Myocardial Complement Depositions- A Possible Biomarker for Outcome of Mechanical Circulatory Support Therapy

Abstract

Purpose Mechanical circulatory support (MCS) treatment of end stage heart failure (HF) is known to induce sensitization. But development of HF by itself is intimately associated with antibody-mediated diseases, T cell-mediated immune reactions and infections, all of which induce activation of the complement system via the classical and lectin pathways, which converge at level C3 to form the membrane attack complex, causing further tissue injury. The potential role of C4d (a split product formed as a result of the activation of both complement pathways) as a biomarker is currently being investigated in various autoantibody-induced diseases which cause tissue damage. This retrospective study investigates the impact of capillary C4d depositions in LV myocardium of pts with HF on MCS therapy outcome. Methods We compared immunohistochemical (IHC) findings of anterior LV of 10 non-heart beating donors with LV apex from the site of MCS implantation of 12 patients, submitted over a 4 year period, from whom follow-up tissue from LV was available at the time of MCS weaning, heart transplantation (HTx) or necropsy. MCS pts were separated into 3 groups according to therapy outcome. HTx was performed in 10 pts [3 pediatric, 3 female, 1 with complex congenital heart defect, 1 with hypertrophic cardiomyopathy, 8 with dilated cardiomyopathy (DCM), age 3- 61 years]. A 3-year-old female with DCM was weaned from MCS, another 32-year-old female myocarditis pt died whilst on MCS. Three µm thick paraffin-embedded sections were analyzed using conventional histology and IHC for capillary depositions of C4d and C1q- the recognition molecule of the classical complement pathway. Results In the HTx group, compared to the explanted heart a stronger (and at least focal 2+) linear capillary C4d staining was observed in the apex. C1q was not detected in all but one non-heart beating donors and in the weaned and fulminant myocarditis pts, but was present in varying amounts in the remainder of samples, often not correlating with C4d depositions. Conclusion Our results suggest that detection of complement activation in native myocardium is an indicator for progression of immune reactions, although MCS appears to limit or silence the autoimmune response. The possible role of C4d as a biomarker to detect patients at risk for autoimmunity-triggered mechanisms associated with HF merits further evaluation.