Congenital Complete Atrioventricular Block: Clinical and Experimental Studies

Complete atrioventricular block (CAVB) is a cardiac conduction defect wherein the trans¬mission of the normal electrical impulse from the atria to the ventricle is interrupted due to structural or functional impairment of the atrioventricular (AV) conduction system. If CAVB is diagnosed in utero or during the first month of life, it is named congenital CAVB. This thesis attempts to enhance our knowledge concerning the AV node anatomy, to evaluate current clinical therapies and propose new strategies using experimental data. Chapter 1 reviews in depth the ECG characteristics and definitions that are applicable to the different types of AV block. It, furthermore, describes congenital CAVB as a distinc¬tive form of AV block, and discusses its pathogenesis and possibilities for therapy. Chapter 2 is a synergy of three published studies. Two of them review the equipment, test protocols and interpretation of cardiopulmonary exercise testing in children with congenital heart disease. In the third study, the discussed techniques have been used to investigate the exercise capacity in a small cohort of children with congenital CAVB. The current therapy of congenital CAVB, implantation of an electronic pacemaker, might be a lifesaving intervention, but it can cause considerable morbidity, and even mortality. The need for instrumentation with an electronic pacemaker, with its possible disadvan¬tages, might be circumvented by future application of stem cell-derived techniques with the aim to provide biological pacemaking or restoration of the damaged AV conduction in congenital CAVB. The attemps that, to date, have been made by the scientific com¬munity, the different types of cells, modes of administration, successes and pitfalls have been reviewed in depth as expressed in Chapter 3. Understandably, cell therapy of the AV conduction system requires knowledge about the precise 3D structure of the normal and diseased AV conduction system. Chapter 4 reports the results of a submitted study that provided an extensive description of the 2D and 3D structure of the canine AV conduction system. Formalin-fixed and paraffin embedded tissue sections were derived from: (1) normal AV junction, (2) AV junction in (natural) acquired CAVB, and (3) AV junction of ablation-induced CAVB. The sections were stained with Masson’s trichrome-, and van Gieson’s stain, and immunolabeled with antibodies against connexin 43, pan-cadherin and neurofilament. Digitalized 2D secti¬ons were transformed into interactive 3D models by surface rendering . Chapter 5 describes the results of a study that aimed to repair CAVB in dogs by trans¬plantation of cardiac progenitor cells (CPCs). In this study, CAVB was induced by radio-frequency ablation. From human and canine heart tissue CPCs were isolated by mag¬netic cell sorting. Three weeks after ablation CPCs were injected into the damaged AV conduction system. Within the study, several sources and amounts of cells have been tested with respect to their potency to restore AV conduction upon transplantation fol¬lowing different regimens. The chapter also includes a discussion regarding the multiple hurdles that are associated with the tested strategies of stem cell therapy. Finally, we provide a summary of all mentioned chapters and, based on the acquired knowledge, also some future perspectives.