Possible mechanism linking sFRP3 release during LV wall stress and non-linear association with survival.

<p>Increased wall stress [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133970#pone.0133970.ref001" target="_blank">1</a>] may induce the release of sFRP3 from fibroblasts [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133970#pone.0133970.ref002" target="_blank">2</a>]. Depending on concentration of sFRP3 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133970#pone.0133970.ref003" target="_blank">3</a>], this may lead to insufficient, balanced or excess inhibition of the Wnt [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133970#pone.0133970.ref004" target="_blank">4</a>] in the presence of inflammation and lead to a non-linear association with survival [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133970#pone.0133970.ref005" target="_blank">5</a>].</p

Kaplan-Meier curves for the primary end point (panel A), as well as for all-cause (B) and CV (C) mortality according to tertile sFRP3 concentration.

<p>T1, lowest tertile serum sFRP3; T3, highest tertile serum sFRP3. Patients with T2 sFRP3 showed a markedly better outcome than patients in T1 and T2; <i>p</i><0.001 for the primary end point and all-cause mortality, <i>p</i><0.002 for CV mortality.</p

Kaplan Meier plots showing the association between tertiles of sFRP3 and all-cause mortality in the GISSI-HF-HF trial stratified according to age and presence of ischemic heart disease.

<p><b>A.</b> ischemic HF <70 years of age <b>B.</b> ischemic HF >70 years of age <b>C.</b> non-ischemic HF > 70 years <b>D.</b> all-cause mortality in CORONA using cut-off derived from the GISSI-HF-HF trial.</p

Effect of sFRP3 on the association between other predictors and outcome.

<p>BMI, body mass index; NYHA, New York Heart Association; eGFR, estimated glomerular filtration rate; ApoB, apolipoprotein B; ApoA-1, apolipoprotein A-1; NT-proBNP, amino-terminal pro-brain natriuretic peptide; CRP, C-reactive protein; T2 sFRP3, middle tertile secreted frizzled related protein 3.</p><p>Effect of sFRP3 on the association between other predictors and outcome.</p

Clinical and biochemical baseline characteristics stratified by tertile values of sFRP3.

<p>NT-proBNP and CRP are displayed as median value (interquartile range). Other variables are shown as number (percentage of total) or as mean (standard deviation) where appropriate. <i>P</i>-value Trend, <i>p</i>-value for trend across all tertiles; <i>P</i>-value 2^nd, <i>p</i>-value for 2^nd tertile compared to 1^st and 3^rd tertile combined.NYHA, New York Heart Association; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; LDL, low-density lipoprotein; HDL, high-density lipoprotein; ApoB, apolipoprotein B; ApoA-1, apolipoprotein A-1; eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease; CRP, C-reactive protein; NT-proBNP, amino-terminal pro-brain natriuretic peptide; sFRP3, secreted frizzled related protein 3; ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker.</p><p>Clinical and biochemical baseline characteristics stratified by tertile values of sFRP3.</p

Multivariable analysis of intermediate levels of sFRP3 as a predictor of outcome.

<p>sFRP3, 2^nd tertile <i>vs</i>. 1^st and 3^rd tertile, as predictor of outcome. All Hazard Ratios (HR) are given as HR (95% confidence interval). C index, Δ; difference in C index between fully adjusted model with and without inclusion of sFRP3, corresponding (<i>p</i>-value). Net Reclassification Improvement (NRI); calculated from C-indexes for fully adjusted models with and without inclusion of sFRP3, corresponding (<i>p</i>-value). Unadjusted (n = 1444). The models are adjusted as follows: Step 1 (n = 1441): Ejection fraction, New York Heart Association functional class, age, body mass index, diabetes mellitus, sex, intermittent claudication and heart rate. Step 2 (n = 1428): All variables from Step 1 as well as ApoB/Apo A-1 ratio and estimated glomerular filtration rate. Step 3 (1194): all variables from Step 2 as well as C-reactive protein and amino-terminal pro B-type natriuretic peptide. CV, cardiovascular; WHF, worsening heart failure.</p><p>Multivariable analysis of intermediate levels of sFRP3 as a predictor of outcome.</p

Discriminatory properties of sFRP3.

<p>Area under curve (AUC) and 95% Confidence interval (CI) of sFRP3 as a categorical (1. and 3. tertile <i>vs</i>. 2. tertile) variable, corresponding <i>p</i>-value.</p