Abstract 12949: Increase in Left Ventricular Fibrosis With LVAD Therapy and in Model of Mechanical Unloading and Potential Anti-Fibrotic Therapy of the Novel Designer Natriuretic Peptide CD-NP in vitro
Introduction: Reports of LVAD unloading on myocardial fibrosis has reported both decreases and increases, the latter supporting a need for co-therapies targeting fibrosis. The natriuretic peptides (NPs) possess anti-fibrotic properties through their receptors NPR-A and NPR-B. Although ANP and BNP bind to NPR-A and CNP binds NPR-B, the novel peptide CD-NP, which is in clinical HF trials, co-activates both NPR-A and NPR-B.
Hypotheses: We hypothesized that extracellular matrix (ECM) genes are elevated in ES-HF and with LVAD therapy would result in continuing or increased fibrosis as well as in an unloading canine model. We also hypothesized that CD-NP suppresses collagen (Col) I production in human cardiac fibroblast (CFs).
Methods: NPs, NPRs, and the ECM mRNA expressions were determined by qPCR in LV tissue from ES-HF patients with (n=5) and without (n=13) LVAD and controls (n=6). Fibrosis was assessed in a canine model of cardiac unloading (n=6) via thoracic inferior vena caval constriction (TIVCC). Col I mRNA and protein expression in CFs with or without CD-NP was determined.
Results: ANP, BNP, NPR-B, NPR-C, Col I, Col III, and FN mRNA expression in HF LV were higher and CNP mRNA expression was lower in HF LV compared to normal LV, with no change in NPR-A mRNA expression. LVAD supported patients had lower plasma BNP and remained CNP suppression, but higher ECM mRNA expressions in LV than patients without LVAD support. TIVCC LV had elevated fibrosis compared to the sham LV. CD-NP suppressed Col I production in CFs. All data were p<0.05.
Conclusions: ES-HF is characterized by activated NP system but with a loss of CNP expression and an increase in ECM genes. Despite unloading, LVAD therapy was associated with increased fibrosis as observed also in an unloading model. Thus, LVAD therapy may paradoxically increase LV fibrosis with maintained NPRs expressions. Notably, CD-NP may be a potential co-therapy with LVAD support to attenuate LV fibrosis.
- © 2011 by American Heart Association, Inc.