Ajay Kher

Sex differences in the myocardial inflammatory response to acute injury

Hemorrhage, trauma, ischemia/reperfusion, burn, and sepsis each lead to cardiac dysfunction. These insults lead to an inflammatory cascade, which plays an important role in this process. Gender has been shown to influence the inflammatory response, as well as outcomes after acute injury. The mechanisms by which gender affects the inflammatory response to and the outcome of acute injury are being actively investigated. We searched PubMed for articles in the English language by using the search words sex, gender, estrogen, testosterone, inflammation, acute injury, ischemia reperfusion, sepsis, trauma, and burns. These were used in various combinations. We read the abstracts of the relevant titles to confirm their relevance, and the full articles were then extracted. References from extracted articles were checked for any additional relevant articles. This review will examine evidence for gender differences in the outcome to acute injury, explain the myocardial inflammatory response to acute injury, and elucidate the various mechanisms by which gender affects the myocardial response to acute injury.

Intracellular signaling mechanisms of sex hormones in acute myocardial inflammation and injury.

Sex hormones are important modifiers of the acute inflammatory response to injury, an important aspect of myocardial depression and apoptosis following ischemia or endotoxemia. Hemorrhage, trauma, ischemia/reperfusion, burn and sepsis each lead to cardiac dysfunction. Gender has been shown to influence the inflammatory response as well as outcomes following acute injury. The mechanisms by which sex affects the inflammatory response and the outcome to acute injury are being actively investigated. It is now recognized that myocardial inflammation plays a crucial role in I/R-induced myocardial dysfunction. Inflammatory mediators, such as TNF-alpha are produced by cardiomyocytes and contribute to myocardial functional depression and apoptosis. Gender differences in the inflammatory response following burn injury have been demonstrated. However, gender differences in the setting of acute I/R-induced inflammation are unclear. In addition, a critical component of the signal transduction pathway leading to myocardial inflammation is the activation of p38 mitogen-activated protein kinase (MAPK). In other systems, it appears that gender differences exist in the p38 MAPK signaling pathway. The inflammatory response, including the p38 MAPK signaling cascade and expression of proinflammatory cytokines such as TNF-alpha and IL-1beta, may precipitate cardiomyocyte apoptosis following I/R injury. Apoptosis may be an essential component in the pathogenesis of heart failure, and there is evidence that myocyte apoptosis in the failing human heart is markedly lower in women than in men. The prevention of cell death attenuates I/R-induced injury on myocardial anatomy and performance. This review will: 1) examine evidence for gender differences in the outcome to acute injury; 2) explain the myocardial inflammatory response to acute injury; and 3) elucidate the various mechanisms by which gender and sex hormones affect the myocardial response to acute injury.

Zaprinast attenuates hypoxic pulmonary artery injury and causes less aortic relaxation than milrinone

Hypoxic pulmonary vasoconstriction is a challenging clinical problem with limited therapeutic options. Milrinone, a phosphodiesterase (PDE)-3 inhibitor, is frequently used to treat perioperative pulmonary hypertension. However, recent evidence suggests that the PDE-5 isoform may be more specific for lung tissue. We hypothesized that the PDE-5 inhibitor zaprinast has greater efficacy for pulmonary vasorelaxation, attenuation of hypoxic pulmonary vasoconstriction, and inhibition of hypoxia-induced pulmonary artery cytokine expression when compared with milrinone. To study this, isolated rat pulmonary artery and thoracic aorta rings suspended in physiologic organ baths for measurement of isometric force transduction were treated with vehicle (dimethyl sulfoxide), milrinone, or zaprinast to assess pulmonary artery relaxation, thoracic aorta relaxation, inhibition of hypoxic (pO2 = 30-35 mmHg) pulmonary vasoconstriction, and hypoxia-induced pulmonary artery TNF-α and IL-1β expression (reverse transcriptase-PCR). Milrinone and zaprinast resulted in dose-dependent pulmonary artery and aortic relaxation, but zaprinast caused significantly less aortic relaxation compared with milrinone (50.12% ± 3.36% versus 91.03% ± 2.97%, P < 0.001). Zaprinast, but not milrinone, significantly inhibited hypoxic pulmonary vasoconstriction (zaprinast, 58.42% ± 5.37%; milrinone, 77.65% ± 4.42% versus vehicle: 74.42% ± 7.54%). Hypoxia-induced upregulation of TNF-α and IL-1β mRNA in pulmonary artery was decreased by zaprinast, but not milrinone, pretreatment. These results suggest that zaprinast, but not milrinone, preferentially vasodilates pulmonary artery over aorta, attenuates hypoxic pulmonary vasoconstriction, and inhibits hypoxia-induced pulmonary artery TNF-α and IL-1β expression. Therefore, PDE-5 inhibition may be advantageous in the treatment of pulmonary hypertension.