489Modifying the Genetic Risk for Myocardial Infarction
Variants in the 5-lipoxygenase–activating protein (FLAP) gene are associated with
risk of myocardial infarction (MI). A randomized, prospective, placebo-controlled,
crossover trial of DG-031 (DeCode Genetics Inc), an inhibitor of FLAP, was con-
ducted in MI patients who carry at-risk variants in the FLAP gene or in the leukotriene
A4 hydrolase gene (Hakonarson et al. 2005 ). In patients with specifi c at-risk variants
of two genes in the leukotriene pathway, DG-031 led to signifi cant and dose-
dependent suppression of biomarkers that are associated with increased risk of MI
events. The investigators, however, do not know whether the drug’s ability to suppress
the biomarkers of infl ammation would translate into a decreased risk of heart attack.
There are some uncertainties about the rationale for the drug. One is that although some
cardiologists theorize that infl ammation is indeed a contributory cause of heart attacks,
others regard it as just a symptom. If it is a symptom, a drug that reduced infl ammation
would do nothing to prevent heart attacks. Further research is needed to confi rm the
link between the gene variant and heart disease. If the drug proves effective, it could be
taken as widely as the statin drugs. The average risk for a man older than 40 of having
a heart attack at some time in his life is 49 % and although just 33 % of Americans have
the at-risk variant, many more might gain a protective effect from the drug.
Personalized Management of Chronic Myocardial Ischemia
Chronic myocardial ischemia is generally due to one or more signifi cant obstructive
lesions in the coronary arteries. Myocardial ischemia leads to a dramatic reduction
in myocardial contractility and impaired activity of the ion pumps involved in myo-
cardial contraction-relaxation processes. An early event is an increase in intracellu-
lar Na+, mainly induced by an increase in the late Na+ current (INa), which increases
action potential duration and impairs Ca++ removal from the cell. High Ca ++ keeps
contractile proteins active, increasing energy consumption and diastolic tone, and
impairing ventricular relaxation. This process might create a vicious circle, poten-
tially increasing coronary vessel resistance and decreasing coronary blood fl ow.
There is still some controversy about selection of medical versus surgical therapy
for long-term management of patients with stable chronic myocardial ischemia.
Patients with coronary artery disease who have prognostically signifi cant lesions or
symptoms despite optimum medical therapy require mechanical revascularization
with coronary artery bypass grafting (CABG), percutaneous coronary intervention
(PCI) or both. CABG has been the predominant mode of revascularization for more
than half a century and is the preferred strategy for patients with multivessel disease,
especially those with diabetes mellitus, left ventricular systolic dysfunction or com-
plex lesions. There have been signifi cant technical and technological advances in PCI
over recent years, and this is now the preferred revascularization modality in patients
with single-vessel or low-risk multivessel disease. Improvements in both CABG
(including total arterial revascularization, off-pump CABG and ‘no-touch’ graft har-
vesting) and PCI (including newer-generation stents, adjunctive pharmacotherapy
Role of Diagnostics in Personalized Management of Cardiovascular Disease