(Circulation. 1998;97:936-937.)
© 1998 American Heart Association, Inc.
Small, Dense LDL Particles and Coagulation
Martin Halle, MD;
Aloys Berg, MD;
; Joseph Keul, MD
Center of Internal Medicine,
Department of Rehabilitation, Prevention and Sports Medicine,
Freiburg University Hospital,
Freiburg, Germany
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.
References
1.
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.[Abstract/Free Full Text]
2.
Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R.
Coronary risk factors and plaque morphology in men with
coronary disease who died suddenly. N Engl J
Med. 1997;336:1276–1282.[Abstract/Free Full Text]
3.
Grundy SM. Small LDL, atherogenic dyslipidemia, and
the metabolic syndrome. Circulation. 1997;95:1–4. Editorial.[Free Full Text]
4.
Ceriello A. Coagulation activation in diabetes mellitus: the
role of hyperglycaemia and therapeutic prospects.
Diabetologia. 1993;36:1119–1125.[Medline]
[Order article via Infotrieve]
5.
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.[Abstract/Free Full Text]
Response
Benoît Lamarche, PhD;
André Tchernof, PhD;
; Jean-Pierre Després, PhD
Lipid Research Center,
CHUL Research Center,
Sainte-Foy (Québec), Canada
Gilles R. Dagenais, MD
Department of Medicine,
University of Montréal,
Québec, Canada
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 IHD1 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
particles2 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.1
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.1 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.3 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.4 In this regard, we have
suggested that hyperinsulinemia may predict IHD
beyond conventional lipoprotein variables partly because of its
association with an impaired
fibrinolysis.5
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,6 may yet provide the best estimate of the
risk related to the presence of small, dense LDL particles.
References
1.
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.
2.
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.
3.
Lamarche B, Després JP, Moorjani S, Cantin B, Dagenais
GR, Lupien PJ. Prevalence of dyslipidemic
phenotypes in ischemic heart disease (prospective
results from the Québec Cardiovascular Study).
Am J Cardiol. 1995;75:1189–1195.[Medline]
[Order article via Infotrieve]
4.
Després JP, Lamarche B, Mauriège P, Cantin B,
Dagenais GR, Moorjani S, Lupien PJ.
Hyperinsulinemia as an independent risk factor for
ischemic heart disease. N Engl J Med. 1996;334:952–957.[Abstract/Free Full Text]
5.
Juhan-Vague I, Alessi MC, Vague P. Increased plasma
plasminogen activator inhibitor 1
levels: a possible link between insulin resistance and
atherothrombosis. Diabetologia. 1991;34:457–462.[Medline]
[Order article via Infotrieve]
6.
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.[Abstract]
