Cardiothoracic
Development of an Ovine Model of Pediatric Complete Heart Block

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Background

Complete heart block is a significant clinical problem that can limit the quality of life in affected children. To understand the pathophysiology of this condition and provide for development of novel therapies, we sought to establish a large animal model of permanent, pacemaker-dependent atrioventricular block (AVB) that mimics the size and growth characteristics of pediatric patients.

Materials and Methods

We utilized nine immature lambs weighing 10.5 ± 1.4 kg. After implantation of dual-chamber pacemaker devices with fixed leads, AVB was produced by interrupting His-bundle conduction using radio-frequency ablation at the base of the non-coronary cusp of the aortic valve. Ablations (30 to 60 s in duration) were performed under fluoroscopic guidance with electrophysiological monitoring. Interrogation of pacemakers and electrocardiography (ECG) determined the persistence of heart block. Ovine hearts were also examined immunohistochemically for localization of conduction tissue.

Results

AVB was produced in eight animals using an atypical approach from the left side of the heart. One animal died due to ventricular fibrillation during ablation proximal to the tricuspid annulus and one lamb was sacrificed postoperatively due to stroke. Four sheep were kept for long-term follow-up (109.8 ± 32.9 d) and required continuous ventricular pacing attributable to lasting AVB, despite significant increases in body weight and size.

Conclusions

We have created a large animal model of pediatric complete heart block that is stable and technically practicable. We anticipate that this lamb model will allow for advancement of cell-based and other innovative treatments to repair complete heart block in children.

Introduction

Complete atrioventricular conduction block (AVB) can result from iatrogenic, congenital, infectious, ischemic, idiopathic, degenerative, or pharmaceutical-based causes. Regardless of the underlying reason for this potentially life-threatening condition, the conventional medical therapy necessitates placement of a pacemaker generator connected to the heart with pacing leads. While this palliative treatment is frequently successful, it can result in complications such as progressive ventricular dysfunction and dyssynchrony, infection, and the need for numerous surgical or catheter-based interventions to replace pacemaker system components 1, 2. These and other complications are often exacerbated in pediatric patients, as continuous cardiac pacing of small, growing children imposes additional clinical obstacles.

To allow for study of AVB in developing mammals that have a comparable cardiovascular anatomy and size to human infants as well as engaging in translational research aimed at devising alternative treatment strategies to the current standard, we have created a large animal model of heart block. To maintain the clinical relevance of our experimental system, we have closely replicated procedures commonly employed in humans. These procedures include endocardial radiofrequency ablation as well as fluoroscopically-guided pacemaker generator and fixed lead implantation.

Although a canine model of atrioventricular (AV) node ablation was established in 1981 3, 4, dog models have become less commonly employed in contemporary cardiovascular research. Porcine [5] and ovine [6] models of AV block have also been described; however, a large mammalian model of pediatric complete heart block has yet to be established. Consequently, we have chosen sheep as our model organism as this species demonstrates a rapid growth potential and is amenable to repeated surgical procedures. The growth of the lamb heart and great vessels are comparable to humans [7], and this species is well-established for testing of tissue engineered structures such as heart valves.

Section snippets

Animals

All procedures were performed according to the Guide for the Care and Use of Laboratory Animals published by National Institutes of Health (publication no. 85-23) and approved by the Institutional Animal Care Committee at Children’s Hospital Boston. A total of nine female, just-weaned lambs (Pine Acres Farm, Norton, MA, USA) with a body weight of 10.5 ± 1.4 kg were used for experiments. Anesthesia was induced with an intramuscular injection of ketamine (20 mg/kg), xylazine (0.1 mg/kg), and

Pacemaker Implantation

Transvenous dual chamber pacemaker implantation was successfully performed in nine lambs. Figure 1A is a fluoroscopic image demonstrating the anatomical positions of atrial and ventricular leads. The pacemaker devices allowed for reliable, atrial-triggered ventricular pacing in a sequential manner. Sufficient perfusion and cardiac output was demonstrated by normal activity levels and weight gain throughout the observational period. Chest X-rays (Fig. 1B) showed the pacemaker in the neck with an

Discussion

In the present study, we established that a catheter-based, closed-chest AV node ablation procedure is both feasible and safe in young lambs. Consequently, we have produced a large animal model of persistent atrioventricular block (AVB) that mimics the size and growth characteristics of pediatric patients. To perform these experiments, we approached the His bundle from the left side of the heart and applied RF current to the site that demonstrated the largest His-deflection. This procedure

Acknowledgments

The authors thank Dr. Alan H. Beggs for providing the anti-α-actinin-2 antibody and Dr. Dorit Knappe for assistance in analyzing ECG data. This work was supported by grants from the National Institutes of Health (HL068915 and HL088206), a fellowship from the Thoracic Surgery Foundation for Research and Education, donations to the Cardiac Conduction Fund, and the Ryan Family Endowment at Children’s Hospital Boston, as well as a generous gift from David Pullman.

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These authors contributed equally to this work.

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