area without overlying fibrous tissue, and angioscopic TCFA was a plaque with b value >23. The frequency of angioscopic TCFA was higher in the VH-TCFA group than in the VH-non-TCFA group (74% vs 23%, P=0.0002). Moreover, yellow color intensity (b value) significantly correlated with plaque classification on VH-IVUS. When TCFA detected with angioscopy was used as the gold standard, the sensitivity, specificity, and accuracy for TCFA with VH-IVUS was 68%, 81%, and 75%, respectively., Conclusions: VH-TCFA strongly correlated with angioscopic TCFA determined by a quantitative analysis with colorimetry.

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

Background: A novel modified tissue-type plasminogen activator, monteplase, has been approved for acute major pulmonary embolism (PE) in Japan. Monteplase has rapid and sustained lytic effects because of a steep rise in concentration after bolus infusion and a longer half-life., Methods and Results: To assess the efficacy and safety of thrombolysis with monteplase in combination with catheter-based treatment, acute hemodynamic changes and clinical outcomes were assessed in 50 patients with angiographically confirmed major PE. Thrombolysis with monteplase in combination with embolus fragmentation and thrombectomy was the acute phase treatment. The study population comprised 31 females and 19 males (mean age 62 years). All patients had right ventricular (RV) overload; 12 patients presented in shock. The mean pulmonary artery pressure decreased significantly from 32+/-9 mmHg to 25+/-6 mmHg after acute phase treatment (P<0.0001). The mean dosage of monteplase was 12,265 IU/kg. Death at 30 days occurred in 3 patients (6%). Major bleeding occurred in 12 patients (24%). RV overload at discharge remained in only 3% of the patients with typically acute onset., Conclusions: Thrombolysis with monteplase, in combination with catheter-based treatment, is an effective and safe therapy for major PE.

A polytetrafluoroethylene (PTFE)-covered stent is specially used to treat coronary perforation complicating percutaneous intervention in order to prevent the aneurysm from rupturing, but until now it has not been known if endothelialization occurs inside this type of stent. A patient with a giant aneurysm of the right coronary artery underwent successful implantation of a PTFE-covered stent. Angiography at 9-month follow-up showed focal restenosis at the proximal edge of the stent and coronary angioscopy revealed restenosis as a result of thrombus formation. Absence of endothelialization in the covered stent was also detected by angioscopy and optical coherence tomography. These findings suggest that in-stent thrombosis must be prevented after PTFE-covered stent implantation.

Background: Carperitide is used to treat acute decompensated heart failure (ADHF), but its effects on long-term prognosis have not been studied., Methods and Results: A multicenter randomized controlled study of 49 patients with ADHF was performed to clarify the drug's effects on long-term prognosis. Low-dose carperitide (0.01-0.05 microg x kg(-1 ) x min(-1)) was infused for 72 h as the initial treatment (n=26), whereas in the control group (n=23), standard medical treatment other than carperitide was given without limitation. Anti-aldosterone drugs were prohibited in both groups. During carperitide infusion, significant increases of the atrial natriuretic peptide and cyclic GMP levels and a significant decrease in the heart-type fatty acid-binding protein/serum creatinine ratio were observed, suggesting inhibition of myocyte cell membrane damage. On the other hand, no significant differences in the plasma brain natriuretic peptide, troponin T, and creatinine levels were noted in either group. During 18-month follow-up, significant reductions of death and rehospitalization occurred in the carperitide vs control group (11.5% vs 34.8%; p=0.0359). Cox regression analysis revealed that randomization to carperitide (p=0.020), pretreatment systolic blood pressure >or=140 mmHg (p=0.043), and beta-blocker therapy (p=0.016) were independent predictors for freedom from cardiac events., Conclusions: Acute-phase low-dose carperitide infusion improved the long-term prognosis of patients with ADHF.

Background: A simple and practical risk prediction tool for coronary heart disease (CHD) to determine the specific risk level in each patient that fits the true clinical practice setting is needed and would be valuable in Japan., Methods and Results: A 5-year risk prediction score and chart for CHD based on the MEGA study data was developed in the present study. The MEGA risk prediction score and chart were constructed based on the coefficient of each risk factor. The risk factors included in these risk prediction tools were: treatment (diet, diet plus pravastatin), sex, age, baseline high-density lipoprotein-cholesterol, baseline low-density lipoprotein-cholesterol, glucose abnormality (diabetes and impaired fasting glucose), hypertension, and smoking. The MEGA risk prediction score comprised the risk score for each risk factor, and it can predict 5-year risk for CHD with 5 levels of risk, based on the total risk score. The MEGA risk prediction chart more accurately predicts risk, by reflecting the accumulation of risk factors and using an 8-color visual chart., Conclusions: The MEGA risk prediction score and chart, developed from the MEGA study data, more easily and accurately assesses the 5-year CHD risk in mild to moderate hypercholesterolemic patients in the usual clinical practice setting in Japan.

Background: Several epidemiologic studies in Japan have shown the risk factors for coronary heart disease (CHD) in the general population. The present analysis determined the risk factors for CHD in the MEGA Study, a large primary prevention trial with pravastatin in Japanese with hypercholesterolemia., Methods and Results: The relationship between each baseline characteristic and the risk of CHD for the 5-year study period were evaluated using the Cox proportional hazard model. The multivariable predictors of CHD were sex, age, high-density lipoprotein-cholesterol (HDL-C), diabetes mellitus (DM), hypertension (HT), and history of smoking. Serum total and low-density lipoprotein-cholesterol were not independent risk factors for CHD in the current analysis. In addition, the effect of pravastatin was evaluated by subgroups in each risk factor using the interaction in a Cox model. Diet plus pravastatin treatment reduced CHD risk by 14-43% compared with diet alone, regardless of the presence or absence of risk factors., Conclusions: The risk factors for CHD were sex, age, DM, HT, smoking, and low HDL-C in the MEGA Study. The pravastatin treatment was effective for reducing the risk of CHD, regardless of the presence of risk factors.

Background: Contrast-induced nephropathy (CIN) frequently complicates cardiac catheterization, so the objectives of present study were to investigate the usefulness of cystatin C before catheterization and establish a cut-off level for CIN, and to examine the changes in cystatin C and several other markers in patients with and without CIN., Methods and Results: Prospective study of consecutive 87 patients who underwent elective catheterization: moderate renal disease defined as glomerular filtration rate 30-59 ml . min(-1) .1.73 mm(-2); cystatin C and creatinine (Cr), urinary liver-type fatty acid-binding protein (L-FABP), alpha1, beta2 microglobulins, N-acetyl-beta-D-glucosaminidase, and microalbumin were measured immediately before, and 1, 2, and 3 days after catheterization. CIN occurred in 18 patients and receiver-operating characteristic analysis showed a higher area-under-the-curve for cystatin C compared with serum Cr (0.933 vs 0.832 p=0.012). At a cut-off level of >1.2 mg/L, cystatin C before catheterization exhibited 94.7% (95% confidence interval: 0.851-1.015) sensitivity and 84.8% specificity for detecting CIN. Cystatin C levels were higher in CIN patients than in those without CIN, even before catheterization (cystatin C: 1.08+/-0.22 vs 1.36+/-0.28 mg/L, p=0.007). Urinary L-FABP was increased on days 1 and 2 in patients with moderate renal disease., Conclusion: Cystatin C was useful for predicting the occurrence of CIN. Urinary L-FABP was the only marker of transient renotubular damage.

Background: Acute aortic dissection (AAD) is a life-threatening cardiovascular disorder that is similar to acute coronary syndrome (ACS), which means differentiating AAD and ACS is sometimes difficult in an emergency., Methods and Results: Specific information from 131 patients with AAD or ACS was analyzed between April 2001 and March 2002. The emergency room AAD (ERAAD) score was defined as the total number of specific indexes for AAD among 15 indexes that were obtainable in the emergency room (Study 1). The clinical applicability of the ERAAD score was also investigated in another 711 patients with AAD or ACS between April 2002 and March 2006 (Study 2). The ERAAD score was based on (1) presence of back pain, (2) mediastinal thoracic ratio >30%, (3) aortic regurgitation and (4) aortic diameter >30 mm on ultrasonography in Study 1. The ERAAD score was significantly higher in patients with AAD than with ACS (3.19+/-0.83 vs 1.17+/-0.99) in Study 2. The sensitivity and specificity for AAD were 93.1% and 77.6%, respectively, when the ERAAD score was >or=3., Conclusion: The ERAAD score enables clinical diagnosis of AAD and correct treatment.

The use of automated external defibrillators (AEDs) has increased the number of survivors of out-of-hospital cardiac arrest. The AED has a high specificity and moderately high sensitivity in detecting rhythms appropriately treated by defibrillation. However, a few shockable rhythms are misdiagnosed by the AED. Two cases of inappropriate analyses by AEDs in patients with in-hospital ventricular fibrillation are presented. In the first case, the AED failed to recognize ventricular fibrillation because of the presence of pacemaker spikes. In the second case, the fine ventricular fibrillation and the presence of artifacts were suspected as the causes of inappropriate analysis by the AED. Both patients were resuscitated by advanced cardiovascular life support with a manual defibrillator. Trained healthcare providers should be aware of the limitations of AED in specific situations.

Background: Recent studies have shown the presence of ongoing myocardial damage in patients with chronic heart failure (CHF) detected by myofibril and membrane damage markers, cardiac troponin T (TnT) and heart-type fatty acid-binding protein (H-FABP), which identifies patients at increased risk of a future cardiac event (CE: death or rehospitalization because of worsening CHF). There is a difference between TnT and H-FABP in their release kinetics following myocardial damage., Methods and Results: TnT and H-FABP were measured in 103 patients with CHF and in 31 controls. Patients were classified into 4 groups based on detectable (>or=0.01 ng/ml) or undetectable TnT (TnT+ or TnT-) and H-FABP >or= or <4.5 ng/ml (mean + 2 standard deviations in controls) (high-H-FABP or low-H-FABP). Kaplan-Meier analysis showed that the CE-free rate (n=43) was significantly lower in patients with TnT+ and high-H-FABP than in patients in the other 3 groups (patients with TnT+ and low-H-FABP, TnT- and high-H-FABP, and TnT- and low-H-FABP; p=0.02, p=0.001 and p=0.0002, respectively). In stepwise multivariate Cox proportional hazard analysis, TnT+ (p=0.01) and high-H-FABP (p=0.04) were independent predictors of future CE., Conclusions: Elevated levels of both TnT and H-FABP predict adverse outcomes in CHF patients.

Background: Multiple angioscopic yellow plaques are associated with diffuse atherosclerotic plaque, and may be prevalent in patients with myocardial infarction (MI), so in the present study the yellow plaques in the coronary arteries of patients with MI was evaluated using quantitative colorimetry, and compared with those of patients with stable angina (SA)., Methods and Results: In the recorded angioscopic images of 3 coronary vessels in 29 patients (15 patients with MI, 14 with SA), yellow plaques were determined as visually yellow regions with b* value >0 (yellow color intensity) measured by the quantitative colorimetric method. A total of 90 yellow plaques were identified (b* =19.35+/-8.3, 3.05-45.35). Yellow plaques were significantly more prevalent in 14 (93%) of 15 culprit lesions of MI as compared with 8 (57%) of 14 of SA (p=0.03). In non-culprit segments, yellow plaques were similarly prevalent in 13 (87%) patients with MI and 11 (79%) with SA (p=0.65). Overall, multiple (> or =2) yellow plaques were prevalent in 13 (87%) patients with MI, similar to the 10 (71%) with SA (p=0.38). The number of yellow plaques was significantly higher in patients with MI (3.8+/-1.9) than in those with SA (2.4+/-1.6, p=0.03)., Conclusion: The present study suggests that patients with MI tend to have diffuse atherosclerotic plaque in their coronary arteries.

Background: The purpose of the study was to characterize the pharmacokinetics of mycophenolic acid (MPA) in Japanese heart transplant recipients and to find the time point that has the best correlation with the MPA area under the plasma concentration curve (AUC)., Methods and Results: Twenty-two Japanese recipients treated with mycophenolate mofetil were evaluated in the study. Approximately 9 months after transplantation, the area under the MPA serum concentration-time curve from 0 to 12 h (AUC(0-12 h)) was evaluated. The MPA AUC(0-12 h) h values in the cyclosporine (CsA) and tacrolimus (FK) groups ranged from 13.11 to 50.98 mug . h/ml and from 39.19 to 93.18 mug . h/ml, respectively. Fourteen models were developed and analyzed for their ability to estimate the MPA AUC(0-12 h) based on a limited number of samples in the CsA group. Sixteen models were developed in the FK group. The best model for predicting the full MPA AUC(0-12 h) in the CsA group was a 3-time-point model that included C(0 h), C(1 h) and C(2 h) (r(2), 0.96; mean prediction error, 0.15+/-7.85%); a 2-time-point model that included C(0 h), and C(2 h) (r(2), 0.94; mean prediction error, 0.495+/-10.35%) was also reliable. In the FK group, a 3-time-point model that included C(1 h), C(2 h) and C(4h) (r(2), 0.73; mean prediction error, 2.73+/-17.09%) was the best model for predicting the full MPA AUC(0-12 h), but it was not reliable in clinical practice., Conclusion: A 3-(C(0 h), C(1 h) and C(2 h)) and a 2-time-point model (C(0 h) and C(2 h)) are useful for predicting the full MPA AUC(0-12 h) in Japanese heart transplant recipients treated with CsA but not with FK.

Background: Cyclosporine (CsA), Mycophenolate mofetil (MMF) and prednisolone (PSL) are widely used for the prevention of acute rejection after heart transplantation. Recently, the serum concentration - time curves (AUC) of CsA and MMF have been demonstrated to be precise predictors of acute rejection., Methods and Results: Fourteen heart transplant patients were treated concomitantly with CsA, MMF, and PSL between May 1999 and November 2005 at the National Cardiovascular Center and of them 3 had acute rejection episodes [International Society for Heart & Lung Transplantation grade 3a]. Two patients (man in his 30 s; woman in her 40 s) had acute rejection with a mycophenolic acid (MPA) AUC(0-12 h) <30 microg x h x ml(-1) and low CsA AUC (AUC(0-4 h); 2,408 ng x h x ml-1, 1,735 ng x h x ml-1). However, 1 patient (man in his 30 s) with a high CsA AUC(0-4 h) (4,019 ng x h x ml-1) did not develop cardiac allograft rejection even if the MMF was temporarily stopped. These 3 patients were investigated to evaluate the relationship between acute rejection and pharmacokinetic parameters, including the CsA C0, C2, AUC(0-4 h) and MPA AUC(0-12 h)., Conclusions: The findings suggest that a high CsA AUC(0-4 h) may prevent rejection of a cardiac allograft, even if MMF is stopped or drastically reduced.

Background: The purpose of this study was to characterize the pharmacokinetics of cyclosporine (CsA) in Japanese heart transplant patients, and to optimise the monitoring strategy based on measurements of the area under the curve of plasma concentration absorption phase or 2 h post-dose concentrations (C(2))., Methods and Results: At defined time periods during the first year after transplantation, the area under the curve for the CsA serum concentration from 0 to 4 h (AUC(0-4 h)) was evaluated. Pharmacokinetic parameters and renal function at 1 month and 12 months after transplantation were compared in 7 Japanese patients. The highest coefficient of determination between CsA AUC(0-4 h) and a single concentration was observed using C2 (r2 =0.838). For CsA pharmacokinetics, the mean measurement of whole blood trough levels value at 12 months was significantly lower than at 1 month after transplantation (p=0.026). The mean serum creatinine level at 12 months was significantly higher than at 1 month (1.00 mg/dl vs 0.73 p=0.0194)., Conclusion: A single-time-point model that includes C2 is useful for predicting CsA AUC(0-4 h) in Japanese heart transplant patients. Mean C2 values >1,000 ng/ml were obtained in patients with no rejection at 1 month and 12 months after transplantation; however, renal impairment may occur.

Background: Green tea, a popular beverage in Japan, contains many polyphenolic antioxidants, which might prevent atherosclerosis. This study was designed to determine whether the consumption of green tea is proportionately associated with a decreased incidence of coronary artery disease (CAD) and the cardiovascular and cerebrovascular prognosis., Methods and Results: The study group comprised 203 patients who underwent coronary angiography (109 patients with significant coronary stenosis and 94 patients without). Predictors for CAD were analyzed and the patients' cardiovascular and cerebrovascular events were followed. Green tea consumption was significantly higher in patients without CAD than in those with CAD (5.9+/-0.5 vs 3.5+/-0.3 cups/day; p<0.001). An inverse relationship between the intake of green tea and the incidence of CAD was observed (p<0.001). The green tea intake per day was an independent predictor for CAD based on a multivariate logistic regression analysis (odds ratio: 0.84 and 95% confidence interval: 0.76-0.91). In contrast, the green tea intake was not a predictor of cardiovascular and cerebrovascular events based on the Cox proportional hazard model., Conclusions: Green tea consumption was associated with a lower incidence of CAD in the present study population in Japan. Therefore, the more green tea patients consume, the less likely they are to have CAD.

Background: Hepatocyte growth factor (HGF) has been reported as a marker of atherosclerosis and of thrombi synthesis, but the relationship between HGF and proven coronary thrombi has not been described. The aim of this study was to investigate this relationship in patients with chest pain., Methods and Results: The study group comprised 107 patients with chest pain (61 acute myocardial infarction (AMI), 18 unstable angina, 15 stable angina, and 13 others; 65 males, 42 females; 66+/-11 years old). The presence of thrombi was evaluated by angiography, intravascular ultrasonography, angioscopy, and computed tomography. Serum HGF concentrations were measured using a new enzyme-linked immunosorbent assay. Serum HGF was significantly higher in the patients with AMI (335.0 +/-197.5 pg/ml), unstable angina (269.1+/-152.7 pg/ml), acute aortic dissection (320.3+/-116.5 pg/ml), and pulmonary thromboembolism (292.5+/-101.9 pg/ml), than in those with stable angina (171.2+/-56.1 pg/ml). Serum HGF concentration was also higher in those patients with proven thrombi than in those patients without (326.7+/-189.7 pg/ml vs 226.9+/-110.8 pg/ml)., Conclusion: Increased serum HGF concentrations correlate with the presence of thrombi in patients with acute coronary syndrome, acute aortic dissection, and pulmonary thromboembolism.

Transient receptor potential protein 4 (TRPC4) has been identified as a candidate for the capacitative calcium entry (CCE) channels, but its functional role is still controversial. Using a RT-PCR technique, a novel isoform of TRPC4, designated rTRPC4gamma, was isolated. It was nearly identical to full-length rTRPC4 (rTRPC4alpha), except that it lacked 53 nucleotides that correspond to the predicted linker between the second and third transmembrane domain of rTRPC4alpha, and its mRNA was expressed in brain and heart. This splice variant encoded a potential protein of 400 residues that consists of an amino-terminal cytoplasmic domain and 2 transmembrane domains by a frameshift mutation. When rTRPC4gamma cDNA was transiently transfected to HEK-293 cells, thapsigargin (TG)-induced Ca2+ entry was suppressed significantly. By contrast, expression of rTRPC4 a did not affect TG-induced Ca2+ entry. To investigate the subcellular localization, plasmids were constructed with green fluorescence protein (GFP) as an amino-terminal fusion to rTRPC4 variants. GFP-rTRPC4gamma fusion protein, unlike GFP-rTRPC4alpha, was localized to the cytoplasm as well as plasma membrane. These results suggest that rTRPC4gamma may play a modulatory role in CCE channel activity in the brain and heart.