Yoshiyuki Miyahara

Antiapoptotic Activity of Akt Is Down-regulated by Ca2+ in Myocardiac H9c2 Cells EVIDENCE OF Ca2+-DEPENDENT REGULATION OF PROTEIN PHOSPHATASE 2Ac

Cell survival signaling of the Akt/protein kinase B pathway was influenced by a change in the cytoplasmic free calcium concentration ([Ca2+]i) for over 2 h via the regulation of a Ser/Thr phosphatase, protein phosphatase 2Ac (PP2Ac), in rat myocardiac H9c2 cells. Akt was down-regulated when [Ca2+]i was elevated by thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-ATPase, but was up-regulated when it was suppressed by 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl)ester (BAPTA-AM), a cell permeable Ca2+ chelator. The inactivation of Akt was well correlated with the susceptibility to oxidant-induced apoptosis in H9c2 cells. To investigate the mechanism of the Ca2+-dependent regulation of Akt via the regulation of PP2A, we examined the transcriptional regulation of PP2Acα in H9c2 cells with Ca2+ modulators. Transcription of the PP2Acα gene was increased by thapsigargin but decreased by BAPTA-AM. The promoter activity was examined and the cAMP response element (CRE) was found responsible for the Ca2+-dependent regulation of PP2Acα. Furthermore, phosphorylation of CRE-binding protein increased with thapsigargin but decreased with BAPTA-AM. A long term change of [Ca2+]i regulates PP2Acα gene transcription via CRE, resulting in a change in the activation status of Akt leading to an altered susceptibility to apoptosis.

Atorvastatin induces associated reductions in platelet P-selectin, oxidized low-density lipoprotein, and interleukin-6 in patients with coronary artery diseases

The development and progression of atherosclerosis comprises various processes, such as endothelial dysfunction, chronic inflammation, thrombus formation, and lipid profile modification. Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that have pleiotropic effects in addition to cholesterol-lowering properties. However, the mechanisms of these effects are not completely understood. Here, we investigated whether atorvastatin affects the levels of malondialdehyde-modified low-density lipoprotein (MDALDL), an oxidized LDL, the proinflammatory cytokine interleukin-6 (IL-6), or platelet P-selectin, a marker of platelet activation, relative to that of LDL cholesterol (LDL-C). Forty-eight patients with coronary artery disease and hyperlipidemia were separated into two groups that were administered with (atorvastatin group) or without (control group) atorvastatin. The baseline MDA-LDL level in all participants significantly correlated with LDL-C (r = 0.71, P < 0.01) and apolipoprotein B levels (r = 0.66, P < 0.01). Atorvastatin (10 mg/day) significantly reduced the LDL-C level within 4 weeks and persisted for a further 8 weeks of administration. Atorvastatin also reduced the MDA-LDL level within 4 weeks and further reduced it over the next 8 weeks. Platelet P-selectin expression did not change until 4 weeks of administration and then significantly decreased at 12 weeks, whereas the IL-6 level was gradually, but not significantly, reduced at 12 weeks. In contrast, none of these parameters significantly changed in the control group within these time frames. The reduction (%) in IL-6 between 4 and 12 weeks after atorvastatin administration significantly correlated with that of MDALDL and of platelet P-selectin (r = 0.65, P < 0.05 and r = 0.70, P < 0.05, respectively). These results suggested that the positive effects of atorvastatin on the LDL-C oxidation, platelet activation and inflammation that are involved in atherosclerotic processes are exerted in concert after lowering LDL-C.

Serial changes in negative T wave on electrocardiogram in acute pulmonary thromboembolism

A negative T wave is frequently observed in precordial ECG leads in patients with acute pulmonary thromboembolism. We investigated the clinical significance of negative T wave in 15 patients with acute pulmonary thromboembolism who were treated with thrombolytic agents by measuring the mean pulmonary artery pressure and ratio of right to left ventricular end-diastolic diameter using echocardiography and ECG. The study included only patients with massive acute pulmonary thromboembolism of a mean age of 65+/-9.7 years (+/-SD). A negative T wave was observed on admission in 10 patients but was later detected in 14 of the 15 patients. The mean amplitude of the negative T wave increased within 1 week then decreased after thrombolytic treatment. The peak negative amplitude of the T wave was observed from 1 to 7 days (mean, 2.6+/-1.8 days) and disappeared afterwards. During this period, improvements in both the mean pulmonary artery pressure (37.8+/-11.2 to 19.1+/-6.7 mmHg) and the ratio of right to left ventricular end-diastolic diameter (0.97+/-0.16 to 0.51+/-0.13) were noted in all patients. Our results suggest that an increase in the amplitude of negative T wave in precordial leads after thrombolytic therapy in patients with massive acute pulmonary thromboembolism reflects improvement in cardiopulmonary hemodynamics.

Assessment of Right Ventricular Diastolic Function by Pulsed Doppler Echocardiography in Chronic Pulmonary Disease and Pulmonary Thromboembolism

We evaluated right ventricular (RV) diastolic performance in 12 healthy subjects (control), 25 patients with chronic pulmonary diseases (CPD) and 6 patients with chronic pulmonary thromboembolism (PTE). Flow velocity patterns were determined by the pulsed Doppler technique. The values determined included acceleration time (AT), deceleration time (DT), and the ratio of the atrial contraction wave (A) to the rapid filling wave (R) (A/R ratio) from flow velocity patterns in the RV inflow tract. DT was significantly prolonged in the CPD and PTE groups compared with the control group, indicating dysfunction during the early (middle) filling period. The prolongation was marked in those patients with pulmonary hypertension. The A/R ratio was significantly higher in the CPD and PTE groups than in the control group, indicating a decrease in RV compliance. The A/R ratio increased slightly with the increase in the end-diastolic volume index. These results suggested that the pressure overload plays an important role in RV diastolic dysfunction in patients with pulmonary disease, and that preload contributes to the dysfunction.

Evaluation of Right-Ventricular Function by Doppler Echocardiography in Patients with Chronic Respiratory Failure

In patients with chronic respiratory failure, right-ventricular function was non-invasively evaluated by Doppler echocardiography. A total of 31 patients (16 men, 15 women; mean age 65.8 ± 7.12 years) with pulmonary tuberculosis sequelae who had received home oxygen therapy during the preceding 6 or more months, were studied. Right-ventricular inflow and outflow waveforms were recorded, and right-ventricular function was evaluated using a new Doppler index combining systolic and diastolic function. On continuous wave Doppler echocardiography, estimated systolic pulmonary arterial pressure was calculated from the gradient between the right atrium and right ventricle. There was no correlation between the new Doppler index and systolic pulmonary arterial pressure, and some patients showed high index values despite low systolic pulmonary arterial pressure. The new Doppler index facilitated evaluation of ventricular function irrespective of right-ventricular afterload.

The echocardiographic Tei-index reflects early myocardial damage induced by anthracyclines in patients with hematological malignancies

Anthracyclines are antineoplastic agents that are effective against solid tumors and hematological malignancies. However, drug-induced cardiotoxicity imposes dose limitations. Myocardial damage due to anthracyclines has been assessed by measuring left ventricular ejection fraction (LVEF) or fraction shortening (FS) by echocardiography and criteria for discontinuing treatment have been established based on these indexes. However, cardiotoxicity is already irreversible when either LVEF or FS fulfills these criteria. The Tei-index has recently been established to assess combined systolic and diastolic myocardial function during echocardiography. It can also detect small changes in cardiac function. We therefore surmised that the Tei-index would reflect early myocardial damage induced by anthracyclines. We treated 23 patients with the anthracycline, doxorubicin (DXR), and examined them at least twice during the treatment. An additional dose of DXR significantly correlated with a change in the Tei-index (ΔTei-index). In contrast, a change in LVEF did not correlate with increased doses of DXR. The ΔTei-index did not correlate with either LVEF or the Tei-index before treatment. These results suggested that the ΔTei-index is a more sensitive indicator of early cardiotoxicity induced by anthracyclines than LVEF regardless of its value before treatment.

Risk factors of acute pulmonary thromboembolism in Japanese patients hospitalized for medical illness: results of a multicenter registry in the Japanese society of pulmonary embolism research

AbstractBackground: Although the prophylaxis of acute pulmonary thromboembolism (APTE) in hospitalized patients has been improving in Japan, there is no report concerning APTE of Japanese medical patients. Therefore, the present study was designed to investigate the characteristics of APTE in Japanese patients hospitalized for medical illness, through a retrospective study. Methods: In a total of 1,438 registry patients with pulmonary thromboembolism for recent 10 years, 1,027 patients with APTE were analyzed with respect to underlying diseases or predisposing factors, and clinical course. Results: A hundred thirty three patients hospitalized for medical illness developed APTE, among 433 in-hospital APTE patients. The prevalence of APTE in women was more than in men. The mean age of the patients at diagnosis was 61 ± 17 years. Main risk factors were a prolonged immobilization, stroke, cancer, indwelling central venous catheter. Fifty-four patients had 3 or more risk factors. In-hospital mortality rate was 23%. Conclusions: Japanese patients in this registry had almost the same findings as in western patients, except for some points that had the possibility of demonstrating a difference between westerners and Japanese in the development of APTE. Our results will be available for establishing the prevention of APTE in medical patients in Japan.

Evaluation of venous thromboembolism and coagulation-fibrinolysis markers in Japanese patients with inflammatory bowel disease.

BackgroundArterial or venous thromboembolism is rarely encountered clinically as an extradigestive tract complication in inflammatory bowel disease (IBD). However, it is one of the important prognostic factors for IBD patients. The present study was designed to evaluate the relationship between pulmonary embolism (PE) and deep vein thrombosis (DVT) with coagulation-fibrinolysis markers in patients with active IBD.MethodsIn 47 consecutive cases hospitalized due to active IBD [26 with Crohn’s disease (CD) and 21 with ulcerative colitis (UC)], we evaluated the disease severity, blood tests, pulmonary ventilation-perfusion scan (V/Q scan), and magnetic resonance venography (MRV) or conventional venography.ResultsPE was diagnosed by V/Q scan in 5 (2 with CD and 3 with UC; 10.6%). DVT was diagnosed in 5 (2 with CD and 3 with UC; 10.6%). Of the 47 patients, 8 (17.0%) had venous thromboembolism (either PE or DVT), and 2 of them (4.3%) had both conditions. In UC patients, the thrombosis group was in more severe stages based on endoscopic grading than the nonthrombosis group. In all patients, the thrombosis group were older (50.3 ± 14.3 years) than the nonthrombosis group (29.2 ± 11.7 years). Furthermore, the thrombosis group had higher thrombin–antithrombin III complex (13.1 ± 17.7 ng/ml) and d-dimer (964 ± 1402 ng/ml) values than the nonthrombosis group (5.3 ± 5.5 ng/ml, P = 0.0245, and 207 ± 192 ng/ml, P = 0.0016, respectively). There were no significant differences in leukocyte and platelet counts, C-reactive protein, and fibrinogen between the two groups.ConclusionsA high incidence of venous thromboembolism was suggested in Japanese patients with active IBD. We should be careful with thrombosis in treatment of IBD patients, especially those who are of older age and in more severe stages.

Simultaneous assessment of right ventricular function and hypertrophy by Tc-99m MIBI.

PURPOSE Tc-99m MIBI allows the simultaneous performance of cardiac blood pool scintigraphy and myocardial SPECT. The authors performed studies to determine whether right ventricular function and hypertrophy can be evaluated simultaneously using Tc-99m MIBI in patients with right heart disease. METHODS Using right heart catheterization, several parameters of pulmonary circulation were measured, including right ventricular ejection fraction, in 23 patients with chronic pulmonary disease and pulmonary vascular disease. Within 1 week, right heart blood pool scintigraphy was performed using the first-pass method using Tc-99m MIBI. The right ventricular ejection fraction calculated from right heart blood pool scintigraphy was compared with that measured using right heart catheterization. Myocardial SPECT was performed 1 hour after right heart blood pool scintigraphy. On the short axis images, which allowed optimal visualization of the right ventricle, the right and left ventricular free walls were established as regions of interest. Myocardial wall counts were determined. The right ventricular uptake: left ventricular uptake ratio was calculated to study the relation of that ratio to mean pulmonary artery pressure and total pulmonary resistance. RESULTS A significant correlation was observed between the right ventricular ejection fraction calculated on right heart catheterization and that calculated on right heart blood pool scintigraphy. The right ventricular uptake:left ventricular uptake ratio correlated positively with pulmonary artery pressure and total pulmonary resistance. CONCLUSION These results suggest that Tc-99m MIBI allows simultaneous noninvasive evaluation of cardiac function and structure, which previously was considered impossible in patients with right heart disease.

Left Ventricular Mass and Global Function in Essential Hypertension after Antihypertensive Therapy

This study compares left ventricular global function in 55 patients (25 with hypertrophy and 30 without hypertrophy) with essential hypertension, whose blood pressure had been stable for longer than 1 year, with that in 35 healthy subjects. Left ventricular global function was calculated using the echocardiographic Doppler index as described by Tei et al. (Tei index). No significant differences were observed in echocardiographic left ventricular systolic function between the three groups. Left ventricular global function differed significantly between the three groups, however, suggesting impaired left ventricular global function even in the absence of left ventricular hypertrophy. Similar changes were observed in the ratio of peak velocity of atrial systole to peak velocity of early diastole during left ventricular inflow waveform (A/E), indicating that this disorder mainly reflects impaired left ventricular diastolic function. Unlike A/E, the Tei index is not affected by increasing age, and, therefore, is appropriate for evaluating left ventricular global function in hypertensive patients, most of whom are middle-aged or older. This index may be useful for determining treatment strategy and evaluating treatment effects.