Elderly patients at risk for coronary heart disease or stroke: selecting an ideal product for lipid lowering.

Coronary heart disease is an affliction of the elderly: 84% of those who die from the disease are over 65 years of age. In patients over 55 years, the incidence of stroke more than doubles with each decade of life. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, have been shown to lower cholesterol and lipids in both middle-aged and elderly patients in large clinical trials. Some statins have been shown to improve endothelial function and vasodilation and to normalize thrombin formation, which may be among the mechanisms involved in both coronary event and stroke prevention.

Cardiovascular basis for cholesterol therapy.

The success of cholesterol treatment in reducing cardiovascular events has suggested addition of a cholesterol paradigm to previous clinical models of stenosis and occlusion in coronary artery disease. Risk factors for coronary artery disease now serve as guidelines for treatment goals for low-density lipoprotein cholesterol reduction. Oxidation of low-density lipoprotein cholesterol within the vessel wall initiates a variety of deleterious mechanisms contributing to atherosclerosis. Hepatic hydroxymethylglutaryl-coenzyme A reductase inhibitors or statin drugs exert a primary action on hepatic cholesterol metabolism, as well as influences on vascular reactivity, thrombus formation, inflammation, ischemia, and plaque stabilization. Trials with statin drugs have reported reduction of cardiovascular events in men and women without clinical evidence of coronary artery disease. Several trials have demonstrated angiographic stabilization with cholesterol lowering and a greater reduction in cardiovascular events, revascularization procedures, and strokes. Recent studies suggest benefits in lowering triglycerides and raising high-density lipoprotein cholesterol with drugs. A clinical approach with available cholesterol-lowering drugs is presented based on National Cholesterol Education Program guidelines and follow-up time tables. Thus, cholesterol therapy offers the opportunity to treat atherosclerotic vascular disease before, during, and after ischemic events.

Advances in treatment of cholesterol abnormalities. The role of HMG-CoA reductase inhibitors.

The introduction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has provided an important new class of agents that reduce levels of total and low-density lipoprotein cholesterol more powerfully than any previously used drugs. Multiple clinical trials have shown a significant decrease in lipid values and cardiovascular events and a slowing of the progression of atherosclerosis in men and women of all ages. The Scandinavian Simvastatin Survival Study demonstrated a significant reduction in all-cause mortality as a result of reduced cardiovascular mortality. The HMG-CoA reductase inhibitors should be considered as first-line therapy for hypercholesterolemia in all patients with established atherosclerosis involving the coronary, carotid, or peripheral vessels.

Monotherapy with HMG-CoA reductase inhibitors and secondary prevention in coronary artery disease.

Although thrombolytic drugs, percutaneous transluminal coronary angioplasty, and coronary artery bypass grafting have provided major advances in the treatment of coronary artery disease, the use of lipid-lowering drugs for secondary prevention has significantly reduced cardiovascular events in the population with coronary artery disease. Secondary prevention trials using HMG-CoA reductase inhibitors include the Familial Atherosclerosis Treatment Study (FATS), the Monitored Atherosclerosis Regression Study (MARS), the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the Asymptomatic Carotid Artery Progression Study (ACAPS), the Multi Anti-Atheroma Study (MAAS), the Scandinavian Simvastatin Survival Study (4S), the Pravastatin Limitation of Atherosclerosis in Coronary Arteries (PLAC I), the Regression Growth Evaluation Statin Study (REGRESS), the Pravastatin Multinational Study, and the Pravastatin, Lipids, and Atherosclerosis in Carotids (PLAC II). Mean changes from baseline of lipid fractions in these trials included: total cholesterol 18 to 35% reduction; low-density lipoprotein (LDL) cholesterol 26 to 46% reduction; high-density lipoprotein (HDL) cholesterol 5 to 15% increase; and triglyceride 7 to 22% reduction. Angiographic regression or lack of progression was statistically demonstrated in the FATS, MARS, CCAIT, MAAS, PLAC I, and REGRESS trials. Cardiovascular events decreased 25 to 92% in all trials, and there was a significant reduction in both cardiovascular and total mortality in the 4S. The greater reduction in cardiovascular events than in anatomic changes suggests that the HMG-CoA reductase inhibitors stabilized the surface of plaques. Monotherapy with HMG-CoA reductase inhibitors provides the clinical opportunity to modify the natural history of coronary artery disease.

Autoantibody titers to oxidized low-density lipoprotein in patients with coronary atherosclerosis.

Oxidation of low-density lipoprotein (LDL) is considered to be the initial step in the atherosclerotic process. Autoantibodies to oxidized LDL (ox-LDL) have been detected in human serum. We used an enzyme-linked immunosorbent assay technique to measure autoantibody titers in 63 normal subjects and patients with coronary artery disease. Thirty-five patients underwent coronary angiography for suspected coronary artery disease. Patients were divided into the following categories: group 1, 20 healthy young volunteers; group 2, 8 patients age-matched to the catheterization patients; group 3, 10 patients with normal coronary angiograms; and group 4, 25 patients with angiographic coronary artery disease. Autoantibody titers to ox-LDL were group 1, 0.142 +/- 0.023; group 2, 0.197 +/- 0.039; group 3, 0.183 +/- 0.038; and group 4, 0.340 +/- 0.026. There was no statistical difference among groups 1, 2, and 3, but the difference between these groups and group 4 was highly significant (p < 0.05). This study demonstrates that (1) autoantibodies to ox-LDL can be detected in normal subjects and in patients with abnormal coronary angiograms and (2) significantly higher titers of autoantibodies to ox-LDL were seen in patients with angiographic evidence of coronary artery disease.

Coronary artery disease in women. Risk factors, evaluation, treatment, and prevention.

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.

Cholesterol and lipoproteins: beyond atherogenesis.

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.

Effects of estrogen replacement therapy on serum lipid values and angiographically defined coronary artery disease in postmenopausal women.

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.

Effects of high-density lipoprotein on acetylcholine-induced coronary vasoreactivity.

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)

Usefulness of the total cholesterol to high-density lipoprotein cholesterol ratio in predicting angiographic coronary artery disease in women.

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)

Relation of serum lipoprotein cholesterol levels to presence and severity of angiographic coronary artery disease.

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.

Myocardial salvage after failed coronary angioplasty.

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.

Reduction in coronary heart disease: clinical and anatomical considerations.

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.

Changing outcome in acute myocardial infarction.

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.