Showing papers by "Scott M. Grundy published in 1998"

Primary Prevention of Coronary Heart Disease: Guidance From Framingham: A Statement for Healthcare Professionals From the AHA Task Force on Risk Reduction

Abstract: The Framingham Heart Study has contributed importantly to understanding of the causes of coronary heart disease (CHD), stroke, and other cardiovascular diseases. Framingham research has helped define the quantitative and additive nature of these causes or, as they are now called, “cardiovascular risk factors.”1 The National Cholesterol Education Program (NCEP)2 3 has made extensive use of Framingham data in developing its strategy for preventing CHD by controlling high cholesterol levels. The NCEP guidelines2 3 adjust the intensity of cholesterol-lowering therapy with absolute risk as determined by summation of risk factors. The National High Blood Pressure Education Program (NHBPEP) has set forth a parallel approach for blood pressure control. In contrast to the NCEP,2 however, earlier NHBPEP reports issued through the Joint National Committee4 did not match the intensity of therapy to absolute risk for CHD. “Normalization” of blood pressure is the essential goal of therapy regardless of risk status. Blood pressure–lowering therapy is carried out as much for prevention of stroke and other cardiovascular complications as for reduction of CHD risk. Nonetheless, risk assessment could be important for making decisions about type and intensity of therapy for hypertension. Thus, the most recent Joint National Committee report5 gives more attention to risk stratification for adjustment of therapy for hypertension. Although Framingham data have already been influential in the development of national guidelines for risk factor management, the opportunity may exist for both cholesterol and blood pressure programs to draw more extensively from Framingham results when formulating improved risk assessment guidelines and recommending more specific strategies for risk factor modification. The American Heart Association has previously used Framingham risk factor data to prepare charts for estimating CHD risk. Framingham investigators of the National Heart, Lung, and Blood Institute prepared the original charts and have now revised …

Hypertriglyceridemia, Atherogenic Dyslipidemia, and the Metabolic Syndrome

Abstract: The importance of high serum cholesterol, especially a high level of low-density lipoprotein (LDL) cholesterol, as a risk factor for coronary artery disease is well established. Likewise, efficacy for decreasing risk for coronary artery disease by LDL-lowering therapy has recently been documented through clinical trials. However, many high-risk patients manifest elevated serum triglyceride levels, and the role of hypertriglyceridemia in causation of coronary artery disease remains to be elucidated. Nonetheless, there is growing evidence that hypertriglyceridemia is a marker for increased risk for coronary artery disease; in fact, it can serve as a marker for several atherogenic factors. These factors include increased concentrations of atherogenic triglyceride-rich lipoproteins; the atherogenic lipoprotein phenotype, or lipid triad; and the metabolic syndrome. The lipid triad consists of elevated serum triglycerides, small LDL particles, and low high-density lipoprotein (HDL) cholesterol. The metabolic syndrome includes the coexistence of the lipid triad, elevated blood pressure, insulin resistance (plus glucose intolerance), and a prothrombotic state. Many previous studies indicate that hypertriglyceridemia is strongly associated with all of these atherogenic factors. The clinical approach to treatment of patients with hypertriglyceridemia thus requires a broad-based strategy that includes reduction of atherogenic triglyceride-rich lipoproteins, reversal of the lipid triad, and favorable modification of the metabolic syndrome. The development of therapeutic regimens to effect these changes poses a challenge for future research on the problem of hypertriglyceridemia.

Obesity: Impact on Cardiovascular Disease

Abstract: The American Heart Association conference entitled “Obesity: Impact on Cardiovascular Disease” was held May 22–24, 1998, in Amelia Island, Fla. It was cosponsored by Futura Media Services and the American Heart Association Councils on Cardiovascular Nursing; Arteriosclerosis, Thrombosis, and Vascular Biology; Cardiovascular Disease in the Young; Clinical Cardiology; Epidemiology and Prevention; and High Blood Pressure Research; the AHA Nutrition Committee; and the AHA Prevention Coordinating Committee. The proceedings are summarized briefly in this report. A monograph of the conference will be published by Futura Publishing Company, Inc. Obesity is an important determinant of cardiovascular disease (CVD). Previous epidemiological studies of obesity have documented a modest association of obesity and risk of CVD, especially in younger age groups. The study of obesity and CVD should now focus on weight change over time, especially differences between childhood versus younger and older adult weight gains, and the distribution of body fat, especially visceral or intra-abdominal fat. Weight gain during young adult life may be one of the most important determinants of cardiovascular risk factors. Increased intra-abdominal fat, or waist circumference, is probably related to a constellation of risk factors, the so-called insulin resistance syndrome. It is also associated with higher levels of inflammatory markers such as C-reactive protein and fibrinogen. The increasing prevalence of obesity in children is cause for great concern. There is no definition of obesity in children that relates body mass index (BMI) to health outcomes. However, >20% of children aged 6 to 17 years are >20% overweight at the 85th percentile of BMI, and 10% of children aged 6 to 17 are overweight at the 95th percentile. It appears that 50% of children who are overweight are also overweight as adults, but it is not possible to identify any individual child who will become an overweight adult. CVD risk …

Statin Trials and Goals of Cholesterol-Lowering Therapy

Abstract: Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are a breakthrough in the treatment of high serum cholesterol. Several recent clinical trials1 2 3 demonstrate that statins can substantially reduce both morbidity and mortality from CHD. They are becoming a mainstay in management of patients with established CHD (secondary prevention), and they hold promise for high-risk patients without evident CHD (primary prevention). The introduction of statins occurred about the same time as the initiation of the NCEP; this program is a national effort to increase public and professional awareness of the dangers of high serum cholesterol and to emphasize the benefits of reducing serum cholesterol concentrations. Besides the NCEP’s public health effort4 to lower serum cholesterol levels in the general public through modification of life habits, the NCEP has established guidelines for cholesterol management in both secondary prevention and high-risk primary prevention.5 6 These guidelines identify LDL cholesterol as the primary target of therapy, and they specify goals for LDL cholesterol–lowering therapy. For example, the NCEP recommended that high-risk patients who have elevated LDL cholesterol levels but not clinical CHD or other atherosclerotic disease should have their LDL cholesterol concentration reduced to <130 mg/dL.5 6 For patients with CHD or other atherosclerotic diseases, the goal of NCEP is an LDL cholesterol of ≤100 mg/dL.5 6 These therapeutic goals derive from judgments based on epidemiological data and clinical trial results available at the time of reporting. Recent statin trials1 2 3 provide a wealth of data documenting the benefit of cholesterol-lowering therapy in both primary and secondary prevention. A major fact has been established: cholesterol lowering with statins is both safe and effective in high-risk patients. Recent statin trials amply underpin the NCEP’s promotion of efforts for decreasing coronary morbidity or mortality. Of some importance, however, is …

Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21.

Abstract: The molecular mechanisms regulating the amount of dietary cholesterol retained in the body as well as the body's ability to selectively exclude other dietary sterols are poorly understood. Studies of the rare autosomal recessively inherited disease sitosterolemia (OMIM 210250) may shed some light on these processes. Patients suffering from this disease appear to hyperabsorb both cholesterol and plant sterols from the intestine. Additionally, there is failure of the liver's ability to preferentially and rapidly excrete these non-cholesterol sterols into bile. Consequently, people who suffer from this disease have very elevated plasma plant sterol levels and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. Identification of this gene defect may therefore throw light on regulation of net dietary cholesterol absorption and lead to an advancement in the management of this important cardiovascular risk factor. By studying 10 well-characterized families with this disorder, we have localized the genetic defect to chromosome 2p21, between microsatellite markers D2S1788 and D2S1352 (maximum lodscore 4.49, theta = 0.0).

Linkage between cholesterol 7alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations.

Abstract: Interindividual differences in plasma low-density lipoprotein cholesterol (LDL-C) levels reflect both environmental variation and genetic polymorphism, but the specific genes involved and their relative contributions to the variance in LDL-C are not known. In this study we investigated the relationship between plasma LDL-C concentrations and three genes with pivotal roles in LDL metabolism: the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and cholesterol 7alpha-hydroxylase (CYP7). Analysis of 150 nuclear families indicated statistically significant linkage between plasma LDL-C concentrations and CYP7, but not LDLR or APOB. Further sibling pair analyses using individuals with high plasma LDL-C concentrations as probands indicated that the CYP7 locus was linked to high plasma LDL-C, but not to low plasma LDL-C concentrations. This finding was replicated in an independent sample. DNA sequencing revealed two linked polymorphisms in the 5' flanking region of CYP7. The allele defined by these polymorphisms was associated with increased plasma LDL-C concentrations, both in sibling pairs and in unrelated individuals. Taken together, these findings indicate that polymorphism in CYP7 contributes to heritable variation in plasma LDL-C concentrations. Common polymorphisms in LDLR and APOB account for little of the heritable variation in plasma LDL-C concentrations in the general population.

Effect of Statins on Metabolism of Apo-B–Containing Lipoproteins in Hypertriglyceridemic Men

Abstract: Our investigations indicate that most patients with moderate hypertriglyceridemia have marked defects in the metabolism of low-density lipoprotein (LDL) apolipoprotein B. Moreover, these patients have 2 major defects in the metabolism of triglyceride-rich lipoproteins, i.e., an accumulation of remnant lipoproteins (due in part to delayed hepatic clearance) and increased fractional conversion of very-low-density lipoprotein (VLDL) to LDL. Defective triglyceride-rich lipoprotein metabolism has been associated with insulin resistance. Statin therapy in hypertriglyceridemic patients improves the lipoprotein profile by decreasing both LDL cholesterol and remnant lipoproteins. However, statin therapy does not normalize LDL apolipoprotein B metabolism, and high-density lipoprotein (HDL) cholesterol levels remain low. Therefore, consideration may be given to combining a statin with a drug that alters triglyceride metabolism (e.g., fibrate or nicotinic acid) in high-risk patients with hypertriglyceridemia.

Abnormal metabolism of free fatty acids in hypertriglyceridaemic men: apparent insulin resistance of adipose tissue

Abstract: Mostaza JM, Vega GL, Snell P, Grundy SM (The Center for Human Nutrition, and the Departments of Clinical Nutrition and Internal Medicine, University of Texas South Western Medical Center, and the Veterans Affairs Medical Center at Dallas, Texas, USA). Abnormal metabolism of free fatty acids in hypertriglyceridaemic men: apparent insulin resistance of adipose tissue. J Intern Med 1998; 243: 265–74. Objective .There is growing evidence that endogenous hypertriglyceridaemia is frequently accompanied by a state of insulin resistance. The present study was performed to determine whether patients with primary endogenous hypertriglyceridaemia commonly have abnormalities in plasma concentrations and turnover rates of free fatty acids (FFA), which could reflect a state of insulin resistance in adipose tissue and could account for raised plasma triglycerides. Design .Hypertriglyceridaemic and normotriglyceridemic control patients underwent measurements of plasma concentrations and turnover rates of FFA. Fat weights in both groups were determined by hydrodensitometry, and fat distribution was assessed by skin-folds and measurement of waist and hip circumferences. Other measurements included plasma glucose, insulin, lipids, and lipoproteins. Subjects .Fifteen men with normal plasma triglycerides and 21 men with primary endogenous hypertriglyceridaemia were studied. Men in both groups varied in body weights and total fat weights, but total fat weights were entirely overlapping for the two groups. Waist-to-hip ratios and waist circumferences also were similar for the two groups. Results .For any total body fat content or waist circumference, most hypertriglyceridaemia patients had higher mean plasma concentrations of FFA and higher turnover rates (flux) for FFA than did normotriglyceridemic patients. Hypertriglyceridaemic patients also had higher fasting insulin concentrations for a given body fat content. In general, both FFA flux and plasma insulin levels were positively correlated with plasma concentrations of triglyceride and inversely with high density lipoprotein (HDL) cholesterol. Conclusions .These studies indicate that many patients with primary endogenous hypertriglyceridaemia have increased flux of FFA and hyperinsulinemia that cannot be explained either by increased total body fat content or by greater waist circumferences than observed in normotriglyceridemic patients.

Problems on the pathway from risk assessment to risk reduction

Abstract: Assessment of risk and reduction of risk are well-accepted responsibilities of the physician. The pathway from assessment of risk to reduction of risk basically involves three steps: (1) measurement of risk factors and collection of clinical data relevant to patient risk; (2) interpretation of risk-related data with estimation of risk in absolute terms (eg, risk of an event per year) as well as relative terms (ie, low, intermediate, or high compared with others of the same age and sex); and (3) on the basis of risk estimation results, intervention to minimize disease risk or to prevent risk factor development in the future. Although the process seems reasonably straightforward, problems occur at each step that weaken the link between risk assessment and risk reduction. Such problems occur in assessment of CVD risk estimation and reduction just as in most other areas of medical practice in spite of the availability of excellent data relating to CVD risk estimation from the Framingham Heart Study and other similar data sets.1 Periodic measurement of CVD risk factors in healthy people (step 1) is routinely recommended by the AHA, the ACC, and the NHLBI, in addition to other authorities on disease prevention.2 3 4 Blood lipid measurements, blood pressure readings, age, sex, cigarette smoking and diabetic status, ECG findings, and other risk …

Effects of crystalline nicotinic acid-induced hepatic dysfunction on serum low-density lipoprotein cholesterol and lecithin cholesteryl acyl transferase

Abstract: Marked lowering of plasma total and low-density lipoprotein cholesterol levels that occur during treatment of dyslipidemia with pharmacologic doses of nicotinic acid result from hepatotoxicity. Therefore, a marked reduction in low-density lipoprotein may suggest generalized liver toxicity and drug treatment should be discontinued.

Cholesterol management in high-risk patients without heart disease

Abstract: PREVIEWThe benefits of aggressive cholesterol-lowering drug therapy are well established in patients with coronary heart disease (CHD) and other atherosclerotic disorders. But what about high-risk patients without clinical CHD? When is primary prevention appropriate for them? In this article, Dr Grundy discusses selection of high-risk patients for treatment and outlines therapeutic goals and drug options.

On the relationship between cholesterol lowering and coronary disease event rate.

Abstract: To the Editor: Dr Grundy’s editorial published in the April 21, 1998, issue of this journal1 provides an insightful summary of the reevaluations of the databases from the major statin trials (CARE, 4S, and WOSCOPS). These studies provide apparently divergent interpretations of the relationship between cholesterol lowering and coronary benefits experienced by study subjects. In his review, Dr Grundy elaborates on all 3 possible scenarios on the relationship between cholesterol lowering and clinical benefits: a linear model, a threshold model, and a curvilinear model. Whereas data from 4S2 seem to support the concept of a curvilinear relationship between cholesterol reduction and relative risk reduction, the analyses of the CARE3 and the WOSCOPS4 trials support the notion of a linear relationship up to a threshold level beyond which no further benefits are detected for further reductions in plasma cholesterol. Advocation of the possibility of a linear relationship between cholesterol reduction and relative risk of coronary heart disease is not based on biologically plausible bases. If the relationship …