Rad-deletion Phenocopies Tonic Sympathetic Stimulation of the Heart.

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.

authors

Levitan BM,Manning JR,Withers CN,Smith JD,Shaw RM,Andres DA,Sorrell VL,Satin J

doi

10.1007/s12265-016-9716-y

subject

Has Abstract

pub_date

2016-12-01 00:00:00

pages

432-444

issue

5-6

eissn

1937-5387

issn

1937-5395

pii

10.1007/s12265-016-9716-y

journal_volume

9

pub_type

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