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Long-term high-fat diet and diabetes mellitus in swine cause coronary microvascular dysfunction (CMD), altering nitric oxide pathways and increasing vasoconstriction, highlighting the time-dependent progression of this cardiovascular disease.

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Area of Science:

  • Cardiovascular Research
  • Endocrinology
  • Pathophysiology

Background:

  • Coronary microvascular dysfunction (CMD) is implicated in diabetes mellitus (DM) and hypercholesterolemia-associated coronary artery disease (CAD).
  • Previous studies showed short-term DM and high-fat diet (HFD) impaired vasodilation and vasoconstriction in swine.
  • The long-term progression of CMD in this model remained uncharacterized.

Purpose of the Study:

  • To investigate the progression of CMD after 15 months of DM and HFD in a swine model.
  • To assess the impact of long-term DM and HFD on coronary artery responses to bradykinin (BK), endothelin-1 (ET-1), and nitric oxide (NO) donors.
  • To evaluate changes in vascular stiffness and receptor-mediated responses.

Main Methods:

  • A swine model with 15 months of HFD or DM + HFD was used.
  • Small coronary arteries were isolated and responses to BK, ET-1, and an NO donor (S-nitroso-N-acetylpenicillamine) were measured in vitro.
  • Blood glucose, cholesterol levels, atherosclerotic plaque presence, and vascular stiffness were assessed.

Main Results:

  • Both HFD and DM + HFD groups exhibited elevated cholesterol and early atherosclerotic plaques.
  • Despite altered NO and endothelium-derived hyperpolarizing factor contributions, BK-induced vasodilation was maintained.
  • ET-1-mediated vasoconstriction was enhanced in HFD and DM + HFD groups, primarily via ETB receptors.
  • Vascular stiffness was significantly increased in both HFD and DM + HFD swine compared to controls.

Conclusions:

  • Fifteen months of DM + HFD, or HFD alone, leads to CMD in swine.
  • The study reveals altered NO and endothelium-derived hyperpolarizing factor pathway balance and enhanced ET-1 vasoconstriction.
  • These findings underscore the time-dependent nature of CMD development in this relevant animal model.