The estrogen receptor (ER) mediates estrogenic activity in a variety of organs, including those in the reproductive, cardiovascular, immune, and central nervous systems. Experimental studies have demonstrated that 17beta-estradiol (E2) protects the heart from ischemia-reperfusion injury. Two estrogen receptors, ER alpha and ER beta, mediate the actions of estrogen; however, it is not certain which ER mediates the cardioprotective effects of E2. In the present study, the ER-selective agonists 4,4',4''-[4-propyl-(1H)-pyrazole-1,3,5-triyl]tris-phenol (PPT; ER alpha) and 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; ER beta) were assessed for their cardioprotective potential in an in vivo rabbit model of ischemia-reperfusion injury. Anesthetized female rabbits were administered PPT (3 mg/kg), DPN (3 mg/kg), E2 (20 microg/rabbit), or vehicle intravenously 30 min before a 30-min occlusion of the left anterior descending coronary artery followed by 4 h of reperfusion. Acute treatment with E2 (17.7 +/- 2.9%; P < 0.001) and PPT (18.1 +/- 2.9%; P < 0.001), but not DPN (45.3 +/- 2.4%) significantly decreased infarct size as a percent of area at risk compared with vehicle (45.3 +/- 2.4%). Coadministration of PPT or E2 with the ER antagonist ICI-182,780 limited the infarct size-sparing effect of the compounds (43.8 +/- 6.6% and 40.6 +/- 5.7% respectively, expressed as a percentage of risk region). PPT reduced the release of cardiac-specific troponin-I and reduced the tissue deposition of the membrane attack complex and C-reactive protein similar to that of E2. The results indicate that activation of ER alpha, but not ER beta, is required for the observed cardioprotective effects of E2.

Cardiac tissue that undergoes an ischemic episode exhibits irreversible alterations that become more extensive upon reperfusion. Estrogen treatment has been reported to protect against reperfusion injury, but the mechanism remains unknown. The cardioprotective effects of 17␤-estradiol, a biologically active form of the hormone, and 17␣-estradiol were assessed in an in vivo occlusion-reperfusion model. Anesthetized, ovariectomized rabbits were administered 17␤-estradiol (20 g), 17␣-estradiol (1 mg), or vehicle intravenously 30 min before a 30-min occlusion of the left anterior descending (LAD) coronary artery followed by 4 h of reperfusion. Infarct size as a percentage of area at risk decreased in the 17␤-estradiol-treated group (18.8 Ϯ 1.7) compared with 17␣-estradiol (41.9 Ϯ 4.8; P Ͻ 0.01) or vehicle groups (48 Ϯ 5.5; P Ͻ 0.001). Similar results were obtained when infarct size was expressed as a percentage of total left ventricle. The second objective of the study was to assess fulvestrant (Faslodex, ICI 182,780), an estrogen receptor antagonist, for its effects on infarct size in ovariectomized female rabbits treated with 17␤-estradiol. ICI 182,780 was administered intravenously 1 h before the administration of 17␤-estradiol (20 g) or vehicle. The hearts were subjected to 30-min LAD coronary artery occlusion and 4 h of reperfusion. Pretreatment with ICI 182,780 significantly limited the infarct size sparing effect of 17␤-estradiol when expressed as a percentage of the risk region (53.0 Ϯ 5.0). The results indicate that 17␤-estradiol protects the heart against ischemia-reperfusion injury and that the observed cardioprotection is mediated by the estrogen receptor.

Before menopause, a woman has a relatively low risk for developing cardiovascular disease. After menopause, however, the risk increases nearly twofold and cardiovascular disease remains the number one cause of death among women. Observational trials and studies in animal models of cardiovascular disease suggested that females have reduced injury after myocardial ischemia and reperfusion injury. However, two large clinical trials, the women's health initiative (WHI) and the heart estrogen and progestin replacement study (HERS), found an increase in cardiovascular incidences in women taking hormone replacement therapy. The discrepancy between these data highlights the need for further research on the mechanism of estrogen in the cardiovascular system. Animal studies have demonstrated protective effects by endogenous estrogen (gender differences) and also by the administration of exogenous estrogen. In vivo studies suggest a possible anti-inflammatory mechanism of estrogen. Exogenous estrogen has been shown to have anti-oxidant activities. Pre-treatment with estrogen prior to myocardial ischemia and reperfusion causes a decrease in neutrophil infiltration into the irreversibly injured myocardium, decrease in C-reactive protein expression, and deposition of the membrane attack complex. This review will summarize the protection afforded by estrogen as well as discuss several possible mechanisms of protection for exogenous estrogen administration.

Several glycosaminoglycans (GAGs) have been demonstrated to protect the ischemic heart against reperfusion injury, in part, by modulating activation of the complement cascade. The present study assessed the cardioprotective effects of sulodexide (KRX-101), a mixture of GAGs composed of 80% lowmolecular mass heparin and 20% dermatan sulfate. KRX-101 differs from other GAGs (e.g., heparin) in that it has limited anticoagulant efficacy and can be administered orally. The experimental protocol was designed to determine whether KRX-101 could protect the ischemic myocardium. Anesthetized New Zealand white rabbits underwent 30 min of coronary artery occlusion. Intravenous doses of KRX-101 (0.5 mg/kg, n ϭ 10) or drug diluent (n ϭ 10) were administered at the end of regional ischemia and at each hour of reperfusion. Infarct size, as a percentage of the area at risk, was calculated for both groups. Myocardial infarct size was 31.3 Ϯ 4.1% in the vehicleand 17.3 Ϯ 3.2% in the KRX-101-treated animals (p Ͻ 0.05 versus vehicle). Activated partial thromboplastin times determined at baseline (preischemia) and at each hour of reperfusion (n ϭ 4) were not significantly different between vehicle-and KRX-101-treated groups (p ϭ N.S.). Myocardial injury was further assessed by measuring serum levels of cardiac-specific troponin I. KRX-101 administration significantly reduced (p Ͻ 0.05) the serum concentration of troponin I during reperfusion. The results suggest that KRX-101 may be an effective adjunctive agent in myocardial revascularization procedures, without the risk of increased bleeding.

Background:The development in the last decade of noninvasive, near infrared spectroscopy (NIRS) analysis of tissue hemoglobin saturation in vivo has provided a new and dramatic tool for the management of hemodynamics, allowing early detection and correction of imbalances in oxygen delivery to the brain and vital organs.Description:The theory and validation of NIRS and its clinical use are reviewed. Studies are cited documenting tissue penetration and response to various physiologic and pharmacologic mechanisms resulting in changes in oxygen delivery and blood flow to the organs and brain as reflected in the regional hemoglobin oxygen saturation (rSO2). The accuracy of rSO2 readings and the clinical use of NIRS in cardiac surgery and intensive care in adults, children and infants are discussed.Conclusions:Clinical studies have demonstrated that NIRS can improve outcome and enhance patient management, avoiding postoperative morbidities and potentially preventing catastrophic outcomes.