CYCLO-OXYGENASE-2 INHIBITION IN ACUTE MYOCARDIAL INFARCTION An experimental animal study Antonio Abbate, MD Department of Internal Medicine Virginia Commonwealth University – Medical College of Virginia Hospitals DISCLOSURE CYCLO-OXYGENASE-2 INHIBITION IN ACUTE MYOCARDIAL INFARCTION PFIZER INC. KINDLY DONATED THE PHARMACOLOGIC AGENT (PARECOXIB) An experimental animal study USED IN THIS STUDY Antonio Abbate, MD Department of Internal Medicine Virginia Commonwealth University – Medical College of Virginia Hospitals ISCHEMIC CASCADE ISCHEMIA CORONARY OCCLUSION EXCITATION/ CONTRACTION UNCOUPLING APOPTOSIS NECROSIS INFARCTION HEART FAILURE ISCHEMIC CASCADE – role of cyclo-oxygenase-2 - COX-2 is not expressed in the healthy myocardium - Ischemia induces new COX-2 mRNA synthesis in myocytes - COX-2 [protein] is detectable 6-24 hours after an ischemic insult Shinmura et al. PNAS 2000 - In post-mortem studies, COX-2 expression is associated with - greater myocyte apoptosis - adverse cardiac remodelling - occurrence of symptomatic heart failure Abbate et al. Heart 2003 ISCHEMIC CASCADE ISCHEMIA CORONARY OCCLUSION CYCLO-OXYGENASE-2 INFARCTION HEART FAILURE CYCLO-OXYGENASE-2 INHIBITION ISCHEMIA POTENTIAL BENEFITS OF COX-2 INHIBITION: CORONARY OCCLUSION 1) REDUCED INFARCT SIZE CYCLO-OXYGENASE-2 HEART FAILURE 2) REDUCED APOPTOSIS (early and late) 3) REDUCED LEFT VENTRICULAR DYSFUNCTION INFARCTION 4) PREVENTION OF HEART FAILURE COX-2 inhibition in AMI in an experimental rat model COX-2 inhibition reduced infarct size and prevented LV dysfunction Saito et al. J Mol Cell Cardiol 2004 COX-2inh COX-2inh AIM OF THE CURRENT STUDY 1)To evaluate whether COX-2 inhibition reduced myocyte apoptosis in animals with AMI (PHASE 1) 2) To evaluate whether such treatment resulted in improved remodelling after AMI (PHASE 2) STUDY DESIGN Experimental AMI (left coronary ligation) in Æ 18 mice (PHASE 1) Æ 20 rats (PHASE 2) Treatment with intraperitoneal injections of Æ parecoxib (0.75 mg/Kg) or Æ saline (500 ul) for 5 days starting on day 2 after AMI Sacrifice of the animals on day 7 STUDY DESIGN (2) PHASE 1 – Evaluation of apoptosis Apoptotic rate was evaluated in the peri-infarct area by means of costaining for • DNA fragmentation (TUNEL) and • caspase-3 activation STUDY DESIGN (3) PHASE 2 – Evaluation of remodelling A transthoracic M-mode echocardiogram was performed to measure: • End-diastolic diameter (EDD) • End-systolic diameter (ESD) • Fractional shortening (FS) • Infarct wall thickness (AWDT and AWST) • Non-infarct wall thickness (PWDT, PWST) RESULTS – PHASE 1 COX-2 myocardial expression and apoptosis COX-2 EXPRESSION WAS FOUND IN ALL CASES APOPTOTIC RATES • 1-8% PERI-INFARCT REGION • 0.01-0.1% REMOTE AREA RESULTS – PHASE 1 apoptotic rate (%) P=0.009 6 4 2 Shamoperated AMI Salinetreated AMI COX-2inhibition RESULTS – PHASE 2 P= 0.018 7 P= 0.050 6 70 60 5 50 P= 0.027 4 40 3 30 2 20 mm % EDD (mm) Prior to surgery ESD (mm) After surgery: FS (%) NaCl 0.9% Parecoxib RESULTS – PHASE 2 P= 0.11 P= 0.008 3.5 3.0 2.5 P= 0.10 2.0 1.5 1.0 mm AWDT (mm) Prior to surgery AWST (mm) After surgery: PWDT (mm) PWST (mm) NaCl 0.9% Parecoxib Echocardiographic parameters at baseline and 7 days after coronary artery ligation Prior to surgery After surgery: NaCl 0.9% Parecoxib CONCLUSIONS COX-2 inhibition by parecoxib (in experimental setting): – inhibits cardiomyocytes apoptosis after AMI – ameliorates remodelling after AMI These results may open the way to studies aimed at preventing ischemic heart failure P= 0.027 P= 0.028 9.5 6.5 45 4.0 9 6 40 3.5 8.5 5.5 35 3.0 8 5 30 2.5 7.5 4.5 25 2.0 7 4 20 1.5 6.5 3.5 25 1.0 EDD (mm) Baseline ESD (mm) FS (%) After 7 days of treatment P= 0.046 EST (mm) EST (mm) Infarct Remote area area Mean and SEM ISCHEMIC CASCADE – role of cyclooxygenase-2 Intense COX-2 staining (%) Shinmura et al. PNAS 2000 ischemic non ischemic COX-2 levels COX-2 is not expressed in the healthy myocardium. Its expression is induced by ischemia by means of new mRNA synthesis * * * 0h 90 P=0.035 6h 12 h hypoxia 24 h In a post-mortem human study, COX-2 expression was associated with unfavorable remodeling and heart failure, and greater apoptosis after AMI 60 30 no heart failure heart failure Abbate et al. Heart 2003 COMPLEXITY OF COX-2 INHIBITION CYCLO-OXYGENASE-2 INHIBITORS PROMOTE THROMBOSIS ? REDUCE REDUCE INFLAMMATION ISCHEMIC DAMAGE ?