Cerebrovascular insufficiency and amyloidogenic signaling in Ossabaw swine with cardiometabolic heart failure.

Journal Article (Journal Article)

Individuals with heart failure (HF) frequently present with comorbidities, including obesity, insulin resistance, hypertension, and dyslipidemia. Many patients with HF experience cardiogenic dementia, yet the pathophysiology of this disease remains poorly understood. Using a swine model of cardiometabolic HF (Western diet+aortic banding; WD-AB), we tested the hypothesis that WD-AB would promote a multidementia phenotype involving cerebrovascular dysfunction alongside evidence of Alzheimer's disease (AD) pathology. The results provide evidence of cerebrovascular insufficiency coupled with neuroinflammation and amyloidosis in swine with experimental cardiometabolic HF. Although cardiac ejection fraction was normal, indices of arterial compliance and cerebral blood flow were reduced, and cerebrovascular regulation was impaired in the WD-AB group. Cerebrovascular dysfunction occurred concomitantly with increased MAPK signaling and amyloidogenic processing (i.e., increased APP, BACE1, CTF, and Aβ40 in the prefrontal cortex and hippocampus) in the WD-AB group. Transcriptomic profiles of the stellate ganglia revealed the WD-AB group displayed an enrichment of gene networks associated with MAPK/ERK signaling, AD, frontotemporal dementia, and a number of behavioral phenotypes implicated in cognitive impairment. These provide potentially novel evidence from a swine model that cerebrovascular and neuronal pathologies likely both contribute to the dementia profile in a setting of cardiometabolic HF.

Full Text

Duke Authors

Cited Authors

  • Baranowski, BJ; Allen, MD; Nyarko, JN; Rector, RS; Padilla, J; Mousseau, DD; Rau, CD; Wang, Y; Laughlin, MH; Emter, CA; MacPherson, RE; Olver, TD

Published Date

  • May 24, 2021

Published In

Volume / Issue

  • 6 / 10

PubMed ID

  • 34027891

Pubmed Central ID

  • PMC8262360

Electronic International Standard Serial Number (EISSN)

  • 2379-3708

Digital Object Identifier (DOI)

  • 10.1172/jci.insight.143141

Language

  • eng

Conference Location

  • United States