Lipoprotein (a) [Lp(a)] is a heterogeneous lipoprotein
that shares many properties with low density lipoprotein
(LDL). Plasma Lp(a) consist of a cholestrol-rich LDL
particle with one molecule apoprotein B100 and an
additional protein, apoprotein (a), attached via a disulfide
bond. Elevated Lp(a) levels can potentially increased the
risk of CVD.
Plasma levels of Lp(a) are nearly similar in men and
women, mean values were 14mg/dl for men and
15mg/dl for women with SD of 17 for both sexes. Levels
above 30 mg/dl are considered elevated. Lp(a) levels
did not significantly differ across the whole age range.
METABOLISM
It is believed that plasma levels of Lp(a) are
determined chiefly by rates of hepatic synthesis of
apo(a); although the site of formation of Lp(a) has not
been definitively identified, evidence suggests that
apo(a) adducts extracellularly and covalently to apo B
100- containing lipoprotein, predominantly LDL.
The apo(a) gene has 10 different types of plasminogenlike K4 domains. The first type and type 3-10 repeats
are present in only one copy each, while K4 type 2 is
present as multiple copies. It is the variable K4 type 2
repeats that are responsible for the heterogeneity in
size variation in the apo(a) glycoprotein.
Lp(a) size is inversely related to Lp(a) plasma levels.
Smaller apo(a) sizes generally correspond to higher
plasma levels, but the relationship between Lp(a)
isoform size and Lp(a) levels is not fixed.
Lp(a) is thought to be catabolized primarily by hepatic
and renal pathways, but these metabolic routes do not
appear to govern plasma Lp(a) levels.
Pathophysiological mechanism
underlying the atherothrombotic
potential of Lp(a)
Lp(a) may bind more avidly retained than LDL to
arterial intima as it binds to the extracellullar matrix
not only through apo(a), but also by its apo B
component, thereby contributing cholesterol to the
expanding atherosclerotic plague.
Lp(a) binds to several extracellular matrix proteins
including fibrin and defensins that are released by
neutrophils during inflammation. It is likely that
defensins provides a bridge between Lp(a) and the
extracellular matrix.
Through its apo(a) moiety also interacts with B2integrin, thereby promoting the adhesion of
monocytes.
Lp(a) has also been shown to bind pro inflammatory
oxidized phospholipids.
Apo(a), a homologue of fibrinolytic proenzyme
plasminogen
can competitively inhibit tissue
plasminogen activator that mediate plasminogen
activation on fibrin surface. Small apa(a) isoform
possess high potency of antifibrinolytic effects.
* Lp(a) elevations have been linked to increased risk for
CHD, ischemic stroke and peripheral vascular disease.
In fact, an increase in Lp(a) level is the most common
inherited lipid disorder in subjects with premature
CHD.
Whom to screen for Lp(a)
Lp(a) should be measured once in all subjects at
intermediate or high risk of CVD/CHD who present
with
i. Premature CVD
ii. Familial hypercholesterolemia
iii. A family history of premature CVD/or elevated
Lp(a)
iv. Recurrent CVD despite statin treatment
v. ≥ 3% 10 –year risk of fatal CVD according to the
European guidelines and
vi. ≥ 10% 10 –year risk of fatal and/or nonfatal
CHD according to US guidelines
*It is consistently reported that lifestyle modifications
such as diet, weight loss, and exercise have little or no
effect on Lp(a) levels . This lack of therapeutic lifestyle
benefit is consistent with the understanding that Lp(a)
levels are genetically determined with plasma
concentrations remaining relatively stable over an
individual’s lifetime.
*Plasma apheresis the most effective way to decrease
Lp(a) levels , although, due to cost and technical
difficulties, apheresis is generally reserved for severe
cases of hyperlipidemia.
*A number of pharmacologic agents will lower Lp(a)
levels,
although compared to other lipid
abnormalities, effective drug treatment for elevated
Lp(a) levels is relatively limited.
*The effect of statins on Lp(a) concentration is variable
and also varies with the statin used. It is not clear by
what molecular mechanism various statins lower, fail
to lower, or even elevate Lp(a) levels. Baseline Lp(a)
concentrations and/or apo(a) isoform sizes may
influence any statin effect.
* Niacin reduces Lp(a) levels by up to 30-40% in dose
dependent manner(1-3g/day). While there are no
direct experimental data explaining the mechanism for
its Lp(a)-lowering effects, at present available data
points to niacin as the most effective drug option
available to address Lp(a) elevation.
*Niaspan, a prescription extended-release (ER)
formulation of nicotinic acid has been effectively used
in doses of 1-3 gm/day to treat patients with mixed
hyperlipidemia and elevated plasma Lp(a) levels. In
response to Niaspan treatment there was a substantial
benefit with a very favorable improvement in the lipid
profile.
Lp(a) in type 2 diabetes mellitus
several studies have examined the possibility that type
2 diabetes could influence Lp(a) concentrations. The
results of several small case–control studies have been
controversial. Subjects with diabetes have been found
to have higher , similar or lower levels of Lp(a) than
controls without diabetes.
A recent prospective study of healthy US women aged
45 years or older revealed an inverse association
between Lp(a) and the risk of incident type 2 diabetes.
The authors replicated their findings in a Danish
population-based cohort with prevalent diabetes.
These findings suggest that Lp(a) has opposite effects
on the risks of cardiovascular disease and diabetes,
increasing the former and decreasing the latter.
Several population-based studies conducted after
adjusting for established risk factors for diabetes (age,
abdominal obesity, blood pressure, and serum levels of
HDL cholesterol and triglycerides), the age-related
increase in the probability of having diabetes was
significantly lower in subjects with higher levels of
Lp(a).
Because both Lp(a) and diabetes increase the risk of
cardiovascular disease, mortality rates may be
increased at earlier ages in subjects with both risk
factors. However, this possibility is inconsistent with
recent data showing that, in contrast to what is
observed in the general population, plasma Lp(a)
levels are not significantly associated with
cardiovascular risk in patients with diabetes
It has been found that the age-related rate of
progression to diabetes is slower in subjects with high
levels of Lp(a). Specifically, the age-related risk of
diabetes was lower for subjects with Lp(a) levels above
46 mg/dl.
The values of HOMA-IR, a surrogate marker of insulin
resistance were lower in subjects with Lp(a) levels
>46 mg/dl, suggesting that extremely high levels of
Lp(a) are associated with less resistance to insulin.
Also a positive correlation was found between insulin
sensitivity and Lp(a) levels in normoglycemic subjects.
Other study demonstrated that Lp(a) levels are
inversely correlated with fasting insulin levels and with
insulin and glucose concentrations measured 2 hours
after an OGTT .
Several studies have shown a positive correlation
between Lp(a) and HDL cholesterol and a negative
correlation between Lp(a) and triglycerides ,
indicating that Lp(a) shows an inverse relationship
with the atherogenic dyslipidemia characteristically
associated with insulin resistance.
There is no obvious explanation for this inverse
correlation between Lp(a) and both diabetes and
insulin resistance. Because Lp(a) levels are determined
mainly by genetic mechanisms, one possibility is that
genetic polymorphisms associated with increased
levels of Lp(a) are in linkage disequilibrium with
gene(s) that protect against insulin resistance.
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