Carotid Artery Vascular Mechanics Serve as Biomarkers of Cognitive Dysfunction in Aortic‐Banded Miniature Swine That Can Be Treated With an Exercise Intervention

Abstract

BackgroundCognitive impairment in the setting of heart failure with preserved ejection fraction remains poorly understood. Using aortic‐banded miniature swine displaying pathological features of human heart failure with preserved ejection fraction, we tested the hypothesis that increased carotid artery stiffness and altered carotid blood flow control are associated with impaired memory independent of decreased cardiac output. Furthermore, we hypothesized that chronic exercise prevents carotid artery vascular restructuring and preserves normal blood flow control and cognition in heart failure with preserved ejection fraction.Methods and ResultsYucatan pigs aged 8 months were divided into 3 groups: control (n=7), aortic‐banded sedentary (n=7), and aortic‐banded exercise trained (n=7). At 6 months following aortic‐banded or control conditions, memory was evaluated using a spatial hole‐board task. Carotid artery vascular mechanics and blood flow were assessed at rest, and blood flow control was examined during transient vena cava occlusion. Independent of decreased cardiac output, the aortic‐banded group exhibited impaired memory that was associated with carotid artery vascular stiffening, elevated carotid artery vascular resistance, and exaggerated reductions in carotid artery blood flow during vena cava occlusion. Chronic exercise augmented memory scores, normalized blood flow control, and improved indices of carotid artery vascular stiffening. Indices of vascular stiffening were significantly correlated with average memory score.ConclusionsCarotid artery stiffness and altered vasomotor control correlate with impaired cognition independent of cardiac systolic dysfunction. Carotid artery vascular mechanics may serve as a biomarker for vascular cognitive impairment in heart failure with preserved ejection fraction. Chronic low‐intensity exercise reduces vascular stiffening and improves cognition, highlighting the utility of exercise therapy for treating vascular cognitive impairment in heart failure with preserved ejection fraction.

Loss of Female Sex Hormones Exacerbates Cerebrovascular and Cognitive Dysfunction in Aortic Banded Miniswine Through a Neuropeptide Y–Ca 2+ ‐Activated Potassium Channel–Nitric Oxide Mediated Mechanism

“…Given that EF and cardiac output remain normal under resting conditions, HFpEF‐induced vascular dementia may occur independently of resting cardiac systolic dysfunction (ie, decreased pumping capacity of the heart at rest). In a translational large animal model that displays similar cardiac features as human HFpEF, we demonstrated that heart failure–induced deficits in spatial memory in male pigs coincided with increased total peripheral resistance and carotid artery vascular resistance, independent of resting cardiac systolic impairment . These data suggest that cerebrovascular dysfunction may contribute to indexes of vascular dementia in this experimental model of heart failure, and support the notion that HFpEF reflects a total‐body disease affecting the peripheral vasculature and the brain .…”

“…Heart failure was induced with AB over a period of 24 weeks, as previously reported by our laboratory, in AB and AB‐OVX miniature swine at 8 months of age. The AB was placed around the ascending aorta, and a systolic transstenotic gradient of ≈70 mm Hg was achieved (73±3 and 72±3 mm Hg for AB and AB‐OVX, respectively; P =0.83).…”

“…Spatial memory was tested using a spatial hole‐board recognition task (modified from Bolhuis et al and previously used by our laboratory) . After standardization of trial performance among groups, the testing procedure consisted of 2 phases: (1) acquisition phase and (2) retention phase.…”

“…Pigs were placed in the supine position, and cardiac output and EF% (5F admittance‐based ADVantage catheter inserted into the left ventricle through an apical incision) as well as heart rate (ECG) and MAP (fluid‐filled 6F arterial catheter) were measured. Carotid artery blood flow (≈2 cm inferior to the bifurcation) was measured using Doppler ultrasonography, as previously published . The Doppler audio signal was converted to a real‐time analog signal by a customized Doppler audio translator, and blood velocity was recorded using a Powerlab data acquisition system.…”

“…Carotid artery blood flow was calculated as the product of the measured blood velocity and cross‐sectional area of the carotid artery, as determined from the measured diameter. Carotid artery vascular resistance was calculated as the quotient of MAP and carotid artery blood flow . Resting blood flow (velocity) and vascular resistance data were averaged over an ≈30‐second period.…”