Matrix-Degrading Enzyme Expression and Aortic Fibrosis During Continuous-Flow Left Ventricular Mechanical Support

J Am Coll Cardiol. 2021 Nov 2;78(18):1782-1795. doi: 10.1016/j.jacc.2021.08.047.

Abstract

Background: The effects of nonphysiological flow generated by continuous-flow (CF) left ventricular assist devices (LVADs) on the aorta remain poorly understood.

Objectives: The authors sought to quantify indexes of fibrosis and determine the molecular signature of post-CF-LVAD vascular remodeling.

Methods: Paired aortic tissue was collected at CF-LVAD implant and subsequently at transplant from 22 patients. Aortic wall morphometry and fibrillar collagen content (a measure of fibrosis) was quantified. In addition, whole-transcriptome profiling by RNA sequencing and follow-up immunohistochemistry were performed to evaluate CF-LVAD-mediated changes in aortic mRNA and protein expression.

Results: The mean age was 52 ± 12 years, with a mean duration of CF-LVAD of 224 ± 193 days (range 45-798 days). There was a significant increase in the thickness of the collagen-rich adventitial layer from 218 ± 110 μm pre-LVAD to 410 ± 209 μm post-LVAD (P < 0.01). Furthermore, there was an increase in intimal and medial mean fibrillar collagen intensity from 22 ± 11 a.u. pre-LVAD to 41 ± 24 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. CF-LVAD led to profound down-regulation in expression of extracellular matrix-degrading enzymes, such as matrix metalloproteinase-19 and ADAMTS4, whereas no evidence of fibroblast activation was noted.

Conclusions: There is aortic remodeling and fibrosis after CF-LVAD that correlates with the duration of support. This fibrosis is due, at least in part, to suppression of extracellular matrix-degrading enzyme expression. Further research is needed to examine the contribution of nonphysiological flow patterns on vascular function and whether modulation of pulsatility may improve vascular remodeling and long-term outcomes.

Keywords: aorta; congestive heart failure; fibrosis; left ventricular assist device; mechanical circulatory support; vascular remodeling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS4 Protein / metabolism
  • Aortic Diseases* / etiology
  • Aortic Diseases* / pathology
  • Aortic Diseases* / physiopathology
  • Assisted Circulation* / adverse effects
  • Assisted Circulation* / instrumentation
  • Assisted Circulation* / methods
  • Extracellular Matrix / enzymology*
  • Female
  • Fibrosis
  • Heart Failure / therapy*
  • Heart-Assist Devices / adverse effects*
  • Humans
  • Immunohistochemistry
  • Long Term Adverse Effects / pathology
  • Male
  • Matrix Metalloproteinases, Secreted / metabolism
  • Middle Aged
  • Sequence Analysis, RNA / methods
  • Vascular Remodeling / physiology

Substances

  • Matrix Metalloproteinases, Secreted
  • matrix metalloproteinase 19
  • ADAMTS4 Protein
  • ADAMTS4 protein, human