Insights into sick sinus syndrome from an inducible mouse model

Abstract

Sick sinus syndrome is a generalized abnormality of cardiac impulse formation and is responsible for a large proportion of pacemaker implantations. Although the exact aetiology is not known, it is widely accepted that age-dependent degenerative fibrosis of nodal tissue is the most common cause. Despite its importance, an animal model for sick sinus syndrome is lacking. We attempted to generate a mouse model phenocopying the pathohistological changes as well as the characteristic arrhythmic manifestations of this syndrome. We crossed two genetically engineered mouse lines, ROSA-eGFP-DTA and HCN4-KiT-Cre, to achieve an inducible deletion of cells specifically in the cardiac pacemaking and conduction system. This deletion resulted in a degenerative fibrosis of nodal tissue, which accurately reflects the pathohistological findings in human sick sinus syndrome. The extent of the sino-atrial fibrosis could be controlled by varying the dosage of the inducing substance, tamoxifen. A high-dose protocol resulted in the complete ablation of all sino-atrial cells as demonstrated by histochemical analysis and quantitative reverse transcriptase-polymerase chain reaction. The animals developed a variety of arrhythmias, including progressive bradycardia, sinus pauses, supraventricular and ventricular tachycardia and chronotropic incompetence. Remarkably, the complete destruction of the primary pacemaker centre resulted in only a small increase in mortality. This study describes the generation and analysis of an inducible mouse model which closely reflects the pathophysiological characteristics of sick sinus syndrome. The model, with the ability to control the extent of nodal cell ablation and fibrosis, offers new insights into sick sinus syndrome and other cardiac conduction diseases.