Surviving Without Nerves: Intracardiac Denervation as an Underrecognized Feature of Cardiac Allograft Vasculopathy...

Background/Objectives: Orthotopic heart transplantation results in complete surgical denervation of the donor heart. Although partial functional reinnervation has been reported in some recipients, the histopathological features of intracardiac innervation in long-term failing cardiac allografts remain poorly characterized. We present a unique case of a cardiac allograft explanted 11 years after transplantation that enabled detailed histological and digital assessment of neural remodeling. Case Description: An explanted cardiac allograft obtained after retransplantation for chronic graft dysfunction was examined using whole-heart histopathological reconstruction and immunohistochemistry (CD3, CD68, C3, C4d, HLA-DR, NLRP3, VEGF, and UCHL-1). Digital quantitative analysis of UCHL-1-positive nerve fibers, including spatial density mapping and comparison with a reference non-diseased myocardium, demonstrated profound and heterogeneous loss of intracardiac innervation. Marked denervation was observed not only within fibrotic and infarcted regions but also in the morphologically preserved myocardium. Neural injury was associated with perineural and endoneurial inflammatory infiltrates, complement deposition, HLA-DR expression within nerve fibers and reduced perivascular and epicardial adipose tissue innervation. Distinct regional patterns of denervation and neural remodeling were also identified in the aortic segments of the transplantation complex. Conclusions: This case demonstrates that chronic cardiac allograft dysfunction may involve extensive injury of the intracardiac nervous system extending beyond areas of ischemic myocardial damage. The findings suggest that immune-mediated inflammation, complement activation, and chronic ischemia contribute to progressive neural remodeling in the transplanted heart. Histopathological evaluation of intracardiac innervation may provide additional insight into mechanisms of long-term graft failure and represents an underrecognized component of cardiac allograft pathology.