The use of continuous-flow (CF) left ventricular assist devices (LVADs) increases the risk of patients developing aortic fibrosis and stiffening, and may contribute to the risks of hypertension, stroke and ventricular failure, new research suggests.
Published online Monday and in the Nov. 2 issue of the Journal of the American College of Cardiology, the study noted that the effects of non-physiological flow generated by CF-LVADs on the aorta remain poorly understood – and set out to quantify indexes of fibrosis in order to determine molecular signatures of post–CFLVAD vascular remodeling.
Led by Amrut V. Ambardekar, MD, from the University of Colorado Anschutz Medical Campus, Aurora, the authors reported that patients with CF-LVADs may develop aortic fibrosis and stiffening that increase with the duration of CF-LVAD support, potentially contributing to the risks of hypertension, stroke, gastrointestinal bleeding, and right ventricular failure.
“The main finding of this study is that there is time-dependent fibrosis and vascular stiffening within the aorta after CF-LVAD placement,” said the authors, noting that there was evidence of adventitial thickening, collagen deposition, and a decrease in the elastin-to-collagen ratio with CF-LVAD support, which are all histological evidence of vascular fibrosis.
“This fibrosis is due, at least in part, to suppression of extracellular matrix–degrading enzyme expression,” they added.
Ambardekar and colleagues collected paired aortic tissue at CF-LVAD implant and subsequently at transplant from 22 patients and quantified aortic wall morphometry and fibrillar collagen content – a measure of fibrosis. Furthermore, whole transcriptome profiling by RNA sequencing and follow-up immunohistochemistry were performed to evaluate CF-LVAD–mediated changes in aortic mRNA and protein expression.
The team reported a significant increase in the thickness of the collagen-rich adventitial layer from 218 mm pre-LVAD to 410 mm post-LVAD (P < 0.01). Furthermore, there was an increase in intimal and medial mean fibrillar collagen intensity from 22 a.u. pre-LVAD to 41 a.u. post-LVAD (P < 0.0001).
“The magnitude of this increase in fibrosis was greater among patients with longer durations of CF-LVAD support,” noted the research team, who added that CF-LVAD also led to “profound” down-regulation in expression of extracellular matrix–degrading enzymes, such as matrix metalloproteinase-19 and ADAMTS4, but no evidence of fibroblast activation was noted.
“The molecular basis for these vascular changes suggests that there is down-regulation of matrix-degrading enzymes with subsequent increased accumulation of ECM as the etiology for the fibrotic deposition of collagen,” noted Ambardekar and colleagues.
“This suggests that strategies to prevent the downregulation of matrix-degrading enzymes could be potential therapeutic targets to prevent vascular fibrosis.”
They added that further research is needed to examine the contribution of non-physiological flow patterns on vascular function and whether modulation of pulsatility may improve vascular remodeling and long-term outcomes.
Writing in an accompanying editorial, Eloisa Arbustini, MD, from the Fondazione IRCCS Policlinico San Matteo teaching hospital in Pavia, Italy, and Navneet Narula, MD, from New York University Langone Health, noted that the study observed time-dependent fibrosis and vascular stiffening, adventitial fibrous thickening, collagen deposition and a decrease in the elastin-to-collagen ratio – adding that these pathologic changes are similar to those seen in previous studies.
“The unexpected finding was that the molecular mechanism associated with aortic fibrosis in CF-LVAD was characterized by down-regulation of matrix-degrading enzymes rather than commonly observed up-regulation of traditional inflammatory pathways and subsequent fibroblast activation and fibrosis,” they added.
The editorialists said the CF-LVAD model of aortic injury reported by Ambardekar and colleagues also adds to the information pertaining to molecular mechanisms and pathways.
“However, as with any good study, it also raises many questions,” they noted – questioning what happens to the aorta away from the proximal segments that were accessible to the investigators, to what extent does remodeling of the aortic wall occur, and whether the pathological changes are reversible after transplantation and restoration to the physiological flow?
They noted that animal studies could hold promise in characterizing the aortic pathology of “detraining.”
Ambardekar AV, Stratton MS, Dobrinskikh E, et al. Matrix-Degrading Enzyme Expression and Aortic Fibrosis During Continuous-Flow Left Ventricular Mechanical Support. J Am Coll Cardiol 2021;78:1782-1795.
Arbustini E, Narula N. Aortic Smooth Muscle Detraining in Continuous Flow LVAD: Out of Practice. J Am Coll Cardiol 2021;78:1796-1799.
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