Local microRNA-133a downregulation is associated with hypertrophy in the dyssynchronous heart

Lars B. van Middendorp*, Marion Kuiper, Chantal Munts, Philippe Wouters, Jos G. Maessen, Frans A. van Nieuwenhoven, Frits W. Prinzen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Aims Left bundle branch block (LBBB) creates considerable regional differences in mechanical load within the left ventricle (LV). We investigated expression of selected microRNAs (miRs) in relation to regional hypertrophy and fibrosis in LBBB hearts and their reversibility upon cardiac resynchronization therapy (CRT).

Methods and results Eighteen dogs were followed for 4 months after induction of LBBB, 10 of which received CRT after 2 months. Five additional dogs served as control. LV geometric changes were determined by echocardiography and myocardial strain by magnetic resonance imaging tagging. Expression levels of miRs, their target genes: connective tissue growth factor (CTGF), serum response factor (SRF), nuclear factor of activated T cells (NFATc4), and cardiomyocyte diameter and collagen deposition were measured in the septum and LV free wall (LVfw). In LBBB hearts, LVfw and septal systolic circumferential strain were 200% and 50% of control, respectively. This coincided with local hypertrophy in the LVfw. MiR-133a expression was reduced by 33% in the LVfw, which corresponded with a selective increase of CTGF expression in the LVfw ( 279% of control). By contrast, no change was observed in SRF and NFATc4 expression was decreased in LBBB hearts. CRT normalized strain patterns and reversed miR-133a and CTGF expression towards normal, expression of other miRs, related to remodelling, such as miR-199b and miR-155f, were not affected.

Conclusions In the clinically relevant large animal model of LBBB, a close inverse relation exists between local hypertrophy and miR-133a. Reduced miR-133a correlated with increased CTGF levels but not with SRF and NFATc4.

Original languageEnglish
Pages (from-to)241-251
Number of pages11
JournalEsc heart failure
Volume4
Issue number3
DOIs
Publication statusPublished - Aug 2017

Keywords

  • MicroRNAs
  • Connective tissue growth factor
  • Dyssynchrony
  • Hypertrophy/remodelling
  • Cardiac resynchronization therapy
  • CARDIAC RESYNCHRONIZATION THERAPY
  • BUNDLE-BRANCH BLOCK
  • TISSUE GROWTH-FACTOR
  • NONCODING RNAS
  • FAILURE
  • FIBROSIS
  • EXPRESSION
  • KINASE

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