Abstract
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. Echocardiography, electrocardiography, micro-computed tomography, quantitative polymerase chain reaction, immunohistochemistry, volume electron microscopy, and sharp microelectrode electrophysiology were used. 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. 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.
Highlights
Purkinje fibers (PFs) control timing of ventricular conduction and play a key role in arrhythmogenesis in heart failure (HF) patients
HF baseline QRS and corrected QT interval were prolonged by 17% and 21%, suggesting PF dysfunction and impaired ventricular repolarization
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
Summary
Echocardiography, electrocardiography, micro-computed tomography, quantitative polymerase chain reaction, immunohistochemistry, volume electron microscopy, and sharp microelectrode electrophysiology were used. Congestive HF was induced in male New Zealand white rabbits (n=23; sham-operated controls, n=21) weighing 2.5 to 3 kg, age ≈3 months (B&K Ltd, United Kingdom), as previously described.[24] Briefly, severe incompetence of the aortic valve was induced with a catheter introduced via the right carotid artery, followed after 3 weeks by abdominal aortic constriction at the level of the renal arteries. HF progression was assessed by 2-dimensional echocardiography (GE Vivid[3, 5] MHz transducer) in conscious rabbits, before and after surgery. Animals were humanely killed at ≈5 weeks after aortic constriction, by pentobarbitone sodium overdose, followed by vertical sternotomy and removal of the heart into oxygenated (95% O2–5% CO2) Tyrode solution (in mM: NaCl, 120; KCl, 4; MgSO4.7H2O, 1.3; NaH2PO4.2H2O, 1.2; CaCl2, 1.2; NaHCO3, 25.2; Glucose, 5.8; pH 7.4)
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