Chyloperitoneum in a peritoneal dialysis patient.

A woman with end-stage renal disease underwent peritoneal dialysis. On initiation of treatment, there was turbid peritoneal dialysis fluid, which proved to be of chylous rather than inflammatory origin. A low-fat and medium-chain triglycerides diet induced visible clearing of the fluid and a decrease in its triglyceride concentration. Challenge with a high-fat diet produced two early recurrences. After 8 months, dietary fat no longer induced chyloperitoneum. The patient was able to continue peritoneal dialysis at home without a recurrence.

Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause.

CONTEXT: Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for coronary heart disease (CHD) events. However, few data exist on the clinical importance of Lp(a) lowering for CHD prevention. Hormone therapy with estrogen has been found to lower Lp(a) levels in women. OBJECTIVE: To determine the relationships among treatment with estrogen and progestin, serum Lp(a) levels, and subsequent CHD events in postmenopausal women. DESIGN AND SETTING: The Heart and Estrogen/progestin Replacement Study (HERS), a randomized, blinded, placebo-controlled secondary prevention trial conducted from January 1993 through July 1998 with a mean follow-up of 4.1 years at 20 centers. PARTICIPANTS: A total of 2763 postmenopausal women younger than 80 years with coronary artery disease and an intact uterus. Mean age was 66.7 years. INTERVENTION: Participants were randomly assigned to receive either conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, in 1 tablet daily (n = 1380), or identical placebo (n = 1383). MAIN OUTCOME MEASURES: Lipoprotein(a) levels and CHD events (nonfatal myocardial infarction and CHD death). RESULTS: Increased baseline Lp(a) levels were associated with subsequent CHD events among women in the placebo arm. After multivariate adjustment, women in the second, third, and fourth quartiles of baseline Lp(a) level had relative hazards (RHs) (compared with the first quartile) of 1.01 (95% confidence interval [CI], 0.64-1.59), 1.31 (95% CI, 0.85-2.04), and 1.54 (95% CI, 0.99-2.39), respectively, compared with women in the lowest quartile (P for trend = .03). Treatment with estrogen and progestin reduced mean (SD) Lp(a) levels significantly (-5.8 [15] mg/dL) (-0.20 [0.53] micromol/L) compared with placebo (0.3 [17] mg/dL) (0.01 [0.60] micromol/L) (P<.001). In a randomized subgroup comparison, women with low baseline Lp(a) levels had less benefit from estrogen and progestin than women with high Lp(a) levels; the RH for women assigned to estrogen and progestin compared with placebo were 1.49 (95% CI, 0.97-2.26) in the lowest quartile and 1.05 (95% CI, 0.67-1.65), 0.78 (0.52-1.18), and 0.85 (0.58-1.25) in the second, third, and fourth quartiles, respectively (P for interaction trend = .03). CONCLUSIONS: Our data suggest that Lp(a) is an independent risk factor for recurrent CHD in postmenopausal women and that treatment with estrogen and progestin lowers Lp(a) levels. Estrogen and progestin therapy appears to have a more favorable effect (relative to placebo) in women with high initial Lp(a) levels than in women with low levels. This apparent interaction needs confirmation in other trials.

Lipoprotein(a) levels and risk of coronary heart disease in men. The lipid Research Clinics Coronary Primary Prevention Trial.

OBJECTIVE: To examine the relationship between elevated levels of lipoprotein(a) [Lp(a)] and coronary heart disease (CHD) risk in a prospective study. DESIGN: Nested case-control study. The cohort consisted of participants in the Lipid Research Clinics Coronary Primary Prevention Trial. SETTING: Lipid research clinics. PARTICIPANTS: The Lipid Research Clinics Coronary Primary Prevention Trial participants (n = 3806) were men, aged 35 to 59 years, with plasma cholesterol levels of 6.85 mmol/L (265 mg/dL) or greater, low-density lipoprotein cholesterol levels of 4.91 mmol/L (190 mg/dL) or greater, and triglyceride levels less than 3.39 mmol/L. Subjects were randomly assigned to either cholestyramine or placebo treatment. The Lp(a) levels were measured in plasma samples obtained prior to randomization in 233 cases (participants who developed CHD in the course of the study) and 390 matched CHD-free controls. A total of 96.95% of the subjects were white, 2.25% were black, and 0.80% were of other race. MAIN OUTCOME MEASURE: Coronary heart disease (either fatal or nonfatal) events during a follow-up of 7 to 10 years. RESULTS: The Lp(a) levels were significantly higher (21%) in cases than in controls (23.7 mg/dL [0.59 mmol/L] and 19.5 mg/dL [0.49 mmol/L], respectively; P < .02). This difference was still statistically significant (P < .01) after controlling for age, body mass index, cigarette smoking, blood pressure, low-density lipoprotein cholesterol level, and high-density lipoprotein cholesterol level. When subjects were divided by treatment, both cholestyramine-treated and placebo-treated CHD subjects had Lp(a) levels 20% to 22% greater than their matched controls. However, possibly because of smaller sample sizes, these differences were no longer statistically significant. CONCLUSIONS: Our data are consistent with the concept that an elevated Lp(a) level is an independent risk factor for CHD in hypercholesterolemic white men.

A quarter century of drug treatment of dyslipoproteinemia, with a focus on the new HMG-CoA reductase inhibitor fluvastatin.

Disorders associated with the overproduction or delayed clearance of beta-very low density lipoprotein and low density lipoprotein (LDL) are strikingly related to premature coronary artery disease. There are five recognized classes of LDL-lowering drugs, each acting through different basic mechanisms. The increased predictability, safety, and efficacy of newer lipid-lowering agents have allowed controlled clinical trials to demonstrate conclusively that reducing LDL leads to a reduction in coronary artery disease. Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is almost completely absorbed, actively targeted to the liver, and secreted in the bile. It has no active circulating metabolites. The safety and efficacy of fluvastatin have been demonstrated in more than 2,500 subjects treated in the United States, Canada, and Europe, and more than 1,000 have been treated for more than 1 year. Combination of fluvastatin with cholestyramine results in additional cholesterol lowering. The Lipoprotein and Coronary Atherosclerosis Study, a randomized, double-blind trial of fluvastatin using quantitative coronary angiography to measure atherosclerotic plaque change and positron emission tomography to evaluate myocardial perfusion (myocardial flow reserve), illustrates the further exploration of lipoproteins and atherogenesis made possible by the availability of this new generation of cholesterol-lowering agents.

Progression of coronary atherosclerosis in patients with probable familial hypercholesterolemia. Quantitative arteriographic assessment of patients in NHLBI type II study.

A computer-assisted method for quantitatively assessing progression and regression of coronary atherosclerosis has been applied, in a fully blinded fashion, to a set of 116 5-year-interval coronary arteriograms obtained between 1972 and 1981 in the National Heart, Lung, and Blood Institute (NHLBI) Type II Study. Coronary changes are described in 54 of these patients who had tendinous xanthomata and hypercholesterolemia consistent with the diagnosis of familial hypercholesterolemia. Among 468 patent lesions of all degrees of severity and among 25 total occlusions identified on the initial arteriogram, 11% progressed by the 95% confidence criterion for assessing change in percent stenosis (+/- 17%), and 1% regressed by using the same criterion. Among 54 patients, 50% had progression only, 6% had regression only, and 4% had mixed progression and regression. Because half of these patients were treated with cholestyramine, these frequencies may underestimate the natural history of their disease progression. Comparable frequencies were obtained by using the 95% confidence criterion for change in stenosis resistance (Rp ratio outside range, 0.35 to 2.9). In properly obtained arteriograms, the Rp parameter is physiologically relevant and is a sensitive index of lesion change with a high signal-to-noise ratio; we advocate its use for detection of progression and regression. Morphologic features, including luminal irregularity and ulceration, increased the likelihood of progression by 1.8- to 5-fold. Surprisingly, significant arterial flexing at the site of the lesion predicted anatomic stability. A lumen narrowed by visible thrombus was 100-fold more likely to regress than were those without it. The initial severity of stenosis correlated strongly with new total occulusion and with disease progression as assessed by Rp change. Because lesion-specific features are important determinants of lesion change, intervention trials that statistically account for the contributions of lesion morphology are likely to provide a more insightful assessment of the therapeutic benefit.

Report on the Lipid Research Clinic trials.

The Lipid Research Clinic Coronary Primary Prevention Trial was a randomized, double-blind, placebo-controlled intervention trial performed in 3806 hypercholesterolaemic (greater than 265 mg dl-1) but asymptomatic men aged 35-59 at entry. The bile acid sequestrant cholestyramine was used to achieve the cholesterol differential in the treatment group. Both groups received a modest low cholesterol-low fat diet. All subjects were followed for at least seven years (mean duration 7.4 years) during which time a mean fall of 8% and 12% in plasma total cholesterol and LDL cholesterol levels respectively relative to levels in placebo controls were achieved and maintained. The cholestyramine group experienced a 19% reduction in risk (P greater than 0.05) of the primary end point-definite coronary heart disease death and/or definite non-fatal myocardial infarction. In addition, the incidence rates for new positive exercise tests, angina, and coronary bypass surgery were all significantly reduced by 25%, 20% and 21%, respectively, in the cholestyramine group. In the treated group, risk reduction was related directly to reduction in total and LDL cholesterol. In a similar but considerably smaller double blind, placebo-controlled, secondary prevention trial where coronary artery lesion change as determined by serial coronary angiography was the end point (The NHLBI Type II Intervention Trial), cholestyramine treatment significantly delayed the progression of atherosclerotic lesions. Plaque progression related directly to both a fall in low density lipoprotein and a rise in high density lipoprotein.

Intermediate-density lipoproteins and progression of coronary artery disease in hypercholesterolaemic men.

Lipoprotein mass concentrations were measured by analytical ultracentrifugation in a subset of 57 hypercholesterolaemic male participants in the National Heart, Lung, and Blood Institute Type II Coronary Intervention Study. 2-year changes in levels of intermediate-density lipoproteins (IDL) of flotation rate 12-20 were strongly predictive of progression of coronary artery disease at 5 years. Changes in serum mass concentrations of low-density lipoproteins (LDL; flotation rate 0-12), very-low-density lipoproteins (VLDL; flotation rate 20-400), high-density lipoproteins (HDL), and the HDL2 and HDL3 subfractions did not differ significantly between men with and without definite progression of coronary artery disease. The relation of IDL mass to disease progression remained significant (p less than 0.05) after adjustment for group assignment to cholestyramine treatment or placebo and was only slightly reduced (p less than or equal to 0.06) by adjustment for changes in LDL mass concentrations. Changes in IDL mass and ratios of HDL-cholesterol to total-cholesterol or LDL-cholesterol were inversely correlated and had a similar ability to predict progression. The findings are consistent with earlier evidence that IDL are directly involved in the development of coronary artery disease and suggest that ratios of HDL-cholesterol to total-cholesterol or LDL-cholesterol may be indicators of coronary disease risk partly owing to relations with IDL metabolism.

Role of dietary intervention in the primary prevention of coronary heart disease. Individuals with high-normal or elevated serum cholesterol levels should be placed on cholesterol-lowering diets.

A large and convincing body of evidence links increased coronary risk with elevated plasma levels of low-density lipoprotein (LDL) cholesterol. Cholesterol in atherosclerotic lesions originates from that circulating in the blood bound to LDL. Even mild degrees of hypercholesterolemia (cholesterol greater than 180 mg/dl) when due to increased levels of LDL are associated with increased risk. Lowering plasma levels of LDL has been clearly shown to reduce coronary risk. We are able to modify plasma levels of LDL by restricting the dietary content of cholesterol and saturated fats. Such diets are safe and can be adhered to by large populations. Available information, reviewed here in detail, supports vigorous efforts to lower cholesterol levels by dietary means, even in the patient with so-called mild hypercholesterolemia. The evidence is overwhelming, the risk is nil, and the potential benefits are substantial.

IAIMS at Columbia: a strategic plan and model project.

This report describes the Integrated Academic Information Management System (IAIMS) prototype project at the Columbia-Presbyterian Medical Center, the factors that led to the selection of this particular project, and the planning for its implementation. The lessons learned to date and implications for the library are summarized.

Changing perspectives in the prevention of coronary artery disease.

Today the question is no longer whether cholesterol reduction is beneficial for those at risk for coronary artery disease; the questions now are when, whom and how to treat. Areas of great interest include extrapolation of current trial results to low density lipoprotein reduction by diet and drugs, and assessment of the value of increasing high density lipoprotein levels by pharmacologic means. We will need to decide what measurements (total cholesterol, lipoprotein cholesterol or lipoprotein apoprotein levels) are of most value to the diagnosis, treatment and follow-up of the at-risk patient. Recommendations, including those of the recently published National Institutes of Health Consensus Panel on Cholesterol Lowering, suggest that our index for diagnosis and treatment should be set considerably lower than it is today. To be successful with a more aggressive approach to cholesterol lowering, we will need to better support, educate and motivate the at-risk patient. Physicians need to become more knowledgeable about what plasma cholesterol is and how to change it. Methods that enhance patient adherence to diet and drug therapy must be developed. We will need to alter lifetime habits and will need the help of both the food industry and better informed consumers, knowledgeable on how to read food labels, if we are to succeed. Ultimately, we will need a 2-pronged approach, focusing on both the physician and the public at large.

Planning and implementation of large clinical trials.

The large-scale collaborative clinical trial has become an important activity in the biomedical research spectrum. It is the clinical trial that determines most precisely the efficacy of treatment of preventive regimens. These large studies, which usually cost tens of millions of dollars and use large numbers of research facilities, have a major impact on research and medical practice. Consequently, it is required that a number of factors be carefully assessed before any such study is undertaken. A formalized decision process has been developed by the National Heart, Lung and Blood Institute to aid in the formulation, design, conduct, analysis and dissemination of the results of clinical trials. This decision process, which provides a planning framework for the trial, is described here. The framework is constructed around three major decision points at which resources are committed: to plan the trial, to conduct the trial, and to terminate and disseminate the results of the trial.

Cholesterol and coronary artery disease. What do clinicians do now?

Coronary atherosclerosis and its clinical sequelae are problems of enormous magnitude. Because the first clinical sign of coronary artery disease may be sudden death, investigators have searched for signs or symptoms of coronary atherosclerosis before it becomes symptomatic. Among these signs or risk factors are elevated plasma levels of total cholesterol or low-density lipoprotein cholesterol, or a reduced level of high-density lipoprotein cholesterol. Recent studies complement older epidemiologic, genetic, metabolic, morphologic, and animal data by demonstrating directly in humans the value of cholesterol change. These studies have shown that a reduction in total plasma cholesterol or in low-density lipoprotein cholesterol and/or an elevation in high-density lipoprotein cholesterol results in decreased development of angina, positive exercise test results, and referral for coronary artery bypass surgery, as well as reductions in more severe cardiovascular end points such as heart attack, heart death, and atherosclerotic plaque progression. In the Lipid Research Clinics Coronary Primary Prevention Trial with hypercholesterolemic men, every 1 percent reduction in plasma cholesterol levels was associated with a 2 percent reduction in coronary risk. Today, the issue is no longer whether a reduction in cholesterol levels is beneficial. The questions now are much more practical: whom to treat, when to treat, and how to treat. The potential public health value of reducing cholesterol levels is enormous. Such a reduction should be espoused by all health care professionals, because it promises a better and longer life for persons at risk for coronary artery disease.