Lipofuscin: Wear Pigment or Alarm Signal for Cardiac AlloGraft Vasculopathy?

Background: CAV (cardiac allograft vasculopathy) is considered the leading cause of late post-transplant mortality and affects approximately 50% of transplant patients at 10 years post-transplant. Its etiopathogenetic mechanism is considered to be immune-mediated, but the identification of other non-immunological risk factors could represent new therapeutic targets for this pathology. Lipofuscin is due to reactive oxygen species (ROS) and appears to have a determining role in CAV. The aim of this study is to investigate the association between the amount of lipofuscin identified on EMB (endomyocardial biopsy) from patients followed up after heart transplantation, and the presence of CAV detected by coronary angiography. Methods: This retrospective study includes 99 EMBs from 47 transplanted patients, who also had coronary angiography. The amount of lipofuscin, damage to intramyocardial small vessels, vasculitis, Quilty effect, and acute cellular and humoral rejection was evaluated microscopically. Results: 19 CAV cases (19.2%) were identified, of which 15 (68.18% of total CAV cases) were insignificant. Grade 3 lipofuscin affected equally the cases with insignificant and significant CAV, 3 cases (37.5%) from each group. Grade 2 lipofuscin was reported in 10 cases (58.8%) of insignificant CAV, respectively 1 case of significant CAV (5.9%), (p-value of 0.0001). Quantitative evaluation of lipofuscin on microscopic sections revealed 8 EMBs (8.1%) with grade 3 lipofuscin. Two cases (25.0%) with lipofuscin score 3 were associated with moderate ACR (acute cellular rejection), ISHLT 2R and 3 cases (37.5%) with lipofuscin score 3 were associated with mild ACR ISHLT 1R, the differences being statistically significant, (p = 0.0001). Lipofuscin grades 2 and 3 were associated with severe fibrosis in 6 cases (35.3%) and 2 cases (25.0%), respectively (p = 0.042). A statistically significant association between the degree of damage to the intramyocardial small vessels and the amount of intracytoplasmic lipofuscin was observed (p = 0.00014). Discussion: Our study revealed that lipofuscin was more frequently associated with CAV, fibrosis, and damaged small vessels. Oxidative stress influences lipofuscinogenesis and CAV, which leads to endothelial dysfunction and neointimal hyperplasia, which over time will produce progressive narrowing of the vascular lumen and dysfunction of the cardiac allograft. Of the total number of 19 cases with CAV, 17 (89.47%) presented a lipofuscin score of 2 or 3 concomitantly with CAV, (p = 0.0001). This could mean that lipofuscin is not a harmless degradation product. At the same time, the association of a large number of cases with lipofuscin score 2, 10 cases (58.8%) with insignificant CAV could lead to the idea of using lipofuscin as a potential biomarker in the early diagnosis of CAV. Conclusions: We evidenced a significant association between the amount of intracytoplasmic lipofuscin and CAV. Accordingly, lipofuscin might be involved in the pathogenesis of CAV. Further research is needed to clarify the exact mechanisms of this association.