Selective upregulation of β1-adrenergic receptors and dephosphorylation of troponin I in end-stage heart failure patients supported by ventricular assist devices

In terminal failing hearts, adrenergic receptors are downregulated and intracellular adrenergic signal transduction is inhibited. Mechanical circulatory support by ventricular assist devices (VAD) is used to bridge patients to heart transplantation. Mechanical unloading by VAD may induce reverse remodeling in heart transplantation (HTx) candidates. However, little is known on β-adrenergic receptor subtype regulation and adrenergic signal transduction under VAD-support. We investigated paired myocardial samples from 16 VAD-supported patients and 9 non-failing donor hearts. We analyzed β-adrenergic receptor subtype regulation by real-time PCR and radioligand binding and cardiac troponin I phosphorylation (by phospho-cTnI-specific antibodies). We found that the β1-adrenergic receptor (β1AR) is downregulated at VAD-implantation on mRNA and protein levels whereas the β2-adrenergic receptor (β2AR) was not. After VAD-support, β1AR protein but not its mRNA was upregulated, whereas the degree of cTnI-phosphorylation was reduced. Upregulation of β1AR was enhanced by beta blocking medication during VAD-support. However, in 9 out of 15 patients, β1AR-density remained below the 0.25 percentile of donor hearts. VAD-support is associated with partial normalization of the βAR-signal transduction pathways. This beneficial effect is related to a posttranscriptional increase in β1AR-density.