Remodeling of the Purkinje network in congestive heart failure in the rabbit

Research output: Contribution to journalArticlepeer-review

Authors

  • Sunil Jit R J Logantha
  • Xue J Cai
  • Joseph Yanni
  • Caroline B Jones
  • Luke Stuart
  • Gillian Quigley
  • Oliver Monfredi
  • Shu Nakao
  • Il-Young Oh
  • Tobias Starborg
  • Ashraf Kitmitto
  • Akbar Vohra
  • Robert C Hutcheon
  • Antonio F Corno
  • Jonathan C Jarvis
  • Halina Dobrzynski
  • Mark R Boyett
  • George Hart

Colleges, School and Institutes

External organisations

  • University of Manchester
  • Alder Hey Children's NHS Foundation Trust
  • University of Liverpool
  • Liverpool John Moores University
  • University of Virginia
  • National Institutes of Health
  • Ritsumeikan University
  • Seoul National University
  • University of Texas

Abstract

BACKGROUND: Purkinje fibers (PFs) control timing of ventricular conduction and play a key role in arrhythmogenesis in heart failure (HF) patients. We investigated the effects of HF on PFs.

METHODS: Echocardiography, electrocardiography, micro-computed tomography, quantitative polymerase chain reaction, immunohistochemistry, volume electron microscopy, and sharp microelectrode electrophysiology were used.

RESULTS: Congestive HF was induced in rabbits by left ventricular volume- and pressure-overload producing left ventricular hypertrophy, diminished fractional shortening and ejection fraction, and increased left ventricular dimensions. HF baseline QRS and corrected QT interval were prolonged by 17% and 21% (mean±SEMs: 303±6 ms HF, 249±11 ms control; n=8/7; P=0.0002), suggesting PF dysfunction and impaired ventricular repolarization. Micro-computed tomography imaging showed increased free-running left PF network volume and length in HF. mRNA levels for 40 ion channels, Ca2+-handling proteins, connexins, and proinflammatory and fibrosis markers were assessed: 50% and 35% were dysregulated in left and right PFs respectively, whereas only 12.5% and 7.5% changed in left and right ventricular muscle. Funny channels, Ca2+-channels, and K+-channels were significantly reduced in left PFs. Microelectrode recordings from left PFs revealed more negative resting membrane potential, reduced action potential upstroke velocity, prolonged duration (action potential duration at 90% repolarization: 378±24 ms HF, 249±5 ms control; n=23/38; P<0.0001), and arrhythmic events in HF. Similar electrical remodeling was seen at the left PF-ventricular junction. In the failing left ventricle, upstroke velocity and amplitude were increased, but action potential duration at 90% repolarization was unaffected.

CONCLUSIONS: Severe volume- followed by pressure-overload causes rapidly progressing HF with extensive remodeling of PFs. The PF network is central to both arrhythmogenesis and contractile dysfunction and the pathological remodeling may increase the risk of fatal arrhythmias in HF patients.

Details

Original languageEnglish
JournalCirculation. Heart failure
Early online date30 Jun 2021
Publication statusE-pub ahead of print - 30 Jun 2021

Keywords

  • electron microscopy, heart failure, ion channels, Purkinje fibers, rabbits, tomography