Melissa A. Austin

Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level : a meta-analysis of population-based prospective studies

Objectives Despite nearly 40 years of research, the role of plasma triglyceride as a risk factor for cardiovascular disease remains elusive. The objectives of the present study were to quantify the magnitude of the association between triglyceride and cardiovascular disease in the general population, and to determine whether this relationship is independent of high-density lipoprotein (HDL) cholesterol, using the semi-quantitative techniques of metaanalysis. Methods and design Seventeen studies were selected for the analysis based on published reports of population-based, prospective studies, including 46413 men and 10864 women. To insure comparability, only studies reporting the association between fasting triglyceride levels and incident cardiovascular endpoints were included. Using standard meta-analysis calculations, relative risks (RR) and 95% confidence intervals (CI) were calculated and standardized with respect to a 1 mmol/l increase in triglyceride. Multivariable-adjusted RRs were determined for the six studies in men and two studies in women that reported adjustments for HDL cholesterol. Results For men and women, the univariate RRs for triglyceride were 1.32 (95% CI 1.26–1.39) and 1.76 (95% CI 1.50–2.07), respectively, indicating an approximately 30% increased risk in men and a 75% increase in women. Adjustment of HDL cholesterol and other risk factors attenuated these RRs to 1.14 (95% CI 1.05–1.28) and 1.37 (95% CI 1.13–1.66), respectively, which were still statistically significant values. Conclusion Based on combined data from prospective studies, triglyceride is a risk factor for cardiovascular disease for both men and women in the general population, independent of HDL cholesterol. These finding demonstrate the necessity for clinical trials to evaluate whether lowering plasma triglyceride decreases the risk of cardiovascular disease.

Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk.

In a community-based study of 301 subjects from 61 nuclear families, two distinct phenotypes (denoted A and B) were identified by nondenaturing gradient gel electrophoretic analysis of low density lipoprotein (LDL) subclasses. Phenotype A was characterized by predominance of large, buoyant LDL particles, and phenotype B consisted of a major peak of small, dense LDL particles. Previous analysis of the family data by complex segregation analysis demonstrated that these phenotypes appear to be inherited as a single-gene trait. In the present study, the phenotypes were found to be closely associated with variations in plasma levels of other lipid, lipoprotein, and apolipoprotein measurements. Specifically, phenotype B was associated with increases in plasma levels of triglyceride and apolipoprotein B, with mass of very low and intermediate density lipoproteins, and with decreases in high density lipoprotein (HDL) cholesterol, HDL2 mass, and plasma levels of apolipoprotein A-I. Thus, the proposed genetic locus responsible for LDL subclass phenotypes also results in an atherogenic lipoprotein phenotype.

Hypertriglyceridemia as a Cardiovascular Risk Factor

To determine the relation between plasma triglyceride levels and the risk of incident cardiovascular disease, the semiquantitative techniques of meta-analysis were applied to 17 population-based prospective studies of triglyceride and cardiovascular disease. Sixteen of these studies represented 2,445 events among 46,413 Caucasian men followed for an average period of 8.4 years, and 5 studies represented 439 events among 10,864 Caucasian women followed for an average period of 11.4 years. Univariate relative risk (RR) estimates for incident cardiovascular disease associated with a 1-mmol/L increase in triglyceride was 1.07-1.98 in men, with a summary RR of 1.32 (95% confidence interval [CI]: 1.26-1.39), indicating a 32% increase in disease risk associated with increased triglyceride. In the studies involving women, individual RR estimates for triglyceride were 1.69-2.05, with a summary RR of 1.76 (95% CI: 1.50-2.07), indicating a 76% increase in disease risk associated with increased triglyceride. After adjustment for high-density lipoprotein cholesterol and other risk factors, these risks were decreased to 14% in men and 37% in women but remained statistically significant. Three recent prospective epidemiologic studies have also shown that plasma triglyceride and low-density lipoprotein particle size predict subsequent coronary artery disease in Caucasian populations. Taken together, these studies demonstrate the importance of triglyceride levels as a risk factor for cardiovascular disease.

PLASMA TRIGLYCERIDE AND CORONARY HEART DISEASE

Although the literature on epidemiological associations between plasma triglyceride and CHD is not completely consistent, trends do emerge from the studies described here. First, the majority of observational studies demonstrate a significant univariate relation, although the results of case-control and cross-sectional studies are more uniform than those from prospective study designs. In many but not all studies, triglyceride remains a significant predictor of CHD in multivariate statistical analyses after controlling for TC or LDL-C. Perhaps the least consistent result is that the triglyceride association does not persist in some analyses controlling for HDL-C, while in other studies, the association remains significant. Although most studies have been conducted in men, the studies providing data on women, normocholesterolemic subjects, and diabetic subjects have generally found triglyceride to be, at the very least, a univariate risk factor. The results of intervention trials differ considerably, but no such study to date has been specifically designed to evaluate triglyceride-lowering effects on primary prevention of CHD. Important statistical properties must be taken into consideration in evaluating triglyceride as a risk factor for CHD. The large variability of triglyceride measurements and the correlation of triglyceride values with other lipid measures appears to result in the underestimation of the association between triglyceride and disease in multivariate analyses. Finally, individual genetic susceptibility may play an important role in the relation between plasma triglyceride levels and CHD. For example, risk of CHD clearly varies among the well-established familial forms of hypertriglyceridemia. A predominance of small, dense, LDL particles (LDL subclass pattern B) also appears to be a genetic trait associated with both increased risk of MI and increases in plasma triglyceride levels.

Family History as a Risk Factor for Primary Cardiac Arrest

BACKGROUND The hypothesis that a family history of myocardial infarction (MI) or primary cardiac arrest (PCA) is an independent risk factor for primary cardiac arrest was examined in a population-based case-control study. In addition, we investigated whether recognized risk factors account for the familial aggregation of these cardiovascular events. METHODS AND RESULTS PCA cases, 25 to 74 years old, attended by paramedics during the period 1988 to 1994 and population-based control subjects matched for age and sex were identified from the community by random digit dialing. All subjects were free of recognized clinical heart disease and major comorbidity. A detailed history of MI and PCA in first-degree relatives was collected in interviews with the spouses of case and control subjects by trained interviewers using a standardized questionnaire. For each familial relationship, there was a higher rate of MI or primary cardiac arrest (MI/PCA) in relatives of case compared with relatives of control subjects. Overall, the rate of MI/PCA among first-degree relatives of cardiac arrest patients was almost 50% higher than that in first-degree relatives of control subjects (rate ratio [RR]=1.46; 95% CI=1.23 to 1.72). In a multivariate logistic model, family history of MI/PCA was associated with PCA (RR=1.57; 95% CI=1.27 to 1.95) even after adjustment for other common risk factors. CONCLUSIONS Family history of MI or PCA is positively associated with the risk of primary cardiac arrest. This association is mostly independent of familial aggregation of other common risk factors.

Inheritance of low density lipoprotein subclass patterns in familial combined hyperlipidemia.

The inheritance of low density lipoprotein (LDL) subclass patterns was investigated in 234 members of seven large kindreds with familial combined hyperlipidemia (FCHL), a disorder characterized by elevated LDL cholesterol and/or triglyceride and increased coronary disease risk in families. Analysis of LDL subclasses by nondenaturing gradient gel electrophoresis showed a predominance of large, buoyant LDL particles (pattern A) in 71% of the family members and a predominance of small, dense LDL particles (pattern B) in 29% of family members. Based on complex segregation analysis, pattern B appeared to be inherited as an autosomal trait with either a dominant or an additive mode of inheritance and a small, but significant, multifactorial inheritance component. The proposed allele for pattern B was common (frequency = 0.3), and reduced penetrance was observed among men under age 20 and among women under age 50. These results in these FCHL families are consistent with those from a previously reported population-based sample of families, in which pattern B showed an apparent dominant mode of inheritance. In that study, reduced penetrance was observed for men under age 20 and for premenopausal women, but a somewhat lower allele frequency was found for pattern B (0.25). In the FCHL family members, LDL subclass pattern B was associated with significantly increased plasma levels of apolipoprotein B and triglyceride and decreased high density lipoprotein cholesterol. In comparison with a group of controls, the FCHL family members with pattern A had similar mean triglyceride levels, but higher mean apolipoprotein B. Thus, in families with FCHL, a predominance of small, dense LDL particles appears to be inherited as a common, single-gene trait, which is closely associated with the higher plasma triglyceride levels found in these families. The increased plasma apolipoprotein B levels found in FCHL cannot, however, be accounted for by this proposed locus.

Effect of hepatic lipase on LDL in normal men and those with coronary artery disease.

Hepatic triglyceride lipase (HL) is thought to play a role in the formation of low density lipoproteins (LDLs) from small very low density lipoproteins (VLDLs) and intermediate density lipoproteins (IDLs). To analyze the possible physiological role of HL in determining LDL buoyancy, size, and chemical composition, HL activity and LDL were studied in 21 patients with coronary artery disease (CAD) and 23 normolipidemic subjects. In both groups, LDL buoyancy and size were inversely associated with HL activity levels. The effect of HL on LDL size was comparable in CAD patients and in normolipidemic subjects. HL appeared to influence LDL lipid composition primarily by affecting the surface lipid components. The free cholesterol content of LDL particles was highly correlated with HL activity in both CAD and normolipidemic individuals. The free cholesterol to phospholipid ratio in LDL particles correlated with HL in both CAD and normolipidemic subjects. When the individuals were separated according to their LDL subclass patterns, pattern B subjects had significantly higher HL than pattern A subjects in both CAD and normolipidemic groups. The analysis of the cholesterol distribution profiles across the lipoprotein density gradient confirmed that LDL buoyancy is affected by HL. These data support the hypothesis that HL modulates the physical and compositional properties of LDL and contributes to the expression of the LDL subclass phenotype, suggesting a physiological role for HL in LDL metabolism.

Cardiovascular Disease Mortality in Familial Forms of Hypertriglyceridemia: A 20-Year Prospective Study

BACKGROUND Familial combined hyperlipidemia (FCHL) and familial hypertriglyceridemia (FHTG) are 2 of the most common familial forms of hyperlipidemia. There is a paucity of prospective data concerning the risk of cardiovascular disease (CVD) in such families. The purposes of this study were to estimate 20-year total and CVD mortality risk among relatives in these families and to evaluate plasma triglyceride as a predictor of death. METHODS AND RESULTS The study was based on lipid and medical history data from 101 families ascertained in 2 studies conducted in the early 1970s. Vital status and cause of death was determined during 1993 to 1997 for 685 family members, including first-degree relatives of the probands and spouse control subjects. Compared with spouse control subjects, 20-year CVD mortality risk was increased among siblings and offspring in FCHL (relative risk 1.7, P=0.02) after adjustment for baseline covariates. In FHTG families, the relative risk was also 1.7 but was not statistically significant (P=0.39). Baseline triglyceride was associated with increased CVD mortality risk independent of total cholesterol among relatives in FHTG families (relative risk 2.7, P=0.02) but not in FCHL families (relative risk 1.5, P=0.16) after adjustment for baseline covariates. CONCLUSIONS This prospective study establishes that relatives in FCHL families are at increased risk for CVD mortality and illustrates the need for effective prevention strategies in this group. Baseline triglyceride level predicted subsequent CVD mortality among relatives in FHTG families, adding to the growing evidence for the importance of hypertriglyceridemia as a risk factor for CVD.

Prospective Study of Small LDLs as a Risk Factor for Non–Insulin Dependent Diabetes Mellitus in Elderly Men and Women

BACKGROUND The excess risk of atherosclerosis among patients with non-insulin dependent diabetes mellitus (NIDDM) is well documented. However, the presence of conventional risk factors cannot fully account for this excess risk, and the underlying mechanism remains to be elucidated. The present study prospectively evaluated the role of small LDL, a known risk factor for coronary heart disease, as a risk factor for the development of NIDDM. METHODS AND RESULTS The study was based on a nested case-control sample of 204 elderly men and women from Kuopio, Finland. LDL subclasses were characterized by size with 2% to 14% polyacrylamide gels produced by recently developed methods. Logistic regression analysis showed that subjects with a predominance of small LDL (LDL subclass phenotype B) had a greater than two fold increased risk for developing NIDDM over the 3.5-year follow-up period. This association was independent of age, sex, glucose intolerance, and body mass index but was not independent of fasting triglyceride or insulin levels. Further, an increase of 5A in LDL diameter was associated with a 16% decrease in risk of NIDDM, and a composite variable of LDL diameter and triglyceride and HDL cholesterol concentrations, identified by principal-components analysis, was also associated with NIDDM. These associations may be attributable to the role of small LDL as a marker for insulin resistance. CONCLUSIONS This study is the first to demonstrate that a predominance of small LDL particles is a risk factor for the future development of NIDDM, and it implies that small LDL contributes to risk of coronary heart disease in prediabetics.

Characterization of low-density lipoprotein subclasses: methodologic approaches and clinical relevance.

Emerging evidence suggests that subclasses of LDL, characterized by variations in density, size, and chemical composition of LDL particles, are of important clinical significance. Accumulating case-control studies demonstrate that a predominance of small, dense LDL particles (LDL subclass phenotype B) is associated with an increased risk of coronary heart llisease, and several potential atherogenic mechanisms have been proposed. New studies also demonstrate that LDL subclass phenotype B is an integral feature of the insulin resistance syndrome. In addition to the well-documented genetic influences on LDL subclass distributions, lipid-altering drugs, diet, and exercise all appear to affect LDL subclasses. A better understanding of this combination of genetic and environmental influences coold lead to the development of effective intervention strategies for the prevention of coronary heart disease.