MD-2 is a new predictive biomarker in dilated cardiomyopathy and exerts direct effects in isolated cardiomyocytes

TY - JOUR

T1 - MD-2 is a new predictive biomarker in dilated cardiomyopathy and exerts direct effects in isolated cardiomyocytes

AU - Riad, Alexander

AU - Gross, Stefan

AU - Witte, Jeannine

AU - Feldtmann, Rico

AU - Wagner, Katharina B

AU - Reinke, Yvonne

AU - Weitmann, Kerstin

AU - Empen, Klaus

AU - Beug, Daniel

AU - Westermann, Dirk

AU - Lindner, Diana

AU - Klingel, Karin

AU - Dörr, Marcus

AU - Hoffmann, Wolfgang

AU - Felix, Stephan B

N1 - Copyright © 2018 Elsevier B.V. All rights reserved.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - BACKGROUND: Myeloid differentiation factor-2 (MD-2) has been shown to be an important modulator of the innate immune system, but its role in cardiac diseases is unknown. We investigated whether MD-2 plays a role as risk predictor and contributor in dilated cardiomyopathy (DCM).METHODS AND RESULTS: We included 174 patients with reduced left ventricular (LV) ejection fraction (LVEF <45%) due to DCM. Coronary artery disease and severe valvular diseases were excluded in all patients by angiography or echocardiography. Cardiac inflammation, viral infection and MD-2 expression were analyzed from right ventricular endomyocardial biopsies. MD-2 was quantified by ELISA in serum upon first hospital admission. Myocyte contractility and inflammatory response after stimulation with recombinant MD-2 protein were analyzed in isolated rat cardiomyocytes. Median follow-up of the patients was 3.51 years (2.73; 4.48) with 34 deaths. Absolute mortality risk increases in patients displaying a MD-2 serum concentration greater than the median (302 ng/ml) was 23% (P < 0.0001). Age- and sex-adjusted Cox regression analyses demonstrated that mortality risk was highly related to MD-2 concentrations (P < 0.001), but not to age or sex. An increase of 100 ng/ml in the MD-2 level was associated with an absolute mortality risk increase of 50.4%. Receiver operating characteristic (ROC) analyses showed no difference between MD-2 and nterminal-pro brain natriuretic peptide (NT-pro-BNP), while the combination of both MD-2 and NT-pro-BNP resulted in a significantly increased capability of risk prediction when compared to NT-pro-BNP alone (P = 0.014). In-vitro, recombinant MD-2 decreases cell shortening and modulates cytokine activation in isolated cardiomyocytes.CONCLUSION: MD-2 predicts long-term outcome in DCM patients and improves mortality risk prediction capability compared to NT-pro-BNP alone. In addition, MD-2 exerts direct negative inotropic effects on isolated cardiomyocytes in-vitro. Further randomized trials should confirm MD-2 as a diagnostic and therapeutic target.

AB - BACKGROUND: Myeloid differentiation factor-2 (MD-2) has been shown to be an important modulator of the innate immune system, but its role in cardiac diseases is unknown. We investigated whether MD-2 plays a role as risk predictor and contributor in dilated cardiomyopathy (DCM).METHODS AND RESULTS: We included 174 patients with reduced left ventricular (LV) ejection fraction (LVEF <45%) due to DCM. Coronary artery disease and severe valvular diseases were excluded in all patients by angiography or echocardiography. Cardiac inflammation, viral infection and MD-2 expression were analyzed from right ventricular endomyocardial biopsies. MD-2 was quantified by ELISA in serum upon first hospital admission. Myocyte contractility and inflammatory response after stimulation with recombinant MD-2 protein were analyzed in isolated rat cardiomyocytes. Median follow-up of the patients was 3.51 years (2.73; 4.48) with 34 deaths. Absolute mortality risk increases in patients displaying a MD-2 serum concentration greater than the median (302 ng/ml) was 23% (P < 0.0001). Age- and sex-adjusted Cox regression analyses demonstrated that mortality risk was highly related to MD-2 concentrations (P < 0.001), but not to age or sex. An increase of 100 ng/ml in the MD-2 level was associated with an absolute mortality risk increase of 50.4%. Receiver operating characteristic (ROC) analyses showed no difference between MD-2 and nterminal-pro brain natriuretic peptide (NT-pro-BNP), while the combination of both MD-2 and NT-pro-BNP resulted in a significantly increased capability of risk prediction when compared to NT-pro-BNP alone (P = 0.014). In-vitro, recombinant MD-2 decreases cell shortening and modulates cytokine activation in isolated cardiomyocytes.CONCLUSION: MD-2 predicts long-term outcome in DCM patients and improves mortality risk prediction capability compared to NT-pro-BNP alone. In addition, MD-2 exerts direct negative inotropic effects on isolated cardiomyocytes in-vitro. Further randomized trials should confirm MD-2 as a diagnostic and therapeutic target.

KW - Animals

KW - Biomarkers/metabolism

KW - Cardiomyopathy, Dilated/diagnosis

KW - Case-Control Studies

KW - Cells, Cultured

KW - Cohort Studies

KW - Dose-Response Relationship, Drug

KW - Female

KW - Humans

KW - Lymphocyte Antigen 96/metabolism

KW - Male

KW - Middle Aged

KW - Myocytes, Cardiac/drug effects

KW - Predictive Value of Tests

KW - Rats

KW - Registries

KW - Retrospective Studies

U2 - 10.1016/j.ijcard.2018.06.025

DO - 10.1016/j.ijcard.2018.06.025

M3 - SCORING: Journal article

C2 - 30082120

VL - 270

SP - 278

EP - 286

JO - INT J CARDIOL

JF - INT J CARDIOL

SN - 0167-5273

ER -