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Nitroglycerin and the long-acting nitrates are widely used in all of the anginal syndromes and have proven effectiveness in relieving or preventing myocardial ischemia. Recent developments into nitrate mechanisms of action provide new insights as to the many anti-ischemic effects of these agents. Important concepts relating to coronary arterial endothelial function are germane to nitrate therapy. Endothelial-derived relaxing factor (EDRF) is presently believed to be nitric oxide (NO), which exerts vasodilatory and/or antiplatelet actions by increasing intracellular cyclic guanosine monophosphate as a result of activation of the enzyme guanylate cyclase. In the setting of coronary atherosclerosis, or even hyperlipidemia without histologic vascular disease, endothelial dysfunction may be present, promoting a vasoconstrictor/proplatelet aggregatory milieu. Nitroglycerin and the organic nitrates are NO donors; NO is the final product of nitrate metabolism, and in the vascular smooth muscle NO induces relaxation, resulting in vasodilation of arteries and veins. In the presence of inadequate EDRF production and/or release, it appears that nitroglycerin may partially replenish EDRF-like activity. Nitrates have long been known to have major peripheral circulatory actions resulting in a marked decrease in cardiac work. Venodilation and arterial relaxation result in a decrease in intracardiac chamber size and pressures, with a resultant decrease in myocardial oxygen consumption. In addition, a variety of direct coronary circulatory actions of the nitrates have been documented. These include not only epicardial coronary artery dilation, but the prevention of coronary vasoconstriction, enhanced collateral flow, and coronary stenosis enlargement. Recent work suggests that the nitrates may also act by preventing distal coronary artery or collateral vasoconstriction, which can reduce blood flow downstream from a total coronary obstruction. Thus, there are many anti-ischemic mechanisms of action by which nitroglycerin and the organic nitrates may be beneficial in both acute and chronic ischemic heart disease syndromes. The unique salutory effects of the nitrates in subjects with left ventricular dysfunction or congestive heart failure make these drugs particularly attractive for patients with abnormal systolic function and intermittent myocardial ischemia. Finally, the emergent role of intravenous nitroglycerin in acute myocardial infarction offers new prospects that nitrate therapy may prove to be beneficial in acute myocardial infarction as well as postmyocardial infarction for the reduction of left ventricular remodeling.
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PMID:Mechanisms of action of the organic nitrates in the treatment of myocardial ischemia. 152 24

It is generally recognized that formation of a platelet-fibrin-rich thrombus in an atherosclerotic coronary artery is the basis of unstable angina and acute myocardial infarction. Platelet hyperactivity has been identified in coronary risk factors such as hyperlipidemia and diabetes mellitus. Persistent activation of these cells results in release of growth factors that may contribute to the progression of atherosclerosis. Several recent studies show that endothelium, by generating or metabolizing a host of vasoactive substances, plays a critical role in the modulation of vascular tone. Important among these substances are prostacyclin (PGI2) and endothelium-derived relaxing factor (EDRF). The endothelium-dependent modulation of coronary artery tone correlates with the severity of atherosclerosis and the number of coronary risk factors. Procedures such as angioplasty and coronary bypass surgery injure the endothelium. The loss of endothelial smooth muscle relaxant function may contribute to the vasoconstriction and thrombosis often observed soon after these procedures. Thrombolysis (and subsequent reperfusion of the coronary artery) is also associated with severe endothelial dysfunction, with a resulting vasoconstrictor influence on the coronary vascular bed. Activation of leukocytes and their presence in the reperfused myocardium contribute to progression of myocardial injury by release of oxygen free radicals and proteolytic enzymes. Thus, it seems that a perturbation in this delicate equilibrium in cellular interactions relates to genesis and progression of myocardial ischemia.
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PMID:Platelet-leukocyte-endothelial interactions in coronary artery disease. 154 43

Despite a marked reduction in cardiovascular morbidity and mortality, treated hypertensive patients remain at increased risk of coronary artery disease and its complications compared with untreated normotensive subjects. Mild hypertension is often associated with other, usually chronic, diseases. The failure of first-line antihypertensive therapy to deal adequately with concomitant disease and associated therapy might account for the poor improvement in the cardiovascular prognosis. This possibility has been addressed in an ongoing trial of novel design, the Perindopril Therapeutic Safety Study, a multicenter, double-blind, randomized and placebo-controlled trial to determine the safety, efficacy, and interaction of angiotensin-converting enzyme (ACE) inhibition with eight of the most common concomitant diseases and their therapies. A total of 480 male and female patients (60 per disease group) aged 30-70 years, with a diastolic pressure of 90-104 mm Hg, were included after a 3-week placebo run-in if they satisfied standard criteria for any of the following: hyperlipidemia, type II diabetes, ischemic heart disease, cardiac arrhythmia, peripheral arterial disease, nephropathy with proteinuria, chronic obstructive lung disease, or rheumatoid arthritis. Of these, 460 patients have completed the 6-week double-blind phase (comprising two assessments, at 3 and 6 weeks), and are currently undergoing assessments every 3 months over a 1-year follow-up period. The end points include the incidence of progression or improvement in concomitant disease, the incidence of positive or negative interaction between ACE inhibition and concomitant therapy, change in blood pressure, adverse biochemical and hemodynamic reactions, self-reported side effects, and quality of life indices. Interim results for the 6-week double blind phase will shortly be available. However, the desirability and feasibility of conducting a study according to this novel design have already been proved.
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PMID:Angiotensin-converting enzyme inhibition in mild hypertension with concomitant diseases and therapies: an efficacy, safety, and compatibility study of novel design, the Perindopril Therapeutic Safety Study. 158 Feb 90

Atherosclerosis is a fundamental cause of life-threatening disorders, such as ischemic heart disease or stroke. Therefore, prevention and treatment of atherosclerosis is a matter of importance. In atherosclerotic lesions, there are many foam cells which contain large amounts of cholesteryl ester. In particular, most of these foam cells in the early stage of atherosclerosis derive from monocytes/macrophages. Today, foam cell transformation of macrophages in subendothelial space is considered to occur by a mechanism in which macrophages take up oxidized low density lipoprotein. We have already discovered that atherosclerosis of Watanabe heritable hyperlipidemic rabbits, an animal model for hereditary hyperlipidemia and severe atherosclerosis, could be prevented by probucol. This drug was originally developed as an antioxidant, and the mechanism of prevention of atherogenesis with this drug is considered that it prevents oxidative modification of LDL. On the other hand, probucol also causes regression of xanthoma in patients with familial hypercholesterolemia. This effect implies that probucol can be effective for treatment of atheromatous lesions, because xanthoma is a lesion which consists of macrophage-derived foam cells. However, the precise mechanism of probucol in causing regression of xanthoma has not been clarified. Considering these observations, we paid special attention to the oxidative modification of high density lipoprotein (HDL). HDL makes contact with foam cells in subendothelial space and stimulates efflux of cholesterol. This is the very place where oxidative modification of LDL is considered to occur. Therefore, it is rational to attempt to determine what would happen when HDL is oxidized and whether probucol could prevent oxidative modification of HDL.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Studies on atherosclerosis with an animal model]. 161 1

Navajo Indians have been reported by earlier investigators to have low concentrations of serum lipids and a low prevalence of hyperlipidemia, as well as low rates of ischemic heart disease. However, no data on serum lipid concentrations among Navajos have been reported for more than two decades. The authors conducted a study to determine the distribution of concentrations of serum total cholesterol (TC), high density lipoprotein cholesterol, low density lipoprotein cholesterol, and triglyceride among persons 25-74 years old living in a representative community on the Navajo Indian reservation. Data are reported for 255 subjects, 105 men and 150 women, ages 25-74 years. The authors compared these data to those for the general population as determined by the second National Health and Nutrition Examination Survey (NHANES II). TC concentrations among Navajo men were similar to those from NHANES II. TC concentrations among younger Navajo women were similar to those for women younger than 55 years from NHANES II, but were significantly lower among older Navajo women. While 27.6 percent of men ages 25-74 years studied in NHANES II had TC concentrations greater than 240 milligrams per deciliter, 33.8 percent of Navajo men had similarly elevated TC. However, the prevalence of serum TC concentrations greater than 240 milligrams per deciliter among Navajo women (17.5 percent) was about half that among women studied in NHANES II (32.9 percent). A similar pattern was found for low density lipoprotein cholesterol. The researchers concluded that Navajo Indians are no longer characterized by low serum lipid concentrations, that increased cholesterol concentrations may be a harbinger of increasing rates of atherosclerotic coronary heart disease among Navajos, and that attention should be directed to primary prevention of hyperlipidemia in Navajo Indian communities.
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PMID:Serum cholesterol concentrations among Navajo Indians. 173 14

Type-I-patients with silent myocardial ischemia (SMI) have a 2-4fold higher longterm-risk for coronary-events than healthy people. With increasing gravity and duration of ischemia type-II-patients have an increased event-risk. Reliable statements about prognosis of type-III-patients are very difficult. Therapy of SMI is equivalent to therapy of "loud" ischemia and comprises: 1) treatment of cardiovascular risk-factors (nicotine, arterial hypertension, hyperlipidemia, adiposis), 2) nitrates as effective straight at the coronary stenosis, 3) beta-blockers, which influence the circadian ischemic rhythm, 4) calcium-channel-blockers with especially for nifedipine little effect, 5) thrombocyte-aggregation inhibitors and 6) invasive therapeutical methods (percutaneous transluminal coronary angioplasty [PTCA] and aorto-coronary bypass grafting [ACBG]).
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PMID:[Silent myocardial ischemia. Current concepts of prognosis and therapy]. 176 84

To clarify the mechanism of the high incidence of ischemic heart disease in the diabetics, we studied the particle size of the lipoprotein with particular attention to the structural abnormality. Using high performance liquid chromatography, the particle size of the lipoprotein was determined with elution volume, which was precisely correlated with the particle size. The particle size of low density lipoprotein (LDL) from the diabetics with normolipidemia is larger than that from the nondiabetics (p less than 0.001) in the elution pattern of triglyceride. The examination of the elution pattern of the triglyceride and cholesterol revealed that this large LDL was composed of a large amount of triglyceride. These characteristics of the large LDL resembled that of the atherogenic intermediate density lipoprotein. The particle size of high density lipoprotein (HDL) from the diabetics with normolipidemia was larger than that from the nondiabetic controls (p less than 0.001), detected by the elution pattern of triglyceride. The comparison of the triglyceride and cholesterol elution pattern indicated that also the large HDL in the diabetics with normolipidemia was rich with triglyceride, which was reported to inhibit the activity of the lipid transfer protein. These facts revealed that the disorder of the lipid metabolism not accompanied with hyperlipidemia produced the large LDL and HDL, which might lead to the excess mortality rate of the ischemic heart disease in the diabetics even with normolipidemia.
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PMID:Abnormal particle size of lipoprotein in non-insulin-dependent diabetics and nondiabetics with and without hyperlipidemia. 176 62

It has been suggested that the presence of ischemic heart disease correlates with an increased risk of cardiac infarction and fatal arrhythmia following noncardiac operations. To prevent these complications, coronary arteriographies were performed on 55 patients before pulmonary surgery for the assessment of the risk of perioperative cardiac complications. A coronary artery obstruction, with a 50% or greater reduction in the internal diameter was recognized on 21 patients (Group 1) and the other 34 patients showed no significant coronary stenotic lesions (Group 2). Discriminant analysis revealed that cardiac index (p less than 0.025), blood sugar level (p less than 0.05), hyperlipidemia (p less than 0.05) and postoperative cardiac failure (p less than 0.005) correlated independently with coronary artery stenosis. Postoperative cardiac complications were observed in the form of atrial arrhythmias (11%), ventricular arrhythmias (16%) and ischemic ECG findings (17%) in all cases. The rate of occurrence of these complications were not different between the two groups. However, the need for therapeutic procedures for perioperative circulatory failure (18%) was much greater in group 1 (p less than 0.005). This study supports the merits of preoperative coronary arterial angiography and the estimation of the left ventricular function in reducing pulmonary perioperative risk.
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PMID:[Perioperative cardiac complications of pulmonary operations in patients with/without coronary stenosis]. 177 81

In 1985 an explanatory report was published about investigation and treatment of hyperlipidaemia. This report, together with a consensus report published subsequently, formed the background for a nationwide cholesterol campaign. The attitudes of general practitioners to measurement of cholesterol and intervention must be considered to have decisive influence on performance of the goal of the consensus report, viz, reduction of the incidence of ischaemic heart disease (IHD). By means of a nine-page questionnaire, an attempt was made to assess the attitudes to measurement of cholesterol and intervention among the general practitioners on Bornholm. Out of the 35 questionnaires sent, 27 were returned (77%). Just under 40% of the general practitioners would screen all men aged between 20 and 59 years. Approximately 25% would screen women in the same age group. Opinions were unanimous about screening patients with diabetes, hypertension or IHD. Attitudes towards intervention were, by and large, in agreement with the cholesterol limits recommended in the explanatory report. In general, the general practitioners had well balanced attitudes towards tracing and treatment of individuals with raised serum cholesterol with relevant consideration of cholesterol as an important risk factor in the development of IHD.
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PMID:[Attitudes to cholesterol measurement and intervention among general practitioners in Bornholm]. 185 87

The relationship between myocardial ischemia and biochemical changes has been well documented. For example, hyperlipidemia is one of the largest risk factors for the development of coronary artery disease. Decreased coronary blood flow produces various changes in cardiac metabolism, which cause severe cardiac function abnormalities, including heart failure and arrhythmias. Many biochemical markers have been used for both diagnosis and evaluation of the severity of myocardial infarction. In this symposium the speakers have discussed: 1) the relationship between the changes in the ionic environments in the intra- and extra-cellular spaces and the genesis of cardiac arrhythmias, with special reference to the role of increased intracellular resistance in conduction delay during ischemia (Dr. Takao Fujino), 2) metabolic basis of ECG abnormalities in ischemic heart disease and the role of intra-coronary ECG recordings in the evaluation of cardiac ischemia (Dr. Tetsunori Saikawa), and 3) biochemical changes associated with exercise and other stresses, with special reference to the roles of increased catecholamines and decreased blood fluidity in the genesis of cardiac abnormalities (Dr. Takehiko Fujino). Prof. Takeshi Kanno gave a special lecture entitled "Approaches from clinical laboratory to hereditary variants". He showed an excellent model of approach from clinical laboratory medicine to detect important biochemical abnormalities which may be overlooked by routine daily analyses in the clinical laboratory.
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PMID:[Cardiac function abnormalities and biochemical changes in myocardial ischemia]. 192 Aug 72


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