Parallele Numerik

TIB: AC 8597 (A) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Soluble glycoprotein 130 predicts fatal outcomes in chronic heart failure: analysis from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)

Background—Glycoprotein 130 (gp130) is the common signal-transducing receptor subunit of the interleukin-6 (IL-6) family, which may be involved in the progression of heart failure (HF). We hypothesized that soluble gp130 would provide prognostic information beyond that of IL-6 in a population with HF from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA).<p></p> Methods and Results—The associations of soluble gp130 and IL-6 with morbidity, mortality, and mode of death were assessed by immunoassays in a subset of 1452 patients enrolled in the CORONA trial, which included patients with HF, aged ≥60 years, in New York Heart Association classes II to IV, who had ischemic heart disease and a reduced left ventricular ejection fraction. In multivariable analyses, including C-reactive protein, IL-6, troponin T, and N-terminal pro-B-type natriuretic peptide, elevated soluble gp130 (fifth quintile versus all lower quintiles) was associated with all-cause mortality (hazard ratio, 1.47 [1.11–1.93]; P=0.006), cardiovascular mortality (hazard ratio, 1.38 [1.01–1.87]; P=0.042), and death from worsening HF (hazard ratio, 1.85 [1.09–3.14]; P=0.002), but not with the primary end point (composite of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke; hazard ratio, 1.12 [0.84–1.50]; P=0.44). Plasma IL-6 was not associated with outcomes in multivariable analyses.<p></p> Conclusions—Marked elevations in soluble gp130 are associated with total and cardiovascular mortality, as well as deaths from worsening HF, in elderly patients with HF of ischemic cause.<p></p&gt

The Effect of Rosuvastatin on Inflammation, Matrix Turnover and Left Ventricular Remodeling in Dilated Cardiomyopathy: A Randomized, Controlled Trial

Background Dilated cardiomyopathy is characterized by left ventricular dilatation and dysfunction. Inflammation and adverse remodeling of the extracellular matrix may be involved in the pathogenesis. Statins reduce levels of low density lipoprotein cholesterol, but may also attenuate inflammation and affect matrix remodeling. We hypothesized that treatment with rosuvastatin would reduce or even reverse left ventricular remodeling in dilated cardiomyopathy. Materials and Methods In this multicenter, randomized, double blind, placebo-controlled study, 71 patients were randomized to 10 mg of rosuvastatin or matching placebo. Physical examination, blood sampling, echocardiography and cardiac magnetic resonance imaging were performed at baseline and at six months’ follow-up. The pre-specified primary end point was the change in left ventricular ejection fraction from baseline to six months. Results Over all, left ventricular ejection fraction improved 5 percentage points over the duration of the study, but there was no difference in the change in left ventricular ejection fraction between patients allocated to rosuvastatin and those allocated to placebo. Whereas serum low density lipoprotein cholesterol concentration fell significantly in the treatment arm, rosuvastatin did not affect plasma or serum levels of a wide range of inflammatory variables, including C-reactive protein. The effect on markers of extracellular matrix remodeling was modest. Conclusion Treatment with rosuvastatin does not improve left ventricular ejection fraction in patients with dilated cardiomyopathy

Wnt5a is associated with right ventricular dysfunction and adverse outcome in dilated cardiomyopathy

The Wingless (Wnt) pathway has been implicated in the pathogenesis of dilated cardiomyopathy (DCM). To explore the role of Wnt modulators Wnt5a and sFRP3 in DCM patients we analyzed the expression of Wnt5a and sFRP3 in plasma and myocardium of DCM patients and evaluated their effects on NFAT luciferase activity in neonatal mouse cardiomyocytes. Elevated circulating Wnt5a (n = 102) was associated with increased pulmonary artery pressures, decreased right ventricular function and adverse outcome, with a stronger association in more severely affected patients. A higher Wnt5a/sFRP3 ratio (n = 25) was found in the right ventricle vs. the left ventricle and was correlated with NFAT activation as well as pulmonary artery pressures. Wnt5a induced NFAT activation and sFRP3 release in cardiomyocytes in vitro, while sFRP3 antagonized Wnt5a. Wnt5a is associated with right ventricular dysfunction and adverse outcome in DCM patients and may promote the progression of DCM through NFAT signaling

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

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