Eiichi Geshi

A Single Nucleotide Polymorphism in the Carboxylesterase Gene Is Associated with the Responsiveness to Imidapril Medication and the Promoter Activity

Imidapril is an angiotensin-converting enzyme inhibitor that is widely used in treating hypertension, although the responses vary among individuals. We investigated whether a single nucleotide polymorphism at position −816 of the carboxylesterase 1 (CES1) gene, which activates imidapril in the liver, is involved in the responsiveness to imidapril medication. A total of 105 Japanese hypertensives with systolic/diastolic blood pressures (SBP/DBP) of 140/90 mmHg or higher were prescribed 5–10 mg/day of imidapril. At baseline, blood pressure levels were not different between patients with and those without the −816C allele (AA vs. AC+CC groups). After 8 weeks of treatment, we classified the responders and non-responders based on the decline in their blood pressures, and found that the responder rate was significantly higher in the AC+CC group than in the AA group (p=0.0331). Also, the reduction in SBP was significantly greater in the AC+CC group than in the AA group (24.7±11.8 vs. 17.6±16.8 mmHg, p=0.0184). Furthermore, an in vitro reporter assay revealed that the −816C construct had significantly higher promoter activity (p<0.0001). These findings suggest that the A(−816)C polymorphism affects the transcriptional activity, and that this may account for the responsiveness to imidapril.

Postprandial changes in LDL phenotypes in patients with myocardial infarction

Background  Low‐density lipoprotein (LDL) particle size is strongly affected by both fasting and postprandial triglyceride levels. We report here that the LDL phenotype shifts toward the smaller phenotype during oral fat tolerance tests (OFTTs) in some patients with myocardial infarction (MI); a condition closely associated with postprandial increases of triglyceride and remnant‐like particles (RLPs).

EFFECT OF NON-SELECTIVE ENDOTHELIN BLOCKADE, TAK-044, ON THE ISCHEMIC CELLULAR INJURY OF RAT HEART

Abstract The aim of this study is to evaluate the role of non-selective endothelin blockade (TAK-044) in ischemic myocardial injury. Forty anesthetized rats were separated into four groups: 1) TAK-I group, after preinjection of TAK-044 (3 mg/kg), LAD was ligated for 60 min and reperfused for 60 min; 2) Saline (SAL)-I group, LAD ligation and reperfusion without TAK-044; 3) TAK-C group, sham operated TAK group; 4) SAL-C group, sham-operated SAL group. Myocardium from each group was separated and analyzed by biochemical and ultrastructural procedures. Reperfusion arrhythmia (VT) was observed in 88 % of the SAL-I Group, in contrast to only 36% of the TAK-I group. At the end of reperfusion, hemodynamics indicated no significant differences between these two groups. The Ca++-ATPase activity of sarcoplasmic reticulum (SR) was 3.9µmoles Pi/mg protein/h (39 % of SAL-C group) in the SAL-I group, while that in the TAK-I group was significantly higher at 6.1 (54%). The ratio of infarct/risk area was 58% in the SAL-I group and 36% in the TAK-I group. In the ultrastructural observations, irreversibly injured cells of the ischemic portion were reduced significantly from 35% (SAL-I group) to 14% (TAK-I group). Thus, our results indicated that endothelin blockade reduced ischemic cellular injury. The mechanism of this reduction was speculated to be a restistance to ischemic injury in the subcellular levels of the myocardium conferred by a reduction of vascular constriction and improvement of imbalance in the energy supply and demand.

Inhibitory effect of valsartan against progression of left ventricular dysfunction after myocardial infarction: T-VENTURE study.

BACKGROUND Angiotensin-converting enzyme inhibitors (ACEI) reduce the mortality in the chronic phase of myocardial infarction (MI), and similar effects of angiotensin receptor blockers (ARB) have been reported. However, these effects of ARB have not yet been established in Japanese patients. A multicenter randomized study was designed for the present study to examine the effect of valsartan as compared to that of ACEI against left ventricular dysfunction after MI. METHODS AND RESULTS Patients with acute MI were randomly allocated to either the valsartan group (n=120; mean age 63 +/-1.0) or the ACEI group (n=121; mean age 62.9 +/-1.0) and followed up until 6 months. Left ventriculography was performed during hospital admission and at 6 months. The blood pressure was similar in the 2 groups throughout the study. The incidences of cardiovascular events and target vessel revascularization were similar, although that of adverse events was significantly higher in the ACEI (12.4%) than in the valsartan group (3.3%; P<0.05). There were no differences in left ventricular ejection fraction and left ventricular end-diastolic volume index between the groups. CONCLUSIONS Valsartan exhibits similar efficacy effective to that of ACEI in preventing left ventricular dysfunction in Japanese patients with acute MI, and is, in addition, better tolerated than ACEI.

Impact of depression on masked hypertension and variability in home blood pressure in treated hypertensive patients.

This study was conducted to determine the effects of depression and/or insomnia on masked hypertension (MHT) compared with other types of HT and on variability in home-measured blood pressure (HBP) and clinic BP (CBP). Three hundred and twenty-eight hypertensives (132 women) aged 68±10 years were classified into four BP types: controlled HT (CHT), white-coat HT, MHT and sustained HT (SHT), based on CBP (140/90 mm Hg) and morning HBP (135/85 mm Hg) measurements. A score of ⩾16 on the Center for Epidemiologic Studies Depression Scale (CES-D) was defined as depression. The mean values and s.d. of BP were calculated from measurements taken during the 14 consecutive days just before the CES-D evaluation. Compared with the CHT group, the risk of depression was 2.77-fold higher in the SHT group and even higher in the MHT group (7.02-fold). The association between depression and MHT was augmented in the presence of insomnia and was somewhat stronger in women. A HBP variability index defined as s.d./mean BPs in both morning and night time was significantly higher in MHT than in the other BP types, whereas that of CBP was not. Both morning and night-time HBP variability were significantly higher in depressive patients than in non-depressives. These suggest that depression is associated with MHT and that increases both morning and night-time HBP variability but not CBP variability. Physicians should be mindful of mental stresses such as depression in their hypertensive patients when forming strategies to control BP over the diurnal cycle.

The role of ATP-sensitive potassium channels in the mechanism of ischemic preconditioning.

We clarified the role of K(ATP) channels in the mechanism of ischemic preconditioning by using K(ATP) channel opener, nicorandil, and K(ATP) channel inhibitor, glibenclamide. Forty anesthetized dogs were divided into five groups: (a) control (C), (b) ischemic preconditioning (PC), (c) intravenous infusion of nicorandil before PC (Ni), (d) glibenclamide pretreated with PC (Gl + PC), and (e) glibenclamide pretreated with Ni (Gl + Ni). All groups were followed by 60-min ischemia and 60-min reperfusion and analyzed by the biochemical procedures. At the end of 60-min reperfusion, percentage of segment shortening in C indicated paradoxic bulging. This value was significantly recovered in PC and Ni, but it was still negative in Gl + PC and Gl + Ni. Ca2+ -adenosine triphosphatase (ATPase) activity of sarcoplasmic reticulum (SR) was significantly decreased in C. In PC and Ni, this activity was significantly maintained; however, in Gl + PC and Gl + Ni, it was similar to that in C. State III respiration of mitochondria showed similarity to the changes in SR. These results indicated that the K(ATP) channel opener enhanced the effects of ischemic preconditioning, and its blockade abolished these phenomena. We conclude that the ATP-sensitive potassium channel may play one of key roles in the mechanisms of ischemic preconditioning in the dog model.

Neutrophil and erythroblast regulate the effects of bone marrow cell implantation

Sir, Efficacy of autologous bone-marrow cell implantation as therapeutic angiogenesis has been reported in patients with severe peripheral artery disease [1]. In addition to containing CD34-positive cells, the main drivers of vasculogenesis and probably the main contributors to this therapy, sorted bone marrow-mononuclear cells (BM-MNC), also contain an abundance of CD34-negative cells. No studies have yet elucidated which types of CD34-negative cells influence the clinical appearance in BM-MNC implantation. We investigated the correlations of morphologically classified cell types of sorted BM-MNCs with changes in the ankle brachial index (ABI) and transcutaneous oxygen pressure (TcO 2 ) as clinical parameters.

Ultrastructural and biochemical studies of ischemic preconditioning using an adenosine receptor blocker and an ATP-sensitive K channel opener

The effect of preconditioning (PC) on acute ischemic myocardial injury was investigated in an openchest dog model. Preconditioned dogs received four 5-min occlusions of the left anterior descending coronary artery (LAD), each separated by 10 min of reperfusion. Four groups were used to assess the effect: non-PC group (G-1), PC group (G-2), 8-phenyltheophylline-(adenosine receptor blocker) infused PC group (G-3), and nicorandil- (ATP-sensitive K-channel opener) infused PC group (G-4). The LAD was occluded for 60 min, followed by 60 min of reperfusion in all dogs. The rate of ultrastructural myocardial severe injury was 26% in G-1, 0% in G-2, 5% in G-3, and 0% in G-4. Biochemical analayses also indicated higher values of myocardial contractile function in G-2 and G-4 than G-1 and G-3. These data suggest that the adenosine receptor and K channel may play a key role in PC.

Biochemical and Morphologic Alterations in Cardiac Myocytes in Streptozotocin-Induced Diabetic Rats

Complication of congestive heart failure in patients with diabetes mellitus has well been known in clinical practice. Impairment of cardiac function was recognized in the absence of arteriosclerotic changes in diabetics, and the concept of “diabetic cardiomyopathy” has been proposed as the diabetes specific myocardial disorder (1,2). In the clinical practice, diabetes mellitus occurs in the mature to elder age and complication of coronary arterio- or athero-sclerosis is usual. Therefore, influence of ischemia could not be excluded in clinical cases. To elucidate effect of hyperglycemic state on cardiac myocytes without vascular changes, experimental diabetes was induced in relatively young rats by single intravenous injection of streptozotocin (STZ), and the effects of abrupt and long-standing severe hyperglycemia on the cardiac micro organs such as the sarcoplasmic reticulum (SR) and the structural proteins were investigated in comparison with the fine structures of cardiac myocytes.

Significance of Small Dense Low-Density Lipoproteins in Coronary Heart Disease

Low-density lipoprotein (LDL) particles are heterogeneous with respect to their size, density, and lipid composition, and the size of LDL particles is chiefly determined by their lipid contents. Small dense LDL particles have been suggested to be highly atherogenic compared to large buoyant LDL. Our case-control studies have shown that the LDL particle size determined by gradient gel electrophoresis was remarkably smaller in patients with coronary heart disease (CHD), irrespective of the presence of diabetes and the differences in clinical situation and severity of CHD. In addition, small dense LDL-cholesterol concentration evaluated by heparin magnesium precipitation was significantly higher in severe stable CHD and acute coronary syndrome compared with non-CHD subjects and patients with mild CHD, while large LDL-cholesterol estimated by subtracting the small dense LDL-cholesterol concentration from the LDLcholesterol concentration, were somewhat lower in stable CHD compared with healthy subjects. Furthermore, reduced LDL particle size and elevated small dense LDL-cholesterol levels were significantly associated with metabolic dyslipidemia in Metabolic syndrome. These suggest that the predominance of small dense LDL and high levels of small dense LDLcholesterol are very promising risk marker for CHD.