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Myocyte necrosis underlies progressive myocardial dystrophy in mouse dsg2-related arrhythmogenic right ventricular cardiomyopathy.

Pilichou K, Remme CA, Basso C, Campian ME, Rizzo S, Barnett P, Scicluna BP, Bauce B, van den Hoff MJ, de Bakker JM, Tan HL, Valente M, Nava A, Wilde AA, Moorman AF, Thiene G, Bezzina CR - J. Exp. Med. (2009)

Bottom Line: Investigation of transgenic lines with different levels of transgene expression attested to a dose-dependent dominant-negative effect of the mutation.These observations were supported by findings in the explanted heart from the patient.Insight into mechanisms initiating myocardial damage in ARVC is a prerequisite to the future development of new therapies aimed at delaying onset or progression of the disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Diagnostic Sciences and Special Therapies, University of Padua, 35121 Padua, Italy.

ABSTRACT
Mutations in the cardiac desmosomal protein desmoglein-2 (DSG2) are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). We studied the explanted heart of a proband carrying the DSG2-N266S mutation as well as transgenic mice (Tg-NS) with cardiac overexpression of the mouse equivalent of this mutation, N271S-dsg2, with the aim of investigating the pathophysiological mechanisms involved. Transgenic mice recapitulated the clinical features of ARVC, including sudden death at young age, spontaneous ventricular arrhythmias, cardiac dysfunction, and biventricular dilatation and aneurysms. Investigation of transgenic lines with different levels of transgene expression attested to a dose-dependent dominant-negative effect of the mutation. We demonstrate for the first time that myocyte necrosis is the key initiator of myocardial injury, triggering progressive myocardial damage, including an inflammatory response and massive calcification within the myocardium, followed by injury repair with fibrous tissue replacement, and myocardial atrophy. These observations were supported by findings in the explanted heart from the patient. Insight into mechanisms initiating myocardial damage in ARVC is a prerequisite to the future development of new therapies aimed at delaying onset or progression of the disease.

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Related in: MedlinePlus

Histological features of Tg-NS/H hearts at high magnification. (A) Normal myocardium (1.7 wk of age). Bar, 50 µm. (B) Cardiomyocyte necrosis with early neutrophil infiltrates (2.1 wk of age). Bar, 20 µm. (C) Diffuse inflammatory cells including macrophages (3.6 wk of age). Bar, 50 µm. (D) Replacement-type fibrosis with spots of calcification (8 wk of age). Bar, 30 µm.
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fig7: Histological features of Tg-NS/H hearts at high magnification. (A) Normal myocardium (1.7 wk of age). Bar, 50 µm. (B) Cardiomyocyte necrosis with early neutrophil infiltrates (2.1 wk of age). Bar, 20 µm. (C) Diffuse inflammatory cells including macrophages (3.6 wk of age). Bar, 50 µm. (D) Replacement-type fibrosis with spots of calcification (8 wk of age). Bar, 30 µm.

Mentions: Trichrome, hematoxylin-eosin (H&E), and von Kossa staining on heart sections revealed no abnormalities in Tg-NS/H mice <2 wk old (Fig. 6, A–C; and Fig. 7 A). Spotty contraction band and coagulative necrosis, followed by massive inflammatory infiltrates, were evident in the myocardium of 2–3-wk-old Tg-NS/H mice (Fig. 6, D–F; Fig. 7 B; and Fig. 8, A and B) but not in Tg-WT and WT mice of the same age. In 3–5-wk-old Tg-NS/H mice, extensive myocyte necrosis and massive calcification were a constant feature in both RV and LV; granulation tissue and early loose connective tissue deposition were also evident (Fig. 6, G–I; and Fig. 7 C). Typically, myocardial damage started in the outer subepicardial layers (Fig. 6, D–F), with progressive extension toward the endocardium to become transmural by 4 wk (Fig. 6, G–I).


Myocyte necrosis underlies progressive myocardial dystrophy in mouse dsg2-related arrhythmogenic right ventricular cardiomyopathy.

Pilichou K, Remme CA, Basso C, Campian ME, Rizzo S, Barnett P, Scicluna BP, Bauce B, van den Hoff MJ, de Bakker JM, Tan HL, Valente M, Nava A, Wilde AA, Moorman AF, Thiene G, Bezzina CR - J. Exp. Med. (2009)

Histological features of Tg-NS/H hearts at high magnification. (A) Normal myocardium (1.7 wk of age). Bar, 50 µm. (B) Cardiomyocyte necrosis with early neutrophil infiltrates (2.1 wk of age). Bar, 20 µm. (C) Diffuse inflammatory cells including macrophages (3.6 wk of age). Bar, 50 µm. (D) Replacement-type fibrosis with spots of calcification (8 wk of age). Bar, 30 µm.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2722163&req=5

fig7: Histological features of Tg-NS/H hearts at high magnification. (A) Normal myocardium (1.7 wk of age). Bar, 50 µm. (B) Cardiomyocyte necrosis with early neutrophil infiltrates (2.1 wk of age). Bar, 20 µm. (C) Diffuse inflammatory cells including macrophages (3.6 wk of age). Bar, 50 µm. (D) Replacement-type fibrosis with spots of calcification (8 wk of age). Bar, 30 µm.
Mentions: Trichrome, hematoxylin-eosin (H&E), and von Kossa staining on heart sections revealed no abnormalities in Tg-NS/H mice <2 wk old (Fig. 6, A–C; and Fig. 7 A). Spotty contraction band and coagulative necrosis, followed by massive inflammatory infiltrates, were evident in the myocardium of 2–3-wk-old Tg-NS/H mice (Fig. 6, D–F; Fig. 7 B; and Fig. 8, A and B) but not in Tg-WT and WT mice of the same age. In 3–5-wk-old Tg-NS/H mice, extensive myocyte necrosis and massive calcification were a constant feature in both RV and LV; granulation tissue and early loose connective tissue deposition were also evident (Fig. 6, G–I; and Fig. 7 C). Typically, myocardial damage started in the outer subepicardial layers (Fig. 6, D–F), with progressive extension toward the endocardium to become transmural by 4 wk (Fig. 6, G–I).

Bottom Line: Investigation of transgenic lines with different levels of transgene expression attested to a dose-dependent dominant-negative effect of the mutation.These observations were supported by findings in the explanted heart from the patient.Insight into mechanisms initiating myocardial damage in ARVC is a prerequisite to the future development of new therapies aimed at delaying onset or progression of the disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Diagnostic Sciences and Special Therapies, University of Padua, 35121 Padua, Italy.

ABSTRACT
Mutations in the cardiac desmosomal protein desmoglein-2 (DSG2) are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). We studied the explanted heart of a proband carrying the DSG2-N266S mutation as well as transgenic mice (Tg-NS) with cardiac overexpression of the mouse equivalent of this mutation, N271S-dsg2, with the aim of investigating the pathophysiological mechanisms involved. Transgenic mice recapitulated the clinical features of ARVC, including sudden death at young age, spontaneous ventricular arrhythmias, cardiac dysfunction, and biventricular dilatation and aneurysms. Investigation of transgenic lines with different levels of transgene expression attested to a dose-dependent dominant-negative effect of the mutation. We demonstrate for the first time that myocyte necrosis is the key initiator of myocardial injury, triggering progressive myocardial damage, including an inflammatory response and massive calcification within the myocardium, followed by injury repair with fibrous tissue replacement, and myocardial atrophy. These observations were supported by findings in the explanted heart from the patient. Insight into mechanisms initiating myocardial damage in ARVC is a prerequisite to the future development of new therapies aimed at delaying onset or progression of the disease.

Show MeSH
Related in: MedlinePlus