Abstract

Abstract Introduction In cardiac amyloidosis (CA), amyloid fibers accumulate in the extracellular spaces of the heart, causing a compression and obliteration of lymphatic vessels, and possibly their disappearance. As lympathic drainage removes proteins from the interstitial spaces, including amyloid precursors, an impairment of lympathic vessels could exacerbate amyloid accumulation, triggering a vicious circle. Methods Lymphatic vessels were visualized by immunohistochemistry using a monoclonal antibody against podoplanin (D2–40, a marker of lymphatic endothelial cells) and the immunopreroxidase technique. We investigated 3 groups of cases: 1) as a reference standard, endomyocardial specimens from the left ventricular (LV) endomyocardium of 10 heart valve donors, deceased for trauma and/or cerebral hemorrhage, with no evidence of cardiac disease on gross and microscopic examination; 2) 15 consecutive LV endomyocardial biopsies (EMBs) from patients with CA, where cardiac amyloid was detected and typed by Congo red staining, immunohistochemistry and proteomics, and 3) 13 surgical endomyocardial biopsies from patients with septal LV hypertrophy, undergoing aortic valve surgery and with CA excluded by histology. Results In donor hearts (n=10), lymphatic vessels were mostly distributed in the subendocardial and subepicardial layers, with some intra–myocardial lymphatic vessels near larger blood vessels. We then examined 15 patients with CA (amyloid transthyretin [ATTR]–CA, n=10; amyloid light–chain [AL]–CA, n=5; 50% men, median age 75 years [interquartile range 71–78]), and 13 patients with CA excluded (55% men, median age 68 years [59–71]). The density of lymphatic vessels in patients with CA was 0.52 vessels/mm2 (0–3.32), vs. 10.90 vessels/mm2 (3.10–26.25) in those without CA (p=0.001). No significant differences were found in LV mass index (p=0.170) or LV ejection fraction (p=0.262). Three patients with ATTR–CA and 2 patients with AL–CA showed no lymphatic vessels on EMB. The density of lymphatic vessels did not differ significantly in patients with ATTR– or AL–CA. Conclusions Patients with CA have significantly decreased endo–myocardial lymphatic vessels as compared to patients without CA, despite no significant difference in the degree of LV wall thickening or LV ejection fraction. These results support the hypothesis that the lymphatic drainage is deranged in patients with CA, possibly promoting further amyloid deposition.

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