Parecoxib inhibits apoptosis in acute myocardial infarction due to permanent coronary ligation but not due to ischemia-reperfusion.

PURPOSE: Myocardial ischemia induces cyclooxygenase 2 (COX-2) expression. We evaluated the effects of parecoxib, a COX-2 inhibitor, in 2 different mouse models of myocardial ischemia: permanent left coronary artery ligation (PI) and transient ligation (30 minutes ischemia) followed by reperfusion (I/R). METHODS: Forty adult male Institute of Cancer Research mice underwent PI (n = 24) or I/R (n = 16), followed by randomization to parecoxib (0.75 mg/kg intraperitoneal daily) or normal saline for 7 days. RESULTS: Parecoxib significantly reduced apoptosis [0.8% vs. 3.4% (saline), P < 0.001] and 7-day mortality [0% vs. 57% (saline), P = 0.040] in the PI group but showed no benefit in the I/R group. Parecoxib-treated mice also exhibited greater fractional shortening in the PI group [22% vs. 14% (saline), P = 0.045) but not in the I/R group. Parecoxib did not affect infarct size in either group. CONCLUSIONS: COX-2 may play a pivotal role in mediating apoptosis in the ischemic peri-infarct myocardium that is not reperfused after infarct.

Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction.

BACKGROUND: Experimental interleukin-1 receptor antagonist gene overexpression has shown that interleukin-1 receptor antagonist is cardioprotective during global cardiac ischemia. The aim of the present study was to test the impact of an exogenous recombinant human interleukin-1 receptor antagonist (anakinra) in experimental acute myocardial infarction. METHODS AND RESULTS: Two animal studies were conducted: one of immediate anakinra administration during ischemia in the mouse and one of delayed anakinra administration 24 hours after ischemia in the rat. Seventy-eight Institute of Cancer Research mice and 20 Wistar rats underwent surgical coronary artery ligation (or sham operation) and were treated with either anakinra 1 mg/kg or NaCl 0.9% (saline). Treatment was administered during surgery and then daily for 6 doses in the mice and starting on day 2 daily for 5 doses in the rats. Twenty-eight mice underwent infarct size assessment 24 hours after surgery, 6 saline-treated mice and 22 mice treated with increasing doses of anakinra (1 mg/kg [n=6], 10 mg/kg [n=6], and 100 mg/kg [n=10]); 6 mice were euthanized at 7 days for protein expression analysis. The remaining animals underwent transthoracic echocardiography before surgery and 7 days later just before death. Cardiomyocyte apoptosis was measured in the peri-infarct regions. The antiapoptotic effect of anakinra was tested in a primary rat cardiomyocyte culture during simulated ischemia and in vitro on caspase-1 and -9 activities. At 7 days, 15 of the 16 mice (94%) treated with anakinra were alive versus 11 of the 20 mice (55%) treated with saline (P=0.013). No differences in infarct size at 24 hours compared with saline were observed with the 1- and 10-mg/kg doses, whereas a 13% reduction in infarct size was found with the 100-mg/kg dose (P=0.015). Treatment with anakinra was associated with a significant reduction in cardiomyocyte apoptosis in both the immediate and delayed treatment groups (3.1+/-0.2% versus 0.5+/-0.3% [P<0.001] and 4.2+/-0.4% versus 1.1+/-0.2% [P<0.001], respectively). Compared with saline-treated animals, anakinra-treated mice and rats showed signs of more favorable ventricular remodeling. In vitro, anakinra significantly prevented apoptosis induced by simulated ischemia and inhibited caspase-1 and -9 activities. CONCLUSIONS: Administration of anakinra within 24 hours of acute myocardial infarction significantly ameliorates the remodeling process by inhibiting cardiomyocyte apoptosis in 2 different experimental animal models of AMI. This may open the door for using anakinra to prevent postischemic cardiac remodeling and heart failure.

Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium.

Emerging research suggests that oxidant-driven transcription of key cytokine/chemokine networks within the myocardium plays a crucial role in producing ischemia-reperfusion (I/R) injury. We recently showed that activation of hypoxia-inducible factor-1 (HIF-1) attenuated cardiac I/R injury. Diminished injury in these prior studies was associated with significant reductions in circulating interleukin-8 levels, suggesting that HIF-1 may play an important role in modulating postischemic cardiac inflammation. In the current study, we examined the role of HIF-1 activation in modulating proinflammatory chemokine [macrophage inflammatory protein (MIP)-2, cytokine-induced neutrophil chemoattractant factor (KC), and lipopolysaccharide-induced CXC chemokine (LIX)] and adhesion molecule [intercellular adhesion molecule (ICAM)-1] expression in murine cardiomyocytes in vitro (HL-1 cell line) and in intact murine hearts following in vivo I/R injury. Our results show that HIF-1 activation induced both pharmacologically by the prolyl hydroxylase inhibitor dimethyloxallyl glycine and via small-interfering RNA (siRNA)-mediated prolyl-4 hydroxylase-2 (P4HA2) gene silencing significantly attenuated tumor necrosis factor-alpha-induced chemokine (KC and LIX) and ICAM-1 expression in cardiomyocytes. In vivo, postischemic hearts obtained from animals receiving the P4HA2 siRNA (HIF-1 activation) exhibited significantly reduced CXC chemokine (MIP-2, KC, and LIX), CC chemokine (monocyte chemoattractant protein-1), and ICAM-1 expression when compared with postischemic hearts from either saline I/R controls or postischemic hearts from animals receiving a nontargeting control siRNA (no HIF-1 activation). Diminished chemokine and adhesion molecule expression in HIF-1-activated postischemic hearts was associated with significantly reduced polymorphonuclear leukocyte infiltration and myocardial infarct size (>60% reduction P4HA2 siRNA I/R vs. saline I/R, P < 0.001, n = 6). In conclusion, these results demonstrate for the first time that HIF-1 activation following infusion of siRNA to P4HA2 plays a key role in modulating I/R-associated cardiac inflammatory responses.

Microbubbles during radiofrequency catheter ablation: composition and formation.

OBJECTIVES: The purpose of this study was to measure tissue temperatures associated with microbubble formation during radiofrequency (RF) ablation. BACKGROUND: Microbubble formation visualized by echocardiography has been used to indicate excessive tissue heating during RF pulmonary vein isolation. However, little is known about the tissue temperatures associated with microbubble formation. METHODS: Optical fluorometric thermometry probes were used to record tissue temperatures in isolated porcine atrium overlying either lung or esophageal tissue in a saline bath. RF energy was delivered through an irrigated ablation electrode during echocardiographic monitoring for microbubble formation. RESULTS: The maximal recorded tissue temperatures were 81.0 +/- 5.0 degrees C and 88.3 +/- 8.1 degrees C at the time of intermittent (type 1) microbubble formation for lung and esophageal preparations, respectively. During continuous (type 2) microbubble formation, the temperatures were 91.4 +/- 8.2 degrees C and 99.2 +/- 7.8 degrees C, respectively (both P < .001 vs type 1). Tissue temperatures averaged >100 degrees C at the time of "pops." The maximal recorded temperature occurred up to 4 mm deep in the tissues and frequently occurred external to the atrial tissue. The total RF lesion volumes for lung and esophageal preparations were related to the pattern of microbubble formation but not to total power delivered. After generation of type 1 bubbles, up to 60% reductions in RF energy were needed to restore target tissue temperatures of 65 degrees C. Gas chromatographic analysis of the microbubbles was consistent with steam formation. CONCLUSIONS: Microbubble formation during RF ablation represents excessive tissue heating to the point of steam formation. Maximal tissue heating may occur in the adjacent lung and esophagus during cooled ablation.