Impact of Continuous Flow Left Ventricular Assist Device on Molecular Genetic Changes in Aortic Tissue

Abstract

A pulsatility decrement caused by implantation of continuous flow left ventricular assist device (LVAD) has been corroborated as an additive factor further compromising aortic wall morphology and function. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression which could reflect individual biologic adaptation to exposure to the low pulsatile environment. We hypothesized that pulsatility deficit caused by CF-LVAD implantation may influence miRNAs expression in aortic wall and that the miRNA profiles may differ between devices with different pulsatility profiles, such as speed modulated artificial pulse wave in HeartMate3. Paired aortic samples obtained at the time of LVAD implantation and at the time of Heart transplantation from CF-LVAD patients were examined for miRNA profiling in ten patients (3 females; mean age 55±13.8 years, ischemic cardiomyopathy 40%; HeartMateII(n=4), HeartMate3 (n=6). Human miRNome profile (miRCURY LNA miRNA PCR panels) of 752 miRNAs using qPCR on QuantStudio6 RT-PCR instrument was performed in all samples. The mean support duration was 383.5±222.4 days (range 162 to 887 days). 25 differently expressed multifunctional miRNAs that contribute to the regulation of multiple signaling pathways were identified. The most significant differences in miRNAs expression between implant/explant samples were found in miR-99b-5p; -144-3p; -23b-3p; -30e-3p and let-7d-5p (all p<0.002) which all play important role in differentiation of endothelial cells, vascular smooth muscle cells, or inflammation. No differences were observed between different types of CF-LVAD. The study provides additional evidence on a negative effect of suppressed physiologic pulsatility amplitude in CF-LVAD patients. Negative changes predominantly in miRNAs participating in vascular tissue engineering in aortic wall and pro-inflammatory changes of miRNA profiles during LVAD duration were observed. Our observations suggest that a programmed artificial pulsatility in HeartMate3 does not provide mitigation of continuous flow effect on aortic wall. Moreover, the most up-expressed miR-99b which target ENO2 gene, a marker of neuronal injury, was detected after explant of LVAD. Larger scale adverse events matched clinical trials are warranted.