Aldehyde dehydrogenase activity and large vessel disease in diabetes mellitus. A preliminary study.

Type II diabetic subjects, 26 with symptoms and/or signs of large vessel disease (LVD group) and 26 free from clinical vascular disease (FVD group), matched for sex, age, body weight, and duration of diabetes after diagnosis, together with 28 healthy controls participated in a preliminary study on new potential risk factors of large vessel disease. The activity of erythrocyte aldehyde dehydrogenase (ALDH) was significantly higher (P less than 0.005) in the LVD than in the FVD group and in the controls, as indicated by a shorter half-life of acetaldehyde in homogenates of erythrocytes and plasma (100 +/- 11, 203 +/- 28, and 180 +/- 21 min, respectively). The results were unaffected by antidiabetes therapy, blood glucose control, alcohol consumption, or by recognized risk factors of angiopathy, such as blood pressure, hyperlipidemia, or smoking. Whether ALDH activity is a primary factor in large vessel disease or is merely a secondary phenomenon is unknown. However, ALDH activity is a critical factor determining chlorpropamide alcohol flush (CPAF), which has been suggested to be an inherited trait in some type II diabetic subjects. In conclusion, high ALDH activity was shown to be associated with an increased risk of large vessel disease in diabetes.

Increase of plasma acetaldehyde. An objective indicator of the chlorpropamide alcohol flush.

Chlorpropamide alcohol flushing (CPAF) in non-insulin-dependent diabetics (NIDDs) has been reported to be associated with a lower tendency to develop late complications. The flush was thought to be mediated by enkephalins and prostaglandins. Early studies could not correlate CPAF to increased levels of acetaldehyde in blood and the flush was not regarded as an antabuse-like reaction. In this study, the increase of plasma acetaldehyde during the flush in 13 CPAF positive diabetics was significantly (P less than 0.005) higher than in the 13 CPAF negative diabetics during a CPAF challenge test. The increase of plasma acetaldehyde was reduced to the level of CPAF negative diabetics in three CPAF positive diabetics when they were exposed to alcohol without premedication with chlorpropamide and they did not flush. The normal breakdown of ethanol to acetic acid via acetaldehyde appears to be inhibited by chlorpropamide in the flushers. Acetaldehyde measurement is an objective method to study the chlorpropamide alcohol flush and it appears superior to the measurement of skin temperature.

Effect of intravenous nitroglycerin on lipid peroxidation after thrombolytic therapy for acute myocardial infarction.

Free oxygen radicals are produced after coronary artery occlusion and reperfusion. Polyunsaturated fatty acids are oxidized by free radicals to lipid peroxides. Measurements of plasma malondialdehyde (MDA) formed by the breakdown of lipid peroxides are often used as markers of lipid peroxidation. The effect of intravenous nitroglycerin on plasma MDA levels was studied in 43 patients who received thrombolytic therapy for acute myocardial infarction. Plasma MDA levels in patients were elevated on admission to the hospital compared with healthy controls, and normalized within 48 hours. A greater increase in plasma MDA concentrations after thrombolysis was found in patients with noninvasive signs of reperfusion than in patients judged to have a persistent occlusion. In the 23 patients receiving immediate intravenous nitroglycerin infusion, plasma MDA levels did not change from baseline to 90 minutes (0.92+/-0.22 and 0.92+/-0.23 micromol/L, p=0.99), whereas a significant increase was found in the 20 control patients who did not receive nitroglycerin (from 0.83+/-0.22 to 1.01+/-0.30 micromol/L, p=0.0004) (p=0.036 for the difference between groups). Successful reperfusion after thrombolytic therapy entails increased lipid peroxidation. Intravenous nitroglycerin reduces lipid peroxidation during myocardial ischemia and reperfusion.

Usefulness of serial electrocardiograms for diagnosis of acute myocardial infarction.

The purpose of this study was to determine whether the automated detection of acute myocardial infarction (AMI) by utilizing artificial neural networks was improved by using a previous electrocardiogram (ECG) in addition to the current ECG. A total of 4,691 ECGs were recorded from patients admitted to an emergency department due to suspected AMI. Of these, 902 ECGs, in which diagnoses of AMI were later confirmed, formed the study group, whereas the remaining 3,789 ECGS comprised the control group. For each ECG recorded, a previous ECG of the same patient was selected from the clinical electrocardiographic database. Artificial neural networks were then programmed to detect AMI based on either the current ECG only or on the combination of the previous and the current ECGs. On this basis, 3 assessors--a neural network, an experienced cardiologist, and an intern--separately classified the ECGs of the test group, with and without access to the previous ECG. The detection performance, as measured by the area under the receiver operating characteristic curve, showed an increase for all assessors with access to previous ECGs. The neural network improved from 0.85 to 0.88 (p = 0.02), the cardiologist from 0.79 to 0.81 (p = 0.36), and the intern from 0.71 to 0.78 (p <0.001). Thus, the performance of a neural network, detecting AMI in an ECG, is improved when a previous ECG is used as an additional input.

Distribution of the methyl acceptor proteins within platelet granules.

Fractionation of platelet alpha-granules and dense bodies demonstrated that methyl acceptor proteins (MAP) were present in the alpha-granule fractions, but seemed to be low or absent in the dense body fraction. MAP activity in four intragranular proteins (albumin, fibrinogen, beta-thromboglobulin and platelet derived growth factor) was low or absent and could not explain the difference in methyl acceptor proteins distribution between alpha-granules and dense bodies.

Elevated levels of the rapid inhibitor of plasminogen activator (t-PAI) in acute myocardial infarction.

Myocardial infarction is frequently caused by acute coronary thrombosis. A previous study in patients three years after myocardial infarction has shown twice as high concentrations of the rapid inhibitor of plasminogen activator (t-PAI) as in healthy controls. The present study involves 29 patients with acute onset of myocardial infarction. Already on admission the mean concentration of t-PAI was 16.5 +/- 7.4 units/ml as compared to 7.5 +/- 2.3 in healthy controls. It is presently unknown if moderately elevated t-PAI levels contribute to a delay of the spontaneous thrombolysis of the coronary occlusion, thus promoting the development of myocardial infarction.

Soluble thrombomodulin antigen in plasma is increased in patients with acute myocardial infarction treated with thrombolytic therapy.

Thrombomodulin (TM) is an integral endothelial cell membrane protein that functions as a cofactor for thrombin mediated activation of protein C. The anticoagulant functions of the protein C system are important in contributing to a hemostatic balance and prevention of thromboembolic disease. It has been suggested that impaired TM cofactor function could also constitute a prothrombotic abnormality leading to thromboembolic diseases. TM exists not only on the surface of endothelial cells but also as soluble fragment(s) circulating in plasma. The concept of a thrombotic occlusion as the critical event in acute myocardial infarction (AMI) forms the rationale for thrombolytic therapy. After successful reperfusion, patients remain at substantial risk for recurrent infarctions due to rethrombosis. The balance between procoagulant and anticoagulant mechanisms in the postthrombolytic phase have not been studied in detail. We have studied whether the plasma levels of soluble TM are influenced by thrombolytic therapy with streptokinase in patients suffering from AMI. Soluble TM concentrations increased significantly by 24 to 48 h after thrombolytic treatment, simultaneously with an increase in C-reactive protein (CRP, a marker of the inflammatory component of the cell damage) and in thio-barbituric acid reactive substances (TBARS, an indirect marker of lipid peroxidation).

Effects of apomorphine and apomorphine-L-dopa-carbidopa on alcohol post-intoxication symptoms.

In a randomised double-blind clinical trial on 58 gamma-alcoholics, the effect of apomorphine given orally in individual subemetic doses was compared with apomorphine-L-dopa-carbidopa and with placebo. No positive effects of treatment with apomorphine, or with the combination apomorphine-L-dopa-carbidopa, on alcohol consumption or post-intoxication symptoms could be demonstrated. In the group which received the combination apomorphine-L-dopa-carbidopa, the post-intoxication symptoms lasted significantly longer than in the other two groups.

A possible role of catecholamines and (Na+ + K+)ATPase in the ethanol withdrawl syndrome.

Chronic ethanol intoxication leads to an increase in the intracellular Na+/K+ ratio. It is suggested that this derangement is counteracted by catecholamines via an activation of (Na+ + K+)ATPase. This hypothesis is discussed in relation to the symptomatology of ethanol withdrawal.

Hydrodynamic properties of a new percutaneous intra-aortic axial flow pump.

Cardiac intervention, myocardial infarction, or postoperative heart failure will sometimes create a need for circulatory support. For this purpose, a new, minimally invasive intra-aortic cardiac support system with a foldable propeller has been developed. In animals, the pump has been shown to have a positive hemodynamic influence, and the present study evaluates the hydraulic properties of the pump in a bench test. The axial flow pump is a catheter system with a distal motor driven foldable propeller (0-15,000 revolutions per minute). To protect the aortic wall, filaments forming a cage surround the propeller. In the present study, tests were done with two different pumps, one with and one without the cage. Two different models were used, one for testing pressure generation and one for obtaining flow-pressure characteristics. Propellers and tubes with different diameters were studied, and pressure and flow characteristics were measured. The mathematical relationships between pressure and rotational speed, pressure, and diameter of propeller and tube were determined. There was a positive relationship between the revolutions per minute and the generated pressure, a positive relationship between the diameter of the propeller and pressure, and a negative relationship between the diameter of the tube and the generated pressure. Within the physiologic range of cardiac output, there was a small drop in pressure with increasing flow in the tubes with a small diameter. With an increasing diameter of the tube, a smaller pressure drop was seen with increasing flow. The present cardiac support system has hydraulic properties, which may be of clinical relevance for patients with left ventricular heart failure.

Initial tests with a new cardiac assist device.

Before, during, and after cardiac intervention, there is occasionally a need for circulatory support because of hemodynamic deterioration. For this purpose, a new minimally invasive cardiac assist device has been developed, and an early prototype has been studied in a bench test and in three pigs. The pump is a catheter system with a distal motor driven propeller (0-15,000 rpm) surrounded by a cage. The catheter was first tested in a tube in a water bath, where efficiency with respect to pressure generation and flow properties was measured. In the pig experiments, the pump was placed in the descending part of the aorta via a graft, and hemodynamic effects were recorded with three different propellers. The bench tests showed a velocity dependent pressure generation in the tube to the second power of the rpm, and 30 cm of water (> 22 mm Hg) could easily be achieved with all propellers. A pressure dependent flow in the tube was observed, with maximum flows of 20 L at 12,000 rpm and 27 L at 15,000 rpm. In the animal experiments, there was a velocity dependent mean pressure difference across the propeller, with up to 48 mm of mercury for the biggest propeller. An increase in cardiac output in all of the pigs was observed as well as a drop in pressure in the proximal part of the aorta. This study demonstrates the efficiency of this new device in vitro and in vivo. Hemodynamic changes are pronounced and are related to the speed and size of the propeller.

Sodium and noradrenaline effluxes from platelets in male relatives to hypertensive individuals.

The efflux rate constants for noradrenaline efflux and 22Na-efflux from platelets, the number of ouabain binding sites on platelets and the influence of plasma on ouabain binding to platelets were determined in 35 normotensive men belonging to families with a high incidence of essential hypertension and 31 men from families, where no hypertension was registered in the close relatives. The earlier finding of a higher efflux rate constant for noradrenaline in relatives was confirmed. There was a significant negative correlation between the total 22Na-efflux rate constant and the noradrenaline rate constant in relatives as well as between the number of ouabain binding sites and the noradrenaline rate constant. No such correlations were registered in the controls. The ouabain resistant 22Na-efflux rate constant was lower in relatives, but the ouabain sensitive 22Na-efflux rate constant did not differ between the groups, nor did the total number of ouabain binding sites on platelets. Number of ouabain-binding sites measured at a low concentration of (3H)-ouabain in the presence of deproteinized plasma samples was the same in both groups, contradicting the presence of an endogenous ouabain-like plasma factor in the relatives.

Effects of ethanol and acetaldehyde on cultured rabbit aortic myocytes and human platelets in vitro.

The recently reported finding that a moderate alcohol consumption may lower the risk of cardiovascular disease prompted a study of the effects of ethanol and acetaldehyde on proliferation, viability and collagen secretion of rabbit aortic myocytes in culture and on the spontaneous efflux reaction of human platelets in vitro. Ethanol had no effects on any of the systems and acetaldehyde did not influence platelets significantly. Fifty mumol 1(-1) acetaldehyde diminished the proliferation and collagen secretion of arterial myocytes by 20% (P less than 0.01) and 100 mumol 1(-1) acetaldehyde by 39% (P less than 0.001) without affecting cell mass or cell death. A metabolic degradation, and some evaporation, of acetaldehyde was taking place and 50 mumol 1(-1) acetaldehyde was halved after approximately 2 h. The more 'physiological' concentration of acetaldehyde (5 mumol 1(-1] influenced cell proliferation significantly (P less than 0.001) if the concentration was restored by 6-h intervals and the incubation time increased from 24 to 48 h. The weak aldehydedehydrogenase inhibitor chlorpropamide did not accentuate the effects of acetaldehyde.

Effects of chlorpropamide and alcohol on aldehyde dehydrogenase activity and blood acetaldehyde concentration.

Aldehyde dehydrogenase (ALDH) activity is increased in Type 2 diabetics with macrovascular disease, and is a critical factor determining the chlorpropamide-alcohol flush (CPAF), a phenomenon possibly related to diabetic complications. To evaluate the possible effects of chlorpropamide (CP) on ALDH activity we studied 8 Type 1 and 20 Type 2 diabetics. Blood acetaldehyde concentration after intake of CP and alcohol was higher in patients with CPAF than in those without CPAF (p less than 0.005), and in those with low basal erythrocyte ALDH activity than in those with high basal enzyme activity (p less than 0.05). Administration of CP reduced ALDH activity in 20 of 26 patients (p less than 0.05). Alcohol intake was observed to have an additional inhibitory effect on ALDH activity. Accordingly, a combination of CP and alcohol decreases the activity of erythrocyte ALDH which might explain the CPAF phenomenon. Absent correlation between CP level and reduction of ALDH activity indicates a major role for alcohol in CPAF. A therapeutic dose of CP or a small amount of alcohol might be used when a reduction of ALDH activity is considered.

Acute myocardial infarction detected in the 12-lead ECG by artificial neural networks.

BACKGROUND: The 12-lead ECG, together with patient history and clinical findings, remains the most important method for early diagnosis of acute myocardial infarction. Automated interpretation of ECG is widely used as decision support for less experienced physicians. Recent reports have demonstrated that artificial neural networks can be used to improve selected aspects of conventional rule-based interpretation programs. The purpose of this study was to detect acute myocardial infarction in the 12-lead ECG with artificial neural networks. METHODS AND RESULTS: A total of 1120 ECGs from patients with acute myocardial infarction and 10,452 control ECGs, recorded at an emergency department with computerized ECGs, were studied. Artificial neural networks were trained to detect acute myocardial infarction by use of measurements from the 12 ST-T segments of each ECG, together with the correct diagnosis. After this training process, the performance of the neural networks was compared with that of a widely used ECG interpretation program and the classification of an experienced cardiologist. The neural networks showed higher sensitivities and discriminant power than both the interpretation program and cardiologist. The sensitivity of the neural networks was 15.5% (95% confidence interval [CI], 12.4 to 18.6) higher than that of the interpretation program compared at a specificity of 95.4% (P<.00001) and 10.5% (95% CI, 7.2 to 13.6) higher than the cardiologist at a specificity of 86.3% (P<.00001). CONCLUSIONS: Artificial neural networks can be used to improve automated ECG interpretation for acute myocardial infarction. The networks may be useful as decision support even for the experienced ECG readers.

Chlorpropamide-alcohol flushing, aldehyde dehydrogenase activity, and diabetic complications.

Many diabetics who take chlorpropamide (a sulphonylurea compound) experience facial flushing after drinking even small amounts of alcohol. These flushers have a noticeably lower prevalence of late complications of diabetes (microangiopathy, macroangiopathy, and neuropathy) than non-flushers. This flush reaction is accompanied by increased blood acetaldehyde concentrations, suggesting an inhibition of aldehyde dehydrogenase activity. In the present study the activity of this enzyme in erythrocytes was assessed in the absence of chlorpropamide. Erythrocyte homogenates obtained from flushers and non-flushers were incubated with acetaldehyde and the rate of metabolism studies. Flushers eliminated acetaldehyde more slowly at a low range of concentrations (0--30 mumol/l), suggesting a difference in aldehyde dehydrogenase activity. Further studies are needed to clarify the role of this enzyme in the pathogenesis of diabetic complications.

Hyperhomocysteinaemia is not associated with increased levels of asymmetric dimethylarginine in patients with ischaemic heart disease.

BACKGROUND: Elevated plasma total homocysteine appears to be related to endothelial dysfunction and impaired nitric oxide production. We aimed to investigate [1] whether elevated levels of plasma total homocysteine are associated with high plasma levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, and [2] whether reduction of plasma total homocysteine levels by folate and vitamin B supplementation lowers plasma concentration of asymmetric dimethylarginine. MATERIALS AND METHODS: Sixty patients with ischaemic heart disease and with plasma total homocysteine levels of 15.0 micromol L-1 were randomized to open therapy with folic acid, pyridoxine and cyancobalamin for 3 months (n = 30) or to no treatment (n = 30). Samples were also obtained from 34 patients with plasma total homocysteine levels of 8.0 micromol L-1 on admission. RESULTS: Plasma asymmetric dimethylarginine concentrations in patients with elevated total homocysteine levels were not significantly higher (0.68 +/- 0.19 micromol L-1) than in patients with low total homocysteine levels (0.61 +/- 0.10 micromol L-1; P = 0.08). Plasma asymmetric dimethylarginine level in the vitamin supplemented group was 0.65 +/- 0.12 micromol L-1 before, and 0.64 +/- 0.12 micromol L-1 after 3 months of vitamin supplementation (NS). Plasma asymmetric dimethylarginine levels were correlated with serum cystatin C levels (P < 0.001). CONCLUSION: A nonsignificant trend to increased plasma levels of asymmetric dimethylarginine in patients with high plasma total homocysteine levels may be explained by concomitant subtle renal dysfunction. Substantial reduction of plasma total homocysteine did not affect the level of plasma asymmetric dimethylarginine.

Transient release of lipid peroxidation products as a non-invasive marker of successful reperfusion after thrombolysis for myocardial infarction.

OBJECTIVES: To evaluate an increase in plasma concentration of thiobarbituric acid reactive substances as a non-invasive biochemical test of reperfusion after thrombolysis and to investigate the relation between the inflammatory response after acute myocardial infarction and the production of the substances. METHODS: Venous samples were taken from 19 patients receiving thrombolysis for acute myocardial infarction before the start of therapy and every hour afterwards up to 5 hours and then at 24 and 48 hours and the concentration of thiobarbituric acid reactive substances measured. These substances are markers of lipid peroxidation induced by free oxygen radicals. Early reperfusion was judged by regression of ST elevation and late coronary artery patency from the results of coronary angiography 24-72 hours after thrombolysis. RESULTS: The concentration of thiobarbituric acid reactive substances increased in only 6 out of 14 patients with signs of early reperfusion. In patients with late coronary artery patency the corresponding number was 6 out of 15. However, a significant increase in the concentration of thiobarbituric acid reactive substances was found for the whole group 24 and 48 hours after treatment. The change in concentration in serum correlated significantly with that of C reactive protein--an acute phase reactant (r = 0.62, P < 0.01)--but not to the serum activities of markers of infarct size such as creatine kinase B and lactate dehydrogenase. CONCLUSIONS: The fluorimetric assay used in this study to measure the concentration of thiobarbituric acid reactive substances seems to be an insensitive method of detecting reperfusion after thrombolysis for myocardial infarction. The increase in concentrations found 24 and 48 hours after treatment correlated with C reactive protein concentrations but not with those of markers of infarct size.

Atherosclerosis and acetaldehyde metabolism in blood.

Acetaldehyde elimination in blood homogenates and erythrocyte aldehyde dehydrogenase (ALDH) activity were studied in 64 patients operated before the age of 60 years because of symptomatic stenosis of aorta, iliac, or carotid arteries and in 38 healthy controls. The disappearance of acetaldehyde in blood homogenates was biphasic. Patients showed an enhanced elimination of acetaldehyde during the second phase (30-60 min), as compared to controls (T1/2 of acetaldehyde was 103 +/- 47 and 198 +/- 93 min, respectively, P less than 0.001). No correlation was found between ALDH activity and acetaldehyde elimination rate. Acetaldehyde elimination in blood homogenates and [14C]acetaldehyde binding to plasma proteins, hemoglobin, and erythrocyte membranes were studied in 10 patients with atherosclerotic disease and in 12 healthy controls. There was a significant correlation between unstable binding of [14C]acetaldehyde to plasma proteins and the half-life of acetaldehyde in the elimination test (p = 0.74, P less than 0.005). Fractionation of plasma proteins after incubation with [14C]acetaldehyde revealed no difference between patients and controls in the distribution of radioactivity. The binding of [14C]acetaldehyde to hemoglobin or erythrocyte membranes did not differ between patients and controls. These results indicate that patients with angiopathy and an enhanced acetaldehyde elimination in blood have reduced binding of acetaldehyde to plasma proteins. As unstable binding of acetaldehyde to proteins is known to involve free amino groups of amino acid residues, modification of these residues in atherosclerotic disease is conceivable.

[3H]noradrenaline efflux from platelets and synaptosomes of ethanol-treated rats.

Platelets have the ability to take up, store and release biogenic amines and have therefore been used as models for neurons in studies of neuropsychiatric disorders and hypertension. We have studied the spontaneous efflux of [3H]noradrenaline from platelets and synaptosomes of rats chronically treated with ethanol. Male control rats had a more rapid [3H]noradrenaline efflux both from synaptosomes and platelets than female control rats. Ethanol treatment increased efflux in female rats, again both in platelets and synaptosomes. These results suggest that a parallelism exists in noradrenaline release between synaptosomes and platelets, both basal and in situations which stimulate the release.