502
The protective effect of a key genetic variant may be overwhelmed by the use of
hormone replacement therapy. The results of these studies give lifestyle guidance
for women who would like to preserve the protective benefi ts conferred by favor-
able genetic variations, and may ultimately lead to new or modifi ed drugs. Men and
women with common variants in the apolipoprotein E (APOE) gene on average
have naturally lower levels of CRP. In the case of women, however, this benefi cial
effect may be largely neutralized by HRT, allowing CRP levels to potentially
increase to dangerous levels.
Therapeutic Alternatives in Patients with Statin Intolerance
A signifi cant number of patients are unable to tolerate statins due to side effects,
including:
- Myopathy: muscle pain or weakness or even muscle breakdown.
- Increased glucose levels and increased the risk of worsening of glycemic control
and of new onset diabetes.
ETC-1002 (Esperion Therapeutics Inc) is an orally available small molecule
designed to lower levels of LDL-C and to avoid side effects associated with existing
LDL-C lowering therapies. ETC-1002 has a unique dual mechanism of action that has
the potential to regulate both lipid and carbohydrate metabolism. ETC-1002 appears
to work by inhibiting ATP citrate lyase, a key enzyme in the cholesterol biosynthetic
pathway, and activating a complementary enzyme, 5′-adenosine monophosphate-
activated protein kinase. Both enzymes are known to play signifi cant roles in the
synthesis of cholesterol and glucose in the liver. By inhibiting cholesterol synthesis in
the liver, ETC-1002 causes the liver to take up LDL particles from the blood, which
reduces LDL-C levels. It has been studies in phase I and II clinical trials.
Thrombotic Disorders
A number of thrombotic disorders cause cardiovascular disease. Venous thrombosis
has an annual incidence of 1 per 1,000 in the general population and is associated
with signifi cant morbidity and mortality. Several genetic variants have been identi-
fi ed that are associated with an increased risk of venous thrombosis, including a
recently discovered mutation in the prothrombin gene. Factor V Leiden mutation is
associated with 15–20 % of the cases of idiopathic thrombotic disorders.
Factor V Leiden Mutation
A mutation in the procoagulant protein Factor V (Factor V Leiden) causes it to be
relatively resistant to degradation by activated protein C (APC), resulting in a
thrombotic tendency. The mutation is a guanine-to-adenine substitution at nucleo-
tide 1651 that results in a glutamine-to-arginine substitution at position 506 (R506Q).
14 Personalized Management of Cardiovascular Disorders