Effects of fatty acids on cardioprotection by pre-ischaemic inhibition of the malate-aspartate shuttle.

1. The malate-aspartate shuttle (MAS) is the main pathway for balancing extra- and intramitochondrial glucose metabolism. Pre-ischaemic shutdown of the MAS by aminooxyacetate (AOA) mimics ischaemic preconditioning (IPC) in rat glucose-perfused hearts. The aim of the present study was to determine the effects of fatty acids (FA) on cardioprotection by pre-ischaemic inhibition of the MAS. 2. Isolated rat hearts were divided into four groups (control; pre-ischaemic AOA (0.2 mmol/L); IPC; and AOA + IPC) and were perfused with 11 mmol/L glucose, 3% bovine serum albumin plus 0, 0.4 or 1.2 mmol/L FA. The perfusion protocol included 30 min global no-flow ischaemia and 120 min reperfusion. Infarct size (IS), haemodynamic recovery, glucose oxidation and lactate release were evaluated in all four groups. 3. Pre-ischaemic AOA reduced the IS of the left ventricle in hearts perfused with 0, 0.4 and 1.2 mmol/L FA compared with that in control hearts (26 ± 2% vs 53 ± 4%, 29 ± 3% vs 53 ± 4% and 61 ± 4% vs 81 ± 3%, respectively; P < 0.01 for all). After 2 h reperfusion, AOA improved haemodynamic recovery in the absence (52 ± 2 vs 27 ± 3 mmHg in the AOA and control groups, respectively; P < 0.001) but not in the presence, of FA. Both IPC and AOA + IPC reduced IS and improved haemodynamic recovery regardless of FA levels. Postischaemic glucose oxidation was suppressed by FA and did not differ significantly between the different groups. 4. In conclusion, the reduction in IS induced by pre-ischaemic MAS shutdown is not compromised by physiological FA concentrations. Transient MAS shutdown may be involved in IPC, but is not sufficient on its own as the underlying mechanism for IPC.

Frequent biomarker analysis in the isolated perfused heart reveals two distinct phases of reperfusion injury.

BACKGROUND: Reperfusion injury and its modulation are incompletely characterized. The purpose of the present study was to characterize the dynamics of reperfusion injury by portraying the temporal release of lactate dehydrogenase (LDH) during ischemia-reperfusion injury in an isolated heart model. METHODS: We studied infarct size and LDH release in the following groups: I) Effect of reperfusion length was evaluated in 79 rats subjected to 40 minute ischemia and 60, 90, 120 or 180 minute reperfusion and a) ischemic preconditioning (IPC) or b) No IPC (control). II) LDH release kinetics was studied in 6 rats subjected to calcium-paradox to verify the applicability of LDH as a dynamic marker of cellular injury. III) Ischemia-reperfusion injury modification was studied in 36 rats subjected to: a) ischemic postconditioning, b) prolonged ischemia, c) Reperfusion Injury Salvage Kinase (RISK) pathway inhibition with wortmannin in IPC hearts, d) RISK activation with insulin or e) mitochondrial permeability transition pore (mPTP) inhibition with cyclosporine A. RESULTS: Infarct size increased from 60 to 180 minute reperfusion in control hearts. LDH was released in two separate peaks from 2 to 20 and 30 to 120 min of reperfusion. IPC attenuated both peaks. Postconditioning and agents known to modify reperfusion injury attenuated the second peak. CONCLUSIONS: Frequent measurement of myocardial ischemia markers for 120 min of reperfusion allows identification of two phases of reperfusion injury that are affected by cardioprotective stimuli. The second phase contributes significantly to final infarct size, which is modifiable and a potential target for cardioprotective interventions.

Protection against myocardial ischemia-reperfusion injury at onset of type 2 diabetes in Zucker diabetic fatty rats is associated with altered glucose oxidation.

BACKGROUND: Inhibition of glucose oxidation during initial reperfusion confers protection against ischemia-reperfusion (IR) injury in the heart. Mitochondrial metabolism is altered with progression of type 2 diabetes (T2DM). We hypothesized that the metabolic alterations present at onset of T2DM induce cardioprotection by metabolic shutdown during IR, and that chronic alterations seen in late T2DM cause increased IR injury. METHODS: Isolated perfused hearts from 6 (prediabetic), 12 (onset of T2DM) and 24 (late T2DM) weeks old male Zucker diabetic fatty rats (ZDF) and their age-matched heterozygote controls were subjected to 40 min ischemia/120 min reperfusion. IR injury was assessed by TTC-staining. Myocardial glucose metabolism was evaluated by glucose tracer kinetics (glucose uptake-, glycolysis- and glucose oxidation rates), myocardial microdialysis (metabolomics) and tissue glycogen measurements. RESULTS: T2DM altered the development in sensitivity towards IR injury compared to controls. At late diabetes ZDF hearts suffered increased damage, while injury was decreased at onset of T2DM. Coincident with cardioprotection, oxidation of exogenous glucose was decreased during the initial and normalized after 5 minutes of reperfusion. Metabolomic analysis of citric acid cycle intermediates demonstrated that cardioprotection was associated with a reversible shutdown of mitochondrial glucose metabolism during ischemia and early reperfusion at onset of but not at late type 2 diabetes. CONCLUSIONS: The metabolic alterations of type 2 diabetes are associated with protection against IR injury at onset but detrimental effects in late diabetes mellitus consistent with progressive dysfunction of glucose oxidation. These findings may explain the variable efficacy of cardioprotective interventions in individuals with type 2 diabetes.

Mouth-to-mouth ventilation is superior to mouth-to-pocket mask and bag-valve-mask ventilation during lifeguard CPR: a randomized study.

AIM: The quality of cardiopulmonary resuscitation (CPR) is a crucial determinant of outcome following cardiac arrest. Interruptions in chest compressions are detrimental. We aimed to compare the effect of mouth-to-mouth ventilation (MMV), mouth-to-pocket mask ventilation (MPV) and bag-valve-mask ventilation (BMV) on the quality of CPR. MATERIALS AND METHODS: Surf lifeguards in active service were included in the study. Each surf lifeguard was randomized to perform three sessions of single-rescuer CPR using each of the three ventilation techniques (MMV, MPV and BMV) separated by 5 min of rest. Data were obtained from a resuscitation manikin and video recordings. RESULTS: A total of 60 surf lifeguards were included (67% male, 33% female, mean age 25 years). Interruptions in chest compressions were significantly reduced by MMV (8.9 ± 1.6 s) when compared to MPV (10.7 ± 3.0 s, P < 0.001) and BMV (12.5 ± 3.5s, P < 0.001). Significantly more effective ventilations (visible chest rise) were delivered using MMV (91%) when compared to MPV (79%, P < 0.001) and BMV (59%, P < 0.001). The inspiratory time was longer during MMV (0.7 ± 0.2 s) and MPV (0.7 ± 0.2s, P < 0.001 for both) compared to BMV (0.5 ± 0.2s). Tidal volumes were significantly lower using BMV (0.4 ± 0.2L) compared to MMV (0.6 ± 0.2L, P < 0.001) and MPV (0.6 ± 0.3 L, P < 0.001), whereas no differences were observed when comparing MMV and MPV. CONCLUSION: MMV reduces interruptions in chest compressions and produces a higher proportion of effective ventilations during lifeguard CPR. This suggests that CPR quality is improved using MMV compared to MPV and BMV.