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Department of Anesthesiology, Pharmacology, and Intensive Care; University Hospital of Geneva; Geneva, Switzerland; marc-joseph.licker{at}hcuge.ch
To the Editor:
Fleisher's editorial (1) and the accompanying pro–con papers (2,3) comprehensively reviewed the indications for ß-blockers in the context of surgery. Unquestionably, ß-blockers have contributed to a reduced incidence and severity of perioperative myocardial ischemia and infarct among high-risk patients with coronary artery disease. However, new data have emerged showing that ß-blockers could even be harmful in subgroups of patients with a low-risk cardiovascular profile (4). Most intriguing are data indicating that ß-blockers are less effective in those receiving chronic ß-blockers and those presenting specific polymorphisms of the ß1-adrenergic receptor.
Although acute withdrawal of ß-blockers in chronically treated patients may provoke severe adverse cardiac events, continuation of ß-blockers throughout the perioperative period fails to confer similar cardioprotective effects as in "naive" patients receiving acute ß-blocker treatment. In a systematic review of five clinical studies including 1769 patients, chronic ß-blockade was even associated with an increased risk of postoperative myocardial infarct (odds ratio 2.14 with 95% confidence interval between 1.3 and 3.6). (5) Upregulation of the ß-adrenergic receptor (increase in number and/or density of ß-adrenergic receptor) could explain the loss of the negative chronotropic effect of ß-blockade and the propensity to develop tachycardia and hypertension in response to isoproterenol infusion or to perioperative release of endogenous catecholamines (6,7). As increased heart rate has been shown to be an independent predictor of ischemic myocardial events, perhaps the doses of ß-blockers should be increased or alternative strategies to control the heart rate might be beneficial (i.e., calcium-channel antagonists or 
2-agonists) (8–10).
Furthermore, although ß-blocker may provide optimal hemodynamic control and prevent subendocardial ischemia, coronary thrombosis may still occur as a result of rupture of vulnerable atheromatous plaque, enhanced platelet activation, and reduced fibrinolytic activity. To date, several observational studies suggest that both statins and antiplatelet medications contribute to further reduce the incidence of perioperative cardiovascular events through their anti-inflammatory and antiaggregant effects (11,12). Antagonism of the surgical stress-induced procoagulant activity with antiplatelet medications and antithrombin is particularly crucial in patients with coronary stents despite the limited risk of increased bleeding (13). Interestingly, treatment with selective ß1-blockers may confer further protection against myocardial injuries by switching of the unblocked type 2 ß-adrenergic receptor from stimulating to inhibitory G protein (14).
Finally, besides poor adhesion to AHA/ACC guidelines for ß-blocker therapy, genetic variability of the ß-adrenergic receptor may explain poor clinical response to ß-blocker treatment and increased susceptibility to cardiovascular disease progression. In a prospective pharmacogenetic cohort study of 735 patients receiving ß-blockers after an acute coronary syndrome, the 79 Gln and 46 Arg alleles of the ß-adrenergic receptor type 2 (representing 39% and 16% of the study population, respectively) were associated with a two- to threefold increased 3-year mortality risk (15). Furthermore, the Arg/Gly 389 polymorphism of the ß-adrenergic receptor type 1 has been shown to influence the agonist-mediated contraction of both nonfailing and failing human hearts as well as the clinical response to ß-blockers in patients with heart failure (16).
Taken together, these results set the stage for further investigations and the development of a multimodal cardioprotective approach and genomics-based treatment including antiadrenergic treatments (e.g., ß-blockers, 2-agonists, thoracic epidural analgesia), anti-inflammatory drugs (e.g., statins) as well as modulators of stress-induced inflammation and thrombosis (antiplatelet, antithrombin).
REFERENCES
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