Intracoronary insulin administered at reperfusion in a porcine model of acute coronary syndrome.

BACKGROUND: Experimental studies have demonstrated that insulin elicits cardioprotection in coronary occlusion-reperfusion models. We studied the effects of intracoronary insulin on regional cardiac function in a porcine model with reperfusion after a critical coronary artery stenosis. METHODS: In 20 anaesthetized pigs with an extracorporeal shunt from the brachiocephalic to the left anterior descending coronary artery, a fixed stenosis was applied, obtaining 50% reduction of shunt flow for 60 min. Intracoronary insulin 1 1U [DOSAGE ERROR CORRECTED] or 0.9% saline was infused for 15 min, starting 5 min prior to initiation of 180 min of reperfusion. Microsphere injections confirmed ischaemia and reperfusion. Epicardial echocardiographic multilayer radial tissue Doppler strain and strain rate and one-layer speckle-tracking strain evaluated myocardial function. Apoptosis was evaluated by cleaved caspase-3 activity. Area at risk and infarct size were determined with Evans Blue and triphenyltetrazolium chloride staining. RESULTS: In both groups, the area at risk constituted approximately 26% of the left ventricular mass. Minor areas of infarction were predominantly seen subendocardially, where tissue blood flow rate was severely reduced during stenosis. After 180 min of reperfusion, recovery of speckle-tracking circumferential strain averaged 57.5 ± 11.4% of baseline values in insulin treated animals compared to 22.3 ± 8.7% in controls (p = 0.025). Multilayer radial strain and strain rate did not differ between groups. Cleaved caspase-3 activity was most prominent in the subepicardial layer in the saline-treated group. CONCLUSIONS: Intracoronary insulin at the onset of reperfusion alleviated regional myocardial dysfunction in acute ischaemia-reperfusion and was associated with a reduction of apoptosis.

Exploring the human plasma proteome for humoral mediators of remote ischemic preconditioning--a word of caution.

Despite major advances in early revascularization techniques, cardiovascular diseases are still the leading cause of death worldwide, and myocardial infarctions contribute heavily to this. Over the past decades, it has become apparent that reperfusion of blood to a previously ischemic area of the heart causes damage in and of itself, and that this ischemia reperfusion induced injury can be reduced by up to 50% by mechanical manipulation of the blood flow to the heart. The recent discovery of remote ischemic preconditioning (RIPC) provides a non-invasive approach of inducing this cardioprotection at a distance. Finding its endogenous mediators and their operative mode is an important step toward increasing the ischemic tolerance. The release of humoral factor(s) upon RIPC was recently demonstrated and several candidate proteins were published as possible mediators of the cardioprotection. Before clinical applicability, these potential biomarkers and their efficiency must be validated, a task made challenging by the large heterogeneity in reported data and results. Here, in an attempt to reproduce and provide more experimental data on these mediators, we conducted an unbiased in-depth analysis of the human plasma proteome before and after RIPC. From the 68 protein markers reported in the literature, only 28 could be mapped to manually reviewed (Swiss-Prot) protein sequences. 23 of them were monitored in our untargeted experiment. However, their significant regulation could not be reproducibly estimated. In fact, among the 394 plasma proteins we accurately quantified, no significant regulation could be confidently and reproducibly assessed. This indicates that it is difficult to both monitor and reproduce published data from experiments exploring for RIPC induced plasma proteomic regulations, and suggests that further work should be directed towards small humoral factors. To simplify this task, we made our proteomic dataset available via ProteomeXchange, where scientists can mine for novel potential targets.

Influence of feeding and intracoronary dose on insulin-mediated relative akt phosphorylation in the porcine myocardium.

AIMS: Insulin promotes Akt-dependent prosurvival signaling and reduces experimental ischemia reperfusion injury, but its clinical impact has been limited. Further understanding of the interplay between insulin and Akt in the myocardium of relevant large animal models is needed. We aimed to investigate (1) Akt phosphorylation, (2) influence of feeding state, and (3) impact of dose on the Akt response following intracoronary insulin administration in the nonischemic porcine heart. METHODS: Pigs fed 2 h preprocedure received 0.1 U (unit) or 1.0 U of insulin in the left coronary artery and fasting pigs 0.1 U. Left and right ventricle tissues harvested 15 min postinsulin administration were analyzed for Akt phosphorylation by densitometric analyses of total Akt and phosphorylated Akt immunoblots expressed as a ratio and normalized against left auricle biopsies at baseline. RESULTS: Median relative Akt phosphorylation across all biopsy locations increased significantly from baseline in both fasting and fed animals after insulin infusion: 371.4% (P < 0.001) in the fasting-0.1 U insulin group, 202.7% (P = 0.003) in the fed-1.0 U group and 131.5% (P < 0.001) in the fed-0.1 U group. The increase was significantly higher for the fasting-0.1 U and the fed-1.0 U groups as compared with the fed-0.1 U group. Baseline serum glucose in fed and fasting pigs was 6.3 ± 0.3 versus 5.2 ± 0.4 mm (P = 0.050), respectively. CONCLUSIONS: Preexperimental feeding attenuates the median relative rise in Akt phosphorylation mediated by exogenous insulin in the porcine heart, and higher insulin doses are therefore required in fed compared with fasting animals.