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Desmoglein 2 mutant mice develop cardiac fibrosis and dilation.

Krusche CA, Holthöfer B, Hofe V, van de Sandt AM, Eshkind L, Bockamp E, Merx MW, Kant S, Windoffer R, Leube RE - Basic Res. Cardiol. (2011)

Bottom Line: Upon histological examination, cardiomyocyte death by calcifying necrosis and replacement by fibrous tissue were observed.Fibrotic lesions were highly proliferative in 2-week-old mutants, whereas the fibrotic lesions of older mutants showed little proliferation indicating the completion of local muscle replacement by scar tissue.Disease progression correlated with increased mRNA expression of c-myc, ANF, BNF, CTGF and GDF15, which are markers for cardiac stress, remodeling and heart failure.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Wendlingweg 2, Aachen, Germany. ckrusche@ukaachen.de

ABSTRACT
Desmosomes are cell-cell adhesion sites and part of the intercalated discs, which couple adjacent cardiomyocytes. The connection is formed by the extracellular domains of desmosomal cadherins that are also linked to the cytoskeleton on the cytoplasmic side. To examine the contribution of the desmosomal cadherin desmoglein 2 to cardiomyocyte adhesion and cardiac function, mutant mice were prepared lacking a part of the extracellular adhesive domain of desmoglein 2. Most live born mutant mice presented normal overall cardiac morphology at 2 weeks. Some animals, however, displayed extensive fibrotic lesions. Later on, mutants developed ventricular dilation leading to cardiac insufficiency and eventually premature death. Upon histological examination, cardiomyocyte death by calcifying necrosis and replacement by fibrous tissue were observed. Fibrotic lesions were highly proliferative in 2-week-old mutants, whereas the fibrotic lesions of older mutants showed little proliferation indicating the completion of local muscle replacement by scar tissue. Disease progression correlated with increased mRNA expression of c-myc, ANF, BNF, CTGF and GDF15, which are markers for cardiac stress, remodeling and heart failure. Taken together, the desmoglein 2-mutant mice display features of dilative cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, an inherited human heart disease with pronounced fibrosis and ventricular arrhythmias that has been linked to mutations in desmosomal proteins including desmoglein 2.

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Homozygous DSG2-mutant mice (DSG2mt) present ventricular dilation and signs of compromised cardiac function. a, b Representative echocardiography (pictures taken in B-mode) at the end of diastole in wild-type (DSG2wt) male mice compared to age-matched male DSG2mt mice. RV right ventricle, LV left ventricle, IVS interventricular septum, LVPW left ventricular posterior wall, LVID left ventricular inner diameter, ao aorta, pm papillary muscle. c, d Comparison of the morphology of a wild-type (c) and a DSG2-mutant heart (d), which presents an enlarged right ventricle and extensive fibrotic lesions (arrows). e, f Representative ECGs from wild-type (e) and mutant mice (f). Note the abnormalities in the ECGs of the mutant mice presenting extrasystole, arrthythmia and conduction abnormalities (f, from top to bottom)
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Fig2: Homozygous DSG2-mutant mice (DSG2mt) present ventricular dilation and signs of compromised cardiac function. a, b Representative echocardiography (pictures taken in B-mode) at the end of diastole in wild-type (DSG2wt) male mice compared to age-matched male DSG2mt mice. RV right ventricle, LV left ventricle, IVS interventricular septum, LVPW left ventricular posterior wall, LVID left ventricular inner diameter, ao aorta, pm papillary muscle. c, d Comparison of the morphology of a wild-type (c) and a DSG2-mutant heart (d), which presents an enlarged right ventricle and extensive fibrotic lesions (arrows). e, f Representative ECGs from wild-type (e) and mutant mice (f). Note the abnormalities in the ECGs of the mutant mice presenting extrasystole, arrthythmia and conduction abnormalities (f, from top to bottom)

Mentions: Echocardiography was performed in 15- to 26-week-old male animals (summary of all results in Table 2). DSG2mt/mt mice exhibited dilation of the left ventricle (increased diameters in M-mode in Fig. 2a, b) and an elevated end-diastolic volume (Table 2). Elevated end-diastolic volume indicated reduced ventricular compliance. In accordance, early left ventricular filling had a tendency to be slower in DSG2mt/mt mice (mitral valve E-wave peak), whereas late diastolic blood flow velocity across the mitral valve was significantly reduced (mitral valve A-wave peak). Consequently, the E-wave to A-wave (E/A) ratio was significantly increased in the mutants, indicating impaired ventricular filling. In addition, systolic left ventricular diameter and systolic left ventricular end volume were increased in mutants indicating altered systolic function. Furthermore, ejection fraction, cardiac output and fractional shortening were all reduced (Table 2). Heart rates were comparable between wild type and mutants. Hemodynamic parameters were invasively examined by micro-conductance catheter to complement non-invasive echocardiography (see Table 2). In agreement with the impaired systolic function observed by echocardiography, left ventricular developed pressure (LVDP), the maximal rate of left ventricular pressure change (dP/dtmax), a parameter of cardiac contractility and the contractility index [40] were decreased in DSG2mt/mt mice (Table 2). Subjecting animals to stress by treatment with norepinephrine demonstrated that mutant hearts were still responsive, resulting in increase of LVDP, dP/dtmax and contractility index, albeit not to the extent of their wild-type counterparts (Table 2). Reflecting diastolic dysfunction, left ventricular relaxation was significantly impaired with reduced −dP/dtmin and relaxation index. Under norepinephrine stimulation, the mutant mice developed ventricular arrhythmias, e.g., ventricular extrasystoles, as well as atrial arrhythmias and repolarization abnormalities (Fig. 2f). One of the mutant animals died during anesthesia. ECG alterations were not recorded in any of the age- and sex-matched wild-type animals in the presence of norepinephrine (Fig. 2e).Table 2


Desmoglein 2 mutant mice develop cardiac fibrosis and dilation.

Krusche CA, Holthöfer B, Hofe V, van de Sandt AM, Eshkind L, Bockamp E, Merx MW, Kant S, Windoffer R, Leube RE - Basic Res. Cardiol. (2011)

Homozygous DSG2-mutant mice (DSG2mt) present ventricular dilation and signs of compromised cardiac function. a, b Representative echocardiography (pictures taken in B-mode) at the end of diastole in wild-type (DSG2wt) male mice compared to age-matched male DSG2mt mice. RV right ventricle, LV left ventricle, IVS interventricular septum, LVPW left ventricular posterior wall, LVID left ventricular inner diameter, ao aorta, pm papillary muscle. c, d Comparison of the morphology of a wild-type (c) and a DSG2-mutant heart (d), which presents an enlarged right ventricle and extensive fibrotic lesions (arrows). e, f Representative ECGs from wild-type (e) and mutant mice (f). Note the abnormalities in the ECGs of the mutant mice presenting extrasystole, arrthythmia and conduction abnormalities (f, from top to bottom)
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Related In: Results  -  Collection

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Fig2: Homozygous DSG2-mutant mice (DSG2mt) present ventricular dilation and signs of compromised cardiac function. a, b Representative echocardiography (pictures taken in B-mode) at the end of diastole in wild-type (DSG2wt) male mice compared to age-matched male DSG2mt mice. RV right ventricle, LV left ventricle, IVS interventricular septum, LVPW left ventricular posterior wall, LVID left ventricular inner diameter, ao aorta, pm papillary muscle. c, d Comparison of the morphology of a wild-type (c) and a DSG2-mutant heart (d), which presents an enlarged right ventricle and extensive fibrotic lesions (arrows). e, f Representative ECGs from wild-type (e) and mutant mice (f). Note the abnormalities in the ECGs of the mutant mice presenting extrasystole, arrthythmia and conduction abnormalities (f, from top to bottom)
Mentions: Echocardiography was performed in 15- to 26-week-old male animals (summary of all results in Table 2). DSG2mt/mt mice exhibited dilation of the left ventricle (increased diameters in M-mode in Fig. 2a, b) and an elevated end-diastolic volume (Table 2). Elevated end-diastolic volume indicated reduced ventricular compliance. In accordance, early left ventricular filling had a tendency to be slower in DSG2mt/mt mice (mitral valve E-wave peak), whereas late diastolic blood flow velocity across the mitral valve was significantly reduced (mitral valve A-wave peak). Consequently, the E-wave to A-wave (E/A) ratio was significantly increased in the mutants, indicating impaired ventricular filling. In addition, systolic left ventricular diameter and systolic left ventricular end volume were increased in mutants indicating altered systolic function. Furthermore, ejection fraction, cardiac output and fractional shortening were all reduced (Table 2). Heart rates were comparable between wild type and mutants. Hemodynamic parameters were invasively examined by micro-conductance catheter to complement non-invasive echocardiography (see Table 2). In agreement with the impaired systolic function observed by echocardiography, left ventricular developed pressure (LVDP), the maximal rate of left ventricular pressure change (dP/dtmax), a parameter of cardiac contractility and the contractility index [40] were decreased in DSG2mt/mt mice (Table 2). Subjecting animals to stress by treatment with norepinephrine demonstrated that mutant hearts were still responsive, resulting in increase of LVDP, dP/dtmax and contractility index, albeit not to the extent of their wild-type counterparts (Table 2). Reflecting diastolic dysfunction, left ventricular relaxation was significantly impaired with reduced −dP/dtmin and relaxation index. Under norepinephrine stimulation, the mutant mice developed ventricular arrhythmias, e.g., ventricular extrasystoles, as well as atrial arrhythmias and repolarization abnormalities (Fig. 2f). One of the mutant animals died during anesthesia. ECG alterations were not recorded in any of the age- and sex-matched wild-type animals in the presence of norepinephrine (Fig. 2e).Table 2

Bottom Line: Upon histological examination, cardiomyocyte death by calcifying necrosis and replacement by fibrous tissue were observed.Fibrotic lesions were highly proliferative in 2-week-old mutants, whereas the fibrotic lesions of older mutants showed little proliferation indicating the completion of local muscle replacement by scar tissue.Disease progression correlated with increased mRNA expression of c-myc, ANF, BNF, CTGF and GDF15, which are markers for cardiac stress, remodeling and heart failure.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Wendlingweg 2, Aachen, Germany. ckrusche@ukaachen.de

ABSTRACT
Desmosomes are cell-cell adhesion sites and part of the intercalated discs, which couple adjacent cardiomyocytes. The connection is formed by the extracellular domains of desmosomal cadherins that are also linked to the cytoskeleton on the cytoplasmic side. To examine the contribution of the desmosomal cadherin desmoglein 2 to cardiomyocyte adhesion and cardiac function, mutant mice were prepared lacking a part of the extracellular adhesive domain of desmoglein 2. Most live born mutant mice presented normal overall cardiac morphology at 2 weeks. Some animals, however, displayed extensive fibrotic lesions. Later on, mutants developed ventricular dilation leading to cardiac insufficiency and eventually premature death. Upon histological examination, cardiomyocyte death by calcifying necrosis and replacement by fibrous tissue were observed. Fibrotic lesions were highly proliferative in 2-week-old mutants, whereas the fibrotic lesions of older mutants showed little proliferation indicating the completion of local muscle replacement by scar tissue. Disease progression correlated with increased mRNA expression of c-myc, ANF, BNF, CTGF and GDF15, which are markers for cardiac stress, remodeling and heart failure. Taken together, the desmoglein 2-mutant mice display features of dilative cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, an inherited human heart disease with pronounced fibrosis and ventricular arrhythmias that has been linked to mutations in desmosomal proteins including desmoglein 2.

Show MeSH
Related in: MedlinePlus