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

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Xue Cai
  • Caroline B Jones
  • Robert S Stephenson
  • Luke Stuart
  • Gillian Quigley
  • Oliver Monfredi
  • Shu Nakao
  • Il-Young Oh
  • Tobias Starborg
  • Robert C Hutcheon
  • Antonio F Corno
  • Jonathan C Jarvis
  • Mark Boyett
  • George Hart

Abstract

Background—Purkinje fibres (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-CT, qPCR, immunohistochemistry, volume electron microscopy, and sharp microelectrode electrophysiology were used. Results—Congestive HF was induced in rabbits by left ventricular (LV) volume- and pressure-overload producing LV hypertrophy, diminished fractional shortening and ejection fraction, and increased LV dimensions. HF baseline QRS and QTc 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-CT imaging showed increased free-running left PF network volume and length in HF. mRNA levels for 40 ion channels, Ca2+- handling proteins, connexins, and pro-inflammatory 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 (APD90: 378±24 ms HF, 249±5 ms control; n=23/38; P<0.0001), and arrhythmic events in HF. Similar electrical remodelling was seen at the left PF-ventricular junction. In the failing LV, upstroke velocity and amplitude were increased, but APD90 was unaffected. Conclusions—Severe volume- followed by pressure-overload causes rapidly-progressing HF with extensive remodelling of PFs. The PF network is central to both arrhythmogenesis and contractile dysfunction and the pathological remodelling may increase the risk of fatal arrhythmias in HF patients.

Bibliographical metadata

Original languageEnglish
JournalCirculation: Heart Failure
Publication statusAccepted/In press - 4 May 2021