Representative microphotographs of immunostaining for β-catenin (A to C), -catenin (D to F), N-cadherin (G to I), and E-catenin (J to L) in the infarct area of ruptured hearts (A, D, G, J), and early (B, E, H, K) and late (C, F, I, L) control infarcts. A similar staining intensity for β-catenin, -catenin, and N-cadherin was observed in the intercalated disk regions of the cardiomyocytes in infarct rupture and the 2 control myocardial infarction (MI) groups. E-catenin staining was undetectable in the infarct area of infarct rupture patients (J). However, staining was observed in the early control infarcts (K) as also in the border zone (bz) of late control MIs (L). (M to O) Shows hematoxylin and eosin staining of the infarct area of ruptured patients (M), characterized by the necrotic cardiomyocytes and the massive influx of inflammatory cells. Hematoxylin and eosin staining of an early control MI (N) and the border zone of a late control MI (O) are also shown.

Representative images of immunostaining for β-catenin (A, B), -catenin (C, D), N-cadherin (E, F), and E-catenin (G, H) in remote parts of ruptured hearts (A, C, E, G) and control myocardial infarction (MI) hearts without rupture (B, D, F, H). Abundant and similar staining for β-catenin, -catenin, and N-cadherin was observed in the intercalated disk regions of the cardiomyocytes in infarct rupture and control MI groups. For E-catenin, abundant staining of intercalated disks between cardiomyocytes was observed in the control MI hearts (H). On the contrary, 90% of the patients from the infarct rupture group showed either weak or no detectable E-catenin staining (G).

(Top) Representative Western blots of tissue obtained from infarct rupture patients and control myocardial infarction (MI) patients, both from remote (nonischemic) and infarct areas. (A) E-catenin, (B) β-catenin, (C) -catenin, and (D) N-cadherin; -tubulin was used for normalization of the samples. (Bottom) Quantitative analysis of adhesion complex proteins, expressed as protein/-tubulin ratio. Significantly less E-catenin was detected in the remote area of infarct rupture patients (n = 10) compared with that seen in control MI patients (n = 10). In the infarct area, E-catenin was undetectable in the infarct rupture group but readily detectable in the control MI group. Similar levels of β-catenin, -catenin, and N-cadherin were observed in the remote areas of infarct rupture and control MI groups, although more extensive degradation of these proteins was detected under ischemic conditions. *p < 0.01; **p < 0.001; #p < 0.05.

(A) Kaplan-Meier curve analysis of heterozygous E-catenin C-terminal deficient mice (n = 9) showed significantly lower rupture-free survival post-myocardial infarction (MI) (#p = 0.038) compared with their wild-type littermates (n = 11). (B) Macroscopic image of infarct rupture (T = tweezers). The arrow points at the tear in the infarct area, showing the blood loss through the ventricular wall. (C) Representative images of immunohistochemical analysis of E-catenin, showing less intense staining of the intercalated disks in the heterozygous mice compared with staining in the wild-type littermates. (D to G) (Top) Representative Western blot analysis for E-catenin (D), β-catenin (E), -catenin (F), and N-cadherin (G) in heterozygous C-terminal E-catenin deficient mice and their wild-type littermates, both from septum (nonischemic) and infarct tissue; β-actin was used for normalization of the samples. (Bottom) Quantitative analysis of adhesion complex proteins, expressed as protein/β-actin ratio, demonstrating significantly lower E-catenin in mice heterozygously deficient for C-terminally truncated E-catenin (n = 9) compared with that in their wild-type littermates (n = 11). The other cell adhesion proteins were unaffected, although N-cadherin showed more degradation under ischemic conditions in the heterozygous mice. *p < 0.01; **p < 0.001; #p < 0.05.

In the left part of the cartoon, the normal components of the cell adhesion complex of cardiomyocytes from patients with normal infarct healing are shown. In the uninjured cardiomyocytes of normal hearts, E-catenin is localized in the intercalated disks. Ischemia induces death of the cardiomyocytes in the infarct area, as shown by the loss of their nucleus. However, the integrity of the infarct area is sufficiently preserved by the adhering cardiomyocytes, and the wound healing and granulation tissue formation continue. As shown in the right side of the cartoon, E-catenin is not localized in the intercalated disks of the cardiomyocytes in rupture-prone hearts. After ischemia, this abnormal cell adhesion complex causes the dead cardiomyocytes in the infarct area to loosen up their connections, causing further deterioration of the integrity of the infarct area and subsequently leading to infarct rupture.