Role of the β-adrenergic receptor kinase in myocardial dysfunction after brain death

Objective: Significant cardiac dysfunction after brain death leading to exclusion from procurement for cardiac transplantation is seen in up to 25% of potential organ donors in the absence of structural heart disease. The cause includes uncoupling of the myocardial β-adrenergic receptor signaling system. The mechanism, however, has not yet been described. This study investigates our hypothesis that brain death causes acute activation of the βAR kinase and leads to desensitization of myocardial β-adrenergic receptors and impaired ventricular function. Methods: Adult pigs underwent a sham operation or induction of brain death by means of subdural balloon inflation (n = 8 in each group). Cardiac function was assessed by using sonomicrometry at baseline and for 6 hours after the operation. β-Adrenergic receptor signaling was assessed at 6 hours after the operation by measuring myocardial sarcolemmal membrane adenylate cyclase activity, β-adrenergic receptor density, β-adrenergic receptor kinase expression, and activity. Results: Induction of brain death led to significantly decreased left ventricular systolic and diastolic function. Basal and isoproterenol-stimulated adenylate cyclase activity was blunted in the brain dead group compared with the sham-operated group (28.3 ± 4.3 vs 48.3 ± 7.6 pmol of cyclic adenosine monophosphate·mg ^-1·min^-1 [P = .01] and 54.8 ± 9.6 vs 114.5 ± 18 pmol of cyclic adenosine monophosphate·mg ^-1·min^-1 [P < .02]). There was no difference in β-adrenergic receptor density between the brain dead and sham-operated groups. Myocardial β-adrenergic receptor kinase expression was 3-fold greater in the brain dead versus sham-operated groups, and membrane β-adrenergic receptor kinase activity was 2.5-fold greater in the brain dead group compared with that seen in the sham-operated group. Conclusion: Induction of brain death leads to significant left ventricular dysfunction in this porcine model. Cardiac β-adrenergic receptors are clearly uncoupled after brain death, and our data suggest that the mechanism is acute increase of myocardial β-adrenergic receptor kinase activity, leading to β-adrenergic receptor desensitization and ventricular dysfunction.