Small, Dense LDL Particles and Coagulation
To the Editor:
The Québec Cardiovascular Study has prospectively shown that the presence of an LDL subfraction profile of increased concentrations of small, dense LDL particles is a significant predictor for the development of ischemic heart disease (IHD) within 5 years in a disease-free, male, middle-aged population.1 Approximately half of the individuals with IHD experienced acute myocardial infarction, whereas the other half developed effort angina. Two major pathophysiological mechanisms are responsible for the development of acute myocardial infarction in these individuals: lipid accumulation in the arterial wall and intracoronary thrombosis.2 Although the association between small, dense LDL particles with other lipids and their role in developing IHD by subendothelial lipid accumulation has been discussed in detail,1 3 the possible role of the LDL subfraction profile in coagulation has not been addressed. This seems particularly important because individuals who developed IHD had an almost 15% higher incidence of diabetes mellitus at baseline than did those who remained free of disease,1 and diabetes mellitus is known to be closely associated with increased coagulation, ie, increased fibrinogen levels; and impaired fibrinolysis, ie, elevated plasminogen activator inhibitor-1 concentrations.4 Even in nondiabetic, healthy subjects, elevated fibrinogen concentrations >2.9 g/L are associated with increased concentrations of small, dense LDL particles, and 40% of the concentration of small, dense LDL particles can be predicted by serum triglycerides and fibrinogen concentrations alone.5 Therefore, it seems important to focus on other factors besides lipids to evaluate the role of small, dense LDL particles in IHD and particularly acute myocardial infarction. It remains to be shown that the independent relationship between LDL peak particle diameter and IHD events in the Québec Cardiovascular Study even holds true when fibrinogen is included in the statistical analysis. If this relationship does persist, then the measurement of the LDL peak particle diameter may emerge as a single parameter to assess the multifactorial coronary risk profile, including insulin resistance, lipids, and coagulation. The development of a routine assay to determine LDL peak particle diameter or concentrations of small, dense LDL particles should then be followed with increased attention.
- Copyright © 1998 by American Heart Association
Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Després J-P. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men: prospective results from the Québec Cardiovascular Study. Circulation. 1997;95:69–75.
Grundy SM. Small LDL, atherogenic dyslipidemia, and the metabolic syndrome. Circulation. 1997;95:1–4. Editorial.
Halle M, Berg A, Keul J, Baumstark MW. Association between fibrinogen concentrations and HDL and LDL subfraction phenotypes in healthy men. Arterioscler Thromb Vasc Biol. 1996;16:144–148.
The measurement of LDL particle size has attracted a great deal of attention over the last 10 years as a way to better assess the risk of ischemic heart disease (IHD). Prospective evidences that have confirmed the significant contribution of small, dense LDL to the risk of IHDR1 should increase further the interest for this new risk factor. In their letter, Halle and colleagues have raised the possibility that LDL particle size, as a marker of insulin resistance, lipoprotein-lipid abnormalities, and impaired fibrinolytic potential, may emerge as the best single indicator of the risk of IHD. We agree with the authors that the impaired fibrinolytic potential that has been associated with the presence of small, dense LDL particlesR2 may be one of several additional mechanisms whereby the small, dense LDL phenotype increases IHD risk beyond what could be explained by the related atherogenic lipoprotein phenotype (hypertriglyceridemia and low HDL cholesterol levels). As mentioned by the authors, diabetes mellitus, a condition frequently associated with small, dense LDL particles, is also characterized by an impaired fibrinolytic activity. Since in our study, the prevalence of diabetes was 15 times greater in case patients than among control subjects, Halle et al have inquired about whether the relationship of the small, dense LDL phenotype to the risk of IHD may be independent of concomitant variations in plasma fibrinogen concentrations. Although we have yet to measure plasma fibrinogen levels in these subjects, we had previously mentioned that exclusion of diabetic men from our study sample did not attenuate the relationship between small, dense LDL and the risk of IHD.R1
At this point, however, we would like to emphasize that before the assessment of LDL particle size can be recommended as a routine laboratory measurement for the determination of IHD risk, other issues must be addressed. First, the assessment of LDL particle size is rather tedious and costly. The cost-effectiveness of performing such an assay should therefore be clearly determined. Second, population-based evidence is clearly warranted because currently published results were derived from nested, case-control studies. Most importantly, we have shown that the risk of developing IHD in men with small, dense LDL particles was dramatically increased when LDL particle number, as estimated by plasma apolipoprotein B concentrations, was also elevated.R1 Our data also suggested that the risk of IHD in men with elevated plasma triglyceride levels (and presumably with small, dense LDL particles) was markedly increased only in those with a concomitant elevation in plasma apolipoprotein B levels.R3 These results emphasize, at least from the clinical perspective, the need to consider apolipoprotein B levels in the determination of the atherogenicity of small, dense LDL particles. Furthermore, the atherogenic lipoprotein phenotype found with small, dense LDL particles is also commonly associated with insulin resistance, which can be crudely detected, at least in nondiabetic individuals, by the presence of fasting hyperinsulinemia, another newly established risk factor for IHD.R4 In this regard, we have suggested that hyperinsulinemia may predict IHD beyond conventional lipoprotein variables partly because of its association with an impaired fibrinolysis.R5
Thus, at this stage, we are not convinced that the measurement of LDL particle size is justified to better assess IHD risk, and additional prospective studies with the simultaneous measurement of a comprehensive set of metabolic risk variables are needed. Until further evidence is available, we believe that the measurement of plasma apolipoprotein B concentrations, combined with plasma triglyceride and HDL cholesterol levels, which are both significant correlates of LDL particle size,R6 may yet provide the best estimate of the risk related to the presence of small, dense LDL particles.
Lamarche B, Tchernof A, Dagenais GR, Cantin B, Lupien PJ, Després J-P. Small, dense LDL particles and the risk of ischemic heart disease: prospective results from the Québec Cardiovascular Study. Circulation. 1997;95:69–75.
Halle M, Berg A, Keul J, Baumstark MW. Association between serum fibrinogen concentrations and HDL and LDL subfraction phenotypes in healthy men. Arterioscler Thromb Vasc Biol. 1996;16:144–148.
Tchernof A, Lamarche B, Nadeau A, Moorjani S, Labrie F, Lupien PJ, Després JP. The dense LDL phenotype: association with plasma lipoprotein levels, visceral obesity and hyperinsulinemia in men. Diabetes Care. 1966;19:629–637.