Cardiovascular Therapeutics - Applications of Biotechnology in Cardiovascular Therapeutics - page 20

Following a condition involving ischemia, the heart has an impaired ability to
efficiently metabolize various fuels that use oxygen to produce energy. This
decreases muscle efficiency, can lead to cell death, and may prolong patient recov-
ery following surgery. Intravenous dichloroacetate has been claimed to protect
heart function by temporarily restoring the lost ability to metabolize glucose once
blood flow is restarted. It was evaluated in phase II clinical trials on high-risk geri-
atric patients undergoing open-heart surgery such as coronary artery bypass to
improve outcomes and recovery times. Further development was suspended due to
the higher incidence of adverse reactions in the treated group compared to the con-
trol group. These adverse events were not seen in earlier phase II trials on lower
risk non-geriatric patients.
Some of the innovative methods for cardioprotection require suitable and effec-
tive methods for delivery. If vascular supply to the myocardium is impaired, sys-
temically delivered therapeutics may not reach the desired site of action in the
myocardium. Injections can be made directly into the myocardium but this is not a
practical method for cardioprotection.
Management of Ischemic/Reperfusion Injury to the Heart
Ischemic reperfusion injury (IRI) may occur spontaneously following myocardial
infarction or may be iatrogenic such as that resulting from revascularization proce-
dures such as coronary artery bypass graft (CABG). Pathogenesis of IRI involves
multiple pathways, including ion channels, reactive oxygen species, intracellular
calcium overload, activated neutrophils, platelet aggregation, and endothelial dys-
function (Turer and Hill 2010 ). Management strategies may require an effective
control of IRI injury as it is important to prevent increase of myocardial infarct size.
Pharmacological strategies include the use of adenosine and carvedilol.
Adenosine
Adenosine, a purine nucleoside, is a critical component of ATP. Its concentration
rises 100-fold during periods of hypoxia and ischemia. Adenosine is released by
ischemic tissue and is an important trigger of ischemic preconditioning. A 1 and to
some extent A 3 receptors of adenosine participate in the intracellular signaling that
triggers cardioprotection by activating phospholipase C and/or protein kinase C
(PKC) directly. Another signaling cascade at reperfusion involves activated PKC,
which initiates binding to and activation of an A 2b adenosine receptor. A 2b agonists,
but not adenosine or A 1 agonists, infused at reperfusion can initiate this second
signaling cascade and mimic preconditioning's protection. The same A 2b receptors
are critical for postconditioning's protection. Thus, adenosine is both an important
trigger and a mediator of cardioprotection (Cohen and Downey 2008 ).
Results of a prospective, randomized, placebo-controlled trial of intracoronary
adenosine administration performed during percutaneous coronary intervention has