Endothelin-B Receptors and Left Ventricular Dysfunction after Regional versus Global Ischaemia-Reperfusion in Rat Hearts

Background. Endothelin-1 (ET-1) is implicated in left ventricular dysfunction after ischaemia-reperfusion. ETA and ETB receptors mediate diverse actions, but it is unknown whether these actions depend on ischaemia type and duration. We investigated the role of ETB receptors after four ischaemia-reperfusion protocols in isolated rat hearts. Methods. Left ventricular haemodynamic variables were measured in the Langendorff-perfused model after 40-and 20-minute regional or global ischaemia, followed by 30-minute reperfusion. Wild-type (n = 39) and ETB-deficient (n = 41) rats were compared. Infarct size was measured using fluorescent microspheres after regional ischaemia-reperfusion. Results. Left ventricular dysfunction was more prominent in ETBdeficient rats, particularly after regional ischaemia. Infarct size was smaller (P = 0.006) in wild-type (31.5 ± 4.4%) than ETBdeficient (45.0 ± 7.3%) rats after 40 minutes of regional ischaemia-reperfusion. Although the recovery of left ventricular function was poorer after 40-minute ischaemia-reperfusion, end-diastolic pressure in ETB-deficient rats was higher after 20 than after 40 minutes of regional ischaemia-reperfusion. Conclusion. ETB receptors exert cytoprotective effects in the rat heart, mainly after regional ischaemia-reperfusion. Longer periods of ischaemia suppress the recovery of left ventricular function after reperfusion, but the role of ETB receptors may be more important during the early phases

Endothelin-B Receptors and Left Ventricular Dysfunction after Regional versus Global Ischaemia-Reperfusion in Rat Hearts

Background. Endothelin-1 (ET-1) is implicated in left ventricular dysfunction after ischaemia-reperfusion. ETA and ETB receptors mediate diverse actions, but it is unknown whether these actions depend on ischaemia type and duration. We investigated the role of ETB receptors after four ischaemia-reperfusion protocols in isolated rat hearts. Methods. Left ventricular haemodynamic variables were measured in the Langendorff-perfused model after 40- and 20-minute regional or global ischaemia, followed by 30-minute reperfusion. Wild-type (n=39) and ETB-deficient (n=41) rats were compared. Infarct size was measured using fluorescent microspheres after regional ischaemia-reperfusion. Results. Left ventricular dysfunction was more prominent in ETB-deficient rats, particularly after regional ischaemia. Infarct size was smaller (P=0.006) in wild-type (31.5±4.4%) than ETB-deficient (45.0±7.3%) rats after 40 minutes of regional ischaemia-reperfusion. Although the recovery of left ventricular function was poorer after 40-minute ischaemia-reperfusion, end-diastolic pressure in ETB-deficient rats was higher after 20 than after 40 minutes of regional ischaemia-reperfusion. Conclusion. ETB receptors exert cytoprotective effects in the rat heart, mainly after regional ischaemia-reperfusion. Longer periods of ischaemia suppress the recovery of left ventricular function after reperfusion, but the role of ETB receptors may be more important during the early phases

Medium-term Electrophysiologic Effects of a Cellularized Scaffold Implanted in Rats After Myocardial Infarction

Background Cardiac repair strategies are being evaluated for myocardial infarctions, but the safety issues regarding their arrhythmogenic potential remain unresolved. By utilizing the in-vivo rat model, we have examined the medium-term electrophysiologic effects of a biomaterial scaffold that has been cellularized with spheroids of human adipose tissue, derived from mesenchymal stem cells and umbilical vein endothelial cells. Methods Mesenchymal stem cells, which exhibit adequate differentiation capacity, were co-cultured with umbilical vein endothelial cells and were seeded on an alginate based scaffold. After in-vitro characterization, the cellularized scaffold was implanted in (n=15) adult Wistar rats 15 min post ligation of the left coronary artery, with an equal number of animals serving as controls. Two weeks thereafter, monophasic action potentials were recorded and activation-mapping was performed with a multi-electrode array. An arrhythmia score for inducible ventricular tachyarrhythmias was calculated after programmed electrical stimulation. Results The arrhythmia score was comparable between the treated animals and controls. No differences were detected in the local conduction at the infarct border and in the voltage rise in monophasic action potential recordings. Treatment did not affect the duration of local repolarization, but tended to enhance its dispersion. Conclusions The fabricated bi-culture cellularized scaffold displayed favorable properties after in-vitro characterization. Medium-term electrophysiologic assessment after implantation in the infarcted rat myocardium revealed low arrhythmogenic potential, but the long-term effects on repolarization dispersion will require further investigation

Prolonged intra-myocardial growth hormone administration ameliorates post-infarction electrophysiologic remodeling in rats.

Experimental studies indicate improved ventricular function after treatment with growth hormone (GH) post-myocardial infarction, but its effect on arrhythmogenesis is unknown. Here, we assessed the medium-term electrophysiologic remodeling after intra-myocardial GH administration in (n = 33) rats. GH was released from an alginate scaffold, injected around the ischemic myocardium after coronary ligation. Two weeks thereafter, ventricular tachyarrhythmias were induced by programmed electrical stimulation. Monophasic action potentials were recorded from the infarct border, coupled with evaluation of electrical conduction and repolarization from a multi-electrode array. The arrhythmia score was lower in GH-treated rats than in alginate-treated rats or controls. The shape and the duration of the action potential at the infarct border were preserved, and repolarization-dispersion was attenuated after GH; moreover, voltage rise was higher and activation delay was shorter. GH normalized also right ventricular parameters. Intra-myocardial GH preserved electrical conduction and repolarization-dispersion at the infarct border and decreased the incidence of induced tachyarrhythmias in rats post-ligation. The long-term antiarrhythmic potential of GH merits further study

Attenuation of post-infarction remodeling in rats by sustained myocardial growth hormone administration

Prevention of left ventricular remodeling is an important therapeutic target post-myocardial infarction. Experimentally, treatment with growth hormone (GH) is beneficial, but sustained local administration has not been thoroughly investigated. We studied 58 rats (322 +/- 4 g). GH was administered via a biomaterial-scaffold, following in vitro and in vivo evaluation of degradation and drug-release curves. Treatment consisted of intra-myocardial injection of saline or alginate-hydrogel, with or without GH, 10 min after permanent coronary artery ligation. Echocardiographic and histologic remodeling-indices were examined 3 weeks post-ligation, followed by immunohistochemical evaluation of angiogenesis, collagen, macrophages and myofibroblasts. GH-release completed at 3 days and alginate-degradation at similar to 7 days. Alginate + GH consistently improved left ventricular end-diastolic and end-systolic diameters, ventricular sphericity, wall tension index and infarct-thickness. Microvascular-density and myofibroblast-count in the infarct and peri-infarct areas were higher after alginate + GH. Macrophage-count and collagen-content did not differ between groups. Early, sustained GH-administration enhances angiogenesis and myofibroblast-activation and ameliorates post-infarction remodeling