Cardiac myocyte-specific knock-out of calcium-independent phospholipase A2γ (iPLA2γ) decreases oxidized fatty acids during ischemia/reperfusion and reduces infarct size

Calcium-independent phospholipase A(2)γ (iPLA(2)γ) is a mitochondrial enzyme that produces lipid second messengers that facilitate opening of the mitochondrial permeability transition pore (mPTP) and contribute to the production of oxidized fatty acids in myocardium. To specifically identify the roles of iPLA(2)γ in cardiac myocytes, we generated cardiac myocyte-specific iPLA(2)γ knock-out (CMiPLA(2)γKO) mice by removing the exon encoding the active site serine (Ser-477). Hearts of CMiPLA(2)γKO mice exhibited normal hemodynamic function, glycerophospholipid molecular species composition, and normal rates of mitochondrial respiration and ATP production. In contrast, CMiPLA(2)γKO mice demonstrated attenuated Ca(2+)-induced mPTP opening that could be rapidly restored by the addition of palmitate and substantially reduced production of oxidized polyunsaturated fatty acids (PUFAs). Furthermore, myocardial ischemia/reperfusion (I/R) in CMiPLA(2)γKO mice (30 min of ischemia followed by 30 min of reperfusion in vivo) dramatically decreased oxidized fatty acid production in the ischemic border zones. Moreover, CMiPLA(2)γKO mice subjected to 30 min of ischemia followed by 24 h of reperfusion in vivo developed substantially less cardiac necrosis in the area-at-risk in comparison with their WT littermates. Furthermore, we found that membrane depolarization in murine heart mitochondria was sensitized to Ca(2+) by the presence of oxidized PUFAs. Because mitochondrial membrane depolarization and calcium are known to activate iPLA(2)γ, these results are consistent with salvage of myocardium after I/R by iPLA(2)γ loss of function through decreasing mPTP opening, diminishing production of proinflammatory oxidized fatty acids, and attenuating the deleterious effects of abrupt increases in calcium ion on membrane potential during reperfusion

Strong-coupling expansion and effective hamiltonians

When looking for analytical approaches to treat frustrated quantum magnets, it is often very useful to start from a limit where the ground state is highly degenerate. This chapter discusses several ways of deriving {effective Hamiltonians} around such limits, starting from standard {degenerate perturbation theory} and proceeding to modern approaches more appropriate for the derivation of high-order effective Hamiltonians, such as the perturbative continuous unitary transformations or contractor renormalization. In the course of this exposition, a number of examples taken from the recent literature are discussed, including frustrated ladders and other dimer-based Heisenberg models in a field, as well as the mapping between frustrated Ising models in a transverse field and quantum dimer models.Comment: To appear as a chapter in "Highly Frustrated Magnetism", Eds. C. Lacroix, P. Mendels, F. Mil

Transchest defibrillation under conditions of hypothermia

This study was conducted to determine whether or not hypothermia changes ventricular defibrillation threshold. Ventricular fibrillation was induced by electrical stimulation of the endocardium in pentobarbital anesthetized dogs, both during normothermia and hypothermia produced by circulating 8 °C water through a rubber bladder implanted in the peritoneal cavity. Defibrillation threshold was determined as the shock strength needed to defibrillate the ventricles and differing no more than 10 percent from a shock strength that failed to defibrillate. Defibrillation threshold current was stable for body temperatures ranging from 37 oC to 22 oC. Threshold energy increased linearly with decreasing temperature in keeping with the expected temperature-dependent changes in body fluid resistance. Normothermic electrical doses are probably appropriate for defibrillation of hypothermic children

Diabetes-induced changes in specific lipid molecular species in rat myocardium

Intrinsic cardiac dysfunction during the diabetic state has been causally linked to changes in myocardial lipid metabolism. However, the precise alterations in the molecular species of myocardial polar and non-polar lipids during the diabetic state and their responses to insulin have not been investigated. Herein we demonstrate four specific alterations in rat myocardial lipid molecular species after induction of the diabetic state by streptozotocin treatment: (i) a massive remodelling of triacylglycerol molecular species including a &amp;gt; 5-fold increase in tripalmitin mass and a 60% decrease in polyunsaturated triacylglycerol molecular species mass (i.e. triacylglycerols containing at least one acyl residue with more than two double bonds); (ii) a 46% increase in myocardial phosphatidylinositol mass; (iii) a 44% increase in myocardial plasmenylethanolamine mass and (iv) a 22% decrease in 1-stearoyl-2-arachidonoyl phosphatidylethanolamine content. Each of the changes in phospholipid classes, subclasses and individual molecular species were prevented by insulin treatment after induction of the diabetic state. In sharp contrast, the alterations in triacylglycerol molecular species were not preventable by peripheral insulin treatment after induction of the diabetic state. These results segregate diabetes-induced alterations in myocardial lipid metabolism into changes that can be remedied or not by routine peripheral insulin treatment and suggest that peripheral insulin therapy alone may not be sufficient to correct all of the metabolic alterations present in diabetic myocardium.</jats:p

Early detection of myocardial infarction in conscious dogs by analysis of plasma MM creatine kinase isoforms.

To determine whether myocardial infarction could be detected early after onset by analysis of subforms of the MM isoenzyme (isoforms) of creatine kinase (MM CK) in plasma, we subjected eight conscious dogs to coronary occlusion and quantified isoforms in serial plasma samples by chromatofocusing. The fractions of MMA (isoelectric point [pI] = 7.91), MMB (pI = 7.74), and MMC (pI = 7.51) in plasma samples before coronary occlusion averaged 11.4 +/- 4.8% (SD), 22.3 +/- 5.5%, and 66.3 +/- 9.6% of total MM CK activity. The fraction of MMA, the isoform of MM CK found in myocardium, increased significantly in plasma 1 hr after coronary occlusion, reached a maximum of 49.7 +/- 8.0% in 4.1 +/- 1.3 hr, and returned to baseline in 12.0 +/- 2.3 hr. The fraction of plasma MM CK activity attributable to MMC, an isoform formed slowly in plasma from MMA via MMB as an intermediate, decreased significantly within 1 hr, reached a minimum of 14.0 +/- 4.1% in 4.8 +/- 1.1 hr, and returned to baseline in 13.0 +/- 2.9 hr after coronary occlusion. Total CK activity did not increase significantly until later, i.e., 5 hr after occlusion, and peaked at 1371 +/- 530 IU/liter in 10.9 +/- 1.9 hr. Within the first 4 hr after coronary occlusion, MMA consistently comprised more than 20% of plasma MM CK activity despite insignificant increase of total CK. Changes in isoform proportions were consistent and independent of peak total CK activity and of cumulative CK release over a 10-fold range. Thus initial CK release indicative of infarction is detectable within 1 hr after the onset of ischemia by quantification of plasma MM CK isoforms.</jats:p

Optimal criteria for rapid detection of myocardial reperfusion by creatine kinase MM isoforms in the presence of residual high grade coronary stenosis

AbstractAnalysis of isoforms of MM creatine kinase (CK) in plasma is being developed as a means for rapid detection of coronary recanalization in patients given thrombolytic agents. To determine whether flow-limiting residual stenosis typical of that seen in patients affects plasma isoform profiles, stenosis sufficient to preclude reactive hyperemia was induced in dogs before coronary occlusion, followed by recanalization in 2 h. Plasma activities of the MM CK isoform released from myocardium (MM3) and its two conversion products elaborated sequentially (MM2and MM1) were assayed in serial samples with a rapid quantitative chromatofocusing procedure.Reperfusion in 10 dogs shortened the mean intervals (±SD) to the occurrence of peak MM3activity (3.7 ± 0.9 h), peak MM3expressed as a percent of total CK activity (MM3%, 2.5 ± 0.3 h) and the maximal ratio of MM3to MM1(2.7 ± 0.3 h) compared with results in 10 control dogs without reperfusion. Nevertheless, the appearance of these peaks was delayed by 8% to 57% when residual stenosis was present. In contrast, the rate of increase of MM3% was delineated before the peak, was fivefold greater with recanalization (1.19 ± 0.46 versus 0.26 ± 0.11% min−1in control dogs) and was not attenuated by residual stenosis. Thus, this criterion appears capable of delineating recanalization early after thrombolysis whether or not high grade residual stenosis is present