Innate immune signaling in hearts and buccal mucosa cells of patients with arrhythmogenic cardiomyopathy

BACKGROUND Nuclear factor KB (NF-KB) signaling in cardiac myocytes causes disease in a mouse model of arrhythmogenic cardiomyopathy (ACM) by mobilizing CCR2-expressing macrophages that promote myocardial injury and arrhythmias. Buccal mucosa cells exhibit pathologic features similar to those seen in cardiac myocytes in patients with ACM.OBJECTIVES We sought to determine if persistent innate immune signaling via NF-KB occurs in cardiac myocytes in patients with ACM and if this is associated with myocardial infiltration of proinflammatory cells expressing CCR2. We also determined if buccal mucosa cells from young subjects with inherited disease alleles exhibit NF-KB signaling.METHODS We analyzed myocardium from ACM patients who died suddenly or required cardiac transplantation. We also analyzed buccal mucosa cells from young subjects with inherited disease alleles. The presence of immunoreactive signal for RelA/p65 in nuclei of active NF-KB signaling. We also counted myocardial CCR2expressing cells.RESULTS RelA/p65 signal was seen in numerous cardiac myocyte nuclei in 34 of 36 cases of ACM but not in 19 age-matched control individuals. Cells expressing CCR2 were increased in patient hearts in numbers directly correlated with the number of cardiac myocytes showing NF -KB signaling. NF -KB signaling was observed in buccal cells in young subjects with active disease.CONCLUSIONS Patients with clinically active ACM exhibit persistent innate immune responses in cardiac myocytes and buccal mu-cosa cells, reflecting a local and systemic inflammatory process. Such individuals may benefit from anti-inflammatory therapy.