Biomarkers of Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 106

In CHF, the b-adrenergic receptor system fails to work properly. One of the
functions of GRK2 is to turn off b-ARs.
GRK2 has now been shown to lead to permanent damage after myocardial
infarction. Over production of GRK2 following a heart attack actually stimulates
pro-death pathways in myocytes outside of the initial zone of damage. There is an
inverse link between GRK2 activity and the production of NO, a molecular mes-
senger that protects the heart against damage caused by a sudden loss of blood.
When there is more GRK2, there is less NO, and vice versa. GRK2 may be affecting
NO production by inhibiting the prosurvival protein kinase Akt, which itself regu-
lates NO. These conclusions are based on a study that used gene therapy to inhibit
GRK2, and found heart muscle cells in mice were substantially protected against
destruction that would otherwise occur after an induced myocardial infarction
(Brinks et al. 2010 ). Conversely, mice engineered to express excess GRK2 had
more damage than would have been expected after myocardial infarction. These
findings suggest that humans experiencing a heart attack might be helped with
prompt delivery of a therapeutic targeting inhibition of GRK2. While it may be
years before this concept can be tested in patients experiencing myocardial infarc-
tion, anti-GRK2 gene therapy could be tested in patients with CHF much sooner.
A phase I clinical trial for GRK2-targeted gene therapy is preparing to be launched,
pending FDA approval.
KIF6 Gene as Biomarker of CHF
Carriers of the KIF6 (kinesin family member 6) wild-type gene are 50-55% more
likely to develop CHF. KIF6 as a biomarker of CHF is the basis of a genetic test,
StatinCheck, developed by Celera and offered through Berkeley HeartLab, which
is owned by Celera. It is now licensed by clinical laboratory of Aurora Health Care
in Milwaukee, Wisconsin.
Physicians can use the KIF6 test to identify the increased risk for CHF and begin
treating their patients with statins. A study investigated whether 35 genetic poly-
morphisms, previously found to be associated with cardiovascular disease, were
associated with MI in the CARE (Cholesterol and Recurrent Events) trial and with
coronary heart disease (CHD) in the WOSCOPS (West of Scotland Coronary
Prevention Study). In both the CARE and the WOSCOPS trials, carriers of the
KIF6 719Arg allele had an increased risk of coronary events, and pravastatin treat-
ment substantially reduced that risk (Iakoubova et al. 2008 ). Carriers of the 719Arg
allele of KIF6 have 34% higher risk of MI and 24% higher risk of CHD compared
with noncarriers among 25,283 women from the Women's Health Study, confirm-
ing and extending previous reports (Shiffman et al. 2008 ).
NT ProBNP as Biomarker of CHF
The PRIDE study showed NT-proBNP to be highly sensitive and specific for the
diagnosis of CHF in patients with shortness of breath and to strongly predict patient