The effect of atorvastatin on prosurvival mechanisms in myocardial ischaemia reperfusion injury.

The treatment of acute myocardial infarction has long involved rapid reperfusion of the area at risk. Reperfusion of ischaemic myocardium, however, is not without hazard and can paradoxically result in myocyte death, in a process known as lethal reperfusion- induced injury. Attenuation of this reperfusion-induced injury has become a focus for the treatment of acute coronary artery disease in a clinical setting. In recent years the "Reperfusion Injury Salvage Kinase pathway" the so-called "RISK" pathway has been proposed as a key factor in ensuring myocardial survival. Several agents have been shown to attenuate lethal reperfusion induced injury via this mechanism, and the identification of clinically effective drugs that influence this pathway has taken on some urgency. Over the last two decades 3-hydroxy-3-methylglutaryl coenzyme A (HMG-Co A) reductase inhibitors called "statins" have revolutionised the treatment of hypercholesterolaemia. Meta-analysis of data from clinical trials investigating the effects of statins, however, have indicated that these drugs may have additional beneficial effects independent of their cholesterol-lowering properties. Amongst the pleiotropic effects which have not yet been fully investigated is their potential cardioprotective action. The aim of the present study was to investigate if atorvastatin reduces reperfusion induced injury by activation of the RISK pathway. Using an isolated perfused mouse heart model, the actions of atorvastatin given at reperfusion on infarct size and on the phosphorylation of the anti-apoptotic phosphatidylinositol-3-OH kinase (PI3K)-AKT, the P44/42 extra-cellular signal-regulated kinases (Erk 1/2), and the molecular chaperone Heat Shock Protein (HSP) 27 were studied. The data presented in this thesis indicate that atorvastatin, when administered at reperfusion, results in a significant reduction in infarct size and causes the phosphorylation of these prosurvival kinases. This reduction is sensitive to wortmannin and U0126, which are inhibitors of PBKinase and P44/42 respectively. In addition to the actions described atorvastatin also increased HSP25 phosphorylation (HSP25 is the murine equivalent of the human HSP27) an effect that was abrogated by the p38MAPK inhibitor SB203580, which prevents phosphorylation of p38 and its down stream target HSP25. In view of these findings the potential therapeutic role of human HSP27 was further investigated. Transgenic mice overexpressing HSP27, were found to be protected from lethal ischaemia compared to their HSP27 negative litter mates. In conclusion, this thesis provides evidence that atorvastatin attenuates lethal reperfusion induced injury in a process involving activation of the RISK pathway, and increase of HSP25 phosphorylation. In addition it is demonstrated that overexpression of HSP27 protects against lethal ischaemia

Ambient temperature and subsequent COVID-19 mortality in the OECD countries and individual United States

Epidemiological studies have yielded conflicting results regarding climate and incident SARS-CoV-2 infection, and seasonality of infection rates is debated. Moreover, few studies have focused on COVD-19 deaths. We studied the association of average ambient temperature with subsequent COVID-19 mortality in the OECD countries and the individual United States (US), while accounting for other important meteorological and non-meteorological co-variates. The exposure of interest was average temperature and other weather conditions, measured at 25 days prior and 25 days after the first reported COVID-19 death was collected in the OECD countries and US states. The outcome of interest was cumulative COVID-19 mortality, assessed for each region at 25, 30, 35, and 40 days after the first reported death. Analyses were performed with negative binomial regression and adjusted for other weather conditions, particulate matter, sociodemographic factors, smoking, obesity, ICU beds, and social distancing. A 1 °C increase in ambient temperature was associated with 6% lower COVID-19 mortality at 30 days following the first reported death (multivariate-adjusted mortality rate ratio: 0.94, 95% CI 0.90, 0.99, p = 0.016). The results were robust for COVID-19 mortality at 25, 35 and 40 days after the first death, as well as other sensitivity analyses. The results provide consistent evidence across various models of an inverse association between higher average temperatures and subsequent COVID-19 mortality rates after accounting for other meteorological variables and predictors of SARS-CoV-2 infection or death. This suggests potentially decreased viral transmission in warmer regions and during the summer season. © 2021, The Author(s)