Published in:
01-12-2016 | Original Article
Rad-deletion Phenocopies Tonic Sympathetic Stimulation of the Heart
Authors:
Bryana M. Levitan, Janet R. Manning, Catherine N. Withers, Jeffrey D. Smith, Robin M. Shaw, Douglas A. Andres, Vincent L. Sorrell, Jonathan Satin
Published in:
Journal of Cardiovascular Translational Research
|
Issue 5-6/2016
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Abstract
Sympathetic stimulation modulates L-type calcium channel (LTCC) gating to contribute to increased systolic heart function. Rad is a monomeric G-protein that interacts with LTCC. Genetic deletion of Rad (Rad−/−) renders LTCC in a sympathomimetic state. The study goal was to use a clinically inspired pharmacological stress echocardiography test, including analysis of global strain, to determine whether Rad−/− confers tonic positive inotropic heart function. Sarcomere dynamics and strain showed partial parallel isoproterenol (ISO) responsiveness for wild-type (WT) and for Rad−/−. Rad−/− basal inotropy was elevated compared to WT but was less responsiveness to ISO. Rad protein levels were lower in human patients with end-stage non-ischemic heart failure. These results show that Rad reduction provides a stable inotropic response rooted in sarcomere level function. Thus, reduced Rad levels in heart failure patients may be a compensatory response to need for increased output in the setting of HF. Rad deletion suggests a future therapeutic direction for inotropic support.