Shinji Mito

Role of Osteoprotegerin in Arterial Calcification Development of New Animal Model

Objectives—Enhanced osteoclastogenesis, increased bone resorption, and osteoporosis have been reported in osteoprotegerin-deficient (OPG (−/−)) mice. OPG (−/−) mice available in Japan usually do not show vascular calcification. We have found that arterial calcification can be quickly induced by a simple procedure in OPG (−/−) mice. Methods and Results—Male OPG (−/−), OPG (+/−), and OPG (+/+) mice were fed a high phosphate diet from 6 to 10 weeks after birth, and then 1&agr;,25-dihydroxyvitamin D3 (calcitriol) was injected for 3 days. We found that severe calcification developed in the media of the aorta in OPG (−/−) mice. Under electron microscopy, calcium deposits were observed in the cytoplasm and extracellular matrix of vascular smooth muscle cells (VSMCs). Neither apoptosis of VSMCs nor infiltration of macrophages was observed. Alkaline phosphatase (ALP) activity of aortic tissue correlated with the calcified lesion area. Mouse aorta and bone extracts revealed an identical pattern by ALP electrophoresis. Conclusions—Our results demonstrated that OPG had anticalcification activity in the aorta, probably through the downregulation of ALP activity. Because the time course of arterial calcification after the injection of calcitriol is accurate and reproducible, this mouse model will be useful for further investigation of vascular calcification.

Myocardial Protection Against Pressure Overload in Mice Lacking Bach1, a Transcriptional Repressor of Heme Oxygenase-1

Bach1 is a stress-responsive transcriptional factor that is thought to control the expression levels of cytoprotective factors, including heme-oxygenase (HO)-1. In the present study, we investigated the roles of Bach1 in the development of left ventricular (LV) hypertrophy and remodeling induced by transverse aortic constriction (TAC) in vivo using Bach1 gene-deficient (Bach1−/−) mice. TAC for 3 weeks in wild-type control (Bach1+/+) mice produced LV hypertrophy and remodeling manifested by increased heart weight, histological findings showing increased myocyte cross-sectional area (CSA) and interstitial fibrosis (picro Sirius red staining), reexpressions of ANP, BNP, and &bgr;MHC genes, and echocardiographic findings showing wall thickening, LV dilatation, and reduced LV contraction. Deletion of Bach1 caused significant reductions in heart weight (by 16%), CSA (by 36%), tissue collagen content (by 38%), and gene expression levels of ANP (by 75%), BNP (by 45%), and &bgr;MHC (by 74%). Echocardiography revealed reduced LV dimension and ameliorated LV contractile function. Deletion of Bach1 in the LV caused marked upregulation of HO-1 protein accompanied by elevated HO activity in both basal or TAC-stimulated conditions. Treatment of Bach1−/− mice with tin-protoporphyrin, an inhibitor of HO, abolished the antihypertrophic and antiremodeling effects of Bach1 gene ablation. These results suggest that deletion of Bach1 caused upregulation of cytoprotective HO-1, thereby inhibiting TAC-induced LV hypertrophy and remodeling, at least in part, through activation of HO. Bach1 repressively controls myocardial HO-1 expression both in basal and stressed conditions, inhibition of Bach1 may be a novel therapeutic strategy to protect the myocardium from pressure overload.

Ablation of the Bach1 Gene Leads to the Suppression of Atherosclerosis in Bach1 and Apolipoprotein E Double Knockout Mice

This study was designed to determine whether Bach1 gene ablation leads to suppression of atherosclerosis in apolipoprotein E (Apo E)/Bach1 double knockout (DKO) mice. Apo E/Bach1 DKO mice were generated by intercrossing Apo E knockout (KO) and Bach1 KO mice. The animals were fed a high-fat diet for 8 weeks, and the atherosclerotic plaques in the thoracic and abdominal aorta were visualized by oil red O staining. In DKO mice, the total plaque area was reduced by 32% compared with that in Apo E KO mice. In DKO mice, heme oxygenase-1 (HO-1) was upregulated in the endothelium and, to a lesser extent, in vascular smooth muscles. In atherosclerotic plaques in Apo E KO mice and DKO mice, HO-1 was abundantly expressed in the endothelium and macrophages. Urine excretion of 8-iso-prostaglandin (PG) F2α, a marker for lipid peroxidation, was reduced in DKO mice compared with that in Apo E KO mice. The effects of Bach1 ablation on the plaque area and 8-iso-PG F2α excretion were almost completely abolished by treating DKO mice with Sn protoporphyrin, an inhibitor of HO activity. Disruption of the Bach1 gene in Apo E KO mice caused inhibition of atherosclerosis through upregulation of HO-1. Inhibition of Bach1, conversely, may be a novel therapeutic strategy to treat atherosclerotic diseases.

Validation of lactate level as a predictor of early mortality in acute decompensated heart failure patients who entered intensive care unit

BACKGROUND The significance of routine measurement of lactate level is unclear in patients with critical acute decompensated heart failure (ADHF). METHODS AND RESULTS Consecutive 754 patients who were admitted to the intensive care unit (ICU) in our hospital from January 2007 to March 2012 and given a diagnosis of ADHF were eligible for retrospective entry into the registry. Lactate level was measured on admission from routine arterial blood sample and we investigated by comparing the lactate level and parameters of conventional in-hospital mortality predictors. Among the patients, 88 (12%) died during hospitalization. The lactate level had great power to predict in-hospital mortality, as suggested by the c-statistics of 0.71. The occurrence of in-hospital death was more pronounced in patients with high levels of lactate (>3.2mmol/l) and the tendency was observed in patients in both the acute coronary syndrome (ACS) group and non-ACS group. In multivariate analysis, elevated lactate levels remained an independent predictor of in-hospital death (odds ratio, 2.14; 95% confidence interval, 1.10-4.21; p=0.03). CONCLUSIONS Elevated levels of arterial lactate on admission were related to worse in-hospital mortality in patients with ADHF either with or without ACS, suggesting that the presence of high lactate in patients who enter the ICU with ADHF could help stratify the initial risk of early mortality.

Comparison of heart-type fatty acid binding protein and sensitive troponin for the diagnosis of early acute myocardial infarction

BACKGROUND The current development of serological biomarkers allows detection of smaller myocardial necrosis and early acute myocardial infarction (AMI). We evaluated the relevance of the heart-type fatty acid binding protein (H-FABP) assay, which has recently been approved in Japan, for early diagnosis of AMI as compared with the sensitive troponin assay. METHODS This is an observational study in a single center. From 2010 July to 2011 January, 114 patients who presented with symptoms suggestive of AMI were enrolled. RESULTS AMI was adjudicated in 45 patients (40%). The diagnostic accuracy of measurements obtained at presentation for AMI, as quantified by the area under the receiver-operating-characteristic curve (AUC), was significantly lower with H-FABP assay than the sensitive troponin assay [AUC for H-FABP, 0.59; 95% confidence interval (CI) 0.48-0.70; and for troponin I, 0.89; 95% CI, 0.83-0.94; P<.0001]. Among patients who presented within 2h after the onset of chest pain, the AUC for H-FABP was even low as compared with sensitive troponin (0.55; 0.39-0.72 vs. 0.89; 0.80-0.98, p<0.001). The clinical sensitivity for the diagnosis of AMI with the cutoff point of 99 th percentile was similar in both assays (81% and 81%, respectively), however, the specificity was extremely low in the H-FABP assay as compared with sensitive troponin assay (19% and 79%, respectively). CONCLUSION The measurement of H-FABP in 114 consecutive patients with chest pain suggestive of AMI showed no improvement of diagnosis for early AMI as compared with the current sensitive troponin assay because of its extremely low specificity.

Clinical usefulness of drug-eluting stents in the treatment of dialysis patients with coronary artery disease

AIMS To investigate the clinical outcomes of paclitaxel-eluting stents (PES) and sirolimus-eluting stents (SES) in patients on dialysis. METHODS AND RESULTS Between May 2004 and December 2008, 95 patients on dialysis with 124 lesions were treated with PES alone, and were compared to 184 patients on dialysis with 244 lesions treated with SES alone, retrospectively. One-year major adverse cardiac event (MACE) including stent thrombosis, target lesion revascularisation (TLR), myocardial infarction (MI) and cardiac death were compared. Baseline characteristics were similar except for previous CABG (p = 0.02) and reference vessel diameter (p = 0.04). During hospitalisation, all cause death was more frequently observed in the PES group (p = 0.004). In-hospital MACE was not significantly different (p = 0.8). The incidence of 1-year MACE in the PES group was lower than that in the SES group (14.7%, 28.3%, p = 0.04), mainly due to the reduction of TLR (11.6%, 25.0%, p = 0.03). Rates of stent thrombosis (0%, 2.7%, p = 0.1), MI (1.1%, 3.8%, p = 0.2), and cardiac death (3.2%, 4.4%, p = 0.6) were not significantly different. CONCLUSIONS PES appears to be more efficient in reducing angiographic and clinical restenosis in dialysis patients compared with SES.

Intravenous administration of adenosine triphosphate disodium during primary percutaneous coronary intervention attenuates the transient rapid improvement of myocardial wall motion, not myocardial stunning, shortly after recanalization in acute anterior myocardial infarction.

BACKGROUND AND PURPOSE Administration of adenosine attenuates myocardial stunning after reperfusion in a canine experimental ischemic model. However, it is unknown whether administration of adenosine triphosphate disodium (ATP) during reperfusion can attenuate myocardial stunning after coronary recanalization in patients with acute myocardial infarction (MI). Therefore, we sought to elucidate the effects of ATP administration on serial changes of left ventricular systolic function before and after coronary recanalization. METHODS In 27 patients with first ST-elevation acute anterior MI, in whom primary percutaneous coronary intervention (PCI) was completed within 10 h after symptom onset, ATP at a mean rate of 103 microg/kg/min (n=16) or normal saline (n=11) was intravenously administered for 1 h during reperfusion. Left ventricular regional wall motion within the initially severely ischemic region was serially analyzed using the standard wall motion score index (WMSI) by transthoracic echocardiography. RESULTS Means of WMSIs were similar shortly before primary PCI in both groups (2.79 in ATP group and 2.69 in controls). They changed to 2.56 and 2.22 shortly after PCI, 2.49 and 2.39 on day 2, 2.34 and 2.30 on day 3, 2.19 and 2.25 on day 10, and 1.85 and 2.02, 6 months later, respectively. Transient improved regional wall motion within the initially severely ischemic region was observed shortly after PCI in controls (10.3% of observed segments); however, it was significantly suppressed in the ATP group (2.55%). The percent recovery of WMSI on day 10, which was defined as WMSI on day 10 normalized by improvement of WMSI for 6 months, was 63.8% in ATP group and 65.7% in controls, implying ATP administration could not reduce myocardial stunning by day 10 after primary PCI. CONCLUSIONS The high-dose administration of ATP during primary PCI prevented transient improved wall motion shortly after coronary recanalization rather than preventing left ventricular stunning. These results suggest that ATP can prevent reperfusion injury during primary PCI.

A case of acute coronary syndrome caused by extrinsic compression of the left main coronary artery due to pulmonary hypertension

Stenosis of the left main coronary artery (LMCA) due to extrinsic compression, producing symptoms of myocardial ischemia, is called left main compression syndrome. We report on a 43-year-old male with acute coronary syndrome who developed left main compression syndrome while waiting for a lung transplantation secondary to interstitial pneumonia, but underwent successful LMCA stenting as emergent treatment. Coronary angiography 3 months after the operation showed good stent patency in the LMCA, and the clinical course was favorable.

Atrial electrical abnormality in patients with Brugada syndrome assessed by signal-averaged electrocardiography

Background Ventricular fibrillation and atrial fibrillation are well-known arrhythmias in patients with Brugada syndrome. This study evaluated the characteristics of the atrial arrhythmogenic substrate using the signal-averaged electrogram (SAECG) in patients with Brugada syndrome. Methods SAECGs were performed during normal sinus rhythm in 23 normal volunteers (control group), 21 patients with paroxysmal atrial fibrillation (PAF; PAF group), and 21 with Brugada syndrome (Brugada group). Results The filtered P wave duration (fPd) in the control, Brugada, and PAF groups was 113.9 ± 12.9 ms, 125.3 ± 15.0 ms, and 137.1 ± 16.3 ms, respectively. The fPd in the PAF group was significantly longer compared to that in the control and Brugada groups (p < 0.05). The fPd in the Brugada group was significantly longer than that in the control group (p < 0.05) and significantly shorter than that in the PAF group (p < 0.05). Conclusion Patients with Brugada syndrome had abnormal P waves on the SAECG. The abnormal P waves on the SAECG in Brugada syndrome patients may have intermediate characteristics between control and PAF patients.

Partial left superior pulmonary vein potential elimination by an inferior ganglionated plexus ablation

Ganglionated plexus (GP) plays an important role in the initiation and maintenance of atrial fibrillation (AF). The GP ablation has been found to be effective for AF treatment. In this case, we reported an AF case in which the pulmonary vein (PV) potentials of the anterior region of the left superior PV were eliminated by an inferior right GP ablation.