Epalrestat improves diabetic wound healing via increased expression of nerve growth factor.

AIMS/INTRODUCTION: Aldose reductase inhibitors (ARIs) are a useful therapy for diabetic neuropathy. Nerve damage is associated with delayed wound healing of skin ulcers in diabetic patients. Therefore, we hypothesized that ARI supplementation would improve diabetic wound healing. MATERIALS AND METHODS: Control and streptozotocin-induced diabetic mice were fed either control diet or diet containing the ARI Epalrestat (40 mg/kg). After 12 weeks, we created skin wounds on the backs of the mice. Wound healing was determined by measuring the reduction in wound area. RESULTS: The wound gap of the diabetic group was significantly larger 9 days after creating the wounds when compared to the other groups (p<0.01). Interestingly, wound healing in the diabetic mice fed Epalrestat was comparable to the non-diabetic mice. To clarify the mechanism(s) behind this improved wound healing, mRNA expression of growth factors reported to be involved in wound healing were examined. Among the growth factors investigated, only the expression of nerve growth factor (NGF) was -significantly decreased (54.0%) in the healing lesions of diabetic mice. Similarly, NGF protein expression was decreased in diabetic mice and recovered in Epalrestat treated diabetic mice. Inhibition of NGF via 2 separate inhibitors (K252a and BSO) reduced the ability of Epalrestat to improve wound healing in diabetic mice. CONCLUSIONS: These findings suggest that Epalrestat is a potential therapy for improving diabetic wound healing and the mechanism involves upregulation of NGF.

Obesity, body fat distribution and coronary atherosclerosis among Japanese men and women.

OBJECTIVE: To investigate the relation of the obesity and body-fat distribution with angiographically defined coronary atherosclerosis. DESIGN: Cross-sectional study in a clinical setting. SUBJECTS: Three hundred and twenty men (median age, 59 y) and 212 women (median age, 67 y) who underwent coronary angiography for suspected or known coronary heart disease at 5 cardiology departments between September 1996 and August 1997. Patients with disease duration >1 y were excluded. MEASUREMENTS: The body mass index (BMI) and the waist to hip circumference ratio (WHR) were used as main exposure variables, and either the presence of significant coronary stenosis or the Gensini's score (> or =10 vs<10) as an outcome variable, in a sex-specific multiple logistic regression analysis controlling for age, hospital, and other coronary risk factors. RESULTS: Among male patients, BMI was progressively higher with an increasing number of vessels involved (P trend=0.05); the adjusted odds ratios for the presence of significant stenosis across quartiles of BMI were 1.0 (reference), 1.1, 1.9 and 2.5 (P trend=0.02), and the positive association was more pronounced for younger patients. Among females, however, such associations were not evident. Employing the Gensini's score as an outcome gave similar results. WHR was not significantly associated with either outcome regardless of sex. CONCLUSION: These results suggested that BMI was predictive of coronary stenosis among male patients, but not among female patients. Unlike most previous studies, this study failed to detect a positive association with WHR.

Alcohol consumption and severity of angiographically determined coronary artery disease in Japanese men and women.

The relation of alcohol consumption to the severity of coronary atherosclerosis was examined among 323 men and 220 women who underwent coronary arteriography. Severity of coronary atherosclerosis was assessed by the number of vessels obstructed > or =75% in diameter and Gensini's severity score. Alcohol consumption was divided into 5 categories in men (never, past, 1-24, 25-49, and > or =50 ml per day) and 3 categories in women (never, past, and current). Among men, odds ratios of severe stenosis (multiple-vessel disease or Gensini's score >15) decreased substantially and significantly in all current drinking categories but without dose-response effect. There was a weak, inverse association of current alcohol consumption with one-vessel disease, but not with moderate stenosis in terms of Gensini's score (< or =15). Past drinkers showed a fairly large, but statistically nonsignificant, decrease in the odds ratios of not only severe stenosis but also of moderate stenosis. Among women, current drinkers showed a small, statistically nonsignificant decrease in the risk of severe stenosis in terms of Gensini's score. These associations with alcohol use did not change after adjustment for known coronary risk factors. The present findings add to evidence that alcohol drinking confers protection against coronary atherosclerosis.

Job strain, Type A behavior pattern, and the prevalence of coronary atherosclerosis in Japanese working men.

OBJECTIVE: To examine the relation of type A behavior pattern and job strain to angiographically documented coronary stenosis. METHODS: Subjects were 197 male Japanese patients with a full-time job. A questionnaire-based interview elicited psychosocial and other factors. Type A behavior pattern was measured by 12 questions, and job strain by the method of Karasek. Significant coronary stenosis was defined when a 75% or greater luminal narrowing occurred at one or more major coronary arteries or when a 50% or greater narrowing occurred at the left main artery. Logistic regression analysis was used to calculate odds ratio (OR) and 95% confidence interval (CI) with adjustment for traditional coronary risk factors and job type. RESULTS: Type A behavior pattern was related to a statistically non-significant lower prevalence of the coronary stenosis especially in the absence of job strain (adjusted OR 0.6, 95% CI 0.3-1.2). Job strain was non-significantly associated with a modestly increased prevalence of coronary stenosis (OR 1.7, 95% CI 0.6-5.2). CONCLUSION: These findings suggest that both the behavioral pattern and psychosocial work environment may be related to coronary artery stenosis.

Relation between green tea consumption and the severity of coronary atherosclerosis among Japanese men and women.

PURPOSE: To examine the relation between green tea consumption and arteriographically determined coronary atherosclerosis. METHODS: Study subjects were 512 patients (302 men and 210 women) aged 30 years or older who underwent coronary arteriography for the first time at four hospitals in Fukuoka City or one hospital in an adjacent city between September 1996 and August 1997. Lifestyle characteristics including green tea consumption were ascertained before arteriography by a questionnaire supported with interview. RESULTS: 117 men (38.7%) and 50 women (23.8%) had significant stenosis of one or more coronary arteries. Green tea consumption tended to be inversely associated with coronary atherosclerosis in men, but not in women. An evident, protective association between green tea and coronary atherosclerosis was observed in a subgroup of 262 men excluding those under dietary or drug treatment for diabetes mellitus. In this subgroup, after adjustment for traditional coronary risk factors and coffee, odds ratios of significant stenosis for consumption of 2-3 cups and 4 or more cups per day were 0.5 (95% confidence interval 0.2-1.2) and 0.4 (0.2-0.9), respectively, as compared with a consumption of one cup per day or less. CONCLUSIONS: The results indicate that green tea may be protective against coronary atherosclerosis at least in men.

High incidence of silent myocardial ischemia in elderly patients with non insulin-dependent diabetes mellitus.

The present study was designed to reveal the incidence of silent myocardial ischemia in asymptomatic elderly non-insulin-dependent diabetic (NIDDM) patients (aged over 60 years). As a first step screening, maximal treadmill exercise test was performed. Of 140 patients studied, 54 (38.6%) were unable or not expected to achieve diagnostic levels of exercise during treadmill testing. A positive exercise test was noted in 39 of 86 (45.3%) subjects. As a second step examination, dipyridamole thallium scintigraphy was performed for 93 subjects who exhibited a positive exercise test and could not perform a maximal exercise test. Abnormal perfusion pattern was found in 39 of 93 (41.9%), who were finally considered to have a silent myocardial ischemia. Coronary angiography was performed in 18 subjects with diagnosis of silent myocardial ischemia, who gave their consent. Significant coronary artery stenosis was in fact found in 17 of 18 (94.4%) subjects studied, confirming a very high positive predictive value of this diagnostic procedure. In conclusion, elderly NIDDM patients (aged over 60 years) had an extremely high prevalence (estimated 26.3%) of silent myocardial ischemia. This evidence suggests that early and intensive detection may be needed as a part of routine care for this group.

QT dispersion in acute myocardial infarction with special reference to left ventriculographic findings.

QT and QT dispersion, which is the time difference between QT maximum and QT minimum, were evaluated in 22 patients with anterior myocardial infarction approximately one month after onset. The purpose of this study was to observe how LV wall motion abnormally is related to these variables. Twenty age-matched patients without overt heart disease were also studied as a control group. QT and QT max in patients with acute myocardial infarction (AMI) were markedly prolonged compared to those in normal controls (472.8 +/- 48.0, 483.2 +/- 32.1 vs 390.2 +/- 18.8, and 418.0 +/- 21.0 msec, respectively). QT dispersion and QTc dispersion in patients with AMI were significantly more prolonged than in normal controls (111.2 +/- 33.9, (113.4 +/- 32.9 vs 54.3 +/- 15.0, and 60.3 +/- 17.2 msec, respectively). QT dispersion has a positive correlation with QT max in AMI patients. Ejection fraction (EF) of the left ventricle was relatively well maintained in cases where only one segment of the left anterior ventricular wall was impaired in its motion. It decreased, however, in accordance with the extent of wall motion abnormality QT max and QTc max were prolonged as the number of LV wall segments with impairment increased. This, however, was not statistically significant. QT dispersion and QTc dispersion had no relation to the extent of LV wall motion abnormality nor to EF of the left ventricle In conclusion, no definite relationships between QT dispersion (QTc dispersion) and EF of the left ventricle, or between these variables and the extent of left ventricular wall motion abnormality were found in patients with anterior myocardial infarction in our study. Although both QT max and QT dispersion were prolonged in patients with myocardial infarction, this suggests that electrical heterogeneity or regional variation in electrical ventricular recovery did not always parallel the severity of mechanical abnormality of the left ventricle.

Exercise-induced silent myocardial ischemia in patients with vasospastic angina.

UNLABELLED: To clarify the incidence and clinical characteristics of exercise-induced myocardial ischemia in patients with vasospastic angina, we performed exercise thallium computed tomography in 25 patients who had no significant coronary artery stenosis greater than 70%. Coronary artery spasm was documented by coronary angiography in all patients. Eleven patients (44%) developed exercise-induced perfusion defects, but only four of them had anginal pain (36%). Diltiazem (90 mg, administered orally) prevented the development of exercise-induced perfusion defects in all patients. Multivessel coronary spasm was documented by coronary angiography in 11 patients, and nine of them (82%) showed exercise-induced perfusion defects (p less than 0.05). CONCLUSION: (1) Exercise-induced myocardial ischemia was demonstrated in 44% of patients who had vasospastic angina without fixed coronary stenosis, and 64% of them were asymptomatic. (2) Patients with multivessel spasm had a greater prevalence of exercise-induced myocardial ischemia than those with single-vessel spasm.

A case of cross stimulation.

Cross stimulation in a dual chamber pacing system, in which the atrial stimulus intermittently captured the right ventricle, occurred immediately after pacemaker implantation in a 71-year-old man. It was prevented temporarily by reducing the pacing rate so that P wave synchronous ventricular (VDD) pacing resulted and by reducing the output of the atrial circuit from 5 to 4 volts. Cross stimulation disappeared spontaneously 14 days after surgery.

Reflex heart rate and blood pressure changes during ST segment elevation in patients with variant angina.

Responses of heart rate and blood pressure to transient myocardial ischemia were analyzed in patients with variant angina. Heart rate changes during ST segment elevation were examined by means of a Holter ECG monitoring system. All 27 ST segment elevations from 10 patients with anterior ischemia were accompanied by an increase in heart rate by 12 +/- 2 bpm (mean +/- SEM, p less than 0.001) at peak ST segment elevation. With inferior ischemia in nine patients, heart rate decreased significantly by 4 +/- 1 bpm (n = 28, p less than 0.001). However, 9 of these 28 ST segment elevations showed a biphasic response of heart rate, that is, an initial increase and subsequent decrease. Such heart rate changes were not different between ST segment elevations with and without chest pain. With chest pain systolic blood pressure rose in anterior ischemia by 42 +/- 5 mm Hg (n = 10, p less than 0.001) but fell in inferior ischemia by 22 +/- 8 mm Hg (n = 7, p less than 0.05). We conclude that a different cardiovascular reflex occurs in response to inferior versus anterior ischemia and it is independent of chest pain.

Provocation of variant angina by alcohol ingestion.

The effect of alcohol on variant angina was studied in six patients who had a history of chest pain occurring with alcohol ingestion. On alcohol testing, Holter ECG monitoring was performed and a 12-lead ECG was recorded at the time of chest pain. In five, chest pain with ST elevation occurred 5.5 to 17.5 h after the ingestion of alcohol (100 to 150 ml as ethanol). These showed recurrent ST elevation on Holter ECG, most episodes being asymptomatic. Results of provocation testing were reproducible in all four patients in whom tests were repeated and ST elevation occurred in the same leads. No complications were observed. The Holter ECG revealed a higher heart rate after alcohol ingestion. The plasma level of alcohol was zero when angina occurred and plasma epinephrine, norepinephrine and serotonin were unchanged following alcohol ingestion. Alcohol ingestion may be a useful method of provoking variant angina, particularly in those who have a history of angina related to alcohol ingestion.

Transient U wave inversion during variant angina.

We studied the prevalence and clinical significance of transient U wave inversion in 43 patients with variant angina. Twenty-four patients (group A) had ST segment elevation in the anterolateral and 19 patients (group B) had this finding in the inferoposterior leads of the ECG during spontaneous angina. In none of these patients was U wave inversion present on the resting 12-lead ECG in the absence of anginal attack. During anginal attacks, U wave inversion developed in association with ST segment elevation in 16 patients (66.7%) of group A but in no patient of group B. To exclude the possibility that a transient rise of systolic blood pressure during angina caused U wave inversion, treadmill exercise testing was done in the 16 patients after the discontinuation of antianginal drugs. In 12 of the 16 patients, exercise testing did not produce angina or U wave inversion despite a marked elevation of systolic blood pressure. These results indicate that transient U wave inversion frequently develops with anterolateral ischemia but not with inferoposterior ischemia during attacks of variant angina. It is likely that transient U wave inversion was caused by myocardial ischemia but not by a rise of blood pressure during angina.

Clinical characteristics and prognosis of patients with postinfarction angina caused by coronary artery spasm.

Clinical features and the course of 15 patients with postinfarction angina caused by coronary artery spasm are described. Episodes of postinfarction angina in the patients recurred at rest in the early recovery phase and were accompanied by transient ST-segment elevation. The area where ST-segment elevations were demonstrated on a 12-lead ECG always included the leads with newly developed abnormal Q waves. Pain resolved spontaneously or after sublingual nitroglycerin in several minutes. Holter ECGs during a 24-h period demonstrated frequent episodes of ST-segment elevation that were not always associated with chest pain. Treatment with calcium antagonist and/or nitrates effectively suppressed angina, and only one patient developed reinfarction. The patient's subjective symptoms were abolished by diltiazem and isosorbide dinitrate. A Holter ECG of the patient revealed silent ST-segment elevations before and after the reinfarction and an increase of the drugs completely suppressed the recurrence of silent ischemic ECG changes. Coronary arteriograms were obtained from 8 patients, which demonstrated more than 75% segmental stenosis on one coronary artery in 5 patients and no significant obstruction in the remaining 3. All patients performed a treadmill exercise stress test before discharge and most demonstrated excellent tolerance. All patients experienced no form of chest pain for an average of 25 months follow-up under medication. We conclude that among patients with postinfarction angina, those cases caused by coronary artery spasm have a relatively good prognosis.

Diurnal distribution of ST-segment elevation and related arrhythmias in patients with variant angina: a study by ambulatory ECG monitoring.

Twenty-four-hour ambulatory ECG recording was performed in 26 patients with variant angina to evaluate the diurnal distribution of ST-segment elevation in relation to chest pain and the incidence of arrhythmias during the episodes. During a recording period of 52 days, 364 ST-segment elevations of 1 mm or greater were observed and 79% were asymptomatic. ST-segment elevation frequently occurred between 0:00 and 9:00 hours (72%) and most frequently between 5:00 and 6:00 hours (13%). Only a few episodes occurred between 10:00 and 18:00 hours. Premature atrial contractions, premature ventricular contractions (PVCs), ventricular tachycardia (VT) and complete atrioventricular block occurred during 12% of the episodes and were more common during painful episodes (32%) than during painless ones (6%). However, VT and severe forms of PVCs (couplets and bigeminy) appeared eight times during painless episodes and nine times during painful ones. Arrhythmias occurred more frequently when the elevated ST segment started to return or was returning to the control level (n = 38) than when the ST segment was rising (n = 8). The incidence of arrhythmias was lower when the daily frequency of ischemic episodes was high. This study shows that episodes of asymptomatic coronary artery spasm predominantly occur early in the morning as symptomatic episodes; complex dysrhythmias appear during the asymptomatic episodes; arrhythmias occur predominantly during a "reperfusion period;" and more arrhythmias accompany infrequent daily episodes of ischemia than frequent ones.

Precordial electrocardiographic map using the IBM-Bonner program.

The precordial electrocardiographic map may be useful for non-invasive assessment of the extent of the acutely infarcted myocardium. Rapid and serial precordial electrocardiographic maps also may be useful to evaluate the effects of intervensions of drugs and efforts on the ischemic myocardium. In this study, the IBM-Bonner program was applied to produce a system for the precordial electrocardiographic map. Six electrodes at one intercostal space were moved in parallel from the second to the seventh intercostal space. Thus electrocardiograms (ECGs) could be recorded from 36 precordial sites, 6 x 6 matrix, and analyzed using the IBM-Bonner program. The measured values of the ECG waveform make feasible the automatic procurement of the precordial electrocardiographic map. Our mapping program can be used readily and anywhere the IBM-Bonner program is in use.

Cardiac effects of aprindine in patients with or without cardiac dysfunction: echocardiographic and clinical evaluation.

Cardiac effects of aprindine, a relatively new antiarrhythmic agent, were investigated by means of echocardiography in nine patients with ventricular arrhythmias. Three patients had normal cardiac function, and six patients had dilated cardiomyopathy. Aprindine was administered orally in a dosage of 50 to 75 mg/d. The plasma concentrations were 0.86 +/- 0.12 micrograms/ml. No worsening of cardiac signs and symptoms was noted within four weeks. An antiarrhythmic effect was noted in six of the nine patients. Significant changes in end-diastolic dimension or ejection fraction were not observed. Changes in contractile state were also assessed using the peak systolic blood pressure-end-systolic dimension relationship in three patients; none of them showed a decrease in cardiac contractility. This study suggests that aprindine, in a dose sufficient to suppress arrhythmias, does not make cardiac function deteriorate, as evaluated echocardiographically, even in patients with cardiac dysfunction.