Electrophysiological and structural remodeling of the atria in a mouse model of troponin-i mutation linked hypertrophic cardiomyopathy: Implications for atrial fibrillation

Wei Wen Lim, Melissa Neo, Shivshankar Thanigaimani, Pawel Kuklik, Anand N. Ganesan, Dennis H. Lau, Tatiana Tsoutsman, Jonathan M. Kalman, Christopher Semsarian, David A. Saint, Prashanthan Sanders

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Abstract

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder affecting one in 500 of the general population. Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM. We sought to characterize the atrial electrophysiological and structural substrate in young and aging Gly203Ser cardiac troponin-I transgenic (HCM) mice. At 30 weeks and 50 weeks of age (n = 6 per strain each group), the left atrium was excised and placed on a multi-electrode array (MEA) for electrophysiological study; subsequent histological analyses and plasma samples were analyzed for biomarkers of extracellular matrix remodeling and cell adhesion and inflammation. Wild-type mice of matched ages were included as controls. Young HCM mice demonstrated significantly shortened atrial action potential duration (APD), increased conduction heterogeneity index (CHI), increased myocyte size, and increased interstitial fibrosis without changes in effective refractory periods (ERP), conduction velocity (CV), inflammatory infiltrates, or circulating markers of extracellular matrix remodeling and inflammation. Aging HCM mice demonstrated aggravated changes in atria elec-trophysiology and structural remodeling as well as increased circulating matrix metalloproteinases (MMP)-2, MMP-3, and VCAM-1 levels. This model of HCM demonstrates an underlying atrial substrate that progresses with age and may in part be responsible for the greater propensity for AF in HCM.

Original languageEnglish
Article number6941
Number of pages17
JournalInternational Journal of Molecular Sciences
Volume22
Issue number13
DOIs
Publication statusPublished - 1 Jul 2021
Externally publishedYes

Keywords

  • Atrial fibrillation
  • Electrophysiology
  • Histology
  • Hypertrophic cardiomyopathy
  • Mice

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