Acute {beta}-blockade prevents myocardial {beta}-adrenergic receptor desensitization and preserves early ventricular function after brain death

doi:10.1016/j.jtcvs.2007.09.038

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Acute β-blockade prevents myocardial β-adrenergic receptor desensitization and preserves early ventricular function after brain death

Prakash K. Pandalai, MD^a, Kelly M. McLean, MD^a^,b, Christian F. Bulcao, MD, MBA^a, Jodie Y. Duffy, PhD^a^,b, Karen M. D'Souza, PhD^a, Walter H. Merrill, MD^a, Jeffrey M. Pearl, MD^b, Shahab A. Akhter, MD^a^,_*

^a Department of Surgery, Section of Cardiothoracic Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio
^b Department of Pediatric Cardiothoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

Received for publication May 31, 2007; accepted for publication September 6, 2007.

^_* Address for reprints: Shahab A. Akhter, Assistant Professor of Surgery, Section of Cardiac & Thoracic Surgery, The University of Chicago, 5841 S. Maryland Avenue, MC 5040, Chicago, IL 60637. (Email: sakhter{at}surgery.bsd.uchicago.edu).

Objective: β-Adrenergic receptor desensitization through activationof the G protein–coupled receptor kinase 2 is an importantmechanism of early cardiac dysfunction after brain death. Wehypothesized that acute β-blockade can prevent myocardialβ-adrenergic receptor desensitization after brain deaththrough attenuation of G protein–coupled receptorkinase 2 activity, resulting in improved cardiac function.

Methods: Adult pigs underwent either sham operation, induction of braindeath, or treatment with esmolol (β-blockade) for 30 minutesbefore and 45 minutes after brain death (n = 8 per group). Cardiacfunction was assessed at baseline and for 6 hours after theoperation. Myocardial β-adrenergic receptor signaling wasassessed 6 hours after operation by measuring sarcolemmal membraneadenylate cyclase activity, β-adrenergic receptor density,and G protein–coupled receptor kinase 2 expression andactivity.

Results: Baseline left ventricular preload recruitable stroke work wassimilar among sham, brain death, and β-blockade groups.Preload recruitable stroke work was significantly decreased6 hours after brain death versus sham, and β-blockade resultedin maintenance of baseline preload recruitable stroke work relativeto brain death and not different from sham. Basal and isoproterenol-stimulatedadenylate cyclase activities were preserved in the β-blockadegroup relative to the brain death group and were not differentfrom the sham group. Left ventricular G protein–coupledreceptor kinase 2 expression and activity in the β-blockadegroup were markedly decreased relative to the brain death groupand similar to the sham group. β-Adrenergic receptor densitywas not different among groups.

Conclusion: Acute β-blockade before brain death attenuates β-adrenergicreceptor desensitization mediated by G protein–coupledreceptor kinase 2 and preserves early cardiac function afterbrain death. These data support the hypothesis that acute β-adrenergicreceptor desensitization is an important mechanism in earlyventricular dysfunction after brain death. Future studies withβ-blocker therapy immediately after brain death appearwarranted.

Abbreviations and Acronyms AD = adenylate cyclase; BD = braindeath; β-AR = β-adrenergic receptor; cAMP = cyclicadenosine monophosphate; GRK = G protein–coupled receptorkinase; HF = heart failure; PRSW = preload recruitable strokework

Cardiopulmonary Support and Physiology

Acute β-blockade prevents myocardial β-adrenergic receptor desensitization and preserves early ventricular function after brain death