Abstract
Prognosis of patients with myocardial infarction is detrimentally affected by comorbidities like diabetes mellitus. In the experimental setting, not only diabetes mellitus but also acute hyperglycemia is shown to hamper cardioprotective properties by multiple pharmacological agents. For Levosimendan-induced postconditioning, a strong infarct size reducing effect is demonstrated in healthy myocardium. However, acute hyperglycemia is suggested to block this protective effect. In the present study, we investigated whether (1) Levosimendan-induced postconditioning exerts a concentration-dependent effect under hyperglycemic conditions and (2) whether a combination with the mitochondrial permeability transition pore (mPTP) blocker cyclosporine A (CsA) restores the cardioprotective properties of Levosimendan under hyperglycemia. For this experimental investigation, hearts of male Wistar rats were randomized and mounted onto a Langendorff system, perfused with Krebs-Henseleit buffer with a constant pressure of 80 mmHg. All isolated hearts were subjected to 33 min of global ischemia and 60 min of reperfusion under hyperglycemic conditions. (1) Hearts were perfused with various concentrations of Levosimendan (Lev) (0.3–10 μM) for 10 min at the onset of reperfusion, in order to investigate a concentration–response relationship. In the second set of experiments (2), 0.3 μM Levosimendan was administered in combination with the mPTP blocker CsA, to elucidate the underlying mechanism of blocked cardioprotection under hyperglycemia. Infarct size was determined by tetrazolium chloride (TTC) staining. (1) Control (Con) hearts showed an infarct size of 52 ± 12%. None of the administered Levosimendan concentrations reduced the infarct size (Lev0.3: 49 ± 9%; Lev1: 57 ± 9%; Lev3: 47 ± 11%; Lev10: 50 ± 7%; all ns vs. Con). (2) Infarct size of Con and Lev0.3 hearts were 53 ± 4% and 56 ± 2%, respectively. CsA alone had no effect on infarct size (CsA: 50 ± 10%; ns vs. Con). The combination of Lev0.3 and CsA (Lev0.3 ± CsA) induced a significant infarct size reduction compared to Lev0.3 (Lev0.3+CsA: 35 ± 4%; p < 0.05 vs. Lev0.3). We demonstrated that (1) hyperglycemia blocks the infarct size reducing effects of Levosimendan-induced postconditioning and cannot be overcome by an increased concentration. (2) Furthermore, cardioprotection under hyperglycemia can be restored by combining Levosimendan and the mPTP blocker CsA.
Highlights
Myocardial infarction (MI) usually presents as an unforeseeable event that is still associated with high rates of mortality and morbidity [1,2]
We focused on the influence of hyperglycemia on postconditioning with Levosimendan and whether increased concentrations or combined inhibition of mitochondrial permeability transition pore (mPTP) could overcome a potential loss of cardioprotection
While our results showed a significant infarct size reduction by combining Levosimendan and cyclosporine A (CsA) under acute hyperglycemia, no hemodynamic improvement was detected during reperfusion, as compared to the other study groups
Summary
Myocardial infarction (MI) usually presents as an unforeseeable event that is still associated with high rates of mortality and morbidity [1,2]. Even after survival of MI, patients are faced with a substantial risk of subsequent cardiovascular events, including sudden cardiac arrest or heart failure [3]. Prognosis after suffering from MI widely varies among patients and is immensely affected by comorbidities like hypertension or diabetes [4,5]. Hyperglycemia seems to be an independent outcome-related risk factor for MI in patients with or without diabetes [6,7,8]. Restoration of coronary blood circulation is essential for all patients suffering from. MI [9]; the paradoxically occurring ischemia-reperfusion (I/R) injury hampers the benefits of reperfusion. I/R injury is characterized as additional cell damage and death caused by restored blood supply to an ischemic organ or tissue, like the myocardium [10]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have