Cardiac Conduction Disease in Huntington's Disease Mouse Model (BACHD)

Objective Huntington's disease (HD) is a progressive neurodegenerative disease caused by a CAG repeat expansion in the gene encoding the huntingtin protein. In addition to the central nervous system, recent evidence indicates cardiac involvement in HD patients. ECG screening in HD patients suggested an increased prevalence of conduction abnormalities and compromised sinoatrial node (SAN) function. Here we tested if the huntingtin gene defect would cause increased arrhythmia susceptibility. Methods We used a conditional human huntingtin (HTT) Bacterial Artificial Chromosome (BACHD) transgenic mouse model at 8 months (motor dysfunction present) and 18+ months of age (advanced disease). Fibrosis level was assessed histologically. Surface ECG was measured in mice anesthetized with isoflurane and arrhythmia susceptibility was tested in response to sympathetic and parasympathetic agonists and their combination (autonomic conflict). Results In 18+ month‐old mice overall cardiac structure was unremarkable. BACHD hearts were slightly larger, but HW/BW ratio was normal. Baseline ECG recordings showed prolonged QRS duration in BACHD mice. Stimulation with carbachol (parasympathetic agonist) resulted in increased premature atrial contractions (PACs), SAN exit block, tachy‐brady syndrome in BACHD mice. Stimulation with combined sympathetic and parasympathetic agonists (norepinephrine, epinephrine and carbachol) resulted in increased premature ventricular contractions, PACs, bigeminy and couplets in BACHD mice. Some of these events occurred also in younger BACHD mice, but to a lesser extent. Conclusions/Broader Impacts The BACHD mice showed signs of cardiac conduction system abnormalities and SA node dysfunction. This was observed in the absence of gross histological changes and during isoflurance anesthesia which dampened the influence of the autonomic nervous system. Stimulation with parasympathetic and sympathetic agonists uncovered increased atrial and ventricular arrhythmia susceptibility. Our study indicates that the huntingtin gene defect may cause progressive cardiac conduction system pathology that might increase the susceptibility to sudden cardiac death. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .