Approaches to Establish Extracardiac Total Cavopulmonary Connections in Animal Models—A Review

Abstract

BACKGROUND Long-term survival of patients with a single ventricle palliated with a Fontan procedure is still limited. No curative treatment options are available. To investigate the pathophysiology and potential treatment options, such as mechanical circulatory support (MCS), appropriate large animal models are required. The aim of this review was to analyze all full-text manuscripts presenting approaches for an extracardiac total cavopulmonary connection (TCPC) animal model to identify the feasibility and limitations in the acute and chronic setting. METHODS A literature search was performed for fulltext publications presenting large animal models with extracardiac TCPCs on Pubmed and Embase. Out of 454 reviewed papers, 23 manuscripts fulfilled the inclusion criteria. Surgical procedures were categorized and hemodynamic changes at the transition from the biventricular to the univentricular condition analyzed. RESULTS Surgical procedures varied especially regarding coronary venous flow handling and anatomic shape of the TCPC. In most studies (n = 14), the main pulmonary artery was clamped and the coronary venous flow redirected by additional surgical interventions. Only in five reports, the caval veins were connected to the right pulmonary artery to create a true TCPC shape, whereas in all others (n = 18), the veins were connected to the main pulmonary artery. An elevated pulmonary vascular resistance was identified as a limiting hemodynamic factor for TCPC completion in healthy animals. CONCLUSIONS A variety of acute TCPC animal models were successfully established with and without MCS, reflecting the most important hemodynamic features of a Fontan circulation; however, chronic animal models were not reported.

Feasibility of an Animal Model for Cavopulmonary Support With a Double-Outflow Pump

“…In three experiments, the sheep was hemodynamically supported by the CPAD for more than 130 min and showed the potential to restore hemodynamic biventricular equivalency in terms of venous return (Figure 5). As previously reported for univentricular animal models, 14 PVR was substantially increased after pump implantation.…”

Diastolic Heart Failure in Patients With the Fontan Circulation

“…Detailed phenotyping of the single ventricle using cardiovascular magnetic resonance imaging to assess fibrosis and extracellular volume might provide a better understanding of the pathogenesis of progressive ventricular stiffness. If human studies of such detail are difficult to accomplish, studies of large animals could be performed to improve understanding of the single-ventricle pathophysiology . However, most animal studies are designed to be short-term and may not be practical for modeling the more chronic effects of a Fontan circulation.…”

Physiological Fontan Procedure

“…Despite all the above limits, mathematical and CFD studies are still justified as methods for the first step in the “ in vitro ” evaluation of the cavopulmonary connections, even though currently they have to deal with all the variables present in the biological environment. Animals with univentricular hearts (such as frogs and turtles), are not suitable for experimental studies of cavopulmonary connections, and all animal models used to perform hemodynamic evaluation of cavopulmonary connections only allowed acute studies, as in our previous experience (66) and as confirmed by a recent systematic review (94).…”