Cardiac Dysfunction in the BACHD Mouse Model of Huntington's Disease

PLoS One. 2016 Jan 25;11(1):e0147269. doi: 10.1371/journal.pone.0147269. eCollection 2016.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Adrenergic beta-Agonists / therapeutic use
  • Aging
  • Animals
  • Apoptosis / genetics
  • Cardiomegaly / diagnostic imaging
  • Cardiomegaly / genetics
  • Cardiomegaly / physiopathology*
  • Disease Models, Animal*
  • Fibrosis
  • Gene Expression Profiling
  • Heart Ventricles / metabolism
  • Heart Ventricles / pathology
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Huntington Disease / physiopathology*
  • Isoproterenol / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Multiplex Polymerase Chain Reaction
  • Myocardial Contraction / drug effects
  • Myocardial Contraction / physiology
  • Nerve Tissue Proteins / genetics
  • Real-Time Polymerase Chain Reaction
  • Tissue Array Analysis
  • Trinucleotide Repeat Expansion
  • Ultrasonography
  • Ventricular Dysfunction, Left / diagnostic imaging
  • Ventricular Dysfunction, Left / drug therapy
  • Ventricular Dysfunction, Left / genetics
  • Ventricular Dysfunction, Left / physiopathology*

Substances

  • Adrenergic beta-Agonists
  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Isoproterenol