Preoperative systemic inflammation and perioperative myocardial injury: prospective observational multicentre cohort study of patients undergoing non-cardiac surgery.

BACKGROUND: Systemic inflammation is pivotal in the pathogenesis of cardiovascular disease. As inflammation can directly cause cardiomyocyte injury, we hypothesised that established systemic inflammation, as reflected by elevated preoperative neutrophil-lymphocyte ratio (NLR) >4, predisposes patients to perioperative myocardial injury. METHODS: We prospectively recruited 1652 patients aged ≥45 yr who underwent non-cardiac surgery in two UK centres. Serum high sensitivity troponin T (hsTnT) concentrations were measured on the first three postoperative days. Clinicians and investigators were blinded to the troponin results. The primary outcome was perioperative myocardial injury, defined as hsTnT≥14 ng L-1 within 3 days after surgery. We assessed whether myocardial injury was associated with preoperative NLR>4, activated reactive oxygen species (ROS) generation in circulating monocytes, or both. Multivariable logistic regression analysis explored associations between age, sex, NLR, Revised Cardiac Risk Index, individual leukocyte subsets, and myocardial injury. Flow cytometric quantification of ROS was done in 21 patients. Data are presented as n (%) or odds ratio (OR) with 95% confidence intervals. RESULTS: Preoperative NLR>4 was present in 239/1652 (14.5%) patients. Myocardial injury occurred in 405/1652 (24.5%) patients and was more common in patients with preoperative NLR>4 [OR: 2.56 (1.92-3.41); P<0.0001]. Myocardial injury was independently associated with lower absolute preoperative lymphocyte count [OR 1.80 (1.50-2.17); P<0.0001] and higher absolute preoperative monocyte count [OR 1.93 (1.12-3.30); P=0.017]. Monocyte ROS generation correlated with NLR (r=0.47; P=0.03). CONCLUSIONS: Preoperative NLR>4 is associated with perioperative myocardial injury, independent of conventional risk factors. Systemic inflammation may contribute to the development of perioperative myocardial injury. CLINICAL TRIAL REGISTRATION: NCT01842568.

Comparison between anagrelide and hydroxycarbamide in their activities against haematopoietic progenitor cell growth and differentiation: selectivity of anagrelide for the megakaryocytic lineage.

Anagrelide (ANA) and hydroxycarbamide (HC) are two distinct pharmacological agents used to treat thrombocythaemia associated with myeloproliferative disorders. Although both drugs have been in clinical use for a number of years, comparative studies of their selectivity and mode of action are still lacking. Here, we have evaluated the activities of ANA and HC on the growth and differentiation of human haematopoietic progenitor cells in liquid culture. Both drugs inhibited thrombopoietin-induced megakaryocytopoiesis in a dose-dependent manner, but with strikingly different potencies (IC(50)=26 nM for ANA and 30 muM for HC) and modes of action. Whereas HC inhibited cell proliferation, ANA acted primarily on the differentiation process. At doses that abrogated megakaryocytopoiesis, HC also inhibited the expansion of CD34(+) cells stimulated by stem cell factor, interleukin-3 and Flt-3 ligand and also induced apoptosis. Furthermore, HC inhibited erythroid and myelomonocytic cell growth, induced by erythropoietin or granulocyte-macrophage colony-stimulating factor, respectively. In contrast, ANA showed none of these additional effects. Taken together, these results demonstrate that ANA is a potent and selective inhibitor of megakaryocytopoiesis, having no significant activity against haematopoietic progenitor cell expansion or differentiation into other lineages. In contrast, the anti-megakaryocytopoietic activity of HC cannot be dissociated from its more general cytoreductive and cytotoxic actions.