Abstract
BackgroundClassical and delayed preconditioning are powerful endogenous protection mechanisms against ischemia-reperfusion damage. However, it is still uncertain whether delayed preconditioning can effectively salvage myocardium in patients with co-morbidities, such as diabetes and the metabolic syndrome. We investigated delayed preconditioning in mice models of type II diabetes and the metabolic syndrome and investigated interventions to optimize the preconditioning potential.MethodsHypoxic preconditioning was induced in C57Bl6-mice (WT), leptin deficient ob/ob (model for type II diabetes) and double knock-out (DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome). Twenty-four hours later, 30 min of regional ischemia was followed by 60 min reperfusion. Left ventricular contractility and infarct size were studied. The effect of 12 weeks food restriction or angiotensin-converting enzyme inhibition (ACE-I) on this was investigated. Differences between groups were analyzed for statistical significance by student’s t-test or one-way ANOVA followed by a Fisher’s LSD post hoc test. Factorial ANOVA was used to determine the interaction term between preconditioning and treatments, followed by a Fisher’s LSD post hoc test. Two-way ANOVA was used to determine the relationship between infarct size and contractility (PRSW). A value of p<0.05 was considered significant.ResultsLeft ventricular contractility is reduced in ob/ob compared with WT and even further reduced in DKO. ACE-I improved contractility in ob/ob and DKO mice. After ischemia/reperfusion without preconditioning, infarct size was larger in DKO and ob/ob versus WT. Hypoxic preconditioning induced a strong protection in WT and a partial protection in ob/ob mice. The preconditioning potential was lost in DKO. Twelve weeks of food restriction or ACE-I restored the preconditioning potential in DKO and improved it in ob/ob.ConclusionDelayed preconditioning is restored by food restriction and ACE-I in case of type II diabetes and the metabolic syndrome.
Highlights
Classical and delayed preconditioning are powerful endogenous protection mechanisms against ischemia-reperfusion damage
Effect of preconditioning in untreated mice Preconditioning without subsequent ischemia, was investigated in wild type (WT) (n=8 sham preconditioned; n=8 sham non-preconditioned) and double knock-out (DKO) (n=7 sham preconditioned; n=7 sham non-preconditioned) mice
Hypoxic preconditioning induces a strong protection in WT and a partial protection in ob/ob mice
Summary
Classical and delayed preconditioning are powerful endogenous protection mechanisms against ischemia-reperfusion damage It is still uncertain whether delayed preconditioning can effectively salvage myocardium in patients with co-morbidities, such as diabetes and the metabolic syndrome. The stimulus to induce preconditioning, such as repeated temporary coronary occlusion or aortic cross-clamping, can be harmful itself and prolongs the procedure It was further debated whether standard maneuvers, such as cardiopulmonary bypass during cardiac surgery, themselves precondition the patient [4]. Another important issue in this failure, is the uncertainty whether this technique can effectively salvage myocardium in patients with co-morbidities, such as type 2 diabetes (T2D) or the metabolic syndrome (MS), that are frequent in the intended patient population [1,5]
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