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

Bradley J Baranowski,Darrell D Mousseau,T Dylan Olver,Craig A Emter,Christoph D Rau,Jaume Padilla,Jennifer N.K Nyarko,Rebecca E.K Macpherson,Matti D Allen,Yibin Wang,R Scott Rector,M Harold Laughlin

doi:10.1172/jci.insight.143141

Abstract

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.

Highlights

The term “cardiogenic dementia” was first introduced in the late 1970s to describe the link between cardiac and cognitive dysfunction [1]
Patients with heart failure (HF) with preserved ejection fraction (HFpEF; HF subtype reflecting ~50% of total HF cases) exhibit cardiogenic dementia, yet the etiology of disease remains unclear in this clinical population [2, 10,11,12,13,14]
The results of the current investigation suggest that the development of cerebrovascular dysfunction is coupled with neuroinflammation and amyloidosis in this swine model of multihit cardiometabolic HF

Summary

Introduction

The term “cardiogenic dementia” was first introduced in the late 1970s to describe the link between cardiac and cognitive dysfunction [1]. Estimates indicate up to 50% of patients with heart failure (HF) experience cardiogenic dementia [2, 3]. Among patients with HF, cardiogenic dementia is associated with increased hospitalization, the loss of independence, and increased risk of mortality [4,5,6,7]. Cardiogenic dementia is not characterized by a singular dementia phenotype and frequently includes aspects of vascular dementia as well as amyloidosis and Alzheimer’s disease (AD) [8]. Patients with HF with preserved ejection fraction (HFpEF; HF subtype reflecting ~50% of total HF cases) exhibit cardiogenic dementia, yet the etiology of disease remains unclear in this clinical population [2, 10,11,12,13,14]. Current evidence indicates that HFpEF occurs more frequently in older women (versus men)

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