title: High-fat diet alters prostanoid balance and perfusion in ischemic myocardium of naproxen-treated swine.
abstract: BACKGROUND
  The effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the cardiovascular system remains controversial, especially in patients with cardiovascular comorbidities. We used a swine model of chronic myocardial ischemia to investigate whether hypercholesterolemia alters the cardiovascular effects of the nonselective NSAID naproxen.
  
  
  METHODS
  Yorkshire swine were fed normal chow (NAP; n = 7) or a high-fat diet (HF-NAP; n = 8). Chronic myocardial ischemia was created in all animals by left circumflex ameroid constrictor placement. All swine were started on oral naproxen (440 mg/day) at the time of ameroid placement. After 7 weeks, myocardial perfusion and microvessel reactivity in the ischemic territory were assessed. Tissue levels of prostanoid metabolites 11-dehydrothromboxane B2 (11-d-TXB₂) and 6-keto-prostaglandin F1-α (6-k-PGF(1α)) were measured. Tissue was analyzed for capillary density and protein expression.
  
  
  RESULTS
  Myocardial perfusion was significantly decreased in the HF-NAP group both at rest and during ventricular pacing. Microvessel relaxation responses to sodium nitroprusside and adenosine 5'-diphosphate were similar between groups. Tissue 11-d-TXB₂ levels were similar between groups, but tissue 6-k-PGF(1α) was significantly decreased in the HF-NAP group (P = .001). Expression of thromboxane synthase was significantly higher in the HF-NAP group (P = .02), while prostacyclin synthase expression was significantly decreased in the HF-NAP group (P = .04). Capillary density was higher in the HF-NAP group (P = .005). Proangiogenic vascular endothelial growth factor (VEGF; P = .0002) and Akt (P = .01) were downregulated in the HF-NAP group.
  
  
  CONCLUSIONS
  A high-fat diet impairs tissue perfusion in ischemic myocardium of naproxen-treated swine by shifting the prostanoid balance to favor production of thromboxane over prostacyclin. Dietary modification may improve myocardial blood flow and alter the safety profile in chronically ischemic cardiac patients taking naproxen.
authors: Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert School of Medicine, Brown University, Providence, RI, USA.
authors: Louis M
authors: LM
authors: Chu
authors: Michael P
authors: MP
authors: Robich
authors: Antonio D
authors: AD
authors: Lassaletta
authors: Jun
authors: J
authors: Feng
authors: Shu Hua
authors: SH
authors: Xu
authors: Robert
authors: R
authors: Heinl
authors: Yuhong
authors: Y
authors: Liu
authors: Eric
authors: E
authors: Sellke
authors: Frank W
authors: FW
authors: Sellke
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D003326:Coronary Circulation / Q000502:physiology; D004041:Dietary Fats / Q000494:pharmacology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006334:Heart Function Tests; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000503:physiopathology*; D015151:Immunoblotting; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009288:Naproxen / Q000008:administration & dosage*; D010477:Perfusion; D011453:Prostaglandins / Q000097:blood / Q000378:metabolism*; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004041:Dietary Fats; D011453:Prostaglandins; D042461:Vascular Endothelial Growth Factor A; D009288:Naproxen