Abstract-Data from the Women's Health Study show that serum levels of growth-differentiation factor-15 (GDF-15), a distant member of the transforming growth factor-␤ superfamily, are an independent risk indicator for adverse cardiovascular events. However, the cellular sources, upstream regulators, and functional effects of GDF-15 in the cardiovascular system have not been elucidated. We have identified GDF-15 by cDNA expression array analysis as a gene that is strongly upregulated by nitrosative stress in cultured cardiomyocytes isolated from 1-to 3-day-old rats. GDF-15 mRNA and pro-peptide expression levels were also induced in cardiomyocytes subjected to simulated ischemia/reperfusion (I/R) via NO-peroxynitrite-dependent signaling pathways. GDF-15 was actively secreted into the culture supernatant, suggesting that it might exert autocrine/paracrine effects during I/R. To explore the in vivo relevance of these findings, mice were subjected to transient or permanent coronary artery ligation. Myocardial GDF-15 mRNA and pro-peptide abundance rapidly increased in the area-at-risk after ischemic injury. Similarly, patients with an acute myocardial infarction had enhanced myocardial GDF-15 pro-peptide expression levels. As shown by immunohistochemistry, cardiomyocytes in the ischemic area contributed significantly to the induction of GDF-15 in the infarcted human heart. To delineate the function of GDF-15 during I/R, Gdf-15 gene-targeted mice were subjected to transient coronary artery ligation for 1 hour followed by reperfusion for 24 hours. Gdf-15-deficient mice developed greater infarct sizes and displayed more cardiomyocyte apoptosis in the infarct border zone after I/R compared with wild-type littermates, indicating that endogenous GDF-15 limits myocardial tissue damage in vivo. Moreover, treatment with recombinant GDF-15 protected cultured cardiomyocytes from apoptosis during simulated I/R as shown by histone ELISA, TUNEL/Hoechst staining, and annexin V/propidium iodide fluorescence-activated cell sorting (FACS) analysis. Mechanistically, the prosurvival effects of GDF-15 in cultured cardiomyocytes were abolished by phosphoinositide 3-OH kinase inhibitors and adenoviral expression of dominant-negative Akt1 (K179M mutation). In conclusion, our study identifies induction of GDF-15 in the heart as a novel defense mechanism that protects from I/R injury. Key Words: growth-differentiation factor-15 Ⅲ ischemia/reperfusion Ⅲ apoptosis Ⅲ PI3K Ⅲ Akt C oronary reperfusion is the primary therapeutic goal in patients with acute myocardial infarction (AMI). Although reperfusion is essential for myocardial salvage, it may at first exacerbate cellular damage sustained during the ischemic period, a phenomenon known as reperfusion injury. 1 There is growing evidence that the myocardium adapts to ischemia/reperfusion (I/R) by synthesizing and responding to a variety of stress-induced growth factors and cytokines, and that identification of these endogenous homeostatic mechanisms may open new avenues to limit I/R injury. 2,3 ...

Background: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used to treat cardiogenic shock. However, VA-ECMO might hamper myocardial recovery. The Impella unloads the left ventricle. The aim of this study was to evaluate if left ventricular unloading in cardiogenic shock patients treated with VA-ECMO was associated with lower mortality. Methods: Data from 686 consecutive patients with cardiogenic shock treated with VA-ECMO with or without left ventricular unloading (using an Impella) at 16 tertiary-care centers in 4 countries were collected. The association between left ventricular unloading and 30-day mortality was assessed by Cox regression models in a 1:1 propensity-score-matched cohort. Results: Left ventricular unloading was used in 337 of the 686 patients (49%). After matching, 255 patients with left ventricular unloading were compared with 255 patients without left ventricular unloading. In the matched cohort, left ventricular unloading was associated with lower 30-day mortality (hazard ratio 0.79, 95% confidence interval 0.63-0.98, p=0.03) without differences in various subgroups. Complications occurred more frequently in patients with left ventricular unloading; e.g. severe bleeding in 98 (38.4%) vs. 45 (17.9%), access-site related ischemia in 55 (21.6%) vs. 31 (12.3%), abdominal compartment in 23 (9.4%) vs. 9 (3.7%) and renal replacement therapy in 148 (58.5%) vs. 99 (39.1%). Conclusions: In this international, multicenter cohort study, left ventricular unloading was associated with lower mortality in cardiogenic shock patients treated with VA-ECMO, despite higher complication rates. These findings support use of left ventricular unloading in cardiogenic shock patients treated with VA-ECMO and call for further validation, ideally in a randomized, controlled trial.

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