Sex differences in cardiac arrest survivors who receive therapeutic hypothermia.

OBJECTIVE: Sex differences have not been well defined for patients undergoing therapeutic hypothermia (TH). We aimed to determine sex differences in mortality and Cerebral Performance Category (CPC) scores at discharge among those receiving TH. METHODS: This retrospective cohort study used data abstracted from an "ICE alert" database, an institutional protocol expediting mild TH for postarrest patients. Quality assurance variables (such as age, time to TH, CPC scores, and mortality) were reviewed and compared by sex. χ2 Test and Wilcoxon rank sum test were used. Stepwise logistic regression was used to assess the association between mortality and sex, while controlling for patient characteristics and clinical presentation of cardiac arrest. RESULTS: Three hundred thirty subjects were analyzed, 198 males and 132 females. Subjects' mean age (SD) was 61.7 years (15.0); there was no significant sex difference in age. There were no statistically significant sex differences in history of coronary artery disease, congestive heart failure, arrhythmia, hypertension, chronic obstructive pulmonary disease, renal disease, type 1 and/or type 2 diabetes mellitus, or those previously healthy. Obesity (body mass index>35 kg/m2) was more likely in females (37, 28.0%) than males (35, 17.7%); P=.03. Females (64, 49.6%) were more likely than males (71, 36.8%) to have shock; P=.02. There was no difference in arrest to initiating hypothermia, but there was a significant difference in time to target temperature (in median minutes, interquartile range): male (440, 270) vs female (310, 270), P=.003. There was no statistical difference in CPC at discharge. Crude mortality was not different between sexes: male, 67.7%; female, 70.5%; P=.594. However, after controlling for differences in age, obesity, shock, and other variables, females were less likely to die (odds ratio, 0.46; 95% confidence interval, 0.23-0.92; P=.03) than males. CONCLUSION: There is no statistically significant difference in CPC or crude mortality outcomes between sexes. After adjusting for confounders, females were 54% less likely to die than males.

Adenosine receptor subtypes and the heart failure phenotype: translating lessons from mice to man.

Adenosine plays an important role in the pathophysiology of heart failure and in myocardial protection during ischemia and reperfusion. The action of adenosine in the heart is mediated by four G-protein-coupled receptors: A(1)-AR and A(3)-AR, which act via Gα(1), and A(2A)-AR and A(2B)-AR, which act via Gα(s). Understanding of cellular signaling pathways triggered by adenosine has been complicated by the availability of only partially specific adenosine agonists/antagonists. Adenosine signaling appears to be at times redundant in receptor function, and cellular signaling pathways for adenosine are multiple, parallel, and interrelated. Data obtained about the specific role of individual adenosine receptors, through the genetic modulation of receptors in murine hearts have provided important information about the role of adenosine receptors in the heart. Here we review existing data and present new results that clarify the function of individual adenosine receptors in the heart and their role in the development of left ventricular dysfunction, and about the downstream signaling systems that are modified by adenosine receptor activation.

Left ventricular dysfunction in murine models of heart failure and in failing human heart is associated with a selective decrease in the expression of caveolin-3.

BACKGROUND: Caveolins are scaffolding proteins that are integral components of caveolae, flask-shaped invaginations in the membranes of all mammalian cells. Caveolin-1 and -2 are expressed ubiquitously, whereas caveolin-3 is found only in muscle. The role of caveolin-3 in heart muscle disease is controversial. METHODS AND RESULTS: The present study was undertaken to assess the effects of left ventricular dysfunction on the expression of caveolin proteins using 2 well characterized models of murine heart failure and failing human heart. Transgenic mice with constitutive overexpression of A(1)-adenosine receptor (A(1)-TG) demonstrated cardiac dilatation and decreased left ventricular function at 10 weeks of age. This was accompanied by a marked decrease in caveolin-3 mRNA and protein levels compared with non-TG control mice. The change in caveolin-3 expression was selective, because levels of caveolin-1 and -2 did not change. Confocal imaging of myocytes isolated from A(1)-TG mice demonstrated a loss of the plate-like appearance of T tubules. Caveolin-3 levels were also reduced in hearts from mice overexpressing tumor necrosis factor α. There was a direct relationship between caveolin-3 expression and fractional shortening in all mice that were studied (r = 0.65; P < .001). Although we could not demonstrate a significant decrease in caveolin-3 levels in failing human heart, we did find a direct correlation (r = 0.7; P < .05) between levels of caveolin-3 protein and Ca(2+)-adenosine triphosphatase, a marker of the heart failure phenotype. CONCLUSIONS: These results suggest a relationship between left ventricular dysfunction and caveolin-3 levels and suggest that caveolin-3 may provide a novel target for heart failure therapy.