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(Circulation. 1997;95:1-4.)
© 1997 American Heart Association, Inc.

Articles

Small LDL, Atherogenic Dyslipidemia, and the Metabolic Syndrome

Scott M. Grundy, MD, PhD

the University of Texas Southwestern Medical Center at Dallas.

Correspondence to Scott M. Grundy, MD, PhD, University of Texas Southwestern Medical Center at Dallas, Center for Human Nutrition, 5323 Harry Hines Blvd, Dallas, TX 75235.

	Introduction

Top Introduction References

 
A high serum cholesterol has been increasingly acknowledged as being a major risk factor for coronary heart disease (CHD). Several types of evidence support the cholesterol-CHD link; these encompass research in laboratory animals, epidemiological studies, findings of premature CHD in genetic forms of hypercholesterolemia, laboratory investigations, and clinical trials of cholesterol-lowering therapy. Most people with a high serum cholesterol also have elevated LDL because much of the serum cholesterol is transported in LDL. The concept therefore has emerged that LDL is the predominant atherogenic lipoprotein. The National Cholesterol Education Program (NCEP)¹ specifically designated LDL cholesterol as the primary target of cholesterol-lowering therapy. This assignment of priority to LDL cholesterol seems to be fully vindicated by recent clinical trials.^{2 3 4} These trials tested HMG CoA reductase inhibitors (statins), which mainly lower LDL, for effects on coronary morbidity and mortality. Statin therapy in these trials produced astonishing reductions in new coronary events; these reductions almost certainly were a result of concomitant decreases in LDL levels.

Among the different risk factors for CHD, a raised LDL level appears to be primary. Strong evidence indicates that high LDL concentrations initiate atherogenesis and promote atherosclerosis at every stage. The remarkable finding that LDL-lowering therapy reduces risk for subsequent coronary events even in patients with advanced atherosclerotic disease discloses a role for LDL in late stages of atherogenesis.^{2 3 4} Moreover, populations devoid of some elevations of LDL levels exhibit relatively low prevalence of CHD even when other coronary risk factors, eg, cigarette smoking, hypertension, and diabetes mellitus, are common.⁵ An elevated LDL thus is at the core of atherogenesis. Table 1 classifies LDL-cholesterol levels according to NCEP guidelines; approximate corresponding values for total cholesterol also are listed. In the United States, most CHD occurs in patients who have borderline high-risk or high-risk LDL levels; CHD rarely develops when LDL-cholesterol levels are optimal (ie, <100 mg/dL).⁶

View this table: [in this window] [in a new window]   Table 1. Classification of LDL Cholesterol

Despite overwhelming evidence that LDL is an atherogenic lipoprotein, the precise mechanisms whereby LDL promotes atherosclerosis remain unknown. According to current concepts, circulating LDL particles filter into the arterial wall, where they elicit an atherogenic response. Most investigators believe that LDL particles must undergo modification before they become pathogenic. Several postulated modifications include oxidation, aggregation, glycation, and enzymatic degradation. A final answer as to which of these or other modifications impart atherogenicity to LDL awaits further research.

Although NCEP singled out LDL cholesterol as the principal target of therapy, several points must be made about LDL in general. First, the LDL-cholesterol concentration fails to precisely count the number of LDL particles; this number derives instead from the LDL–apolipoprotein B (apo B) level. There is one apo B molecule per LDL particle; hence, the LDL–apo B level accurately defines LDL particle number. The ratio of cholesterol to apo B varies from person to person; this explains why the LDL-cholesterol level does not necessarily indicate the number of LDL particles in a given volume of serum.⁷ Second, usual estimates of LDL cholesterol include the cholesterol content of IDL as well as true LDL. IDL typically contributes about 10% to 15% of the cholesterol in the estimated "LDL-cholesterol" value. This seems acceptable, however, because IDL probably rivals LDL in atherogenic potential.

Nonetheless, the LDL+IDL fraction may not include all atherogenic lipoproteins; some lipoproteins within the class of VLDLs probably promote atherosclerosis too. The total apo B level gives the total number of lipoprotein particles in LDL+IDL+VLDL; if most apo B–containing lipoproteins in each fraction are atherogenic, then the total concentration of apo B should indicate CHD risk better than the LDL-cholesterol level does. Furthermore, our studies reveal that the cholesterol content of LDL+IDL+VLDL correlates strongly with total apo B levels.^{7 8} This cholesterol value equates to total cholesterol minus HDL cholesterol; thus, LDL+IDL+VLDL cholesterol may be called non-HDL cholesterol. Some investigators^{7 8 9 10} suggest that the non-HDL cholesterol, a marker for all apo B–containing lipoproteins, better represents "atherogenic cholesterol" than does LDL cholesterol. Other issues nonetheless remain: for example, do all apo B–containing lipoproteins truly possess similar atherogenic potential? The possibility that they do not has been considered for many years; as far back as 1950, Gofman et al¹¹ attributed unusually high atherogenicity to the IDL fraction. Even now, more than 46 years later, we still do not know the relative atherogenic potentials of LDL, IDL, and VLDL. More recently, controversy surrounding this question has been heightened by the discovery of heterogeneity within the various lipoprotein fractions. Fisher¹² first reported heterogeneity within LDL. He used the term "polydisperse" to describe LDL having a wide range of particle sizes; this contrasted to "monodisperse" LDL, which has a narrow range of particle size. Later, Krauss and Burke¹³ and Austin et al^{14 15 16} simplified the approach to defining LDL particle size; these workers divided the LDL pattern into two categories: pattern A and pattern B. The former signifies a predominance of larger particles; the latter denotes a preponderance of smaller LDL particles. Pattern A typically contains "monodisperse" LDL, whereas pattern B often reflects "polydisperse" LDL; most particles in polydisperse LDL consist of small LDL. Pattern A is the most common and most normal LDL pattern. Several retrospective surveys^{14 15 16} suggest that the more abnormal pattern B confers increased risk for CHD. The prospective data from the Quebec Cardiovascular Study¹⁷ uphold this hypothesis; they disclose that high levels of small LDL particles (pattern B) are associated with increased risk of subsequently developing CHD in men. The data further imply that this associated risk is partly independent of other lipoprotein abnormalities.

The Quebec Cardiovascular Study¹⁷ thus provides additional support for the concept that small LDL particles are unusually atherogenic. Its major finding is the apparent independence of the association between LDL particle size and CHD risk. Austin et al^{14 15 16} make similar claims but without the benefit of such a large prospective study. Despite their apparent "independence," small LDLs often coexist with other lipoprotein abnormalities, notably slightly raised triglycerides and low HDL cholesterol; in fact, these three abnormalities are metabolically intertwined. Each one may be atherogenic, but separation of their relative contributions to atherogenesis is difficult. Because of this, the coexistence of slightly raised triglycerides, small LDL, and low HDL cholesterol has called forth the umbrella term "atherogenic lipoprotein phenotype."⁶

In our view, raised triglycerides, small LDL, and low HDL together are not enough to justify the term "atherogenic" independently of some elevation of LDL cholesterol. In populations without raised cholesterol, CHD risk remains low even in the presence of the so-called "atherogenic lipoprotein phenotype." An alternative term that includes LDL cholesterol as a component may be "atherogenic dyslipidemia." The word dyslipidemia implies that lipoproteins are abnormal but plasma total lipids (cholesterol and triglycerides) are in the accepted "normal" range.

Atherogenic dyslipidemia thus can be defined as a fourfold entity (Table 2). Its components include a borderline high-risk LDL cholesterol (130 to 159 mg/dL), moderately raised (often high normal) triglycerides, small LDL particles, and low HDL cholesterol. Most patients in the Quebec study¹⁷ who developed CHD exhibited this constellation of lipoprotein abnormalities. Atherogenic dyslipidemia probably imparts a risk for CHD at least equal to that of isolated, moderate hypercholesterolemia, ie, an isolated LDL cholesterol in the range of 160 to 220 mg/dL; the latter is the major focus of the NCEP for primary prevention.¹ Furthermore, atherogenic dyslipidemia may equal or exceed moderate hypercholesterolemia in prevalence. An issue of considerable interest is the relative contribution of each component of atherogenic dyslipidemia to CHD risk.

View this table: [in this window] [in a new window]   Table 2. Atherogenic Dyslipidemia

There is little doubt that high levels of LDL and IDL raise CHD risk. The contribution of raised VLDL to CHD risk is less certain. Most investigators agree that small VLDL particles (VLDL remnants) have atherogenic potential perhaps equal to that of LDL and IDL. Remnants contain much cholesterol in VLDL; thus, the apparent atherogenicity of VLDL remnants probably justifies adding VLDL cholesterol to "atherogenic cholesterol." Larger VLDL particles, which are rich in triglyceride, probably are less directly atherogenic. Nonetheless, raised VLDL triglycerides may promote atherosclerosis independently of the VLDL-cholesterol level. For example, high triglycerides induce modifications in other lipoproteins; they generate small LDL particles and lower HDL-cholesterol levels.^{15 18} In addition, high triglycerides may produce a procoagulant state that further increases risk.¹⁸ Effects of elevated triglycerides on risk factors that are not usually measured may partly account for claims that high triglycerides are an "independent" risk factor for CHD. Nonetheless, the effects of raised triglycerides per se are difficult to dissociate from those of the LDL and HDL components of the "atherogenic lipoprotein phenotype."^{14 15 16}

Low HDL cholesterol counts as another component of atherogenic dyslipidemia. Epidemiological studies¹⁹ reveal a strong inverse relation between HDL-cholesterol levels and CHD risk. Studies in laboratory animals also suggest that low HDL levels are directly atherogenic. These latter studies are consistent with the concept that low HDL is truly an independent cause of atherosclerosis. Again, however, the common association of low HDL levels with other components of atherogenic dyslipidemia makes it difficult to tease out the quantitative contribution of low HDL per se to CHD risk. A low HDL cholesterol in fact frequently points to the presence of other lipoprotein abnormalities, especially small LDL particles and increased VLDL levels.

The Quebec study¹⁷ and previous investigations^{14 15 16} suggest that a reduced particle size for LDL adds independently to the risk accompanying atherogenic dyslipidemia. The detection of small LDL particles usually means that more LDL particles are present than indicated by LDL-cholesterol levels; and it is possible that the number of LDL particles is more closely related to CHD risk than are levels of LDL cholesterol. This excess of LDL particles could account in part for the independent increment in risk accompanying small LDL. Nonetheless, the Quebec data¹⁷ imply that the presence of small LDL per se enhances risk more than can be explained by higher apo B levels alone. Smaller LDL particles may be more atherogenic than larger ones. The reasons, however, are not clear. Perhaps smaller LDL particles filter more readily into the arterial wall than larger ones. Perhaps they are more prone to modification once they enter the wall. At present we are uncertain.

Despite the results of the Quebec study,¹⁷ it is still difficult to define the independent contributions of several interrelated abnormalities in lipoproteins to atherogenesis. The problem is compounded by the fact that the multiple lipoprotein changes of atherogenic dyslipidemia commonly aggregate with other CHD risk factors,^{16 20} including hypertension, insulin resistance (with or without non–insulin-dependent diabetes mellitus), and a procoagulant state. This frequent aggregation of abnormalities in a single person can be called the syndrome of multiple metabolic risk factors or, for simplicity, the metabolic syndrome (Table 3). The metabolic syndrome has a multifactorial etiology and results from the combination of obesity (especially truncal obesity), physical inactivity, high intakes of cholesterol-raising nutrients, aging, and various genetic factors. All of these factors frequently coexist in single individuals in our society. Thus, any attempt to delineate the independent atherogenicity of one lipoprotein abnormality presumably requires adjustment for all the components of the metabolic syndrome. Such an attempt will undoubtedly prove problematic because of uncertainty in defining the severity of each risk factor. Indeed, it may ultimately be impossible to accurately delineate the independent contributions of each of the elements of the metabolic syndrome to CHD risk because of the confounding effects of the others. Different investigators tend to be advocates for the independent atherogenicity of one or another constituent of the metabolic syndrome; this is appropriate because the role of each deserves more investigation. Still, overemphasis on one factor may underestimate the influence of others.

View this table: [in this window] [in a new window]   Table 3. The Metabolic Syndrome

Defining the overall impact of the metabolic syndrome on atherogenesis nonetheless is a need of increasing importance. It is well established that hypercholesterolemia promotes atherosclerosis and enhances CHD risk. Effective therapeutic modalities for reducing elevated LDL are now in place. Establishing the role of hypercholesterolemia and the development of effective management are major steps forward. The next step in prevention of CHD should focus on control of the metabolic syndrome, which appears to rival hypercholesterolemia in atherogenic potential. Other metabolic risk factors assume increased importance once the LDL-cholesterol level is raised. Recent clinical trials using statin therapy^{2 3 4} document substantial risk reduction through lowering LDL cholesterol even in the presence of the other risk components of the metabolic syndrome. Therefore, decreasing LDL levels is the centerpiece of therapy for reducing CHD risk in patients with the metabolic syndrome as well as in the treatment of hypercholesterolemia. This strategy gives appropriate attention to raised LDL as the primary cause of coronary atherosclerosis.

Nonetheless, another need is to develop therapeutic strategies that will modify the metabolic syndrome as a whole. The possibility of discovering new drugs that can strike at the heart of the metabolic syndrome has been proposed; at present, however, this approach is in its infancy. From a public health perspective, the major causes of the metabolic syndrome are unhealthy life habits (Table 3); thus, for the general public, the best approach to favorably modifying the whole syndrome is through weight control, increased physical activity, and decreased intake of LDL-raising nutrients. For individuals, one or another metabolic abnormality may predominate; when this occurs, genetic aberrations most likely are at fault. In such cases, drug therapy directed toward individual risk factors may be needed. It must be recognized, however, that for many patients this piecemeal approach will incompletely control several coexisting risk factors. More investigation of the key metabolic steps that affect multiple pathways simultaneously thus will be required to yield a satisfactory therapy for high-risk patients exhibiting the metabolic syndrome.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

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