Estrogen and coronary artery disease in postmenopausal women.
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Biomedical subjects
Publications and source records attributed to C E Rackley.
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Cardiovascular disease is the leading cause of death in women. Unfortunately, the problem of cardiovascular disease in women has been largely ignored as women have been enrolled in limited numbers or excluded entirely from many of the major trials on which treatment of cardiovascular disease have been based. Furthermore, recent evidence suggests that a gender bias against aggressive intervention and treatment of cardiovascular disease in women may exist. This article reviews the risk factors, methods of identification, and treatment of coronary artery disease in women, as well as the potential benefits of postmenopausal estrogen.
To examine the effects of estrogen replacement on lipids and angiographically defined coronary artery disease (CAD) in postmenopausal women, lipid profiles were obtained in 90 consecutive postmenopausal women undergoing diagnostic coronary angiography. Eighteen women (20%) were receiving estrogen and 72 (80%) were not. CAD (defined as greater than or equal to 25% luminal diameter narrowing in a major coronary artery) was present in only 22% of women (4 of 18) receiving estrogen and in 68% (49 of 72) who were not (p less than 0.001), with an odds ratio of 0.13. Mean high-density lipoprotein (HDL) cholesterol level was significantly higher (63 +/- 6 vs 48 +/- 2; p less than 0.01) and mean total/HDL cholesterol ratio significantly lower in women receiving estrogen than in those who were not (4.2 +/- 0.5 vs 5.1 +/- 0.2; p less than 0.05). The other lipid values were similar in both groups. On multiple logistic regression analysis, absence of estrogen use was the most powerful independent predictor of the presence of CAD (p less than 0.001), with total/HDL cholesterol ratio as the only other variable selected (p less than 0.01). Thus, among 90 consecutive postmenopausal women undergoing diagnostic coronary angiography, estrogen replacement therapy was associated with an 87% reduction in the prevalence of CAD, and those receiving estrogen had a significantly higher mean HDL cholesterol level and lower mean total/HDL cholesterol ratio.
Although much emphasis has been placed on the role of cholesterol and lipoproteins in atherosclerotic plaque formation, recent studies suggest that lipids have other vascular actions which may contribute to the pathogenesis of myocardial ischemia. These include deleterious effects of lipids on platelet and endothelial cell function, coagulation, fibrinolysis, and prostacyclin metabolism. The purpose of this report is to review recent data regarding the nonatherogenic effects of lipids and provide insight as to how lipid lowering might contribute to clinically important improvements in vascular biology.
To investigate the relation between lipids and angiographic coronary artery disease (CAD) in women, fasting lipid profiles were obtained on 108 women undergoing coronary angiography (group I). CAD, defined as greater than or equal to 25% luminal diameter narrowing in a major coronary artery, was present in 57 (53%). Neither serum total cholesterol nor triglyceride levels correlated with the presence of CAD. Mean total/high-density lipoprotein (HDL) cholesterol ratio was higher among women with than without CAD (5.5 +/- 0.3 vs 4.2 +/- 0.2, p less than 0.0001). Multiple regression analyses identified a higher total/HDL cholesterol ratio as the variable most predictive of the presence (p less than 0.001), extent (number of narrowed arteries) (p less than 0.0001), and severity (% maximum stenosis) (p less than 0.001) of CAD. Age and lack of estrogen use were also independently associated with the presence of CAD, age and low-density lipoprotein cholesterol level were additional indicators of extent, and age was the only other discriminator of severity of CAD. In 56 women with total cholesterol less than 200 mg/dl (group II), mean total/HDL cholesterol ratio was higher in women with (n = 24) than without CAD (4.3 +/- 0.2 vs 3.5 +/- 0.2, p = 0.01). Higher total/HDL cholesterol ratio was the variable most predictive of the presence of CAD (p = 0.01), and the lone variable associated with severity (p less than 0.001) after adjustment for other risk factors. Age was independently associated with presence and extent, and hypertension was also independently related to extent.(ABSTRACT TRUNCATED AT 250 WORDS)
Recent evidence suggests that high-density lipoprotein (HDL) cholesterol has important vasoactive properties which may contribute to its beneficial effects on atherosclerotic coronary artery disease. The endothelium-dependent vasodilator acetylcholine has been used in a number of experimental studies to assess endothelial function. The relation between serum lipoproteins and acetylcholine-induced coronary vasoreactivity was investigated in patients (n = 27) undergoing elective coronary arteriography. Mean serum cholesterol, low-density lipoprotein cholesterol, HDL cholesterol and triglyceride levels were 189 +/- 7 (4.84 +/- 0.18 mmol/liter), 134 +/- 6 (3.47 +/- 0.15 mmol/liter), 41 +/- 3 (1.06 +/- 0.08 mmol/liter) and 106 +/- 30 mg/dl (1.20 +/- 0.03 mmol/liter), respectively. After a baseline arteriogram, acetylcholine was infused into the left main coronary artery and percent change from baseline dimension was determined in 27 angiographically smooth coronary artery segments and in 14 arterial segments with evidence of mild atherosclerotic disease. Intact vascular smooth muscle function was then confirmed in all segments by dilation to intracoronary nitroglycerin. Acetylcholine produced significant vasoconstriction of both angiographically smooth (13 +/- 4%, p less than 0.05 vs baseline) and diseased (19 +/- 4%, p less than 0.05 vs baseline) coronary segments. A positive correlation was observed between HDL cholesterol and normal acetylcholine-induced coronary vasoreactivity in both angiographically smooth (r = 0.59, p less than 0.001) and diseased (r = 0.62, p less than 0.02) coronary segments. No significant correlation was observed, however, between total and low-density lipoprotein cholesterol, or between total cholesterol to HDL ratio and the response of coronary artery diameter to acetylcholine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
To assess the relation of lipid levels to angiographic coronary artery disease (CAD), lipid profiles were obtained on 125 men and 72 women undergoing diagnostic coronary angiography. CAD, defined as greater than or equal to 25% diameter narrowing in a major coronary artery, was present in 106 men (85%) and 54 women (75%). Multiple regression analyses revealed that only high-density lipoprotein (HDL) cholesterol level in men, and age and total/HDL cholesterol ratio in women, were independently associated with the presence of CAD after adjustment for other risk factors. HDL cholesterol level and age were significantly correlated with both extent (number of diseased vessels) and severity (percent maximum stenosis) of CAD in men. In women, age was the only independent variable related to severity, whereas age and total/HDL cholesterol ratio were related to extent. Of 71 patients with total cholesterol less than 200 mg/dl, 79% had CAD. With multiple regression analyses, HDL cholesterol was the only variable independently related to the presence and severity of CAD in these patients after adjustment for age and gender; extent was significantly associated with age and male gender, and was unrelated to any of the lipid parameters. With use of multiple logistic and linear regression analyses of the group of 197 patients, HDL cholesterol was the most powerful independent variable associated with the presence and severity of CAD after adjustment for age and gender. HDL cholesterol was also an independent predictor of extent. Age was independently associated with each of the end points examined, and was the variable most significantly related to extent. These data add to the growing body of information demonstrating an important association between HDL and CAD.
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UNLABELLED: Patients undergoing coronary angioplasty have a 2% to 7% risk of requiring emergency coronary artery bypass graft surgery for impending infarction. These patients provide a unique model of early reperfusion because the exact time of compromise to blood flow and the composition of the reperfusion solution are known. However, the amount of myocardium salvaged is unknown. Between December 1981 and September 1985, 859 patients underwent coronary angioplasty. Forty-two patients had emergency surgery for objective evidence of impending infarction. Five patients died. Thirty-six patients were contacted for follow-up; 21 (58%) of 36 had a radionuclide ventriculogram performed at a mean of 39 +/- 13 months after surgery. These radionuclide studies were compared with the patient's preangioplasty contrast ventriculogram. One patient had a myocardial infarction 3 years after surgery. Eleven (55%) of the remaining 20 patients had a normal radionuclide ventriculogram at follow-up study (ejection fraction 65 +/- 9%). Five (25%) of the 20 patients had a depressed ejection fraction (46 +/- 4%) with wall motion abnormalities, but these were unchanged from the preangioplasty studies. Four patients (20%) had a significant decrease in ejection fraction over baseline (37 +/- 10%) with new wall motion abnormalities. IN CONCLUSION: 1) there is an 80% chance that left ventricular function will be unchanged at 3 year follow-up study in patients surviving emergency bypass grafting for failed angioplasty; 2) these data suggest that early revascularization for impending infarction in this setting is associated with a good late outcome; and 3) this patient group offers a unique opportunity to study the effects of early reperfusion in a human model.
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Coronary artery bypass surgery, percutaneous transluminal coronary angioplasty and thrombolytic therapy in acute myocardial infarction have relieved symptoms, preserved myocardium, and prolonged life but have not modified the progression of atherosclerosis in the coronary arteries. In the last 10 years, however, progress has been made in establishing the cholesterol-atherogenesis hypothesis. Epidemiologic studies have demonstrated that the higher the total plasma cholesterol and low density lipoprotein cholesterol (LDL-C), the greater the risk that coronary artery disease will develop. Recently, clinical trials including the Coronary Drug Project, the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), and the Helsinki Heart Study provided evidence that lowering cholesterol reduces the frequency of fatal and nonfatal coronary events. In addition, the National Heart, Lung, and Blood Institute (NHLBI) Type II Coronary Intervention Study and the Cholesterol Lowering Atherosclerosis Study demonstrated that lowering of cholesterol was associated with a decreased incidence of progression of coronary disease, as well as with the potential for reduction in the atherosclerotic plaque. Beneficial effects of diet and lifestyle changes also have an important effect on atherosclerosis. The impact of lowering cholesterol has been limited primarily by pharmacologic programs which lower cholesterol only 10-20% and are associated with a high incidence of intolerable side effects. With the recent introduction of the HmG co-A reductase inhibitors and their more profound effect on serum lipids, it may be possible to further promote plaque regression. The future of all these interventions, however, must still be assessed by overall mortality; studies to date have demonstrated beneficial effects on cardiovascular mortality but age-adjusted total mortality has remained unchanged. Future management of patients with acute and chronic coronary artery disease will involve a collaboration of cardiologists, endocrinologists, and epidemiologists to coordinate screening, recognition, and treatment of this disease.
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Beta blockers, glucose-insulin-potassium, nitrates, and thrombolytic interventions have been demonstrated to reduce the mortality of acute MI. Because of the number of interventions available, it will become progressively more difficult to isolate their additional benefits. The next challenge will be to determine the ideal combination of interventions to limit infarct size maximally in the context of early reperfusion, thereby limiting reperfusion injury and further improving salvage.
Emergency percutaneous transluminal coronary angioplasty (PTCA) is accepted as an important reperfusion intervention for acute myocardial infarction (AMI). Although its primary success rate is well documented, the frequency of restenosis after this procedure is unclear. The frequency of restenosis was determined in patients undergoing emergency PTCA at least 6 months after PTCA was performed during AMI. Of 66 consecutive patients undergoing emergency PTCA, 25 had a second, elective catheterization at an average of 22 months after AMI and 6 underwent repeat catheterization because of recurrent chest pain. Restenosis of the PTCA site was found in 10 of the 31 patients (32%) restudied. Also, 14 (45%) of these 31 patients showed progression of narrowing in the non-infarct-related coronary arteries. In summary, patients in whom AMI is treated by PTCA are at risk for restenosis and for progressive narrowing of the non-infarct artery.
Maximal myocardial salvage appears to be related to the severity of residual coronary arterial stenosis after thrombolysis. The degree of residual infarct vessel stenosis was assessed in 119 consecutive patients with patent arteries who received streptokinase during acute myocardial infarction. After administration of streptokinase, 99 of 119 patients (83%) had a residual stenosis 70% or more in diameter. Assuming that a residual diameter stenosis of at least 70% is flow limiting, the feasibility for percutaneous transluminal coronary angioplasty (PTCA) was determined by the following criteria: length less than 10 mm, no significant distal narrowing or left main stenosis, and an adequate-sized distal artery. In 81 of 99 patients (82%), arterial anatomy was suitable for PTCA. Thus, after therapy with streptokinase for acute myocardial infarction, most patients have a significant infarct arterial residual stenosis and are candidates for PTCA.
The limitation of infarct size by thrombolysis could potentially be improved by an early metabolic intervention. We therefore evaluated the effects of a 48-hour infusion of glucose-insulin-potassium (GIK) in patients with anterior infarctions. Seventeen patients were randomized to receive intravenous GIK (n = 10) or placebo (n = 7). All patients additionally received streptokinase. Changes in left ventricular function were assessed by comparing the global ejection fractions and the regional infarct area ejection fractions of the first ventriculogram with the 10-day second ventriculogram. There was a significantly greater improvement in the global ejection fraction of patients receiving GIK (increases 0.07 +/- 0.04) than in those randomized to placebo (decreases 0.08 +/- 0.04) (p less than 0.02). There was also a much greater improvement in the area ejection fractions of the group receiving GIK vs the group receiving placebo in the anterolateral (increases 0.24 +/- 0.07 vs decreases 0.02 +/- 0.04 [p less than 0.02]) and diaphragmatic (increases 0.08 +/- 0.08 vs decreases 0.17 +/- 0.05 [p less than 0.005]) segments. Thus in patients with anterior infarctions receiving streptokinase, GIK improves ventricular function and reduces the size of the segmental wall motion abnormality.
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