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Published on: March 27, 2018
Effects of cyclooxygenase inhibition on cardiovascular function in a hypercholesterolemic swine model of chronic
Louis M Chu1, Michael P Robich, Cesario Bianchi
1Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert School of Medicine, Brown University, Providence, RI 02903, USA.
Insights
Cyclooxygenase (COX) inhibition, particularly selective COX-2 inhibition with celecoxib, improved heart function and blood flow in a swine model of hypercholesterolemia and chronic ischemia. These findings suggest potential beneficial myocardial effects, though cardiovascular risk modulation in patients requires further study.
Area of Science:
- Cardiovascular Pharmacology
- Ischemic Heart Disease Research
- Inflammation and Cardiovascular Function
Background:
- Cardiovascular effects of cyclooxygenase (COX) inhibition are debated, especially in patients with comorbidities.
- Hypercholesterolemia and chronic ischemia create a challenging environment for cardiovascular health.
Purpose of the Study:
- To investigate the impact of nonselective and selective COX inhibition on cardiovascular function.
- To assess these effects in a hypercholesterolemic swine model with chronic ischemia.
Main Methods:
- Utilized a hypercholesterolemic swine model with induced chronic ischemia.
- Administered no drug (HCC), naproxen (nonselective COX inhibitor), or celecoxib (selective COX-2 inhibitor).
- Evaluated myocardial function, perfusion, microvessel relaxation, and biochemical markers.
Main Results:
- Selective COX-2 inhibition (celecoxib) improved regional function and myocardial perfusion in the ischemic area-at-risk (AAR).
- Both naproxen and celecoxib enhanced endothelium-dependent microvessel relaxation and reduced vasoconstriction.
- Celecoxib reduced apoptosis and fibrosis in the AAR, while both inhibitors decreased oxidative stress.
Conclusions:
- Nonselective and selective COX inhibition demonstrate beneficial myocardial effects in hypercholesterolemia with chronic ischemia.
- Selective COX-2 inhibition showed particular promise in improving cardiac function and perfusion.
- Further research is needed to determine if these effects translate to modulation of cardiovascular risk in patients.
Abstract:
The cardiovascular effects of cyclooxygenase (COX) inhibition remain controversial, especially in the setting of cardiovascular comorbidities. We examined the effects of nonselective and selective COX inhibition on cardiovascular function in a hypercholesterolemic swine model of chronic ischemia. Twenty-four intact male Yorkshire swine underwent left circumflex ameroid constrictor placement and were subsequently given either no drug (HCC; n = 8), a nonselective COX inhibitor (440 mg/day naproxen; HCNS; n = 8), or a selective COX-2 inhibitor (200 mg/day celecoxib; HCCX; n = 8). After 7 wk, myocardial functional was measured and myocardium from the nonischemic ventricle and ischemic area-at-risk (AAR) were analyzed. Regional function as measured by segmental shortening was improved in the AAR of HCCX compared with HCC. There was no significant difference in perfusion to the nonischemic ventricle between groups, but myocardial perfusion in the AAR was significantly improved in the HCCX group compared with controls at rest and during pacing. Endothelium-dependent microvessel relaxation was diminished by ischemia in HCC animals, but both naproxen and celecoxib improved vessel relaxation in the AAR compared with controls, and also decreased the vasoconstrictive response to serotonin. Thromboxane levels in the AAR were decreased in both HCNS and HCCX compared with HCC, whereas prostacyclin levels were decreased only in HCNS, corresponding to a decrease in prostacyclin synthase expression. Chronic ischemia increased apoptosis in Troponin T negative cells and intramyocardial fibrosis, both of which were reduced by celecoxib administration in the AAR. Capillary density was decreased in both the HCNS and HCCX groups. Protein oxidative stress was decreased in both HCNS and HCCX, whereas lipid oxidative stress was decreased only in the HCCX group. Thus nonselective and especially selective COX inhibition may have beneficial myocardial effects in the setting of hypercholesterolemia and chronic ischemia. Whether these effects modulate cardiovascular risk in patients taking these drugs remains to be seen, but evidence to date suggests that they do not.
