Limits...
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.

Show MeSH

Related in: MedlinePlus

Epicardial mapping experiments in Langendorff-perfused hearts. (A) Examples of RV and LV activation maps for WT, Tg-WT, and Tg-NS/H hearts during sinus rhythm (SR) and stimulation from the center of the electrode (stim). Crowding of isochrones in Tg-NS/H hearts indicates areas of conduction slowing. (B) Examples of extracellular electrograms showing fractionation of the extracellular signal (a sign of excessive conduction slowing) in Tg-NS/H but not in WT or Tg-WT mice. (C) Induction of VT in a Tg-NS/H heart after administration of two short-coupled extrastimuli (S1 and S2). (D) Ventricular activation map during beats 1–3 of the VT depicted in C. (E) Mean RV and LV activation times during SR and central stimulation (CS). (F) Mean incidence of inducible arrhythmias. Data represent means ± SEM from single independent epicardial mapping experiments from five WT, six Tg-WT, and five Tg-NS/H mice (#, P < 0.05 vs. WT; ‡, P < 0.01 vs. WT; $, P < 0.05 vs. Tg-WT; Table S4).
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig4: Epicardial mapping experiments in Langendorff-perfused hearts. (A) Examples of RV and LV activation maps for WT, Tg-WT, and Tg-NS/H hearts during sinus rhythm (SR) and stimulation from the center of the electrode (stim). Crowding of isochrones in Tg-NS/H hearts indicates areas of conduction slowing. (B) Examples of extracellular electrograms showing fractionation of the extracellular signal (a sign of excessive conduction slowing) in Tg-NS/H but not in WT or Tg-WT mice. (C) Induction of VT in a Tg-NS/H heart after administration of two short-coupled extrastimuli (S1 and S2). (D) Ventricular activation map during beats 1–3 of the VT depicted in C. (E) Mean RV and LV activation times during SR and central stimulation (CS). (F) Mean incidence of inducible arrhythmias. Data represent means ± SEM from single independent epicardial mapping experiments from five WT, six Tg-WT, and five Tg-NS/H mice (#, P < 0.05 vs. WT; ‡, P < 0.01 vs. WT; $, P < 0.05 vs. Tg-WT; Table S4).

Mentions: Data from epicardial mapping experiments performed on isolated Langendorff-perfused hearts are reported in Fig. 4 and Table S4. In hearts from Tg-NS/H mice, both RV and LV showed abnormal activation patterns in addition to crowding of isochrones, indicating the presence of conduction block (Fig. 4 A). During sinus rhythm, total ventricular activation time was significantly increased in both RV and LV of Tg-NS/H as compared with WT and Tg-WT mice (Fig. 4 E). When the hearts were stimulated from the center of the electrode at a basic cycle length of 120 ms, total activation time was greatly increased in LV of Tg-NS/H mice, whereas there was only a trend toward increased activation time observed for the RV (Fig. 4 E). Excessive conduction slowing in Tg-NS/H hearts was further associated with fractionation of the extracellular electrogram, a feature not observed in WT or Tg-WT hearts (Fig. 4 B). Tg-NS/H hearts also displayed increased inducibility of ventricular arrhythmias as compared with WT and Tg-WT hearts, both in LV and RV (Fig. 4, C, D, and F). A phenotype of intermediate severity was again observed on epicardial mapping in Tg-NS/L compared with Tg-NS/H hearts (Table S4).


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)

Epicardial mapping experiments in Langendorff-perfused hearts. (A) Examples of RV and LV activation maps for WT, Tg-WT, and Tg-NS/H hearts during sinus rhythm (SR) and stimulation from the center of the electrode (stim). Crowding of isochrones in Tg-NS/H hearts indicates areas of conduction slowing. (B) Examples of extracellular electrograms showing fractionation of the extracellular signal (a sign of excessive conduction slowing) in Tg-NS/H but not in WT or Tg-WT mice. (C) Induction of VT in a Tg-NS/H heart after administration of two short-coupled extrastimuli (S1 and S2). (D) Ventricular activation map during beats 1–3 of the VT depicted in C. (E) Mean RV and LV activation times during SR and central stimulation (CS). (F) Mean incidence of inducible arrhythmias. Data represent means ± SEM from single independent epicardial mapping experiments from five WT, six Tg-WT, and five Tg-NS/H mice (#, P < 0.05 vs. WT; ‡, P < 0.01 vs. WT; $, P < 0.05 vs. Tg-WT; Table S4).
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig4: Epicardial mapping experiments in Langendorff-perfused hearts. (A) Examples of RV and LV activation maps for WT, Tg-WT, and Tg-NS/H hearts during sinus rhythm (SR) and stimulation from the center of the electrode (stim). Crowding of isochrones in Tg-NS/H hearts indicates areas of conduction slowing. (B) Examples of extracellular electrograms showing fractionation of the extracellular signal (a sign of excessive conduction slowing) in Tg-NS/H but not in WT or Tg-WT mice. (C) Induction of VT in a Tg-NS/H heart after administration of two short-coupled extrastimuli (S1 and S2). (D) Ventricular activation map during beats 1–3 of the VT depicted in C. (E) Mean RV and LV activation times during SR and central stimulation (CS). (F) Mean incidence of inducible arrhythmias. Data represent means ± SEM from single independent epicardial mapping experiments from five WT, six Tg-WT, and five Tg-NS/H mice (#, P < 0.05 vs. WT; ‡, P < 0.01 vs. WT; $, P < 0.05 vs. Tg-WT; Table S4).
Mentions: Data from epicardial mapping experiments performed on isolated Langendorff-perfused hearts are reported in Fig. 4 and Table S4. In hearts from Tg-NS/H mice, both RV and LV showed abnormal activation patterns in addition to crowding of isochrones, indicating the presence of conduction block (Fig. 4 A). During sinus rhythm, total ventricular activation time was significantly increased in both RV and LV of Tg-NS/H as compared with WT and Tg-WT mice (Fig. 4 E). When the hearts were stimulated from the center of the electrode at a basic cycle length of 120 ms, total activation time was greatly increased in LV of Tg-NS/H mice, whereas there was only a trend toward increased activation time observed for the RV (Fig. 4 E). Excessive conduction slowing in Tg-NS/H hearts was further associated with fractionation of the extracellular electrogram, a feature not observed in WT or Tg-WT hearts (Fig. 4 B). Tg-NS/H hearts also displayed increased inducibility of ventricular arrhythmias as compared with WT and Tg-WT hearts, both in LV and RV (Fig. 4, C, D, and F). A phenotype of intermediate severity was again observed on epicardial mapping in Tg-NS/L compared with Tg-NS/H hearts (Table S4).

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