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

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

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

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

Improved survival in CCR7 deficient mice after myocardial infarction.

<p>Kaplan-Meier curve demonstrating increased survival in CCR7^−/− mice as compared to wild type mice after myocardial infarction. Differences in survival were tested with the log-rank test.</p

Myocardial gene expression of inflammatory markers in wild type and CCR7 deficient mice during post-MI HF.

<p>Left sided panels show gene expression of monocyte chemoattractant protein (MCP)-1 (<b>A</b>) and tumor necrosis factor (TNF)α (<b>B</b>) in the LV one and six weeks following sham operation or MI in Wt (1w: n = 7+8; 6w: n = 5+7) and CCR7 deficient (1w: n = 6+9; 6w: n = 8+9) mice (numbers denote sham operation and post-MI HF, respectively). mRNA levels were quantified by real-time RT-PCR and are presented relative to the gene expression of GAPDH. Data are mean±SEM. *p<0.05, and ***p<0.001 versus sham operation in the same genotype. Right sided panels show representative images of immunohistochemical staining of CD45 as a pan-leukocyte marker (magnification 40×) in LV tissue from a Wt mouse (<b>C</b>) and a CCR7^−/− mouse (<b>D</b>) one week post-MI. Arrows indicate CD45-positive cells.</p

The myocardial expression of markers of myocardial hypertrophy and wall stress in CCR7^−/− and Wt mice one and six weeks post-myocardial infarction (MI).

<p>The panels show the gene expression of ANP (<b>A</b>), BNP (<b>B</b>), β-myosin heavy chain (MHC) to αMHC ratio (<b>C</b>), and α-skeletal actin (αSKA; <b>D</b>) in the left ventricle one and six weeks following sham operation or myocardial infarction (MI) in Wt (1w: n = 7+8; 6w: n = 5+7) and CCR7 deficient (1w: n = 6+9; 6w: n = 8+9) mice (numbers denote sham operation and post-MI HF, respectively). mRNA levels were quantified by real-time RT-PCR and are presented relative to the gene expression of GAPDH. Data are mean±SEM. *p<0.05, **p<0.01 and ***p<0.001 versus sham operation in the same genotype. †p<0.05, ††p<0.01 and †††p<0.001 versus Wt post-MI HF. Lower panels are representative images of Masson trichrome stained non-ischemic LV (magnification 10×) from Wt mouse (<b>E</b>) and CCR7^−/− mouse (<b>F</b>) six weeks after MI.</p