Abstract 14648: The Immune Protein Md-2 is a Novel Independent Predictor for Long Term Mortality in Dilated Cardiomyopathy and Has Stimulatory Capacity in Monocytes and Cardiomyocytes
Myeloid differentiation protein 2 (MD-2) is a known cofactor of Toll-like receptor 4 (TLR4) enhancing lipopolysaccharide (LPS) recognition. Its role in cardiac diseases is unknown. In the present study we investigated the impact of MD-2 on the clinical outcome and cell specific activation in patients with DCM.
Methods: MD-2 protein expression in serum from patients (n=174) with biopsy-guided DCM was quantified by ELISA at first hospital admition. Cell specific translocation of NFkB in human peripheral blood after stimulation with recombinant MD-2 was measured by single cell imaging flow cytometry (AMNIS IS-X®). Activation of rat cardiomyocytes after stimulation with MD-2 and LPS was analysed by RT-RTPCR.
Results: All-cause mortality in DCM patients with MD-2 level ≥ overall median (302.44 ng/ml) was strongly associated with increased mortality when compared to patients with MD-2 level < overall median (31.0% versus 8.1%, p<0.001). Multivariable Cox regression analyses demonstrate, that this effect was independent from age, LV ejection fraction and other cardiovascular risk factors including diabetes, BMI, arterial systolic and diastolic blood pressure and smoking (HR 1.004 p<0.001) for MD-2 as continuous variable.
Stimulation of whole blood from DCM patients with recombinant MD-2 showed a significantly increased nuclear translocation of the TLR4-regulated transcription factor NFkB in monocytes (p<0,01; n=8), but not in peripheral eosinophiles, neutrophils and lymphocytes. Healthy control blood showed no immune cell activation due to MD-2-stimulation (n=5). Costimulation with LPS and MD-2 of cardiomyocytes led to a significant upregulation of IL-6 and iNOS (p<0,01; n=10), while stimulation with LPS alone did not reach significance compared to controls. For TNFα expression costimulation proved greater significance (p<0,01) than LPS alone (p<0,5; n=10).
Conclusion: MD-2, quantified at first hospital admission, is an independent predictor for mortality in DCM contributed by direct activation of peripheral monocytes and cardiomyocytes. This suggests a relevant role of this protein in the pathophysiology of DCM.
- © 2013 by American Heart Association, Inc.