الفهرس 
Myocardial InfarctionOnly 14 pages are availabe for public view
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Abstract
Myocardial infarction (MI) is the rapid development of myocardial necrosis caused by a critical imbalance between oxygen supply and demand of the myocardium. This usually results from plaque rupture with thrombus formation in a coronary vessel, resulting in an acute reduction of blood supply to a portion of the myocardium (Thygessan et al., 2007).
The pathophysiology of early perioperative MI seems to be related to a prolonged imbalance between myocardial oxygen supply and demand in the setting of coronary artery disease (CAD) (Morrow et al., 2001).
Perioperative ß-blocker therapy has been listed asa ‘top-tier’ patient safety practice by the Instituteof Medicine (Shojania, 2002). Perioperative ß-blockade improves cardiacoutcome in patients with or at risk CAD (Mangano et al., 1996) and in patientswith documented inducible myocardial ischaemia undergoing non-cardiacsurgery(Boersma et al., 2001). It has been suggested that ß-adrenoceptor-antagonists(‘ß-blockers’) should be administeredto almost all patients with one or more factors that are knownto be associated with a higher perioperative cardiac risk (Kertai et al., 2004).
Recent evidence, however, suggests that there is substantial interindividual difference in how patients respond to β-blockers: Some patients experience strong side effects such as excessive hypotension and bradycardia, whereas others experience no measurable response. Several lines of evidence suggest that the individual genetic background is responsible for these observed response differences (Peter and Stephen, 2011).
Polymorphisms (defined as a genetic variation with a prevalence of more than 5% in a population) of the alpha2A- and the alpha2C-AR, which partially control norepinephrine release, could alter beta blocker responsiveness(Bristow et al., 2010).
The polymorphism, termed alpha2CDel 322–325, has been associated with increased norepinephrine (or its transporter) in the cardiac presynaptic cleft (Gerson et al., 2003) increased risk for heart failure (Small et al., 2000)and a significantly reduced survival benefit in heart failure patients when taking the beta-blocker bucindolol (Bristow et al., 2010).
The originally cloned beta1adrenergic receptor had a Glycine at this position, but it is now clear that in African-Americans, Glycine and Arginine allele frequencies are approximately the same, and in Caucasians the Arginine allele frequency is approximately 70%. In transfected cells, it was found that beta1Arg389 exhibited a threefold-greater stimulation of adenylyl cyclase and cyclic adenosine monophosphate compared with beta1Gly389 (Mason et al., 1999).
In addition to those variations in the relevant receptors, one polymorphism in the second messenger system within a G protein- coupled receptor kinase (GRK5) has recently shown in vitro and in vivo evidence for relevance to beta-blocker responsiveness (Liggett et al., 2008).
The GRKs phosphorylate multiple G-protein coupled receptors during agonist activation, which acts to partially uncouple the receptor form Gs, and is a major mechanism of desensitization. A nonsynonymous polymorphism of GRK5, where the major allele Glutamine at amino acid position 41 is substituted by Leucine, has been found (Liggett et al., 2008).
A recent study of the gene encoding the alpha subunit of Gs (GNAS) showed that patients with a certain haplotype had a significantly different Gαs expression, cyclic adenosine monophosphate production, and cardiac performance during cardiac surgery, indicating that genetic variation within the adrenergic second messenger system may also play an important role for how patients respond to beta-blockade(Frey et al., 2009).
Most beta-blockers, such as metoprolol and propranolol, are extensively metabolized in the liver by cytochrome P450 2D6, or CYP2D6, a hepatic enzyme of the cytochrome P450 family (Gardiner et al., 2006).
Those CYP2D6 gene variants have a major impact on the CYP2D6 enzyme activity, with some variants resulting in a complete loss-of-function phenotype whereas others lead to a gain-of-function (Peter and Stephen, 2011).
The ability of the CYP2D6 enzyme to metabolize substrates has been stratified into four classes: ultra-rapid metabolizers (UM), extensive metabolizers (EM, considered the normal phenotype), intermediate metabolizers (intramuscular) and poor metabolizers (PM) (Zanger et al., 2004).
UM subjects have been reported to not achieve a therapeutic effect of standard dosing of metoprolol (Goryachkina et al., 2008).
Genetic variation in CYP2D6-dependent metabolism as well as adrenergic signaling may influence outcomes. Particularly the apparent decreased risk associated with atenolol, which is not metabolized by CYP2D6, compared with metoprolol, which undergoes extensive CYP2D6-dependent metabolism, is very interesting (Wallace et al., 2011).
Whether, however, the conditions of perioperative MI are such that these polymorphisms have a significant impact on outcomes, remains a critical question that needs to be addressed. The idea that “one drug fits all” is being questioned in virtually all of clinical medicine. Given the apparent interindividual variation in efficacy and adverse effects of β-blockers for prevention of perioperative MI, the biologic plausibility, and the low costs of genotyping by modern methods, it seems to us that a rigorous pharmacogenomic investigation is indicated. Ultimately, this could lead to a “genetic scorecard” that would recommend when a β-blocker should be used and the dose, for prevention of perioperative MI(Peter and Stephen, 2011).
In conclusion, polymorphisms in the adrenergic signaling pathway and CYP2D6-dependent beta-blocker metabolism influence efficacy, safety and toxicity of beta-blocker therapy in prevention and treatment of perioperative MI. It is to be expected that the emphasis on careful beta-blocker dose titration, might lessen the disparate effects of genetic polymorphisms (Fleischmann et al., 2009).