Abstract 17536: Cardiac Macrophage is Required to Avoid Atrioventricular Block After Right Heart Pressure Overload
Right heart dysfunction is of current interest in managing severe heart failure and pulmonary hypertension, and cardiomyocyte-immune cell interactions play an important role after myocardial infarction. However, the contributions of cardiac immune cells to right heart function is not well understood. We assessed the hypothesis that immune cells contribute to stress responses to right heart stress. We analyzed a right heart pressure overload model in mice using pulmonary artery banding (PAB) to develop right heart hypertrophy and fibrosis without lung injury. All wild-type mice with PAB could survive for at least several months. After PAB, macrophages, CD4 T cells, CD8 T cells, and B cells were increased in the heart. To analyze the function of these cells, PAB was performed in macrophage-depleted, CD4, CD8 T cell, or B cell knockout mice. Only macrophage-depleted mice showed a complete atrioventricular block (CAVB) and sudden death two hours after PAB. Gap junction protein Cx40 was significantly reduced in macrophage depleted mice. Only cardiac macrophages specifically expressed secreted factor Amphiregulin (AREG), while other kinds of cardiac cells and other organs’ macrophages did not. PAB augmented AREG expression levels. Myeloid cell-specific Areg-/- mice also showed CAVB and sudden death after PAB. Cardiomyocytes co-cultured with cardiac macrophages significantly enhanced hypertrophy of cardiomyocytes and gap junction formation between cardiomyocytes compared to those without cardiac macrophages. In addition, these effects were completely suppressed by the administration of AREG-neutralizing antibody and EGF receptor antagonist into this co-culture system. Moreover, cardiac macrophages sorted from the heart of Areg-/- abolished the enhanced cardiomyocytes’ gap junction in the co-culture system. These results indicate that AREG secretion from cardiac macrophages facilitated cardiac conduction by reinforcing cardiomyocytes’ gap junction through EGF receptor signaling in cardiomyocytes. In conclusion, the gap junction formation of cardiomyocytes by AREG secreted from cardiac macrophages needs to be enhanced to avoid cardiac sudden death and right ventricular dysfunction after right heart pressure overload.
Author Disclosures: J. Sugita: None. K. Fujiu: None. Y. Nakayama: None. T. Matsubara: None. J. Matsuda: None. I. Manabe: None. I. Komuro: None.
- © 2016 by American Heart Association, Inc.