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

15) and reflects a total body syndrome affecting multiple organ systems and tissues beyond the heart, including the peripheral vasculature and the brain Mounting evidence suggests metabolic dysregulation and chronic low-grade inflammation represent a unifying link between cerebrovascular insufficiency and AD pathology Owing to structural and functional similarities between human and swine cardiovascular systems and brains (human and pig brains are gyrencephalic, containing >60% white matter) (19-21), swine models of disease may provide unique translational insight into multiorgan/system-level pathologies. Recently, our group characterized a large animal (e.g., swine) model of cardiometabolic HF ( This preclinical model exhibits key comorbidities of HF, including physical inactivity (decreased home-cage activity), obesity, dyslipidemia, insulin resistance, and elevated aortic systolic pressure. In addition, these animals display pathological features of HF, including lung congestion, systemic inflammation, concentric left ventricular remodeling, cardiac diastolic dysfunction, and preserved EF (22). Importantly, work from our lab demonstrates this model of HF induction impairs working memory performance (24), possibly in part through deficits in spatial learning or navigation (25). This model of HF induction was highlighted in the American Heart Association Scientific Statement for its utility as a model to better understand the pathogenesis of hypertensive cerebral damage (23). Using this disease platform to gain further insight into the heart-brain axis in HF, the purpose of the current study was to test the hypothesis that swine with cardiometabolic HF would exhibit a complex dementia phenotype involving cerebrovascular dysfunction as well as indices of neuroinflammation and AD-like amyloidosis. Specifically, we investigated indices of cerebral blood flow control in vivo as well as pial and brain parenchymal artery vasomotor control in isolated cerebral arterioles ex vivo. Further, because it interfaces with the heart-brain axis (26, 27), we examined the transcriptomic profile in the stellate ganglia. Last, given the established role of aberrant mitogenic signaling in AD pathology (28-31), transcriptomic profiling of the stellate ganglia was coupled with examination of MAPK pathway activation as well as key regulators of the generation of the -amyloid peptide in the prefrontal cortex and hippocampus. The results of this study demonstrate swine with cardiometabolic HF displayed a combination of cerebrovascular and neuronal pathologies, indicating swine models of multiorgan disease may provide an excellent model to interrogate cardiogenic dementia.