Antioxidant effect of a new calcium antagonist, azelnidipine, in cultured human arterial endothelial cells.

Azelnidipine is a novel dihydropyridine-type calcium antagonist with long-acting anti-hypertensive action and a low reported incidence of tachycardia. We aimed to evaluate its antioxidant activity in cultured human arterial endothelial cells under oxidative stress. Endothelial cells were exposed to 1 mM H2O2 and treated with 100 microM alpha-tocopherol, 1 nM, 10 nM or 100 nM azelnidipine, 100 nM nifedipine or 100 nM amlodipine. After 3 h, the cell number and level of lipid peroxidation were evaluated by measuring the total protein and 8-iso-PGF2 alpha concentrations, respectively. The total protein concentration was similar with each treatment. Inhibition of 8-iso-PGF2 alpha was greatest with 10 nM azelnidipine (compared with the other drugs); the difference between 10 nM and 100 nM azelnidipine was not significant. We conclude that azelnidipine has a potent antioxidative effect that could be of significant clinical benefit when combined with its long-lasting anti-hypertensive action and low incidence of tachycardia.

Long-term evaluation of nutritional status using dual-energy X-ray absorptiometry in chronic hemodialysis patients.

BACKGROUND: Hemodialysis patients very often suffer from malnutrition with net loss of body muscle and fat stores. Since protein-calorie malnutrition has been considered to be highly associated with increased morbidity and mortality, it is important that the nutritional status is evaluated accurately and that long-term evaluation of the nutritional status is performed to obtain good outcome. PATIENTS AND METHODS: Forty-six patients (28 men and 18 women) undergoing maintenance hemodialysis were studied. Nutritional status of the patients was examined by dual-energy X-ray absorptiometry (DXA) and anthropometry measurements after a hemodialysis session and 4 years after the initial measurement. RESULTS: Percent fat, the ratio of body fat (BF) to weight, determined by DXA correlated positively with body mass index (BMI) calculated from weight and height. There was also a significant positive correlation between lean body mass (LBM) determined by DXA and arm muscle circumference (AMC) calculated using the anthropometric method. In the study period of 4 years, LBM and bone mineral content (BMC) observed at the end point were significantly lower than those at the start. In contrast, BF and %fat at the end point were significantly higher as compared with those at the initial measurement. CONCLUSION: These results indicate that DXA is a reliable method for body composition analysis in chronic hemodialysis patients. Because the detection of early alterations in body composition may provide an early indication of the development of malnutrition, serial evaluation of body composition using DXA should be valid for assessment of the nutritional status.

Fulminant myocarditis in polymyositis.

Cardiac involvement in patients with polymyositis is usually asymptomatic and associated with a mild clinical course. A female patient with muscle weakness and cardiogenic shock, who was diagnosed with polymyositis and fulminant myocarditis, is described. A large amount of methylprednisolone, in addition to intra-aortic balloon pumping and percutaneous cardiopulmonary support, led to the recovery of her cardiac function. However, a massive cerebral embolism occurred and she died. Postmortem histopathological examination showed necroses of muscles and diffuse invasion of mononuclear cells in both the myocardium and the biceps muscle of her arm. Although the mechanism of cardiac dysfunction is not clear, immunosuppressive therapy was effective for fulminant myocarditis in the present case.

Pioglitazone improves left ventricular diastolic function and decreases collagen accumulation in prediabetic stage of a type II diabetic rat.

This study investigated the effect of pioglitazone, an insulin sensitizer, on metabolic abnormalities and oxidative stress as a cause of myocardial collagen accumulation in prediabetic rat hearts. Twenty male diabetic rats and 9 male nondiabetic age-matched rats were used. The diabetic rats were divided into two groups: diabetic treated and untreated. Pioglitazone was mixed in rat chow fed to the diabetic treated group (0.01%). Treatment duration was 5 weeks. At baseline (15 weeks) and 20 weeks of age, blood glucose, lipid, insulin, and plasma malondialdehyde-thiobarbituric acid (MDA) levels were measured and Doppler echocardiography was tracked. At 20 weeks of age, left ventricular collagen content was studied. Blood glucose, plasma insulin, and triglyceride levels in the diabetic treated group were significantly lower than those in the untreated diabetic group. Deceleration time (ms) of early diastolic inflow in the treated diabetic group decreased significantly compared with the untreated diabetic group (65 +/- 8 vs. 77 +/- 8, p < 0.01). Ratio of left ventricular weight to body weight (mg/g) and ratio of left ventricular collagen content to dry weight (mg/100 mg) were decreased in the treated diabetic group (1.5 +/- 0.1, 1.3 +/- 0.3) compared with the untreated diabetic group (1.7 +/- 0.2, p < 0.01; 1.7 +/- 0.3, p < 0.05). Plasma MDA concentration (nmol/ml) significantly decreased (2.9 +/- 0.3 at baseline to 2.3 +/- 0.3 at 20 weeks, p = 0.001) in the treated diabetic group, and was lower than that in the untreated diabetic group (3.2 +/- 0.7 at 20 weeks, p < 0.05). Pioglitazone improved glucose and lipid metabolism and reduced oxidative stress in the left ventricle, which decreased left ventricular collagen accumulation and improved left ventricular diastolic function of prediabetic rat hearts.

Ultrasonographic assessment of coronary flow reserve and abdominal fat in obesity.

Recent technological advances in transthoracic Doppler echocardiography (TTDE) have provided noninvasive measurement of coronary flow velocity reserve (CFVR). We aimed to quantitate a correlation between endothelial dysfunction and fat distribution. In 36 patients with obesity, 16 with noninsulin-dependent diabetes mellitus (DM) and 12 healthy volunteers, coronary flow velocity was measured at the distal site of the left anterior descending branch. CFVR was defined as the ratio of hyperemic (IV infusion of 0.15 mg/kg/min adenosine) to basal peak diastolic flow velocity. Abdominal wall fat index (AWFI) was estimated by ultrasonography. Insulin resistance was quantified by the euglycemic hyperinsulinemic clump method. AWFI was significantly related to CFVR (r = -0.46, p = 0.011) and insulin resistance (r = -0.71, p < 0.0001). CFVR could be noninvasively evaluated using TTDE. Coronary endothelial dysfunction indicated as CFVR, body fat distribution and insulin resistance was quantitatively correlated in obesity.

Recurrence of idiopathic thromboembolism during anticoagulant therapy.

Patients with acute pulmonary embolism and venous thromboembolism are usually treated with anticoagulant therapy for at least 3 months as the optimum duration. A patient with recurrent idiopathic venous thromboembolism at the eighth month during anticoagulation (warfarin to target international normalized ratio of 2.0-3.0) is described. The case suggests that patients with idiopathic venous thromboembolism have a high risk of recurrence, even if a strict anticoagulant regimen is followed.

Second primary cardiac B-cell lymphoma after radiation therapy and chemotherapy--a case report.

A 76-year-old man was found to have esophageal squamous cell carcinoma and had been treated with radiational therapy and chemotherapy. Five years later, he was readmitted with dyspnea and marked edema of his extremities and face. An echocardiographic examination revealed a mass lesion in the pericardium with pericardial effusion behind the left ventricular posterior wall, which was near the site of the original esophageal cancer. Coronary arteriography revealed a feeder artery to the mass from the left circumflex branch. No findings indicated a recurrence of the esophageal cancer; cytologic studies showed malignant lymphoma cells of B-cell origin. A second primary cancer of some organs including blood cells might be induced by the carcinogenic effects of ionizing radiation or chemotherapeutic agents. This is the first case of second primary cardiac B-cell lymphoma after combination therapy.

Ultrasonic tissue characterization can predict beta-blocker efficacy in dilated cardiomyopathy.

The aim was to determine if the combination of cyclic variation of myocardial integrated backscatter (variation IB) and left ventricular mass measurements can predict the efficacy of beta-blocker treatment in dilated cardiomyopathy. In 32 patients, left ventricular mass and variation IB were measured at baseline and during 6 microg/kg/min dobutamine infusion before the initiation of beta-blocker therapy. Variation IB was measured at left and right ventricular halves in the ventricular septum. The baseline left ventricular mass index and transseptal variation IB gradient during dobutamine were significantly greater in the effective group (1.16 +/- 0.18 g/mL and 1.8 +/- 0.6 dB) than in the ineffective group (0.94 +/- 0.28 g/mL, p = 0.032 and 0.4 +/- 0.6 dB, p < 0.005). When both baseline left ventricular mass index > or = 1.05 g/mL and transseptal variation IB gradient during dobutamine > or = 1.5 dB were defined as predictive criteria for the effective group, the sensitivity was 78% and the specificity was 86%. Analysis of transseptal variation IB during dobutamine may provide useful information predicting the efficacy of beta-blocker therapy in dilated cardiomyopathy.

Hypotension and functional left ventricular obstruction during dobutamine stress echocardiography--two case reports.

Although hypotension during dobutamine stress echocardiography has been reported, the mechanism of this response is still controversial. In two patients, a 72-year-old woman and 64-year-old man, with exercise-induced ST-T change, continuous-wave Doppler examination of the left ventricular cavity was performed at baseline and peak dobutamine infusion. No echocardiographic abnormalities at rest or angiographic coronary lesions were observed in either patient. The intracavitary pressure gradient at peak dosage of dobutamine for both patients was 121 mm Hg and 100 mm Hg, and was reproducibly confirmed by cardiac catheterization. During dobutamine infusion, echocardiography or left ventriculography revealed that papillary muscle motion was dramatically augmented by dobutamine and mid-left ventricular obstruction was produced at the systolic phase. Although blood pressure response improved following beta-blocker treatment, intracavitary pressure gradient during dobutamine infusion remained the same. A hypotensive response during dobutamine stress echocardiography may be produced by the development of dynamic intraventricular obstruction and a vasodepression reflex. The exercise-induced electrocardiographic changes may have been related to the systolic pressure augmentation in the mid-to-apical left ventricular cavity.

Angiotensin-converting enzyme inhibition with enalapril slows progressive intima-media thickening of the common carotid artery in patients with non-insulin-dependent diabetes mellitus.

BACKGROUND AND PURPOSE: Whether angiotensin-converting enzyme (ACE) inhibitors have any clinically significant antiatherogenic effects in humans remains unproven. We undertook a prospective randomized clinical trial of 98 patients with non-insulin-dependent diabetes mellitus (NIDDM) to examine the efficacy of ACE inhibition with enalapril for preventing intima-media (IM) thickening of the carotid wall as measured ultrasonographically. METHODS: Ninety-eight NIDDM patients were randomly assigned either to enalapril at 10 mg/d (n=48) or to a control group (n=50); the planned duration of the trial was 2 years. All patients were seen at baseline (study entry) and 2 subsequent formal annual evaluations, in addition to standard clinical management for NIDDM. IM thickening and vascular lumen diameters were determined for all patients on the basis of baseline and 2 subsequent annual evaluations with carotid ultrasonography. We performed an intent-to-treat analysis to assess changes in IM thickening over the course of the study. RESULTS: Annual IM thickening measurements of the right and left common carotid arteries were 0.01+/-0.02 and 0.01+/-0.02 mm/y in the enalapril-treated group and 0.02+/-0.03 and 0.02+/-0.02 mm/y in the control group, respectively (P<0.05). From regression analysis, annual IM thickening was found to be predicted by enalapril use, sex, and insulin use (F(3,94)=3.86, P=0.012). When we controlled for these other variables, enalapril use reduced annual IM thickening of right and left common carotid arteries by 0.01+/-0.004 mm/y relative to the control group over the course of this study. CONCLUSIONS: Long-term treatment with an ACE inhibitor (enalapril) slows progressive IM thickening of the common carotid artery in NIDDM patients.

Inhibition by eicosapentaenoic acid of oxidized-LDL- and lysophosphatidylcholine-induced human coronary artery smooth muscle cell production of endothelin.

The objectives of the present study were (1) to determine whether oxidized low-density lipoprotein (LDL) and lysophosphatidylcholine (lyso-PC), a major phospholipid component of oxidized LDL, stimulate the production of endothelin-1 (ET)-1 in cultured human coronary artery smooth muscle cells (SMCs), and (2) to examine the possible effect of an antiatherogenic agent, eicosapentaenoic acid (EPA), on oxidized-LDL- and lyso-PC-stimulated ET-1 production in these cells. Oxidized LDL (10-50 microg/ml) and lyso-PC (10(-7) to 10(-5) mol/l) stimulated ET-1 production in a concentration-dependent manner. By contrast, the effects of native LDL and phosphatidylcholine were modest or absent. Lyso-PC (10(-7) to 10(-5) mol/l) and oxidized LDL (10-50 microg/ml) significantly induced particulate protein kinase C (PKC) activation. Lyso-PC- and oxidized-LDL-stimulated ET-1 production was significantly inhibited by PKC inhibitor, PKC (19-36). EPA (80-160 micromol/l) clearly suppressed ET-1 production stimulated by oxidized LDL and lyso-PC in a concentration-dependent manner. Furthermore, EPA (160 micromol/l) significantly inhibited lyso-PC (10(-5) mol/l)- and oxidized LDL (50 microg/ml)-induced particulate PKC activation. Results suggest that oxidized LDL and lyso-PC stimulate ET-1 production by a mechanism involving activation of PKC, and that EPA suppresses ET-1 production stimulated by lyso-PC as well as oxidized LDL probably through the modulation of PKC in human coronary artery SMCs. EPA may exert an antiatherosclerotic effect, in part, through these mechanisms.

Contrast harmonic power Doppler imaging of congenital ventricular diverticulum--a case report.

A case of an 81-year-old woman with a left ventricular diverticulum who underwent myocardial contrast echocardiography is reported. After administration of the contrast agent, a pulsed Doppler flow measurement clearly revealed the biphasic waveform of the ejection flow in the pre-systolic and systolic phase at the ostium of the diverticular cavity. A harmonic power Doppler image showed that part of the diverticulum wall had similar acoustic properties to the ventricular septal wall. Intracardiac blood flow and myocardial perfusion could be clearly evaluated and a ventricular diverticulum was correctly diagnosed using contrast echocardiography.

Thrombin inhibition attenuates neurodegeneration and cerebral edema formation following transient forebrain ischemia.

The disturbance of microcirculation following cerebral ischemia leads to an enlargement of cerebral infarct volume. Endogenous thrombin may play a role in this disturbance of microcirculation following cerebral ischemia. Therefore, the inhibition of thrombin may improve neurodegeneration and the accumulation of cerebral edema following cerebral ischemia in gerbils. The effects of thrombin inhibitor (argatroban) on cerebral ischemia were investigated in comparison with thromboxane A2 synthase inhibitor (ozagrel) and cyclooxygenase inhibitor (aspirin) following bilateral common carotid artery occlusion and reperfusion (CCA:O/R) in male Mongolian gerbils. This study consisted of three experiments: (1) morbidity and survival ratio (n=40 for each), (2) histopathology (n=12 for each), and (3) mean arterial blood pressure, local cerebral blood flow (CBF), and cerebral specific gravity (n=8 for each). Argatroban treatment improved survival ratio and stroke index, and decreased ischemically injured cell numbers in cortex and hippocampus and cerebral edema in cortex compared with aspirin and saline, in concert with the fast recovery of local CBF without reactive hyperemia following bilateral CCA:O/R. Ozagrel treatment also improved those factors compared with saline, in concert with the fast recovery of local CBF with reactive hyperemia. Aspirin treatment improved survival ratio and stroke index, and decreased ischemically injured cell numbers in cortex. Thrombin inhibition with argatroban decreases neurodegeneration and cerebral edema following bilateral CCA:O/R in gerbils.

Assessment of myocardial postreperfusion viability by intravenous myocardial contrast echocardiography: analysis of the intensity and texture of opacification.

BACKGROUND: Although defects on intracoronary myocardial contrast echocardiography (MCE) indicate loss of viability after reperfusion, opacified segments may also exhibit persistent dyssynergy. Therefore, we related the intensity and texture of opacification produced by an intravenous contrast agent to histological findings to determine the characteristics of necrotic tissue by postreperfusion MCE. METHODS AND RESULTS: MCE was performed by intravenous injection of 0.15 mL/kg QW7437 in 14 dogs who underwent 3-hour coronary occlusion followed by 3-hour reperfusion. At baseline and 3 hours after reperfusion, midventricular short-axis images were digitized and segmented. Infarction fraction (IF) for each segment was determined by triphenyltetrazolium chloride stain. Of 224 segments, 140 showed no or small infarction and served as a control group. Of 84 segments with significant infarction (IF>30%), 52 exhibited a defect on MCE, and 32 exhibited no defect. Echo texture was quantified by computing entropy based on the co-occurrence matrix analysis of gray-level pairs within each segment. Three hours after reperfusion, average and maximal entropies in the infarct segments without opacification defects were significantly higher than control levels. Histologically, the degree of intracapillary erythrocyte stasis was less in this group than in the infarcted segments with MCE defects with similar magnitude of tissue injuries. CONCLUSIONS: Opacification defects by MCE may be present or absent in myocardium with histologically confirmed infarction. The texture of MCE from opacified but infarcted myocardium differed significantly from control segments and may assist in determination of segmental viability after reperfusion.

Effects of olprinone, a phosphodiesterase 3 inhibitor, on regional cerebral blood flow of cerebral cortex in stroke patients.

The effects of olprinone (0.2 microg/kg per minute, i.v.) on cerebral blood flow were examined using technetium-99m-ethyl cysteinate dimer (99mTc-ECD) brain single-photon emission computed tomography in 14 stroke patients (69.0 +/- 5.6 years) and 12 normal subjects (68.1 +/- 6.2 years). The regional cerebral blood flow of the cerebral cortex was measured at six sites for each stroke patient (stroke group: n = 68, excluding 16 infarct areas confirmed on computed tomography image) and for each normal subject (normal group: n = 72). 99mTc-ECD brain single-photon emission computed tomography was repeated as the baseline 7 days after olprinone treatment study. The percent increment of the rCBF was 14.4 +/- 9.8% in the normal group and 10.7 +/- 11.7% in the stroke group (p = 0.002). The baseline value of the regional cerebral blood flow had a significant negative correlation with the increase of the regional cerebral blood flow in the normal group (r = -0.73, p < 0.0001) and in the stroke group (r = -0.43, p < 0.001). Although olprinone could dilate the cerebral vessels of stroke patients as well as those of normal subjects, smooth muscle dysfunction of the cerebral vessels due to advanced arteriosclerosis may reduce this effect.

Prevention of cerebral thromboembolism by low-dose anticoagulant therapy in atrial fibrillation with mitral regurgitation.

Controversy exists regarding the influence of mitral regurgitation (MR) on thromboembolic risk in patients with atrial fibrillation. We aimed to investigate retrospectively a reduction of risk for stroke due to MR in atrial fibrillation and to evaluate the effectiveness of low-intensity anticoagulation therapy. In 313 patients with atrial fibrillation, transthoracic echocardiography was performed and MR was graded. Between the groups with no or mild MR (n = 209) and with moderate or severe MR (n = 104), age, sex, treatment, history of diabetes, hypertension, hyperlipemia and mitral stenosis, and previous stroke were compared. No significant differences in clinical characteristics, treatment, or history were observed between the two groups. The incidence of thromboembolism was significantly higher in the group with no MR (48 patients [23%]) than in the group with MR (14 patients [13%], p < 0.05). In the MR group, previous stroke was frequently observed in patients without warfarin treatment (11 of 51 patients) compared with patients with low-dose warfarin treatment (international normalized ratio of 1.6-1.8) (3 of 53 patients, p < 0.05). Consequently, the thromboembolic event was markedly prevented by low-dose warfarin treatment.

Characterization of contraction and perfusion in the lateral border zone between normal and ischemic myocardium following coronary occlusion by myocardial contrast echocardiography.

We performed myocardial contrast echocardography with power Doppler imaging during left anterior descending occlusion in 10 dogs, and found that video intensity and dyssynergy in lateral border zones of ischemic myocardium were present, but the video intensity was significantly lower than adjacent nonischemic zones. The results of this study demonstrate that levels of perfusion and contraction, which are intermediate between normal and central ischemic zones, are observed in the border zone with coronary occlusion by myocardial contrast echocardography, and may have implications in identifying myocardium that will be spared necrosis and in measuring ultimate infarct size.