Abstract
While Huntington’s disease (HD) is classified as a neurological disorder, HD patients exhibit a high incidence of cardiovascular events leading to heart failure and death. In this study, we sought to better understand the cardiovascular phenotype of HD using the BACHD mouse model. The age-related decline in cardiovascular function was assessed by echocardiograms, electrocardiograms, histological and microarray analysis. We found that structural and functional differences between WT and BACHD hearts start at 3 months of age and continue throughout life. The aged BACHD mice develop cardiac fibrosis and ultimately apoptosis. The BACHD mice exhibited adaptive physiological changes to chronic isoproterenol treatment; however, the medication exacerbated fibrotic lesions in the heart. Gene expression analysis indicated a strong tilt toward apoptosis in the young mutant heart as well as changes in genes involved in cellular metabolism and proliferation. With age, the number of genes with altered expression increased with the large changes occurring in the cardiovascular disease, cellular metabolism, and cellular transport clusters. The BACHD model of HD exhibits a number of changes in cardiovascular function that start early in the disease progress and may provide an explanation for the higher cardiovascular risk in HD.
Highlights
Over the course of a lifetime, Huntington’s disease (HD) patients are subject to a progressive neurodegenerative process that inflicts cognitive, psychiatric and motor dysfunction [1, 2]
The hearts of WT mice slowly increased in dimension as they aged, with significance in enddiastolic dimension (EDD) and posterior wall thickness (PWT) starting at 12 mo while left ventricle (Lv) Mass and end-systolic dimension (ESD) were significantly larger at 15mo (Fig 1A and 1B; Table 1)
The hearts of BACHD mice increased in size as they aged, with a significant increase in Lv Mass and PWT measures starting at 9 mo of age (Fig 1A; Table 1)
Summary
Over the course of a lifetime, Huntington’s disease (HD) patients are subject to a progressive neurodegenerative process that inflicts cognitive, psychiatric and motor dysfunction [1, 2]. Cardiovascular events are a major cause of early death in the HD. The limited cardiovascular studies in HD patients attribute the increased cardiovascular susceptibility in part to a dysfunctional autonomic nervous system (ANS) that can be detected early in the disease progression [8,9,10,11,12,13]. Additional studies are needed to better understand the time-course and cause of cardiovascular pathology in HD that could potentially help improve symptoms and prevent early death
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