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The effects of the intravenous administration of 100 mg of trapidil on systolic and diastolic left ventricular functions and coronary sinus blood flow, as well as on myocardial lactate metabolism and platelet aggregation, were investigated before and after pacing in 12 patients with coronary artery disease. Pacing without administration of trapidil provoked angina in 6 of these patients. During rest, trapidil decreased the mean blood pressure by an average of 5 mmHg (from 112 +/- 15 to 107 +/- 8 mmHg, p less than 0.05) and the left ventricular end-diastolic pressure by an average of 4 mmHg (from 10 +/- 3 to 6 +/- 2 mmHg, p less than 0.05). Trapidil also caused both the max dp/dt and the coronary sinus blood flow to increase slightly, although it had no significant effect on diastolic function, myocardial lactate metabolism, or platelet aggregation. During the pacing that followed trapidil administration, chest pain was not provoked in the same 6 patients who had previously experienced chest pain on pacing. The extent of ST-segment depression also improved from -1.6 +/- 0.3 to -0.9 +/- 0.7 mm (p less than 0.05) and there was a significant suppression of the production of myocardial lactate. When pacing was terminated, trapidil caused a decrease in left ventricular systolic pressure from 173 to 156 mmHg (p less than 0.05), and also caused a decrease of the left ventricular end-diastolic pressure, from 16 +/- 4 to 8 +/- 2 mmHg (p less than 0.05). Trapidil had no significant effect on platelet aggregation activity with either a 1 microM or a 2 microM dose of ADP (adenosine diphosphate). However, the beta-TG level was suppressed, decreasing from 119 +/- 14 to 99 +/- 19 ng/ml in the arterial blood (p less than 0.1) and from 114 +/- 9 to 103 +/- 17 ng/ml (p less than 0.1) in the coronary sinus blood. Reductions in the preload and afterload by trapidil were of far greater magnitude than either its coronary dilatory or positive chronotropic effects in patients with coronary artery disease. Thus trapidil, a new antianginal agent appears to inhibit the production of platelet derived growth factors and may, therefore, protect the arteries from atherosclerosis as it promotes beneficial systemic hemodynamics in patients with depressed ventricular function.
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PMID:The effects of trapidil on left ventricular function and platelet aggregation in patients with coronary artery disease subjected to pacing. 183 67

Epidemiologic studies have shown that insulin is a risk factor for coronary heart disease (CHD). Clinical studies have also demonstrated positive correlations between insulin and blood pressure, triglycerides, total cholesterol, fibrinogen, and plasminogen activator inhibitor. Moreover, there is an inverse correlation between insulin and high-density lipoprotein (HDL). These studies have provided evidence in support of the biologic plausibility of epidemiologic observations, but they have not clearly established insulin's role in the pathogenesis of human cardiovascular diseases (CVD) such as hypertension. In fact, there is considerable evidence that insulin resistance (abnormal nonoxidative glucose disposal), not hyperinsulinemia, is the primary insulin-related abnormality in human hypertension, and that hyperinsulinemia occurs as a response to insulin resistance. Skeletal muscle appears to be the primary site of insulin resistance in essential hypertension, although other organs, such as the kidneys and liver--key sites for cell and water homeostasis and lipoprotein regulation, respectively--may respond normally to insulin. Adipocytes also appear to be a site of insulin resistance. Thus, the putative interrelationship between hyperinsulinemia and insulin resistance, on the one hand, and with blood pressure and lipoproteins, on the other, is a complex one and may involve organ-specific insulin resistance. Altered cation transport is one of several mechanisms by which insulin resistance might raise blood pressure. The Na+, K(+)-ATPase and Ca(2+)-ATPase pumps are insulin sensitive. Thus, when insulin resistance is present, the activity of these pumps in the smooth muscle of the arterial wall might be reduced. This would lead to an intracellular accumulation of sodium and calcium, thereby sensitizing the vascular wall to pressor substances. Moreover, secondary hyperinsulinemia will occur, and insulin has been shown to stimulate sympathetic nervous system activity and to increase renal tubular absorption of sodium. Insulin is also a growth factor and therefore might have a trophic effect on the vessel wall, one that could initiate and/or sustain hypertension as well as atherosclerosis. Abnormal lipoprotein metabolism is yet another possible explanation for the accelerated atherosclerosis that has been observed in persons with abnormal carbohydrate tolerance and insulin resistance. Hyperinsulinemia and insulin resistance both play a role in the expression of elevated very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels as well as in the depression of HDL levels. Coronary risk reduction has been disappointing when blood pressure has been lowered with treatment regimens based on thiazide diuretics and/or beta blockers. Thiazides and some beta blockers may further impair tissue insulin sensitivity and often cause blood lipoprotein abnormalities.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Epidemiologic and clinical aspects of insulin resistance and hyperinsulinemia. 186 24

The effect of drinking pattern on plasma lipoproteins and body weight was examined in three groups of squirrel monkeys: (1) controls fed isocaloric liquid diet; (2) regular drinkers given liquid diet containing ethanol (EtOH) substituted isocalorically for carbohydrate at 12% of calories daily; and (3) binge drinkers fed 6% EtOH calories daily for a four-day period followed by three days of 20% EtOH to mimic a weekend bout drinking cycle. The number of calories offered per day was the same for all groups, and the average weekly EtOH consumption (12% calories) was identical for the two alcohol treatments. The entire study lasted six months. There were no significant differences in plasma cholesterol, triglyceride or liver function tests. Regular drinkers had the highest high density lipoprotein2/high density lipoprotein3 (HDL2/HDL3) protein and apolipoprotein A-I/B ratios of any group and exhibited a significant elevation in the molar plasma lecithin:cholesterol acyltransferase (LCAT) rate (nmol/min/ml). Binge drinking produced a selective increase in low density lipoprotein (LDL) cholesterol and apolipoprotein B, and a depression in the fractional LCAT rate (% esterified/min). During the course of the study, controls ate 92% of their diet while the alcohol groups each consumed 95% of the liquid diet. Despite this difference, body weight and Quetelet index (weight/height2) decreased progressively in the order controls greater than regular drinkers greater than binge drinkers. Results from our study indicate that moderate, regular daily consumption of EtOH at 12% of calories causes a modest reduction in body weight and produces a coronary protective lipoprotein profile (increases HDL2/HDL3, increases apolipoprotein A-I/B, low LDL cholesterol). By contrast, when this same average weekly dose is concentrated in a binge cycle, unfavorable alterations in lipoprotein composition (increases LDL cholesterol, increases apolipoprotein B) and metabolism (decreases LCAT activity) occur along with weight loss and depletion of body fat. These studies point to the value of the squirrel monkey model in evaluating both favorable and pathophysiological effects of chronic EtOH intake.
Atherosclerosis 1991 May
PMID:Effect of drinking pattern on plasma lipoproteins and body weight. 187 9

It is well established that cardiac dysfunction independent of atherosclerosis develops in both humans and animals with diabetes mellitus. The etiology is complex, involving many different processes, one of which may be increased fatty acid utilization and/or a concomitant decrease in glucose utilization by the diabetic heart. We compared control and 6-wk streptozotocin (STZ)-induced diabetic isolated working rat hearts and were able to demonstrate cardiac dysfunction in the diabetic as assessed by depressed heart rate (HR), heart rate peak systolic pressure product (HR.PSP), left ventricular developed pressure (LVDP), and rate of pressure rise (+dP/dt). Paralleling depressed cardiac function in the diabetic were hyperglycemia, hyperlipidemia, and decreased body weight gain compared with age-matched controls. The addition of free fatty acids, in the form of 1.2 mM palmitate, to the isolated working heart perfusate had no effect on either control or diabetic heart function, with the exception of a depressive effect on +dP/dt of diabetic hearts. But diabetic hearts perfused with palmitate-containing perfusate plus the glucose oxidation stimulator dichloroacetate (DCA) showed a marked improvement in function. HR and HR.PSP in spontaneously beating hearts, as well as LVDP and +dP/dt in paced hearts were all restored to control heart values in diabetic hearts perfused in the presence of DCA. Creatine phosphate and ATP levels were similar under all perfusion conditions, thus eliminating energy stores as the limiting factor in heart function. Results indicate that DCA will acutely reverse diabetic cardiac function depression. Therefore glucose oxidation depression in the diabetic heart may be a significant factor contributing to cardiac dysfunction.
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PMID:Effects of free fatty acids and dichloroacetate on isolated working diabetic rat heart. 192 88

A spectrum of cholesterol oxidation derivatives (oxysterols) is generated in food products exposed to heat or radiation in the presence of oxygen. One of these derivatives (cholestan-3 beta,5 alpha,6 beta-triol) was shown to compromise the selective barrier function of cultured vascular endothelial cell monolayers, an action that may initiate atherosclerotic lesion formation. This study sought to investigate the relationship of cholesterol synthesis inhibition by several naturally occurring oxysterols to depression of vascular endothelial cell monolayer barrier function, determined as an increase in albumin transfer across cultured endothelial monolayers. All oxysterols tested caused a variable time- and dose-dependent elevation in trans-endothelial albumin transfer, and they were also able to inhibit cholesterol biosynthesis to varying degrees. Pure cholesterol was without effect on both counts. The correlation between the increase in albumin transfer related to oxysterol exposure and the ability of oxysterols to suppress cholesterol biosynthesis was, however, poor. Moreover, mevinolin, a water-soluble competitive inhibitor of cholesterol synthesis, reduced the rate of cholesterol synthesis to 0.9% of control but did not significantly increase albumin transfer. Cholestan-3 beta,5 alpha,6 beta-triol caused a 660% elevation in albumin transfer while cholesterol synthesis remained at 11% of control. We conclude that changes in endothelial barrier function caused by exposure to the oxysterols examined, but not pure cholesterol, are probably related to factors other than the well-known action of cholesterol biosynthesis inhibition. These findings may have implications in the development of atherosclerosis.
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PMID:Oxysterols, cholesterol biosynthesis, and vascular endothelial cell monolayer barrier function. 199 10

Infective aneurysm showing dilatation of all three coronary sinuses of Valsalva due to infective endocarditis is extremely rare. We present the first report of such a case complicated by left single coronary artery. The patient was a 55-year-old man with a past history of untreated diabetes mellitus, cerebral infarction, aortic regurgitation and high-grade fever. He was admitted with a complaint of easy fatigability. In a treadmill exercise test, asymptomatic ischemic depression of the ST segment was observed. Two-dimensional echocardiography revealed marked dilatation of all three sinuses of Valsalva, and a mural thrombus within the dilated right sinus of Valsalva. On magnetic resonance imaging, an abnormal signal in the markedly dilated right sinus of Valsalva was revealed. Coronary arteriography showed left single coronary artery (L1 type by Sharbaugh's classification). The histopathological features of the affected aorta were thought to represent the healing stage of infective endocarditis. With regard to the myocardial ischemia in this patient, it was thought to have arisen mainly through aortic regurgitation and coronary atherosclerosis due to single coronary artery, and partly influenced by untreated diabetes mellitus.
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PMID:A rare case of infective aneurysm involving all three sinuses of Valsalva complicated by left single coronary artery. 202 86

In patients with coronary artery disease, angina pectoris provides an unreliable underestimation of disease activity and risk. Unheralded myocardial infarction and sudden death are common clinical presentations. Furthermore, objective testing, in hospital and more recently during the patient's normal daily activities, has demonstrated frequent and asymptomatic episodes of ischemia, as indicated by transient ST-segment depression. Since the underlying pathophysiologic disturbances of myocardial perfusion appear to be similar in painful and painless episodes, it seems appropriate to consider them together as the "total ischemic burden" on the myocardium. Research into this functional expression of coronary disease has indicated that active ischemia is associated with an increased risk of morbid events in all clinical subgroups of patients, including those with stable angina, unstable angina, peripheral vascular disease and following myocardial infarction. If this is confirmed in prospective trials, the assessment of total ischemic burden is likely to become part of the clinical investigation of patients with coronary disease. Clinical trials testing the efficacy of interventions will need to examine the effect on ischemic activity during normal daily life, in addition to symptoms and exercise tolerance. Evidence is still required to demonstrate whether therapy aimed at reducing the total ischemic burden will prolong life. The total ischemic burden provides a marker to follow the dynamic changes of the atherosclerotic lesion. Future research may have to concentrate on treatment aimed at altering the natural history of obstructive coronary atherosclerosis in order to affect the long-term outlook for patients with coronary artery disease.
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PMID:Total ischemic burden in patients with coronary artery disease. 209 78

The results of several major trials of i.v. thrombolysis in patients with acute myocardial infarction have demonstrated the efficacy of the treatment in reducing mortality. Streptokinase and rt-PA have been shown to be effective (APSAC = anisoylated plasminogen streptokinase activator complex; GISSI = Gruppo Italiano per lo Studio della Streptochinasi nell' Infarto miocardico, ASSET = Anglo Scandinavian study of early thrombolysis, rt-PA). This treatment is associated with the potential for cerebral and major bleeding, especially in elderly patients. The benefit of this treatment in patients with cardiogenic shock or hypotension (ISIS-2) is discussed. There is no convincing evidence that patients with ST-segment depression or those with an equivocal electrocardiogram had been benefited from i.v. thrombolysis. Further studies with i.v. thrombolysis and/or other strategies need to be explored. Overall the use of i.v. thrombolytic agents in combination with PTCA in patients with acute myocardial infarction have resulted in improvement in ventricular function and survival in patients eligible for this therapy. However, new techniques and therapeutic approaches to prevent reocclusion, to prevent reperfusion injury, to prevent restenosis after PTCA, to prevent atherosclerosis in the infarct and non-infarct related arteries, and to reduce the potential for ventricular arrhythmias and sudden death as well as the potential for mural thrombi and embolization after infarction are needed. The 1990's will see attempts to determine the optimum adjunctive therapy or "cocktail" of agents to be used with i.v. thrombolysis.
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PMID:Thrombolysis in acute myocardial infarction: need for a change in strategy and future directions. 212 41

Intraindividual comparisons of diets supplemented with sunflowerseed oil (rich in linoleic acid, LA, C18:2n-6), linseed oil (enriched with alpha-linolenic acid, LNA, C18:3n-3) and canned mackerel (rich in eicosapentaenoic acid, EPA, C20:5n-3 and docosahexaenoic acid, DHA, C22:6n-3) were made in 30 patients with primary hyperlipoproteinemia (HLP) of phenotypes IIa (n = 9), IIb (n = 7), IV (n = 7) and V (n = 7). The lipid- and blood pressure-lowering effects of polyunsaturated fatty acids (PUFA), particularly those of the EPA- and DHA-rich diet, were confirmed irrespective of the type of HLP. Apolipoproteins A-I and B remained unchanged. The most remarkable finding was a substantial depression of free fatty acids (FFA) within a standardized glucose tolerance test (GTT) associated with the fall of serum triglycerides after diets enriched with n-6 and especially after those supplemented with n-3 PUFA. It was suggested that the decrease of FFA indicates reduced peripheral lipolysis, which might be a hitherto ignored factor involved in the triglyceride-lowering action of n-6 and, more pronounced, of n-3 PUFA.
Atherosclerosis 1990 Aug
PMID:A possible contribution of decrease in free fatty acids to low serum triglyceride levels after diets supplemented with n-6 and n-3 polyunsaturated fatty acids. 214 66

In 2208 boys aged 15 to 22 years the incidence of risk factors of atherosclerosis were determined. The risk factors were found in 33.7% of boys. The level of risk factors in youth has increased with age (p = 0.001), especially hypertension (p = 0.001) and smoking (p = 0.001). The authors concluded that the most important methods of prevention of atherosclerosis in youth should be: identification of high-risk individuals (overweight, hypertension, hyperlipidemia, family history of CHD and PAD, ischemic postexercise ST segment depression), health education and motivation for change, modification nutritional habits in cases of hyperlipidemia and overweight (prevention of early atherosclerotic lesions in childhood), early diagnosis and control of hypertension, practice of low salt intake, avoidance of smoking, sufficient physical activity (prevention of atherosclerotic disease mainly in adulthood).
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PMID:Epidemiology of risk factors of atherosclerosis and preventive program for youth. 221 95


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