Reverse remodeling of the myocardial extracellular matrix after prolonged left ventricular assist device support follows a biphasic pattern

Background: Collagens are important components of the extracellular matrix (ECM). Alterations in collagen structure and composition can lead to end-stage heart failure. Left ventricular assist devices (LVADs) are frequently used as a bridge to heart transplantation (HTx). In this study, we analyzed changes in composition of the collagens as well as the synthesis or degradation of these collagens after prolonged LVAD support. Methods: The ECM volume was quantified after Picro-Sirius red staining. With immunohistochemistry (IHC), Type I and Type III collagen proteins were analyzed and, using quantitative polymerase chain reaction (PCR), collagen mRNA expression was analyzed. Collagen synthesis and degradation was studied by measuring N-terminal pro-peptide for Type I collagen (PINP), N-terminal pro-peptide for Type III cotlagen (PIIINP) and carboxyterminal telopeptide for Type I collagen (ICTP) in plasma. Collagen composition was measured using the hydroxyproline/Sircol assay. Results: The ECM volume increased in the first 200 days after LVAD implantation. At between 200 and 400 days the ECM volume decreased, but remained higher than pre-LVAD. After 400 days the ECM volume was smaller than the pre-LVAD volume. IHC did not show a significant difference pre- and post-LVAD for collagen composition. Collagen mRNA expression did not change but an augmented synthesis of collagen during the first month after LVAD support was detected upon measurement of plasma PINP and PIIINP levels. In addition, the quality of the collagen network improved. Conclusions: Reverse remodeling during LVAD support follows a biphasic pattern. Initially, an increase in Type I and Type III collagen turnover occurs, which is paralleled by a volume increase of the ECM. Subsequently, this turnover decreases as ECM volume decreases, which results in a restoration of the collagen network.