Yoshihiro Dohi

Characterization of Noncalcified Coronary Plaques and Identification of Culprit Lesions in Patients With Acute Coronary Syndrome by 64-Slice Computed Tomography

OBJECTIVES We sought to characterize noncalcified coronary atherosclerotic plaques in culprit and remote coronary atherosclerotic lesions in patients with acute coronary syndrome (ACS) with 64-slice computed tomography (CT). BACKGROUND Lower CT density, positive remodeling, and adjacent spotty coronary calcium are characteristic vessel changes in unstable coronary plaques. METHODS Of 147 consecutive patients who underwent contrast-enhanced 64-slice CT examination for coronary artery visualization, 101 (ACS; n = 21, non-ACS; n = 80) having 228 noncalcified coronary atherosclerotic plaques (NCPs) were studied. Each NCP detected within the vessel wall was evaluated by determining minimum CT density, vascular remodeling index (RI), and morphology of adjacent calcium deposits. RESULTS The CT visualized more NCPs in ACS patients (65 lesions, 3.1 +/- 1.2/patient) than in non-ACS patients (163 lesions, 2.0 +/- 1.1/patient). Minimum CT density (24 +/- 22 vs. 42 +/- 29 Hounsfield units [HU], p < 0.01), RI (1.14 +/- 0.18 vs. 1.08 +/- 0.19, p = 0.02), and frequency of adjacent spotty calcium of NCPs (60% vs. 38%, p < 0.01) were significantly different between ACS and non-ACS patients. Frequency of NCPs with minimum CT density <40 HU, RI >1.05, and adjacent spotty calcium was approximately 2-fold higher in the ACS group than in the non-ACS group (43% vs. 22%, p < 0.01). In the ACS group, only RI was significantly different between 21 culprit and 44 nonculprit lesions (1.26 +/- 0.16 vs. 1.09 +/- 0.17, p < 0.01), and a larger RI (> or = 1.23) was independently related to the culprit lesions (odds ratio: 12.3; 95% confidential interval: 2.9 to 68.7, p < 0.01), but there was a substantial overlap of the distribution of RI values in these 2 groups of lesions. CONCLUSIONS Sixty-four-slice CT angiography demonstrates a higher prevalence of NCPs with vulnerable characteristics in patients with ACS as compared with stable clinical presentation.

Heme Induces Ubiquitination and Degradation of the Transcription Factor Bach1

ABSTRACT The transcription repressor Bach1 is a sensor and effector of heme that regulates the expression of heme oxygenase 1 and globin genes. Heme binds to Bach1, inhibiting its DNA binding activity and inducing its nuclear export. We found that hemin further induced the degradation of endogenous Bach1 in NIH 3T3 cells, murine embryonic fibroblasts, and murine erythroleukemia cells. In contrast, succinylacetone, an inhibitor of heme synthesis, caused accumulation of Bach1 in murine embryonic fibroblasts, indicating that physiological levels of heme regulated the Bach1 turnover. Polyubiquitination and rapid degradation of overexpressed Bach1 were induced by hemin treatment. HOIL-1, an ubiquitin-protein ligase which recognizes heme-bound, oxidized iron regulatory protein 2, was found to bind with Bach1 when both were overexpressed in NIH 3T3 cells. HOIL-1 stimulated the polyubiquitination of Bach1 in a purified in vitro ubiquitination system depending on the intact heme binding motifs of Bach1. Expression of dominant-negative HOIL-1 in murine erythroleukemia cells resulted in higher stability of endogenous Bach1, raising the possibility that the heme-regulated degradation involved HOIL-1 in murine erythroleukemia cells. These results suggest that heme within a cell regulates the polyubiquitination and degradation of Bach1.

Effects of lipid-lowering therapy with strong statin on serum polyunsaturated fatty acid levels in patients with coronary artery disease

Residual risk of cardiovascular events after treatment with stain might be explained in part because patients have low levels of n−3 polyunsaturated fatty acids (PUFA). We examined how lipid-lowering therapy with strong statin affected serum PUFA levels in patients with coronary artery disease. The study population consisted of 46 patients with coronary artery disease whose low-density lipoprotein (LDL) cholesterol was more than 100 mg/dl. Lipid-lowering therapy was performed with a strong statin including atorvastatin (n = 22), rosuvastatin (n = 9) or pitavastatin (n = 15). Serum PUFA levels were determined by gas chromatography. The treatment with strong statin decreased the sum of dihomo-γ-linolenic acid (DGLA) and arachidonic acid (AA) levels (195 ± 41 to 184 ± 44 μg/ml, P < 0.05) as well as the sum of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels (233 ± 71 to 200 ± 72 μg/ml, P < 0.001). These effects of strong statin resulted in a significant decrease in ratio of the sum of EPA and DHA levels to the sum of DGLA and AA levels (1.20 ± 0.27 to 1.10 ± 0.35, P < 0.05). The percent decrease in the LDL cholesterol level correlated significantly with that in the sum of EPA and DHA levels (r = 0.38, P < 0.01). In conclusion, our results showed that lipid-lowering therapy with strong statin mainly reduced n−3 PUFAs in proportion to the decrease in the LDL cholesterol level in patients with coronary artery disease.

Genetic ablation of transcription repressor Bach1 reduces neural tissue damage and improves locomotor function after spinal cord injury in mice.

Heme oxygenase (HO)-1 is an inducible cytoprotective enzyme that degrades heme to iron, carbon monoxide (CO), and biliverdin, the latter two of which are thought to mediate the anti-inflammatory and antioxidant actions of HO-1. Bach1 is a transcriptional repressor of the HO-1 gene (Hmox-1). Previous reports have demonstrated that the genetic ablation of Bach1 engenders an increased HO-1 expression and a marked reduction in the degree of oxidative tissue damage in vivo. However, the function of Bach1 in spinal cord injury is still not understood. In the present study, we examined whether Bach1 deficiency increases HO-1 expression and reduces neural tissue damage in a spinal cord injury model using Bach1 knock-out (KO) mice and wild-type (WT) mice. The expression of HO-1 protein in the spinal cord was significantly higher in the Bach1 KO mice than in the WT mice before and after injury. The KO mice also had significantly higher Basso mouse scale scores for locomotor function and larger areas of spared white matter than the WT mice at 6 weeks after injury. Neuronal loss and apoptotic cell death in the injured spinal cord was significantly reduced in the KO mice in comparison to the WT mice. These results suggest that Bach1 deficiency engenders a constitutively higher expression of HO-1 and a dramatic increase in cytoprotection against spinal cord injury.

Comparison of electrocardiographic findings between the midventricular ballooning form and apical ballooning form of takotsubo cardiomyopathy.

Several reports have recently described the variant form of takotsubo cardiomyopathy exhibiting midventricular ballooning. The purpose of this study was to assess electrocardiographic (ECG) findings on admission in patients with midventricular ballooning.

Identification of senescence-associated genes and their networks under oxidative stress by the analysis of Bach1.

Cellular senescence is induced in response to DNA damage, caused by genotoxic stresses, including oxidative stress, and serves as a barrier against malignant transformation. Tumor-suppressor protein p53 induces genes critical for implementing cellular senescence. However, the identities of p53 target genes and other regulators that achieve senescence under oxidative stress remain to be elucidated. Effector genes for oxidative stress-induced cellular senescence were sought, based on the fact that transcription factor Bach1 inhibits this response by impeding the transcriptional activity of p53. pRb became hypophosphorylated more rapidly in Bach1-deficient MEFs than in wild-type cells, suggesting that pRb activation was involved in their senescence. Bach1-deficient MEFs bypassed the senescence state when the expression of a subset of p53 target genes, including p21, Pai1, Noxa, and Perp, was simultaneously reduced by using RNAi. Combined knockdown of p21 and pRb resulted in vigorous re-proliferation. These results suggest that oxidative stress-induced cellular senescence is registered by multiple p53 target genes, which arrest proliferation redundantly, in part by activating pRb. Our elucidations contrast with previous reports describing monopolistic regulations of senescence by single p53 target genes.

Influence of left ventricular geometry on thallium-201 gated single-photon emission tomographic findings in patients with known or suspected coronary artery disease.

BackgroundRecent studies have shown good correlations between echocardiography and Tl-201 gated single-photon emission computed tomography (SPECT) for the assessment of left ventricular volumes and ejection fraction. We assessed how left ventricular geometry affected correlations between these values measured by the 2 methods in patients with known or suspected coronary artery disease.Methods and resultsThere were 109 patients with normal left ventricular geometry, 20 patients with concentric remodeling, 32 patients with eccentric hypertrophy and 28 patients with concentric hypertrophy. In all 4 groups, there were good correlations between end-diastolic volume (EDV) and end-systolic volume (ESV) values measured by echocardiography and quantitative gated SPECT (QGS). EDV and ESV values measured by QGS were significantly underestimated than those measured by echocardiography except for ESV in eccentric hypertrophy. In all 4 groups, ejection fraction (EF) value measured by echocardiography significantly correlated with that measured by QGS, but Bland–Altman plot showed a proportional error. EF value measured by QGS was likely to be overestimated when EF value increased from the median value, and to be underestimated when EF value decreased from the median value especially in concentric remodeling.ConclusionsTl-201 gated SPECT is a useful tool for the assessment of left ventricular volumes and function, but it requires methodological considerations according to left ventricular geometry.

Effects of myocardial perfusion abnormalities on the accuracy of left ventricular volume and ejection fraction measured by thallium-201 gated single-photon emission tomography: comparison with echocardiography as the reference standard.

BackgroundWe assessed the accuracy of left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) using quantitative gated single-photon emission computed tomography (QGS) in comparison with echocardiography as the reference standard. We also assessed the effects of total perfusion deficit (TPD) on the accuracy of QGS measurements. MethodsA total of 258 patients underwent single-photon emission computed tomography and transthoracic echocardiography within 4 weeks of each investigation for evaluating coronary artery disease. Patients were divided into four groups according to TPD scores. ResultsThere were 138 patients with no/minimal TPD, 64 patients with small TPD, 35 patients with middle TPD, and 21 patients with large TPD. There were good correlations and agreements in EDV (r=0.87, 0.90, 0.71, and 0.94, respectively), ESV (r=0.92, 0.94, 0.79, and 0.94, respectively), and EF (r=0.61, 0.79, 0.61, and 0.83, respectively) between QGS and echocardiography in patients with any TPD. QGS significantly underestimated EDV and ESV in patients with no/minimal or small TPD, and significantly overestimated ESV in patients with large TPD. QGS significantly underestimated EF in patients with middle or large TPD. ConclusionOur results suggest that QGS is a useful tool for assessing the left ventricular volume and function in patients with any TPD, but myocardial perfusion abnormalities should be taken into consideration when interpreting QRS measurements.

Prognostic Factors for Survival in Pulmonary Hypertension Due to Left Heart Disease

BACKGROUND The epidemiological data of pulmonary hypertension (PH) due to left heart disease (LHD) are limited. This study investigated hemodynamic and clinical factors associated with mortality in patients with PH due to LHD. METHODS AND RESULTS We conducted a retrospective review in 243 patients with PH due to LHD, defined as mean pulmonary arterial pressure ≥25 mmHg and pulmonary wedge pressure >15 mmHg at rest in right heart catheterization. Kaplan-Meier and Cox proportional hazard regression analyses were performed. Seventy-five patients died during an average follow-up of 52 months (range, 20-73 months). On multivariate analysis, only diastolic pulmonary vascular pressure gradient (DPG) ≥7 mmHg among hemodynamic measurements was a predictor of mortality. Elevated N-terminal pro-brain natriuretic peptide (NT-pro BNP), more severe New York Heart Association (NYHA) class, anemia, and renal dysfunction were more strongly associated with mortality. Mean right atrial pressure (RAP) and currently available markers of pulmonary vascular remodeling including transpulmonary pressure gradient (TPG) and pulmonary vascular resistance (PVR) had no effect on survival. CONCLUSIONS DPG is weakly associated with mortality in PH due to LHD. Clinical factors such as NT-pro BNP, NYHA class, anemia and renal dysfunction are superior predictors. The prognostic ability of hemodynamic factors such as mean RAP, TPG, PVR and DPG is limited.

Effects of aliskiren on the fibrinolytic system in patients with coronary artery disease receiving angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor blocker

Aliskiren is a novel blood pressure-lowering agent acting as an oral direct renin inhibitor. We evaluated the effects of aliskiren on the fibrinolytic system in patients with coronary artery disease who were receiving angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs). We studied 17 patients with coronary artery disease whose systolic blood pressure was more than 130 mmHg despite treatment with ACEIs or ARBs. Aliskiren (150 mg) was added to ACEIs or ARBs, and was continued for 6 weeks. Aliskiren significantly decreased systolic blood pressure (140 ± 6–128 ± 8 mmHg, P < 0.001) and plasma renin activity (1.8 ± 2.3–0.6 ± 0.9 ng/ml/h, P < 0.01) after 6 weeks. However, it did not affect plasminogen activator inhibitor-1 (28.8 ± 14.5–30.6 ± 13.6 ng/ml, P = 0.84), fibrinogen (305 ± 72 vs 301 ± 71 mg/dl, P = 0.33), or D-dimer (0.49 ± 0.24–0.51 ± 0.28 μg/ml, P = 0.70) levels. Our data suggested that patients receiving ACEIs or ARBs would not be expected to have any changes in biomarkers of the fibrinolytic system with additional pharmacologic inhibition of the renin–angiotensin–aldosterone system.