Logantha, SJRJ, Cai, XJ, Yanni, J, Jones, CB, Stephenson, RS, Stuart, L, Quigley, G, Monfredi, O, Nakao, S, Oh, I-Y, Starborg, T, Kitmitto, A, Vohra, A, Hutcheon, RC, Corno, AF, Jarvis, JC, Dobrzynski, H, Boyett, MR and Hart, G (2021) Remodeling of the Purkinje Network in Congestive Heart Failure in the Rabbit. Circulation: Heart Failure, 14 (7). pp. 800-816. ISSN 1941-3289

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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.

Item Type:	Article
Uncontrolled Keywords:	Science & Technology; Life Sciences & Biomedicine; Cardiac & Cardiovascular Systems; Cardiovascular System & Cardiology; electron microscopy; heart failure; ion channels; Purkinje fibers; rabbits; tomography; SINUS NODE FUNCTION; VENTRICULAR-ARRHYTHMIAS; CONDUCTION SYSTEM; EXPRESSION; FIBERS; RESYNCHRONIZATION; SUDDEN; CELLS; MODEL; Heart Ventricles; Animals; Rabbits; Electrocardiography; Cardiac Pacing, Artificial; Models, Animal; Action Potentials; Heart Rate; Ventricular Remodeling; Male; Heart Failure; X-Ray Microtomography; Purkinje fibers; electron microscopy; heart failure; ion channels; rabbits; tomography; Action Potentials; Animals; Cardiac Pacing, Artificial; Electrocardiography; Heart Failure; Heart Rate; Heart Ventricles; Male; Models, Animal; Rabbits; Ventricular Remodeling; X-Ray Microtomography; 0601 Biochemistry and Cell Biology; 1102 Cardiorespiratory Medicine and Haematology; 1116 Medical Physiology; Cardiovascular System & Hematology
Subjects:	R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC1200 Sports Medicine R Medicine > RM Therapeutics. Pharmacology
Divisions:	Sport & Exercise Sciences
Publisher:	Lippincott, Williams & Wilkins
SWORD Depositor:	A Symplectic
Date Deposited:	09 Jun 2022 11:06
Last Modified:	09 Jun 2022 11:15
DOI or ID number:	10.1161/CIRCHEARTFAILURE.120.007505
URI:	https://researchonline.ljmu.ac.uk/id/eprint/17041

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