Telocytes in human isolated atrial amyloidosis: ultrastructural remodelling

Abstract

The human heart can be frequently affected by an organ-limited amyloidosis called isolated atrial amyloidosis (IAA). IAA is a frequent histopathological finding in patients with long-standing atrial fibrillation (AF). The aim of this paper was to investigate the ultrastructure of cardiomyocytes and telocytes in patients with AF and IAA. Human atrial biopsies were obtained from 37 patients undergoing cardiac surgery, 23 having AF (62%). Small fragments were harvested from the left and right atrial appendages and from the atrial sleeves of pulmonary veins and processed for electron microscopy (EM). Additional fragments were paraffin embedded for Congo-red staining. The EM examination certified that 17 patients had IAA and 82% of them had AF. EM showed that amyloid deposits, composed of characteristic 10-nm-thick filaments were strictly extra-cellular. Although, under light microscope some amyloid deposits seemed to be located within the cardiomyocyte cytoplasm, EM showed that these deposits are actually located in interstitial recesses. Moreover, EM revealed that telopodes, the long and slender processes of telocytes, usually surround the amyloid deposits limiting their spreading into the interstitium. Our results come to endorse the presumptive association of AF and IAA, and show the exclusive, extracellular localization of amyloid fibrils. The particular connection of telopodes with amyloid deposits suggests their involvement in isolated atrial amyloidosis and AF pathogenesis.

Fig 1

(A and B) Light microscopy on toluidine blue stained semithin sections. (A) Cross-sectioned atrial cardiomyocytes showing smaller profiles and irregular contours. The interstitial area is enlarged, clearly isolating the cardiomyocytes. The cardiomyocytes show small interstitial recesses (arrows). Ob. 20×. (B) Higher magnification of the area enclosed by rectangle in Figure 1A. Several atrial cardiomyocytes (my) with stellate profiles show many small interstitial recesses (invaginations) marked by arrows. Ob. 1003. (C and D) Electron microscopy details of rectangular marked area in Figure 1A. Atrial cardiomyocytes (CM) showing cellular oedema (C) or centrally gathered myofibrils and peripherally placed mitochondria (#), glycogen granules and lipofuscin (D). Both images show small recesses (arrowheads) in the periphery of cardiomyocytes. Atrial natriuretic peptide (ANP) granules (white arrows). A telopode (Tp) surrounding a cardiomyocyte is close to a nerve fibre.

Fig 2

(A) Chart shows the relationship of isolated atrial amyloidosis (IAA) with atrial fibillation (AF). Total number of patients: 37. n, number of patients. −IAA-AF: patients without IAA or AF. −IAA1AF: patients with AF and IAA negative. +IAA-AF: patients with IAA and no AF. +IAA+AF: patients having both IAA and AF. (B) Schematic figure highlighting the association IAA and AF. From a total of 37 patients (black circle), 17 developed IAA (45.94%-lilac circle) and 23 suffered of AF (62.16%-red circle). Fourteen patients had both IAA and AF (37.84% from all investigated cases).

Fig 3

Electron microscopy image showing interstitial amyloid deposit in between an atrial cardiomyocyte (CM) and a telopode (Tp). Note the cardiomyocyte recess filled with amyloid fibrils (white arrow).

Fig 4

Electron microscopy showing sarcolemmal small recess of an atrial cardiomyocyte loaded with amyloid fibrils (arrow). A telopode (Tp) borders the interstitial face of amyloid deposit.

Fig 5

Electron micrograph showing longitudinally (black arrowheads) and transversally (stars) sectioned deep cardiomyocytic invaginations. Z line streaming (white arrows) next to the plasma membrane of a cardiomyocyte (CM).

Fig 6

Electron micrograph showing randomly arranged, unbranched amyloid fibrils (star) loaded in a recess of the cardiomyocyte (CM) close to an intercalated disc (ID).

Fig 7

Cardiomyocyte (CM) recess with unbranched amyloid fibrils (8–12 nm diameter) surrounded by plasma membrane (arrows).

Fig 8

Electron microscopy of atrial interstitial area. A telopode (Tp) surrounds a bunch of amyloid fibrils (star). Coll, collagen fibres; E, elastin.

Fig 9

Telopodes (Tp) surrounding an amyloid deposit (stars) in the periphery of a blood vessel. Small shed vesicles (arrowheads) can be seen in the vicinity of telopodes. CM, cardiomyocyte; End, endothelium; P, pericyte.

Fig 10

Electron microscopy image showing how interstitial amyloid fibrils (star) are wrapped by a telopode (Tp). Cardiomyocytes (CM) recesses (arrows) containing amyloid fibrils close to intercalated disks.

Fig 11

Telopode (Tp) surrounding (arrowheads) an amyloid deposit fragmented in small bunches (stars). The atrial myocyte (CM) contains atrial natriuretic peptide granule (arrows) next to the plasma membrane.

Fig 12

Electron micrograph showing the honeycomb-like structure of a telopode (Tp) containing small bunches of amyloid filaments (stars).