Background-Both statins and thiazolidinediones have antiinflammatory properties. However, the exact mechanisms underlying these effects are unknown. We investigated whether atorvastatin (ATV) and pioglitazone (PIO) increase the myocardial content of lipoxin-A 4 and 15(R)-epi-lipoxin-A 4 (15-epi-LXA 4 ), both arachidonic acid products with strong antiinflammatory properties. Methods and Results-In experiment 1, rats received 3-day pretreatment with water; PIO 2, 5, or 10 mg · kg Ϫ1 · d Ϫ1 ; ATV 2, 5, or 10 mg · kg Ϫ1 · d

Ye Y, Martinez JD, Perez-Polo RJ, Lin Y, Uretsky BF, Birnbaum Y. The role of eNOS, iNOS, and NF-B in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin. Am J Physiol Heart Circ Physiol 295: H343-H351, 2008. First published May 9, 2008 doi:10.1152/ajpheart.01350.2007.-Pretreatment with atorvastatin (ATV) reduces infarct size (IS) and increases myocardial expression of phosphorylated endothelial nitric oxide synthase (p-eNOS), inducible NOS (iNOS), and cyclooxygenase-2 (COX2) in the rat. Inhibiting COX2 abolished the ATV-induced IS limitation without affecting p-eNOS and iNOS expression. We investigated 1) whether 3-day ATV pretreatment limits IS in eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ mice and 2) whether COX2 expression and/or activation by ATV is eNOS, iNOS, and/or NF-B dependent. Male C57BL/6 wild-type (WT), University of North Carolina eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ mice received ATV (10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ; ATV ϩ ) or water alone (ATV Ϫ ) for 3 days. Mice underwent 30 min of coronary artery occlusion and 4 h of reperfusion, or hearts were harvested and subjected to ELISA, immunoblotting, biotin switch, and electrophoretic mobility shift assay. As a result, ATV reduced IS only in the WT mice. ATV increased eNOS, p-eNOS, iNOS, and COX2 levels and activated NF-B in WT mice. It also increased myocardial COX2 activity. In eNOS Ϫ/Ϫ mice, ATV increased COX2 expression but not COX2 activity or iNOS expression. NF-B was not activated by ATV in the eNOS Ϫ/Ϫ mice. In the iNOS Ϫ/Ϫ mice, eNOS and p-eNOS levels were increased but not iNOS and COX2 levels; however, NF-B was activated. In conclusion, both eNOS and iNOS are essential for the IS-limiting effect of ATV. The expression of COX2 by ATV is iNOS, but not eNOS or NF-B, dependent. Activation of COX2 is dependent on iNOS. endothelial nitric oxide synthase; inducible nitric oxide synthase; nuclear factor-B THE 3-HYDROXY-3-METHYLGLUTARYL coenzyme A (HMG-CoA) reductase inhibitors (statins) protect against ischemia-reperfusion injury and, when administered before ischemia (2, 5, 7, 25, 26, 34 -36, 43, 44, 46 -48, 52, 53) or immediately upon reperfusion (4, 17, 47), limit myocardial infarct size (IS) in various animal models. Several investigators have shown that the activation of endothelial nitric oxide synthase (eNOS) is essential for this protective effect, since nonspecific nitric oxide synthase (NOS) inhibitors blunt the IS-limiting effect of statins (5, 48) and since statins do not reduce IS in eNOS Ϫ/Ϫ mice (1, 4, 18, 25, 52). However, most of these studies used a particular eNOS Ϫ/Ϫ line (Harvard). As reported by Sharp et al. (37), there are two distinct lines of eNOS Ϫ/Ϫ mice: the Harvard line lacks compensatory increases in inducible NOS (iNOS) and has an IS bigger than the corresponding wild-type (WT) mice, and the University of North Carolina line, which has compensatory increases in iNOS expression and an IS smaller than the corresponding WT mice. It has been suggested that iNOS can be protective and compensate for the lack in eNOS and that ...

We assessed whether aspirin (acetylsalicylic acid, ASA), administered before reperfusion, abrogates the infarct size (IS)-limiting effect of atorvastatin (ATV). Statins reduce IS. This dose-dependent effect is mediated by upregulation of cycloxygenase-2 (COX2) and PGI(2) production. Administration of selective COX2-inhibitors either with ATV for 3 days or immediately before coronary occlusion blocks the IS-limiting effect of ATV. Sprague-Dawley rats received 3-day ATV (10 mg x kg(-1) x day(-1)) or water alone. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion (IS protocol, n=8 in each group), or rats underwent 30 min coronary artery occlusion and 10 min reperfusion (enzyme expression and activity protocol, n=4 in each group). Immediately before reperfusion rats received intravenous ASA (5, 10, or 20 mg/kg) or saline. Area-at-risk (AR) was assessed by blue dye and IS by triphenyltetrazolium chloride. ATV reduced IS (10.1 +/- 1.4% of the AR) compared with controls (31.0 +/- 2.2%). Intravenous ASA alone did not affect IS (29.0 +/- 2.6%); however, ASA dose dependently (5, 10, and 20 mg/kg) attenuated the protective effect of ATV on IS (15.8 +/- 0.9%, 22.0 +/- 1.6%, and 23.7 +/- 3.8%, respectively). ASA dose dependently blocked the upregulation of COX2 by ATV. COX2 activity was as follows: control, 8.93 +/- 0.90 pg/mg; ATV, 75.85 +/- 1.08 pg/mg; ATV + ASA5, 34.39 +/- 1.48 pg/mg; ATV + ASA10, 19.87 +/- 1.10 pg/mg; and ATV + ASA20, 9.36 +/- 0.94 pg/mg. ASA, administered before reperfusion in doses comparable to those used in the clinical setting, abrogates the IS-limiting effect of ATV in a model with mechanical occlusion of the coronary artery. This potential adverse interaction should be further investigated in the clinical setting of acute coronary syndromes.

Elevated cardiac biomarkers in conjunction with electrocardiographic (ECG) changes are valuable in diagnosing acute coronary syndrome (ACS). Elevated troponin I (TnI), while commonly seen in ACS, can also occur in entities such as sepsis and pulmonary thromboembolic disease. Raised TnI levels in patients with sepsis result from various mechanisms, including hypoperfusion or direct extension of infection to cardiac tissue, and can also serve as an important prognostic indicator. Electrocardiographic changes in sepsis are not as well described. Some of the ECG findings associated with septic shock include loss of QRS amplitude, increase in QTc interval, bundle branch blocks, and development of narrowed QRS intervals with deformed, positively deflected J waves (commonly known as Osborn waves). ST-segment elevations in sepsis are rare and have only previously been noted in a handful of case reports involving patients with septic shock. We present a case of a 59-year-old woman with ST-segment elevations and increased levels of cardiac troponin from Escherichia coli septic shock in the setting of normal coronary angiography.

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