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Increased SERCA2a sub-cellular heterogeneity in right-ventricular heart failure inhibits excitation-contraction

M Holmes1, M E Hurley2, T M D Sheard3

  • 1Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.

Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
|October 3, 2022
PubMed

Insights

Heart failure alters the spatial distribution of SERCA2a in cardiomyocytes, impacting calcium handling and increasing arrhythmia risk. This study quanties these changes and their functional consequences.

Area of Science:

  • Cardiovascular Biology
  • Cellular Physiology
  • Cardiac Electrophysiology

Background:

  • The intracellular calcium handling system in cardiomyocytes is crucial for excitation-contraction coupling (ECC) and is implicated in heart failure (HF)-related arrhythmias.
  • SERCA2a regulates calcium homeostasis, and its functional remodeling is linked to cardiac dysfunction in disease.
  • While global SERCA2a expression changes are studied, its sub-cellular spatial profile and role in disease remain unclear.

Purpose of the Study:

  • To develop and apply a method for characterizing sub-cellular SERCA2a heterogeneity.
  • To quantify adaptations in SERCA2a length-scale of heterogeneity in right-ventricular heart failure (RV-HF).
  • To predict the functional impact of SERCA2a heterogeneity and its remodeling on ECC, calcium alternans, and triggered activity.

Main Methods:

  • Image analysis to characterize sub-cellular SERCA2a heterogeneity and its length-scale.
  • Quantification of SERCA2a length-scale adaptations in RV-HF models.
  • Computational simulations to predict the functional consequences of observed heterogeneity on ECC and arrhythmogenesis.

Main Results:

  • RV-HF is associated with an increased length-scale of SERCA2a heterogeneity and greater inter-cellular variability.
  • Simulations indicate that increased SERCA2a length-scale can impair ECC.
  • The increased length-scale critically modulates vulnerability to calcium transient alternans and spontaneous triggered activity.

Conclusions:

  • Sub-cellular spatial heterogeneity of SERCA2a is remodeled in RV-HF.
  • Increased SERCA2a length-scale contributes to impaired cardiac function and increased arrhythmia susceptibility.
  • Understanding SERCA2a spatial distribution is vital for comprehending cardiac dysfunction in disease.

Keywords:
arrhythmiacalcium handlingexcitation-contraction couplingheart failureheterogeneityserca

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