Medical Director,
Rockford Cardiology Lipid Clinic,
Rockford, Ill
To the Editor:
The age-standardized mortality rates for coronary artery
disease among women is about one half to one fourth that of men,
although this rate varies more than 10-fold among men as well as women
worldwide. This phenomenon is due to the well-known premenopausal
protection, delaying the development of coronary artery disease
by 10 to 15 years in women.1 Coronary
artery disease is considered to be premature when it occurs before the
age of 65 in women, in contrast to 55 in men. Because the average age
of menopause has been 50 to 51 years for centuries, coronary
artery disease in premenopausal women represents the most
premature form of coronary artery disease and is extremely
rare, except perhaps among Asian Indians.2 For
example, each year only
The strong correlation of serum lipoprotein(a) levels with
coronary artery disease in premenopausal women in this study
adds significantly to our growing understanding of the importance of
lipoprotein(a) as a powerful risk factor for premature coronary
artery disease in both sexes.7 Because stable
lifelong levels of lipoprotein(a) are attained in infancy, the
pathological processes associated with elevated lipoprotein(a) also
begin in infancy (20 years earlier than other risk factors such as
hypertension, cigarette smoking, and diet-related
dyslipidemias). This early onset of high-risk status, along
with the high atherogenicity (10 times higher than LDL) and the high
thrombogenicity of lipoprotein(a), appears to explain its strong
association with premature coronary artery
disease.2
Other investigators have focused on diabetes mellitus as the dominant
determinant of coronary artery disease in premenopausal women.
Diabetes is associated with a relative risk of coronary artery
disease that is approximately twice as high in women as in
men.1 In the Rancho Bernardo
Study,8 after a 12 year follow-up, women with
diabetes had a relative risk of fatal coronary artery disease
similar to that of men with or without diabetes. No other risk factor
so nearly erases the female advantage.1 This
study by Orth-Gomér et al3 offers a unique
opportunity to ascertain if elevated lipoprotein(a) is a stronger risk
factor for coronary artery disease (higher prevalence, odds
ratio, or attributable risk) than diabetes in premenopausal women.
In patients with combined elevations of serum LDL and lipoprotein(a),
Maher et al9 found a marked reduction in the
angiographic progression of coronary artery disease as well as
clinical event rates, with substantial lowering of LDL without any
lowering of the lipoprotein(a) level. They argue that the pathogenicity
of lipoprotein(a) is modulated by concomitant LDL levels and recommend
lowering the latter as the preferred treatment of the
former.9 Solymoss et al10
found a powerful multiplicative adverse effect of elevated serum levels
of lipoprotein(a) with low levels of HDL cholesterol. In
women younger than 60 years of age, the risk of coronary artery
disease increased 100-fold when a lipoprotein(a) level >55 mg/dL was
accompanied by a high total cholesterol/HDL ratio of 6. On
the other hand, no such interaction was observed by Bostom et
al11 in the Framingham Offspring Study.
It appears that in patients with elevated serum levels of
lipoprotein(a), the interaction of lipoprotein(a) with other
lipoproteins is a crucial factor affecting the choice of treatment:
whether to lower lipoprotein(a) or LDL to reduce the risk of recurrent
coronary artery disease. LDL levels can be lowered easily,
rapidly, and markedly (by 50% to 60%) with minimal side effects by
using the newer "statins," such as atorvastatin. On the other hand,
lowering of lipoprotein(a) levels requires large doses of niacin (2000
to 4000 mg) and is often unsuccessful due to troublesome side effects.
The combined use of high-dose niacin and high-dose "statins" is
even more problematic. Such therapy requires very close
monitoring of liver functions and is not recommended by the
manufacturers of any of the statins. Nonetheless, such combined therapy
may be necessary in most patients with coronary artery disease
and elevated levels of lipoprotein(a) if the interaction between LDL
and lipoprotein(a) is insignificant. It would be highly educational to
find out whether lipoprotein(a) had any significant interaction with
LDL or other lipoproteins in Swedish women.
Finally, the increased risk of coronary artery disease in
postmenopausal women appears to be mediated in part by a 25% increase
in the serum lipoprotein(a) levels that occurs after
menopause.12 A decrease in lipoprotein(a) levels
of similar magnitude has been reported as a result of estrogen
replacement therapy with or without
progesterone.12 More importantly, estrogen
replacement therapy produces a greater reduction of lipoprotein(a) in
those with elevated levels. For example, estrogen replacement therapy
results in a 50% reduction in lipoprotein(a) levels in subjects with
baseline levels >20 mg/dL compared with a 10% reduction in those with
<20 mg/dL.13 The beneficial effects of estrogen
replacement therapy on other lipoproteins are well known. Evidence has
accumulated regarding the antiatherogenic and cardioprotective effects
of estrogen replacement therapy, which include a 50% reduction in the
risk of coronary artery disease in humans and a 72% reduction
in coronary plaque size in monkeys.14
Considering these benefits and the low cost and low side effect
profile, estrogen replacement therapy appears to be the right thing to
do in women with coronary artery disease and elevated
lipoprotein(a), even though the benefits of lowering the lipoprotein(a)
levels have not yet been proven.
References
1.
Barrett-Connor E. Sex differences in
coronary heart disease: why are women so superior?
Circulation. 1997;95:252–264.
2.
Enas EA, Mehta J. Malignant coronary artery
disease in young Asian Indians: thoughts on pathogenesis, prevention
and therapy. Clin Cardiol. 1995;18:131–135.[Medline]
[Order article via Infotrieve]
3.
Orth-Gomér K, Mittleman MA, Schenck-Gufstafsson KS,
Wamala SP, Eriksson M, Belkie K, Kirkeeide R, Svane B, Rydén L.
Lipoprotein(a) and coronary heart disease in young women.
Circulation.. 1997;95:329–334.
4.
Assmann G, Schulte H, Eckardstein AV. Hypertriglyceridemia
and elevated lipoprotein(a) are risk factors for coronary events in
middle-aged men. Am J Cardiol.. 1996;77:1179–1184.[Medline]
[Order article via Infotrieve]
5.
Enas EA. Rapid angiographic progression of coronary artery
disease in patients with elevated lipoprotein(a).
Circulation.. 1995;92:2353–2354. Letter.
6.
Enas EA. Elevated lipoprotein(a) and risk of primary and
recurrent myocardial infarction. J Am Coll Cardiol.. 1997;29:886–889. Letter.[Medline]
[Order article via Infotrieve]
7.
Maher VMG, Brown BG. Lipoprotein (a) and coronary artery
disease. Curr Opin Lipidol.. 1995;6:229–235.[Medline]
[Order article via Infotrieve]
8.
Barrett-Connor E, Cohn BA, Wingard DL, Edelstein SL. Why is
diabetes mellitus a strong risk for fatal ischemic heart disease in
women than in men? The Rancho Bernardo Study. JAMA.. 1991;265:627–631.
9.
Maher VMG, Brown GB, Marcovina SM, Hillger LA, Zhao X-O,
Abers JJ. Effects of lowering elevated low density lipoprotein
cholesterol on the cardiovascular risk of lipoprotein (a).
JAMA.. 1995;274:1771–1774.
10.
Solymoss BC, Marcil M, Wesolowska E, Grifix BM,
Lesperence J, Campeu L. Relation of coronary artery disease in women 60
years of age to the combined elevation of serum lipoprotein (a) and
total cholesterol to high density lipoprotein cholesterol ratio.
Am J Cardiol.. 1993;72:1215–1219.[Medline]
[Order article via Infotrieve]
11.
Bostom AG, Cupples A, Jenner JL, Ordovas JM, Seman LJ, Wilson
PWF, Schaefer EJ, Castelli WP. Elevated lipoprotein(a) and coronary
heart disease in men aged 55 years and younger. JAMA.. 1996;276:544–548.
12.
Kim CJ, Ryu WS, Kwak JW, Park CT, Ryoo UH. Changes in
lipoprotein(a) and lipid levels after cessation of female sex hormone
production and estrogen replacement therapy. Arch Intern
Med.. 1996;156:500–504.
13.
Taskinen MR, Puolaka J, Pyrola T, Luotola H, Bjorn M,
Kaariainen J, Lahdenpera S, Ehnholm C. Hormone replacement therapy
lowers plasma lipoprotein(a) concentrations: comparison of cyclic
transdermal and continuous estrogen-progestin regimens.
Arterioscler Thromb Vasc Biol.. 1996;16:1215–1221.
14.
Adams MR, Register TC, Golden DL, Wagner JD, Williams JK.
Medroxyprogesterone acetate antagonizes inhibitory effects of
conjugated equine estrogens on coronary artery atherosclerosis.
Arterioscler Thromb Vasc Biol.. 1997;17:217–221.
Division of Preventive Medicine,
Karolinska Institutet,
Huddinge, Sweden
We acknowledge the thoughtful comments and questions from Dr Enas. We have conducted several new analyses to address some of his questions.
Although the five-fold increase (odds ratio [OR]=5.1; 95% CI, 1.4 to 18.4) in coronary
artery disease (CAD) risk associated with elevated lipoprotein(a) [Lp(a)] in
premenopausal women appears to be higher than the increase in risk among
postmenopausal women (OR=2.4; 95% CI, 1.3 to 4.5), the CIs are fairly wide, and
a test of homogeneity revealed that the ORs were not statistically significantly
different from each other (P=.28). Therefore, the apparent differences
in risk conferred by Lp(a) in these subgroups of women need to be interpreted cautiously.
In order to evaluate the role of Lp(a) in the absence of diabetes, we repeated the original analyses of ORs that included diabetic subjects but now restricted
them to nondiabetic women. The age-adjusted OR of CAD comparing the highest with
the lowest quartile of LP(a) was 2.6 (95%, 1.6 to 4.3), and the multivariable
adjusted OR was 3.2 (95% CI, 1.8 to 5.7). In the subgroup analyses, the
age-adjusted OR of CAD in the premenopausal women was 3.9 (95% CI, 1.4 to 10.8),
and in the postmenopausal women, the OR was 2.2 (95% CI, 1.2 to 4.0). These results
were not materially different from the results in the original analysis presented in our paper.
To evaluate whether the risk of CAD associated with high levels of Lp(a) was modified by lipids, we estimated the effect of LP(a) among subsets of women with varying lipid levels.
As can be seen from the Table
The points raised by Dr Enas are important, and further study of the
determinants of CAD among young women, particularly premenopausal
women, are required to better address these and other issues regarding
this challenging public health problem.
© 1998 American Heart Association, Inc.
Correspondence
Lipoprotein(a) as a Determinant of Coronary Heart Disease in Young Women: A Stronger Risk Factor Than Diabetes?
3000 women versus 123 000 men in the United
States develop a myocardial infarction before the age of 45. This low
incidence makes it difficult to identify the risk factors for
coronary artery disease in premenopausal women. Therefore, I
read with great interest the report by Orth-Gomér et
al3 about the 5.1-fold higher risk of
hospitalization for acute coronary artery disease in
premenopausal women with serum lipoprotein(a) levels >30 mg/dL. The
risk of coronary artery disease in Swedish women with elevated
lipoprotein(a) is significantly higher than the 3-fold higher risk
reported in middle-aged German men with similar elevation of
lipoprotein(a) and is nearly equal to the 5.3-fold risk in men with
lipoprotein(a) >70 mg/dL.4 Elevated serum levels
of lipoprotein(a) have been associated with rapid progression of
atherosclerosis,5 resulting in
greater severity and extent of coronary artery disease as well
as poor survival after myocardial infarction. Therefore, the risk of
acute coronary artery disease could have been even
higher6 if the subjects with prehospital deaths
and those who died within 3 months of hospitalization were not excluded
from the study.
Response
View this table:
[in a new window]
Table 1. Effect of Lp(a) Among Women With Various Lipid Levels 
, the relative risk of CAD
associated with Lp(a) >0.55 g/L appeared to be greater among women
with LDL cholesterol >5.0 mmol/L or HDL 
1.15
mmol/L than among women with lower LDL levels or higher HDL levels,
respectively. However, caution is required in interpreting these
subgroup analyses. Because there was limited statistical power
for these analyses, the confidence limits around each of the
estimated OR are wide, and the estimates are thus imprecise.
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