Elucidating the Mechanisms of Pial and Paraenchymal Cerebral Small Vessel Disease in a Novel Porcine Model of HFpEF
Authors: Olver T. Dylan , Edwards Jenna C , Jurrissen Thomas J , Ivey Jan R , Thorne Pamela K , Padilla Jaume J , Laughlin M. Harold , Baines Chris P , Ford David A , Rector R. Scott J , Emter Craig A 
Published: November 2023

Vascular dementia accounts for ~35% of all forms of dementia in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. HFpEF comprises 50% of all HF cases and is clinically characterized by comorbidities including aging, obesity, hypertension, and type 2 diabetes (T2D), with increased prevalence in females. Animal models accurately representing clinical HFpEF are lacking, thus the purpose of this study was to examine the relationship between HFpEF, cerebral perfusion and vasomotor control in a novel swine model of HFpEF induced by combined T2D and cardiac pressure‐overload. We hypothesized that HFpEF‐induced deficits in cerebral perfusion would be associated with impaired endothelial and vascular smooth muscle responses to neurotransmitters. Female Ossabaw pigs were divided randomly into control (CON; n=6) and HFpEF (n=5) groups. The HFpEF group was fed a Western diet (starting at 3 mo. of age) and aortic‐banded (at 6 mo. of age) prior to euthanasia (at 12 mo. old). Carotid artery stiffness, cerebral perfusion (Doppler ultrasound) and mean arterial pressure (MAP) were examined in vivo (under anesthesia) at rest and during vena cava occlusion. Isolated pial and parenchymal arterial function was examined in vitro (pressure myography; KCl, neuropeptide‐Y (NPY), GABA, somatostatin, ACh, bradykinin (BK), nitric oxide synthase (NOS) inhibition and sodium nitroprusside (SNP) dose responses). At 12 mo. of age, HFpEF animals were obese, T2D (increased HOMA‐IR), and exhibited concentric cardiac hypertrophic remodeling, preserved EF%, and diastolic dysfunction. In vivo, the HFpEF group showed increased carotid artery elastic modulus (CON = 209 ± 68 vs. HFpEF = 707 ± 134 mmHg; P<0.05), decreased cerebral blood flow (CON = 40 ± 7 vs. HFpEF = 21 ± 2 mL·min·100 g wet brain mass−1; P<0.05) and impaired autoregulation indicated by a depressed rate of regulation ([Δvascular resistance/time]/ΔMAP) during vena cava occlusion (CON = 11 ± 5 vs. HFpEF = −16 ± 9%; P<0.05) compared to CON. Brain mass was lower in the HFpEF group (CON = 110 ± 3 vs. HFpEF = 93 ± 2 g; P<0.05). In isolated cerebral arteries, HFpEF animals exhibited decreased NOS contribution to resting tone and vasodilation to GABA (P<0.05), as well as increased KCl, somatostatin and NPY‐induced vasoconstriction (P<0.05). Vasodilatory responses to BK and SNP were decreased equally, but vasoconstrictor responses were greater in pial vs. parenchymal arteries in the HFpEF group. In conclusion, our porcine model of HFpEF is associated with cerebral small vessel disease, evidenced by cerebral hypoperfusion, increased carotid stiffness, impaired autoregulation, and depressed vasoreactivity to neurotransmitters that occur in a vessel‐specific manner.

Support or Funding Information

RO1 HL112998, PI: Emter, CA. University of Missouri Research Board Grant, PI: Emter, CA and Rector, RS. K01HL125503, PI: Padilla, J. AHA Postdoctoral Fellowship Award, PI: Olver, TD.