Abstract 18191: Secreted Frizzled Related Protein 3, an Inhibitor of Wnt-signaling, is Upregulated in Clinical and Experimental Heart Failure
Background: In response to pathological stress the heart reactivates fetal signaling pathways from a quiescent state in the adult myocardium. One of these pathways is the Wnt pathway, which has been linked to hypertrophic cardiac growth in experimental studies. We hypothesized that secreted frizzled related protein (sFRP) 3, a modulator of Wnt signaling, would be up-regulated in heart failure (HF) and investigated this by studies in experimental and clinical HF, including the ability of sFRP3 to prognosticate adverse advents in a predefined cohort of patients from the GISSI-HF trial.
Methods: sFRP3 gene expression was measured in myocardium from mice subjected to myocardial infarction (MI) or aortic banding (AB), and compared to sham-operated animals. Human left ventricle (LV) specimens harvested at time of LVAD implantation and/or from explanted hearts were analyzed for BNP and sFRP3 expression. Finally, plasma sFRP3 was measured by ELISA in 1202 stable HF patients (NYHA II-IV) enrolled in the GISSI-HF trial and association with outcomes evaluated.
Results: Our main findings were: (1) sFRP3 mRNA levels were elevated in infarcted mouse LV at 3, 7 (65-fold increase) and 21 days post-MI as well as in pressure overloaded (AB) murine hearts compared with sham-operated animals. (2) sFRP3 gene expression was increased in end-stage human LV compared to controls (n=28 vs 12, p<0.0001), correlated with BNP expression (r=0.6, p=0.001), and decreased during reverse LV remodeling in patients on LVAD therapy (n=18, p=0.037). (3) During a median follow-up of 47 (37-55) months, 315 (28%) patients died in the GISSI-HF substudy. Univariate Cox proportional hazard models showed significant associations between tertiles of baseline sFRP3 levels and all-cause and CV mortality. After multivariable adjustment (age, sex, BMI, NYHA, LVEF, eGFR, ischemic etiology, CRP and NT-proBNP) the associations were no longer significant, but a trend (p=0.053) was observed for the third tertile of sFRP3 in relation to CV mortality.
Conclusion: In this study we show myocardial up-regulation of sFRP3 in experimental and clinical HF and demonstrate for the first time an association of circulating sFRP3 with outcomes in a large, well characterized, representative HF population.
- © 2012 by American Heart Association, Inc.