Influence of Mechanical Circulatory Support on Endothelin Receptor Expression in Human Left Ventricular Myocardium from Patients with Dilated Cardiomyopathy (DCM)

by Florian Gärtner, Getu Abraham, Astrid Kassner, Daniela Baurichter, Hendrik Milting

Background

In terminal failing hearts ventricular assist devices (VAD) are implanted as a bridge to transplantation. Endothelin receptor (ETR) antagonists are used for treatment of secondary pulmonary hypertension in VAD patients. However, the cardiac ETR regulation in human heart failure and during VAD support is incompletely understood.

Methods

In paired left ventricular samples of 12 dilated cardiomyopathy patients we investigated the density of endothelin A (ET_A) and B (ET_B) receptors before VAD implantation and after device removal. Left ventricular samples of 12 non-failing donor hearts served as control. Receptor quantification was performed by binding of [¹²⁵I]-ET-1 in the presence of nonselective and ET_A selective ETR ligands as competitors. Additionally, the ETR mRNA expression was analyzed using quantitative real-time-PCR.

Results

The mRNA of ET_A but not ET_B receptors was significantly elevated in heart failure, whereas total ETR density analyzed by radioligand binding was significantly reduced due to ET_B receptor down regulation. ET_A and ET_B receptor density showed poor correlation to mRNA data (spearman correlation factor: 0.43 and 0.31, respectively). VAD support had no significant impact on the density of both receptors and on mRNA expression of ET_A whereas ET_B mRNA increased during VAD. A meta-analysis reveals that the ET_A receptor regulation in human heart failure appears to depend on non-failing hearts.

Conclusions

In deteriorating hearts of patients suffering from dilated cardiomyopathy the ET_A receptor density is not changed whereas the ET_B receptor is down regulated. The mRNA and the proteins of ET_A and ET_B show a weak correlation. Non-failing hearts might influence the interpretation of ET_A receptor regulation. Mechanical unloading of the failing hearts has no impact on the myocardial ETR density.

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