Abstract
Post-menopausal women with heart failure (HF) frequently exhibit cardiogenic dementia. Using a pre-clinical swine model of post-menopausal HF, we recently demonstrated that experimental menopause (ovariectomy; OVX) and HF (6-month cardiac pressure overload/aortic banding; AB) independently altered cerebral vasomotor control and together impaired cognitive function. The purpose of this study was to examine the prefrontal cortex and hippocampus tissues from these animals to assess whether OVX and HF are associated with neurologic alterations that may contribute to cardiogenic dementia. We hypothesized that OVX and HF would independently alter neuronal cell signaling in swine with post-menopausal cardiogenic dementia. Immunoblot analyses revealed OVX was associated with reduced estrogen receptor-α in both brain regions and HF tended to exacerbate OVX-induced deficits in the hippocampus. Further, OVX was associated with a reduction in the ratio of phosphorylated:total Akt and ERK in the hippocampus as well as decreased total Akt and synaptophysin in the prefrontal cortex. In contrast, HF was associated with a trend toward reduced phosphorylated:total ERK in the prefrontal cortex. In addition, HF was associated with decreased β-amyloid (1–38) in the prefrontal cortex and increased β-amyloid (1–38) in the hippocampus. Regional brain lipid analysis revealed OVX tended to increase total, saturated, and monounsaturated fatty acid content in the prefrontal cortex, with the greatest magnitude of change occurring in the AB-OVX group. The data from this study suggest that OVX and HF are independently associated with regional-specific neurologic changes in the brain that contribute to the cardiogenic dementia profile in this model. This pre-clinical swine model may be a useful tool for better understanding post-menopausal cardiogenic dementia pathology and developing novel therapies.
Highlights
The term “cardiogenic dementia” describes the association between the failing heart and the failing mind [1]
The loss of female sex hormones coincided with impaired reference and working memory scores, with impairments being most pronounced in the aortic banding (AB)-OVX group
The data indicate the loss of female sex hormones alone reduces brain blood flow and impairs cognition, and such effects are exacerbated in the setting of cardiac pressure overload
Summary
The term “cardiogenic dementia” describes the association between the failing heart and the failing mind [1]. Cardiogenic dementia is associated with reduced quality of life, increased hospital readmission, and risk of mortality [2,3,4,5]. In the setting of heart failure with preserved ejection fraction (HFpEF; HF subtype where EF% is maintained ≥50%), it is estimated up to 50% of patients experience cardiogenic dementia [6, 7]. HFpEF disproportionally affects older women (∼2:1 vs men) implicating the loss of female sex hormones in the onset of the disease [8]. The underlying causes of cognitive impairment in HFpEF are difficult to elucidate as dementia phenotypes are non-uniform in this population [9]. The development of HF as well as any loss of sex hormones, e.g., with menopause, could contribute to the cardiogenic dementia phenotype in female patients
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