Intercalated Disc Junctions

The ID is the area of end-to-end connections between cardiomyocytes, and consists of three junc-tional complexes: desmosomes, fascia adherens, and gap junction (also called the nexus). The desmosome is composed of a cytoplasmic electron-dense plaque of intracellular filaments containing desmoplakin, plakoglobin, plakophilin, and transmembrane calcium-sensitive proteins, i.e., desmoglein and desmo-collin. In addition to cell-to-cell adhesion, this type of junction provides a structural connection to the intermediate filaments system (i.e., desmin) [20,21]

responsible for mechanical cell-cell stability. The fascia adherens junction consists of complex proteins that link a transmembrane protein, N-cadherin, to catenin and further to sarcomeric actin. This structure transmits contractile force across the sarcolem-ma [20]. The gap junction consists of transmembrane channels called connexons, which do not connect to the cytoskeleton system, but allow intercellular metabolic communication by transmitting small molecules and electrical stimuli [22].

The growing interest in the intercellular junction is due, in part, to the identification of desmosomal protein-encoding gene mutations in ARVC/D. Also there is evidence that plakoglobin null-mutant mouse embryos show decreased myofiber compliance and reduced cell-cell adhesion as a consequence of defects in desmosome number and structure [23]. Impairment of myocyte cell-to-cell adhesion has been advocated as a possible common pathway in ARVC/D, since failure of desmosome to couple cells will invariably lead to tissue and organ fragility.

The major ultrastructural findings reported in ARVC/D were "pale" junctional structures and flattened ID convolutions [16, 17]. "Paleness" of desmosomes and fascia adherens at the cytoplasmic plaque was confirmed in our study (Fig. 6.2a); however, morphometric analysis of samples from 21 ARVC/D hearts showed normal convoluted ID in comparison with normal hearts (Table 6.2). These findings suggest an abnormal composition of proteins located in the plaque area, i.e., cadherins and cytoplasmic tails of P-catenin, respectively.

Desmosome Arvc

Fig.6.2 • ID region of cardiomyocytes from ARVC/D hearts. a Pale ID with visible long desmosome (D) Bar = 200 nm. b Abnormal junctional structures of the ID:the fascia adherens junction (FA) and long desmosome (D) and intersected actin filaments (arrows) Bar = 200 nm. c Fragment of the ID exhibiting desmosomes of various length. Bar = 200 nm

Table 6.2 • Ultrastructural morphometry of ID junctions

ID

ARVC/D (21)

DCM (10)

Controls (10)

ARVC/D vs. Controls

ARVC/D vs. DCM

DCM vs. Controls

Convolution index

3,0 ±

0,9

2,8 ± 0,5

2,8 ± 0,6

0.34

0.18

0.76

D mean length (^m)

0,31 ±

0,08

0,23 ± 0,1

0,16 ±0,08

<0.001

0.04

0.11

n. D/10 ^m unity length

3,34 ±

0,9

4,2 ± 0,8

5,54 ± 2,3

0.01

0.02

0.10

D percent length of ID (%)

9,8 ±

3,2

8,4 ± 2,2

5,7 ±1,4

<0.001

0.16

0.008

Nexus mean length (^m)

0,34 ±

0,15

0,31 ± 0,07

0,32 ±0,16

0.78

0.47

0.69

n. Nexus/10 ^m unity length

0,29 ±

0,86

0,23 ± 0,32

0,78 ± 0,54

0.03

0.64

0.02

Nexus percent length of ID (%)

1,2 ±

1,8

1,14 ±1,5

3,0 ± 2,5

0.07

0.93

0.08

D mean gap (nm)

29,33 ±

: 8,95

24,21±2,1

21,78 ± 3,42

0.004

0.03

0.19

FA mean gap (nm)

41,49 ±

20,36

28,39 ± 5,1

27,18 ±10,72

0.03

0.02

0.67

After Bonferroni correction, only p <0.016 are significant.

D, desmosome;DCM,dilated cardiomyopathy; FA,fascia adherens; n, number; ID, intercalated disc

After Bonferroni correction, only p <0.016 are significant.

D, desmosome;DCM,dilated cardiomyopathy; FA,fascia adherens; n, number; ID, intercalated disc

Fig.6.2 • ID region of cardiomyocytes from ARVC/D hearts. a Pale ID with visible long desmosome (D) Bar = 200 nm. b Abnormal junctional structures of the ID:the fascia adherens junction (FA) and long desmosome (D) and intersected actin filaments (arrows) Bar = 200 nm. c Fragment of the ID exhibiting desmosomes of various length. Bar = 200 nm

Other characteristic features of ID in ARVC/D hearts are abnormally elongated desmosomes (Figs. 6.2a, b) and a series of short desmosomes (Fig. 6.2c), similar to those observed in Carvajal syndrome, which is related to desmoplakin mutation [8, 24]. The biological significance of these abnormalities is unknown. Desmosomes were often abnormally displaced from the cell membrane to the cell contractile apparatus area and, simultaneously, desmin filaments in the proximity of these desmosomes were intersected. Morphometric analysis confirmed an increase of mean desmosome length and revealed a decreased number of desmosomes and widened gaps between membranes of adjoining cells (Table 6.2). These features probably influence the mechanical coupling of adjoining cells. Additionally, impaired desmin organization in the proximity of desmosomes may affect the mechanical strength that can be provided by normal junctions [21].

At the level of the fascia adherens, widening of the ID gap (Table 6.2) and abnormal organization of actin filaments have been observed in ARVC/D (Fig. 6.2b) These might be due to a specific impairment of fascia adherens protein, but might also be the result of a "symbiotic" relationship with a defect of desmosome structure.

The length and ultrastructure of nexuses seem to be normal, while their number is decreased in ARVC/D, as shown by morphometric analysis. In Naxos disease, a decrease of both average profile length and number of nexuses was observed by Kaplan et al. [25] in a patient who died before ARVC/D became clinically manifest. They suggested that abnormal linkage between mechanical junctions and the cytoskeleton due to mutant plakoglobin was responsible for this remodeling. The decreased number of nexuses probably led to increased tissue anisotropy, which may potentially account for lack of homogeneity in the propagation of action potentials.

In summary, remodeling of cellular junctions seen at the ultrastructural level probably affects the response of myocardial tissue to mechanical stretching and electrical conduction. This might explain why structural abnormalities occur mainly in areas subjected to high strain, i.e., in the triangle of dysplasia (the right ventricular outflow, the apex and subtricuspid area).

Noteworthy, in nearly half of the cases, we found evidence of desmosomal gene mutations, i.e., desmo-plakin, plakophilin-2, and desmoglein-2. Desmosome remodeling was present at the ultrastructural level in both gene-positive and gene-negative ARVC/D patients. This supports the view that other ARVC/D genes are as yet undiscovered.

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