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Potential new mechanisms of pro-arrhythmia in arrhythmogenic cardiomyopathy: focus on calcium sensitive pathways

C J M van Opbergen1, M Delmar2, T A B van Veen3

  • 1Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.

Netherlands Heart Journal : Monthly Journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation
|January 20, 2017
PubMed

Insights

Arrhythmogenic cardiomyopathy involves heart muscle tissue turning into fibrous and fatty tissue. A specific mutation in phospholamban (PLN R14Del) plays a key role in this condition, impacting calcium handling in heart cells.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Genetics

Background:

  • Arrhythmogenic cardiomyopathy (ACM), particularly arrhythmogenic right ventricular cardiomyopathy (ARVC), is characterized by myocardial replacement with fibrous and fatty tissue.
  • ARVC is often linked to desmosomal protein mutations affecting intercalated disk integrity.
  • The Dutch founder mutation PLN R14Del is a significant factor in ARVC patients in the Netherlands.

Purpose of the Study:

  • To explore the role of intracellular cardiac calcium dynamics in arrhythmogenic cardiomyopathy.
  • To investigate the link between disturbed calcium handling and signaling pathways like CaMKII and calcineurin A.
  • To postulate a novel role for calcium-sensitive signaling proteins in intercalated disk remodeling.

Main Methods:

  • Review of intracellular cardiac calcium dynamics.
  • Analysis of pathophysiological signaling pathways.
  • Correlation of calcium handling with protein complex remodeling.

Main Results:

  • The phospholamban (PLN) protein, involved in calcium regulation, plays a major role in ARVC.
  • Disturbed calcium handling activates calmodulin-dependent kinase II (CaMKII) and calcineurin A (CnA).
  • These signaling proteins may contribute to maladaptive remodeling of the intercalated disk.

Conclusions:

  • The PLN R14Del mutation highlights a significant genetic factor in Dutch ARVC patients.
  • Calcium dysregulation and associated signaling pathways are implicated in ARVC pathogenesis.
  • Calcium-sensitive signaling proteins may represent a new therapeutic target for arrhythmogenic cardiomyopathy.

Keywords:
ArrhythmiaArrhythmogenic cardiomyopathyCaMKIICalciumPhospholamban

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