Coronary heart disease prevention in women: focus on lipids.

Coronary heart disease (CHD) remains an urgent and leading threat to women's health and well-being. Clinical trials have demonstrated a clear cut benefit of low density lipoprotein cholesterol (LDL-C) lowering in both women as well as men with coronary disease. While the case for primary prevention of CHD with LDL-C lowering is less secure in both men and women, there is little doubt that patients at high risk of CHD, even without a prior history of vascular events, will in the long run benefit from LDL-C lowering. Thus, all available evidence indicates that lipid interventions should be pursued aggressively in both women and men at risk of CHD.

Prevention and treatment of coronary heart disease: who benefits?

Coronary heart disease (CHD) remains a leading cause of morbidity and mortality in the United States, despite our better understanding of the pathobiology of atherosclerosis, our knowledge of risk factors, the widespread availability of inexpensive cholesterol screening, and the availability of effective and well-tolerated cholesterol-lowering agents. Advances in these areas have created controversies regarding who should be screened and treated for primary or secondary prevention of coronary events. The advent of the statin class of lipid-lowering agents represented a major advance, because they are much more effective and better tolerated than previous agents. There is general agreement that patients with hypercholesterolemia and established CHD require treatment for secondary prevention of recurrent coronary events. Primary prevention is controversial in all patient groups except those with diabetes, because their risk of developing CHD is dramatically increased. Postmenopausal women and the elderly are undertreated, whereas young adults may be underdiagnosed and undertreated. Several ongoing trials may resolve the controversies about which patient groups will benefit from different prevention and treatment strategies.

Triglycerides and coronary risk in women and the elderly.

There seems little doubt that triglycerides are causally related to the progress of atherogenesis. Mechanisms for this effect include adverse quantitative and qualitative changes in circulating lipoproteins. In particular, the effects of lower high-density lipoprotein levels and the production by hypertriglyceridemia of small, dense low-density lipoproteins are of great significance. The role of triglyceride-rich remnant particles in atherogenesis is likely important. These remnants, which are lipoproteins rich in both cholesterol and triglycerides, can be shown to produce cholesteryl ester-laden macrophages in vitro and are probably atherogenic in vivo. Triglyceride levels are a significant risk factor for coronary artery disease in women, more so than in men. Triglyceride levels also increase in older patients and continue to be predictors of coronary risk in both men and women older than 65 years. It is unclear whether triglyceride intervention efforts should be directed at lowering triglyceride levels (such as is accomplished with niacin or fibric acid derivatives) or lowering low-density lipoprotein levels in patients with high triglyceride levels, assuming triglyceride levels are only a passive marker of atherosclerotic risk. Until more is known about the precise role of hypertriglyceridemia in atherogenesis in women and older patients, use of triglyceride-lowering drugs should be conservative and limited to those individuals with high triglyceride levels (> 4.5 mmol/L [> 400 mg/dL]) who do not respond to diet modifications and who are at risk of coronary disease either because of a history of vascular disease or the presence of other risk factors.

Effect of long-term moderate physical exercise on plasma lipoproteins. The National Exercise and Heart Disease Project.

As part of the National Exercise and Heart Disease Project, 223 postcoronary men, aged 30 to 64, were randomly assigned to moderate exercise or control groups. Levels of total plasma cholesterol, high- and low-density lipoprotein (HDL and LDL) cholesterol, and triglycerides were measured. At baseline, alcohol intake, weight, and skin-fold thickness but not treadmill work capacity correlated with triglyceride or HDL cholesterol levels. After one year, no clinically important change in lipid levels was observed in either group. Using multiple regression analysis of the combined groups, changes in several independent variables, including work capacity change, were not predictive of changes in lipid levels. Thus, changes in levels of fitness and/or regular exercise did not substantially influence HDL cholesterol or other lipid levels.

Comparison of psyllium hydrophilic mucilloid and cellulose as adjuncts to a prudent diet in the treatment of mild to moderate hypercholesterolemia.

The effects of the administration of 5.1 g of psyllium or placebo (cellulose) twice daily for 16 weeks were compared as adjuncts to a prudent diet in the management of moderate hypercholesterolemia in a parallel, double-blind study. Psyllium decreased the total cholesterol level by 5.6% and the low-density lipoprotein cholesterol level by 8.6%, whereas the levels were unchanged in the placebo group. The high-density lipoprotein cholesterol level decreased during the diet stabilization period in both groups and returned to near-baseline values by week 16. Plasma triglyceride levels did not change substantially in either group. Subject compliance to treatment was greater than 95%. These data suggest that psyllium hydrophilic mucilloid in a twice-daily regimen may be a useful and safe adjunct to a prudent diet in the treatment of moderate hypercholesterolemia.

Cholesterol lowering in the elderly. Results of the Cholesterol Reduction in Seniors Program (CRISP) pilot study.

BACKGROUND: Total and lipoprotein cholesterol levels continue to be predictors of coronary heart disease risk in men and women over 65 years old. Cholesterol-lowering trials, however, while sometimes including such subjects, have not concentrated on this age group. The Cholesterol Reduction in Seniors Program was a five-center pilot study to assess feasibility of recruitment and efficacy of cholesterol lowering in this age group. METHODS: The study was a randomized, double-masked clinical trial with placebo, 20-mg lovastatin, and 40-mg lovastatin arms. Major efforts were made to recruit women and minorities. Participants were followed up for 1 year on a cholesterol-lowering diet plus placebo or study drug. End points were changes in blood lipid levels. Data on other blood chemistry values, as well as quality-of-life measures and coronary heart disease morbidity and mortality, were also collected. RESULTS: Four hundred thirty-one subjects with low-density lipoprotein cholesterol levels greater than 4.1 and less than 5.7 mmol/L (159 and 221 mg/dL) were randomized, of whom 71% were women and 21% were African Americans; the mean age was 71 years. In the 20- and 40-mg lovastatin groups, total cholesterol levels fell 17% and 20%; low-density lipoprotein cholesterol levels fell 24% and 28%; triglyceride levels fell 4.4% and 9.9%, respectively. High-density lipoprotein cholesterol levels rose 7.0% and 9.0%, respectively. No changes were observed in the placebo group. Gender, race, and age did not significantly affect responses. Coronary heart disease morbidity and mortality data were collected but not analyzed for this study. CONCLUSION: Older subjects of both genders and a variety of racial and ethnic groups can be successfully recruited into a cholesterol-lowering trial. Lovastatin has effects similar to those reported in younger subjects in previous controlled trials. There is little advantage to the higher lovastatin daily dose. Side effects were remarkably low in all groups.

Efficacy and safety of pravastatin in African Americans with primary hypercholesterolemia.

BACKGROUND: Coronary artery disease strikes early and may prove particularly severe in persons of African-American descent. Therefore, we studied the lipid-lowering efficacy and safety of pravastatin sodium (20 mg/d), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in 245 African-American patients with primary hypercholesterolemia. METHODS: After 4 weeks on an American Heart Association phase I low-fat diet, patients were randomized in a double-blind manner to either pravastatin or placebo in a 3:1 ratio. RESULTS: After 12 weeks of pravastatin treatment, low-density lipoprotein cholesterol levels declined 25.8%, total cholesterol levels 20.3%, and triglyceride levels 6.2%, while high-density lipoprotein cholesterol levels remained essentially unchanged. Overall, 72% of pravastatin-treated patients achieved reductions in low-density lipoprotein cholesterol level in excess of 20%, and 44% attained declines in excess of 30% (both P < .01 vs placebo). Pravastatin was generally well tolerated in this population, with one patient (0.5%) exhibiting a reversible myopathy with creatine kinase elevations to 10 times the upper limit of normal. No substantial elevations of aminotransferase levels of two to three times the upper limit of normal occurred in either the pravastatin or the placebo group. Drug compliance was high, exceeding 90%. CONCLUSION: Pravastatin appears to be an effective and safe lipid-lowering agent and is the first 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor to be studied extensively in this underrepresented population.

Effects of unopposed conjugated equine estrogen on lipoprotein composition and apolipoprotein-E distribution.

Administration of conjugated equine estrogen to 31 postmenopausal women for 3 months produced 14.6% and 9.4% decreases in low density lipoprotein cholesterol (LDL-C) and apolipoprotein-B (apoB), and 11.5%, 12.7%, and 9.6% increases in high density lipoprotein cholesterol (HDL-C), apoA-I and apoA-II, respectively. Phospholipids of HDL2 and HDL3 were increased 57.9% and 19.3%, respectively, while relatively small increases in cholesterol of the two subfractions were not significant. Compositions of LDL and HDL and its subfractions were altered substantially with estrogen treatment. The proportion of LDL triglyceride to LDL-C was increased. The phospholipid content in both the HDL2 and HDL3 subfractions (compared to cholesterol) was increased significantly (34.8% and 10.7%, respectively), while the triglyceride content was increased only in the HDL2 subfraction (43.6%). Estrogen use also caused a 9.1% reduction in total apoE levels and a redistribution of apoE to the very low density lipoprotein (VLDL) from the LDL plus HDL fraction, resulting in a significant 19.5% decrease in apoE in the LDL plus HDL fraction. Changes in apoE in the VLDL fraction were associated positively with changes in the cholesterol levels of the VLDL fraction and inversely with changes in LDL-C and apoB levels, while changes in apoE in the LDL plus HDL fraction were associated positively with changes in the levels of HDL-C. Thus, estrogen causes alterations in lipoproteins that could potentially affect their metabolism and/or function.

Hypocholesterolemic effects of a dietary fiber supplement.

The cholesterol-lowering effects of a fiber supplement were evaluated in patients with mild to moderate hypercholesterolemia. After a 9-wk diet stabilization period, patients were randomly assigned to treatment with 10 or 20 g/d of the fiber supplement or with a matching placebo. Among patients who completed the 15-wk treatment period, total cholesterol, LDL cholesterol, and the ratio of LDL to HDL (LDL/HDL) were significantly reduced (P < 0.05) for the 10- (n = 40) and 20-g/d (n = 39) groups compared with the placebo group (n = 48). In the placebo group and 10- and 20-g/d groups, the percent changes in total cholesterol were 0.4%, -5.8%, and -4.9%, in LDL cholesterol were -0.4%, -8.1%, and -7.3%, and in LDL/HDL were 1.0%, -5.6%, and -8.7%, respectively. The fiber supplement had no significant effects (P > 0.05) on HDL cholesterol or triglycerides. The changes in lipoprotein concentrations could not be attributed to changes in diet or body weight because there were no significant changes in these variables during the 15-wk treatment period.

Cholesterol and public policy.

Cholesterol lowering in both primary and secondary prevention has been clearly demonstrated to lower coronary morbidity and, in secondary prevention, to lower coronary mortality as well. Putative dangers of cholesterol lowering remain unproven. Population studies linking low cholesterol to noncoronary mortalities do not demonstrate cause-and-effect relations. In fact, based on current studies, the opposite is more likely to be the case. Neither gender nor age should automatically exclude persons from cholesterol screening. Drug intervention, however, should be used conservatively, particularly in young adults and the elderly. Drugs should be used only after diet and lifestyle interventions have failed. The evidence linking high blood cholesterol to coronary atherosclerosis and cholesterol lowering to its prevention is broad-based and definitive. Concerns about cholesterol lowering and spontaneously low cholesterols should be pursued but should not interfere with the implementation of current public policies to reduce the still heavy burden of atherosclerosis in Western society.

Management of postmenopausal women who have hyperlipidemia.

Dyslipoproteinemia is prevalent in women as well as in men. In both, its consequences of premature atherosclerosis and coronary artery disease (CAD) morbidity and mortality are common. Although clinical evidence of the benefits of cholesterol lowering is less abundant in women, it is not entirely absent. As in men, cholesterol lowering in women is associated with a decline in CAD risk and regression of coronary atherosclerosis.

Androgens and women's health: genetic and epidemiologic aspects of lipid metabolism.

Lipoprotein metabolism may be viewed as a process whereby large, triglyceride-carrying particles from the intestine and liver are broken down into smaller cholesterol-enriched lipoprotein particles. In the process, triglyceride is transported from the intestine and liver to adipose and other storage tissues. Androgen appears to affect lipoprotein metabolism in a number of ways. These include: increasing the activity of lipoprotein lipase and hepatic triglyceride lipase, resulting in higher levels of triglyceride in adipose tissue and a drop in total circulating high-density lipoprotein levels, respectively, and decreasing catabolic removal of low-density lipoproteins from circulating plasma. In pre- and postmenopausal women, androgen progestins in some oral contraceptives, especially the older 19-nortestosterone derivatives such as norgestrel, lower high-density lipoprotein and raise low-density lipoprotein levels. Newer 19-nortestosterone derivatives, such as desogestrel and norgestimate, have a lesser effect on circulating lipoproteins. Nonoral androgenic progestins (e.g., subcutaneous norgestrel) have little effect on circulating lipids, however, which indicates the significance of the "first pass" through the liver for oral agents. The effects of androgens on atherogenesis are largely unexplored, although preliminary studies indicate that they may promote the atherogenic process.

Long-term treatment of hypercholesterolemia with dietary fiber.

PURPOSE: To evaluate the hypocholesterolemic effects of long-term treatment (36 to 51 weeks) with a mixture of dietary fibers (guar gum, pectin, soy, pea, corn bran) administered twice a day. PATIENTS AND METHODS: Fifty-nine subjects with moderate hypercholesterolemia who completed a 15-week, placebo-controlled study with the dietary fiber were treated for an additional 36 weeks with 20 g/day of fiber. Subjects were counseled and monitored on a National Cholesterol Education Program (NCEP) Step-One Diet before starting and during treatment. Analyses of changes in lipoprotein values during the additional 36 weeks of treatment took into account changes in weight, diet, and other variables that might have affected the response to treatment. RESULTS: There were no significant effects on the levels of either triglycerides or high-density lipoprotein cholesterol (HDL-C). Levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and the LDL/HDL ratio were significantly reduced during treatment. The mean percentage reductions from baseline after 51 weeks of treatment were approximately 5% for TC, 9% for LDL-C, and 11% for the LDL/HDL ratio. Changes were apparent after 3 weeks of treatment, with the maximum reductions occurring by the 15th week of treatment. CONCLUSIONS: For subjects on a Step-One Diet who complied with the treatment regimen, the moderate cholesterol-lowering effects of the fiber persisted throughout the 36-to-51 week treatment period.

Women, dyslipoproteinemia, and estrogens.

The most common cause of death in both men and women is coronary atherosclerosis, although atherosclerotic death in women occurs 5 to 10 years later than it does in men. Major risk factors predict coronary risk in both. Available evidence suggests that women benefit from cholesterol lowering just as men do. The role of exogenous estrogenic compounds in favorably affecting lipoprotein levels and promoting antiatherogenesis in both men and women is a promising area for future research.

At what levels of total low- or high-density lipoprotein cholesterol should diet/drug therapy be initiated? United States guidelines.

Guidelines for the detection, evaluation and treatment of hypercholesterolemia in adults have been established in the United States. These guidelines recommend that total cholesterol levels be used for screening purposes. Total cholesterol levels greater than 240 mg/dl are considered "high," those from 200 to 239 mg/dl "borderline," and those less than 200 mg/dl "normal," regardless of the person's age or gender. All persons in the high category, as well as those in the borderline category who have other risk factors or established vascular disease, require measurements of low-density lipoprotein (LDL) cholesterol levels. LDL cholesterol levels are used to guide the selection of treatment. Patients with LDL cholesterol levels greater than 130 mg/dl are candidates for active diet therapy. Those whose LDL cholesterol levels are 160 to 190 mg/dl after 3 to 6 months of diet therapy are candidates for drug therapy. A high-density lipoprotein (HDL) level less than 35 mg/dl is considered a risk factor and may influence the level of LDL at which drug therapy is initiated. Some observers have expressed concern that these guidelines overemphasize LDL cholesterol at the expense of total cholesterol, HDL cholesterol and triglyceride levels. Nevertheless, the guidelines have been broadly accepted and currently serve as the basis for a widespread public-health education program.

Cholesterol lowering, low cholesterol, and mortality.

Cholesterol lowering in both primary and secondary prevention has been clearly demonstrated to lower coronary morbidity and, in secondary prevention, to lower coronary mortality as well. Putative dangers of cholesterol lowering remain unproven. Population studies linking low cholesterol to noncoronary mortalities do not demonstrate cause-and-effect relations. In fact, based on current studies, the opposite is more likely to be the case. Neither gender nor age should automatically exclude persons from cholesterol screening. Drug intervention, however, should be used conservatively, particularly in young adults and the elderly. Drugs should be used only after diet and lifestyle interventions have failed. The evidence linking high blood cholesterol to coronary atherosclerosis and cholesterol lowering to its prevention is broad-based and definitive. Concerns about cholesterol lowering and spontaneously low cholesterols should be pursued but should not interfere with the implementation of current public policies to reduce the still heavy burden of atherosclerosis in Western society.

Unresolved issues in early trials of cholesterol lowering.

A reexamination of early intervention trials in patients with coronary artery disease (CAD) shows that a pessimistic view of cholesterol reduction in such patients is inappropriate. In observational studies, individuals with documented coronary artery disease and elevated cholesterol levels fare worse than individuals with normal or low cholesterol levels. Early trials of cholesterol reduction in individuals with coronary artery disease succeeded in lowering total cholesterol levels by only 5-15%. Nevertheless, when reviewed in meta-analysis, these trials demonstrated borderline effects on total mortality, statistically significant benefits in terms of morbidity and mortality due to cardiovascular disease and CAD, and no increase in mortality from noncardiovascular causes. Substantially greater lowering of low density lipoprotein (LDL) levels was achieved in early regression studies. In these studies, examples of improvement were noted in individual coronary artery segments. What was not appreciated initially was the dramatic reduction in coronary events. Older secondary prevention trials did not definitively address the benefits of cholesterol reduction in individuals whose cholesterol levels were only modestly elevated (total cholesterol, 160-240 mg/dl [4.14-6.21 mmol/liter], and LDL cholesterol levels 100-160 mg/dl [2.59-4.14 mmol/liter]). Several other issues were not addressed in these early studies, including the effect of declines in triglyceride levels, increases in high density lipoprotein (HDL) levels, and the effects in women and individuals aged > 60 years. Even with these limitations, a comparison of meta-analyses of other medical interventions--i.e. beta blockade and aspirin therapy--indicates that declines in coronary mortality are in the same range as obtained in older studies with modest cholesterol reduction--i.e., 20-25%.(ABSTRACT TRUNCATED AT 250 WORDS)

Future cardiovascular end point studies: where will the research take us?

Coronary artery disease is the most common cause of death in the world. Emerging concepts of atherosclerosis imply that atherosclerosis is a diffuse disease, and cannot be definitively treated with local, anatomic interventions, such as coronary artery bypass graft surgery or angioplasty. Cholesterol lowering, on the other hand, has been shown to dramatically lower the rate of both morbid and mortal coronary events. In trials with new statin drugs, coronary risk has been lowered by approximately 30%. Additional risk reduction will require other approaches, including (1) intervention for other risk factors, (2) more aggressive cholesterol lowering, or (3) increased attention to primary prevention. The last requires a combination of public health measures to change harmful diet and life-style patterns as well as case findings to identify and treat at-risk subjects. For all these approaches, measures that will increase compliance by both physicians and patients to regimens with proven benefits are required.

Serum magnesium levels in symptomatic atrial fibrillation and their relation to rhythm control by intravenous digoxin.

To study the effect of hypomagnesemia on control of atrial fibrillation (AF), serum magnesium levels were determined in 45 consecutive patients with symptomatic AF; 20% were hypomagnesemic (serum magnesium less than 1.5 mEq/liter). In a blinded treatment protocol, hypomagnesemic patients required twice the amount of intravenous digoxin to effect control of AF (p less than 0.05). Underlying diagnoses, blood chemistries and the use of other medications that could affect digoxin therapy were similar for the 2 groups. Diuretic therapy before inclusion into the study was not significantly associated with hypomagnesemia. Thus, hypomagnesemia is common among patients with symptomatic AF. Moreover, it appears to interfere with the effect of intravenous digoxin on AF. These results suggest that monitoring of serum magnesium and, where necessary, replacement of magnesium deficiency may be beneficial in patients with symptomatic AF for whom digoxin therapy is being contemplated.

Lipoprotein and apolipoprotein levels in angiographically defined coronary atherosclerosis.

Recent studies suggest that apolipoproteins and subfractions of high-density lipoprotein (HDL) cholesterol may be better predictors of atherosclerotic coronary artery disease (CAD) than are plasma cholesterol and total HDL cholesterol. To examine this hypothesis, plasma cholesterol and triglyceride, cholesterol of low-density lipoprotein, HDL and its subfractions 2 and 3, apolipoprotein A-I, the apolipoprotein B of low-density lipoprotein, the ratio of apolipoprotein EII to EIII, and ratios of several of these variables were measured in a selected series of 126 patients (83 men and 43 women) who underwent coronary angiography for suspected CAD. Mean values of many of these variables differed significantly between the men with CAD and the men without significant CAD, when controlled for age, use of beta blockers and diuretic drugs. Using multivariate logistic regression analysis, the only variable that made a significant independent contribution in predicting CAD in men was the ratio of HDL cholesterol to total plasma cholesterol (p less than 0.0001). The mean of this ratio was 0.17 +/- 0.01 mg/dl in the men with CAD and 0.23 +/- 0.02 mg/dl in the male controls. All men with ratios of less than 0.15 mg/dl had significant CAD, defined as 50% or greater luminal diameter narrowing of 1 or more of the major coronary arteries. No measurement was a significant univariate or multivariate predictor of CAD in the women, but the power to detect such predictors was reduced because of small group sizes. In conclusion, the ratio of HDL cholesterol to plasma cholesterol may be superior to many of the more recently described lipoprotein and apolipoprotein-derived predictors of CAD.