Validation of an animal model of right ventricular dysfunction and right bundle branch block to create close physiology to postoperative tetralogy of Fallot

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Abstract

Background

In the past 5 years a few number of studies and case reports have come out focusing on biventricular (BiV) stimulation for treatment of congenital heart disease related ventricular dysfunction. The few available studies include a diverse group of pathophysiological entities ranging from a previously repaired tetralogy of Fallot (TOF) to a functional single ventricle anatomy. Patient's status is too heterogeneous to build important prospective study. To well understand the implication of prolonged electromechanical dyssynchrony we performed a chronic animal model that mimics essential parameters of postoperative TOF.

Methods

Significant pulmonary regurgitation, mild stenosis, as well as right ventricular outflow tract (RVOT) scars were induced in 15 piglets to mimic repaired TOF. 4 months after hemodynamics and dyssynchrony parameters were compared with a control group and with a population of symptomatic adult with repaired TOF.

Results

Comparing the animal model with the animal control group on echocardiography, RV dilatation, RV and LV dysfunction, broad QRS complex and dyssynchrony were observed on the animal model piglets. Moreover, epicardial electrical mapping showed activation consistent with a right bundle branch block. The animal models displayed the same pathophysiological parameters as the post TOF repair patients in terms of QRS duration, pulmonary regurgitation biventricular dysfunction and dyssynchrony.

Conclusion

This chronic swine model mimics electromechanical ventricular activation delay, RV and LV dysfunction, as in adult population of repair TOF. It does appear to be a very useful and interesting model to study the implication of dyssynchrony and the interest of resynchronization therapy in TOF failing ventricle.

Introduction

Isolated right heart failure is a relatively common disorder with multiple causes such as congenital heart disease, pulmonary arterial hypertension, right ventricular infarction, and acquired right heart valvular disease. The pathophysiology and clinical course of these diseases are often poorly understood. As a result of major improvements in surgical technique, postoperative care and medical management in recent years the population of adults with repaired tetralogy of Fallot (TOF) and other congenital heart diseases is increasing. The growth of this population is linear [1] and the mortality rate, at least in the early adult years, is relatively low [2]. This nascent demographic phenomenon is creating major issues concerning the optimal management of adults with congenital heart disease [3]. The surgical repair of TOF is highly successful, though may be later complicated by right ventricular dysfunction due to volume and pressure overload and by late sudden death. The incompletely understood mechanisms of these delayed adverse developments may be partially due to the surgically-induced permanent right bundle branch block (BBB) and ventricular dyssynchrony [4], [5], [6], [7], [8], [9]. Therapeutic options remain limited. Implantation of a cardiac resynchronization therapy defibrillator has recently been proposed in TOF patients to decrease sudden death and to improve hemodynamic status. However, studies of the safety and efficacy of cardiac resynchronization in patients with congenital heart disease and RV dysfunction are limited to case reports, retrospective analyses of heterogeneous populations and small crossover trials conducted in the immediate postoperative period [10], [11], [12], [13], [14], [15]. To identify risk factors leading to sudden death in TOF patients [16], [17], [18] and to define mechanisms involved in hemodynamic improvement induced by cardiac resynchronization [8], [19], we aimed to develop a viable and reproducible swine model recapitulating the findings of right heart failure and right bundle branch block observed after prior surgical repair of TOF.

The aims of the present study were to 1) develop a reliable and reproducible long-term swine model of RV dysfunction and RV dyssynchrony and 2) to compare echocardiographic measurements of right ventricular dysfunction, dilatation and dyssynchrony in this animal model and adult patients with previously repaired TOF.

Section snippets

Studies in an animal model of repaired TOF

Our experimental protocols were in compliance with the Guiding Principles in the Use and Care of Animals published by the National Institutes of Health (NIH Publication No. 85-23, Revised 1996).

Characteristics of the animal model

Compared to the control group, the operated animals developed prominent pulmonic stenosis and regurgitation, RV pressure and volume overload, marked RV enlargement, depressed LV and RV function, bilateral intraventricular dyssynchrony and increased QRS duration (Table 1, Fig. 3).

Electroanatomic activation

Epicardial electroanatomic maps created during sinus rhythm (SR) showed an activation sequence consistent with right BBB. The first activated area was the baso-lateral LV, and the last was the RV free wall (Fig. 4).

Echocardiographic study in TOF patients

Discussion

Tetralogy of Fallot is the most common cyanotic congenital cardiac defect characterized by the association of 4 anatomic features (1) subpulmonary infundibular stenosis, (2) ventricular septal defect, (3) rightward deviation of the aortic valve with overriding of the ventricular septum, and (4) right ventricular hypertrophy [21]. Before the advent of surgical intervention, it was unusual for a patient to reach adult age. The history of the surgical treatment of TOF is over 60 years old with a

Acknowledgement

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [26].

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