[show abstract][hide abstract] ABSTRACT: Glucagon-like peptide 1 (GLP1) analogues are promising new treatment options for patients with type 2 diabetes, but may have both potentially beneficial and harmful cardiovascular effects. This may also be the case for the analogues of GLP1 for clinical use. The present study examined the effect of treatment with liraglutide, a long-acting GLP1 analogue, on myocardial ischemia and reperfusion in a porcine model.
Danish Landrace Pigs (70-80 kg) were randomly assigned to liraglutide (10 mug/kg) or control treatment given daily for three days before ischemia-reperfusion. Ischemia was induced by balloon occlusion of the left anterior descending artery for 40 minutes followed by 2.5 hours of reperfusion. The primary outcome parameter was infarct size in relation to the ischemic region at risk. Secondary endpoints were the hemodynamic parameters mean pulmonary pressure, cardiac output, pulmonary capillary wedge pressure as measured by a Swan-Ganz catheter as well as arterial pressure and heart rate.
The infarct size in relation to ischemic risk region in the control versus the liraglutide group did not differ significantly: 0.46 +/- 0.14 and 0.54 +/- 0.12) (mean and standard deviation (SD), p = 0.21). Heart rate was significantly higher in the liraglutide group during the experiment, while the other hemodynamic parameters did not differ significantly.
Liraglutide has a neutral effect on myocardial infarct size in a porcine ischemia-reperfusion model.
[show abstract][hide abstract] ABSTRACT: Levosimendan is a positive inotropic drug with vasodilator action and proposed myocardioprotective properties. In a canine model, levosimendan increased coronary collateral flow and reduced myocardial infarct size (IS). We investigated the effect of levosimendan on IS and hemodynamics in the closed-chest porcine ischemia-reperfusion model, which is devoid of coronary collaterals.
Infusion with levosimendan (0.2 microg/kg/min following a bolus of 24 microg/kg) or saline was initiated 30 min prior to ischemia in anaesthetized pigs (n = 10 in both groups). Balloon occlusion of the left anterior descending coronary artery for 45 min was followed by 2 1/2 h of reperfusion. Hemodynamics were monitored with a Swan-Ganz catheter and a left ventricular pressure micromanometer. Left ventricular systolic and diastolic function was estimated by dP/dt(max) and tau, respectively. Myocardial area at risk (AAR) and IS were assessed in vivo by myocardial perfusion imaging (MPI) and ex vivo by histopathology (fluorescein staining for AAR, tetrazolium staining for IS).
Prior to ischemia, levosimendan improved left ventricular systolic and diastolic function with coincident preload and afterload reduction. Cardiac output increased by 10 +/- 4% (p = 0.04), dP/dt(max) by 15 +/- 5% (p = 0.01). Pulmonary capillary wedge pressure decreased by 18 +/- 3% (p = 0.04), tau by 11 +/- 2% (p = 0.001), and mean arterial pressure by 11 +/- 2% (p < 0.001). A similar trend was observed during ischemia-reperfusion. The ratio of IS/AAR was not reduced by levosimendan compared to saline as evaluated by histopathology (76 +/- 4% vs. 64 +/- 7%, p = 0.12) and by MPI (94 +/- 2% vs. 87 +/- 5%, p = 0.14).
Levosimendan improves hemodynamics but does not reduce IS in an ischemia-reperfusion model without coronary collaterals.
Cardiovascular Drugs and Therapy 10/2006; 20(5):335-42. · 2.67 Impact Factor
[show abstract][hide abstract] ABSTRACT: ATP-sensitive potassium channels are opened during the course of ischemic preconditioning (IP). As experimental data suggest that opening of sarcolemmal ATP-sensitive potassium channels underlie ST elevation during myocardial ischemia, one would expect to observe increased ST elevation during ischemia following IP. However, clinical studies have reported IP to attenuate ST elevation during repeated brief coronary occlusions. The objective of this study was to characterize the temporal course of ST elevation during coronary occlusion following IP. Twenty-eight closed-chest pigs were subject to catheter-based left anterior descending coronary artery occlusion/ reperfusion for 45/120 minutes. Thirteen animals were preconditioned by two occlusion/reperfusion cycles of 10/30 minutes. Fifteen pigs served as controls. The electrocardiographic ST vector magnitude was continuously monitored. IP reduced the infarct size normalized for area at risk (IP 9.6 +/- 15.8%; control 71.2 +/- 14.7%; p < 0.001). IP increased the time between coronary artery occlusion and appearance of significant rise in ST vector magnitude from 51 +/- 17 to 94 +/- 33 seconds (p < 0.01). IP reduced the rise in ST vector magnitude after 120 seconds of occlusion from 202 +/- 85 microV to 68 +/- 28 microV (p < 0.001) and increased the rise in ST vector magnitude after 600 seconds from 265 +/- 106 microV to 427 +/- 232 microV (p < 0.001). CONCLUSION: Ischemic preconditioning reduced and delayed early ST elevation during subsequent coronary artery occlusion, but increased late ST elevation. Thus, ischemic preconditioning causes a dynamic and critically time-dependent biphasic pattern of ST elevation during repeated coronary occlusions.
Archiv für Kreislaufforschung 03/2006; 101(2):140-8. · 5.90 Impact Factor
[show abstract][hide abstract] ABSTRACT: The oral hypoglycaemic sulphonylurea glibenclamide stimulates endogenous insulin secretion through blockade of ATP-sensitive potassium (KATP) channels on pancreatic beta cells, but also blocks cardiovascular KATP channels, leading to increased peripheral vascular resistance and reduced peripheral blood flow in non-diabetic subjects. Therefore, this study examined whether a single oral dose of glibenclamide adversely affected the pain-free or maximal walking distance in patients with intermittent claudication.
In a double-blind, randomized crossover study, 12 non-diabetic patients with intermittent claudication were given a single oral dose of glibenclamide (5.25 mg) or placebo separated by a washout period of 1 week. A treadmill test was carried out 180 min after glibenclamide/placebo intake for determination of pain-free and maximal walking distance. Plasma glucose concentrations were kept constant by an euglycemic clamp. Changes in ankle/brachial blood pressure index (ABI), serum insulin, and serum glibenclamide were also assessed.
The pain-free walking distance was 62.8 +/- 9.8 metres (mean +/- sem) after glibenclamide and 52.6 +/- 5.9 metres after placebo (P = 0.52). The maximal walking distance was 142.7 +/- 18.7 metres after glibenclamide and 132.6 +/- 16.6 metres after placebo (P = 0.23). The ABI was not significantly changed by glibenclamide compared with placebo. Serum glibenclamide was 0.51 +/- 0.08 microm 180 min after administration of the drug. Glibenclamide produced an 8-fold increase in circulating insulin compared with placebo (P < 0.001).
Glibenclamide given as a single oral dose commonly used in glucose-lowering drug therapy does not reduce pain-free or maximal walking distance in non-diabetic patients with intermittent claudication.
Diabetic Medicine 03/2006; 23(3):327-30. · 3.24 Impact Factor
[show abstract][hide abstract] ABSTRACT: We previously described a method for regional myocardial cooling that reaches the target temperature within 4 min. The present study evaluated whether this method for regional myocardial cooling during reperfusion reduces myocardial infarct size (IS) in 75-kg pigs. Myocardial infarction was induced by inflation of an angioplasty balloon in the left anterior descendent artery for 45 min followed by 3 h reperfusion. First, 15 pigs were randomized to regional myocardial cooling during reperfusion (n = 8) or control (n = 7). As further control experiments, systemic hypothermia was induced prior to ischemia (n = 3) and during reperfusion (n = 3). IS and area at risk (AAR) were evaluated in vivo by single photon emission cardiac tomography (SPECT) and by standard histochemical staining. Regional cooling during reperfusion did not reduce IS/AAR as assessed by histochemistry (cooling: 0.71 +/- 0.8; control: 0.68 +/- 0.10; p = ns) and SPECT (cooling: 0.90 +/- 0.20; control: 0.88 +/- 0.32; p = ns). Systemic hypothermia during ischemia reduced IS/AAR (histochemistry: 0.09 +/- 0.11; SPECT: 0.25 +/- 0.22; p < 0.001 and p = 0.01 vs control, respectively). Induction of systemic hypothermia during reperfusion had no significant effect on IS/AAR (histochemistry: 0.63 +/- 0.07; SPECT: 0.74 +/- 0.09; p = ns vs control for both comparisons). In conclusion, hypothermia during ischemia is strongly myocardioprotective while hypothermia during reperfusion does not reduce myocardial infarct size in human-sized pigs.
Archiv für Kreislaufforschung 01/2006; 101(1):61-8. · 5.90 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recombinant human erythropoietin (rhEPO) has been proposed to possess important tissue protective, apart from haematopoietic, effects. Cardioprotective effects have thus been reported in rodents exposed to myocardial ischaemia. Pathways common to the mediation of ischaemic preconditioning may be involved. Before clinical testing such possible cardioprotective effects needs assessment in an experimental large animal model with closer similarity to human ischaemic pathophysiology.
A control group and two rhEPO groups were studied. EPO1 pigs were given EPO corresponding to the early window and EPO2 pigs to the early and late window of ischaemic preconditioning in a closed chest, catheter-based, porcine coronary occlusion model (45 min of occlusion of the left anterior descending artery). Infarct size as a proportion of the ischaemic area (IS/AAR) was measured in vivo by myocardial perfusion imaging (MPI) and postmortem by a histochemical procedure (at 150 min of reperfusion).
IS/AAR did not differ significantly between control (C), EPO1 and EPO2 groups, neither measured by MPI (mean+/-SD for C: 0.87+/-0.13; EPO1: 0.92+/-0.08; EPO2: 0.87+/-0.11), nor histochemically (mean+/-SD for C: 0.64+/-0.20; EPO1: 0.75+/-0.17; EPO2: 0.80+/-0.07). In the EPO2 group mean arterial pulmonary pressure and dP/dtmax were increased compared with control group.
Despite promising results from studies in rodents, rhEPO did not reduce infarct size measured after 2.5 h of reperfusion in our porcine model.
[show abstract][hide abstract] ABSTRACT: Previous experimental studies indicate that glutamine or glutamate may provide cardioprotection by improving the oxidative metabolism in myocardial ischemia. We investigated the effect of glutamine or glutamate, given during reperfusion, on resulting infarct size and hemodynamic recovery.
A porcine coronary occlusion model was applied. Infusions were initiated 15 min before reperfusion and supplemented with intracoronary bolus doses at reperfusion. The primary outcome measure was infarct size in relation to area at risk determined by a standard tissue staining procedure. Secondary outcome measures were the hemodynamic variables.
The infarct sizes as a proportion of the area at risk (mean+/-SD) were: control group, 0.64 +/- 0.19 (n = 9); glutamine group, 0.87 +/- 0.07 (p < 0.05 vs control group) (n = 8); glutamate group, 0.72 +/- 0.11 (n = 9). Glutamine increased systemic vascular resistance, while glutamate preserved cardiac output during infusion.
Substrate supplementation with the anaplerotic precursors glutamine and glutamate is ineffective as adjunctive therapy for severe myocardial ischemia. Beneficial effects documented in less complex experimental systems could not be transferred to a more pathophysiological relevant model.
[show abstract][hide abstract] ABSTRACT: We report of two patients with severe ketoacidosis, minute elevations of myocardial biomarkers (troponin T and CK-MB) and initial ECG changes compatible with myocardial infarction (MI). All successive investigations, including coronary arteriography, were normal, and the patients recovered fully without further evidence of ischemic heart disease. We suggest that acidosis and very high levels of free fatty acids could cause membrane instability and biomarker leakage. Regardless of the pathogenesis, these two case stories suggest that nonspecific myocardial injury may occur in severe diabetic ketoacidosis and that the presence of minute biomarker elevation and ECG changes does not necessarily signify MI.
Journal of Diabetes and its Complications 01/2005; 19(6):361-3. · 2.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: Reliable methods for assessment of tissue reperfusion early after revascularizing therapy for acute myocardial infarction are needed. Myocardial perfusion imaging with Tc sestamibi (MIBI MPI) may serve this purpose. Usage during early reperfusion may be problematic e.g. due to ischaemic preconditioning (IP), which is important in inducing ischaemic tolerance. It is mediated through the opening of mitochondrial K ATP channels, reducing mitochondrial membrane potential. This may, as well as ischaemia per se, affect cellular uptake of Tc sestamibi. We therefore studied the reliability of MIBI MPI during early reperfusion as a measure of infarct size and its reduction by ischaemic preconditioning.
We compared MIBI MPI (cut-off, 45% of maximum pixel count) with a histochemical method in a porcine model, nine controls and eight IP pigs, using 45 min catheter based coronary occlusion of the left anterior descending artery. Infarct size (IS) was determined relative to the area at risk (AAR). The relative infarct size (IS/AAR) after 120 min reperfusion estimated by MPI was 0.83 (0.17) in controls vs 0.07 (0.12) in the IP group (mean (SD), P<0.001). The corresponding values for histochemistry were controls 0.77 (0.19) vs IP 0.07 (0.11), P<0.001. IS/AAR measured by MPI and histochemistry were correlated significantly (r=0.93, P<0.001). Furthermore, IS relative to left ventricular mass (IS/LV) determined by autoradiography and histochemistry correlated (r=0.93, P<0.001). MPI overestimated IS/LV and AAR/LV by approximately a factor of 2 compared with histochemistry or autoradiography.
MIBI MPI during early reperfusion is a reliable measure of relative infarct size reduction after ischaemic preconditioning, supporting use for stratification for adjunctive therapy and for assessment of prognosis.
Nuclear Medicine Communications 06/2004; 25(5):495-500. · 1.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: Whole body hypothermia has been suggested to reduce myocardial injury in patients with ST-segment elevation myocardial infarction. Because of the large human thermal mass, induction of generalized hypothermia is slow and the technique has encountered considerable side effects. The aim was to develop and validate a method for regional cooling during myocardial reperfusion using hypothermic autologous blood.
In a myocardial ischemia-reperfusion pig model (n = 10), arterial blood was cooled in a closed circuit, and returned to the myocardium during reperfusion either through a perfusion catheter or through the guiding catheter. Myocardial temperatures were recorded using temperature electrodes.
Stabile regional myocardial cooling was induced without complications within 4 min. Both flow rate and blood temperature had significant impact on temperature in the reperfused myocardium but did not influence systemic temperature.
A method for organ specific hypothermic autologous arterial blood reperfusion has been developed and validated. The method is a simple and much faster alternative to systemic cooling and may have the potential to reduce myocardial injury in patients with acute myocardial infarction.
[show abstract][hide abstract] ABSTRACT: A reduced coronary flow reserve is considered indicative of significant coronary stenosis. As experimental data suggest that adenosine and dipyridamole induce vasodilatation by opening of ATP-sensitive potassium channels, we sought to determine the effect of glibenclamide, an antidiabetic blocker of ATP-sensitive potassium channels, on adenosine- and dipyridamole-induced coronary flow reserve.
Coronary flow velocities were measured in 15 pigs using a Doppler flow wire. The effect of increasing glibenclamide concentrations (0.1-10 microM) on adenosine-induced coronary flow reserve was examined in five animals. Ten pigs served as time controls. The time controls were subsequently treated by 3 microM glibenclamide (n = 5) or corresponding vehicle (n = 5) and the flow response to 0.56 mg/kg dipyridamole determined.
Glibenclamide elicited a concentration-dependent inhibition of adenosine-induced coronary flow reserve, reaching significance at glibenclamide concentrations of 3 and 10 microM. The coronary flow reserve stimulated by dipyridamole was reduced significantly by 3 microM glibenclamide.
Glibenclamide blunts coronary flow reserve stimulated by adenosine and dipyridamole. This interaction may have clinical implications in diabetics undergoing adenosine- or dipyridamole-dependent diagnostic procedures.
[show abstract][hide abstract] ABSTRACT: Ischaemic preconditioning (IP) is a strong endogenous infarct reducing stimulus which has not previously been evaluated with myocardial perfusion imaging using 99mTc-MIBI. Factors responsible for cellular MIBI uptake are affected by both IP and acute ischaemia (plasma membrane and mitochondrial membrane potential and oxidative metabolism). IP seems to involve mitochondrial K-ATP channels affecting mitochondrial membrane potential and thereby potentially MIBI uptake. The study evaluated the performance of MPI with MIBI as a tracer to characterise the extent that severely ischaemic compromised myocardium was salvaged by IP. In a closed chest model, an ischaemic preconditioned group (8 pigs) subjected to IP before introducing a 45 min period of catheter based coronary occlusion was compared with a control group (9 pigs). Area at risk'(AAR), infarct size (IS) and IS relative to AAR was determined by MIBI SPECT and by a standard histochemical method. The results demonstrated that infarct size was significantly smaller in the IP group both relative to left ventricle (IS/LV) and to area at risk (IS/AAR). Both AAR/LV and IS/LV, however, were greater when measured by MPI than with histochemistry. There was no difference in the ratio between infarct size and area at risk (IS/AAR). In conclusion, MPI with MIBI is a reliable measurement of infarct reduction by ischaemic preconditioning. Myocardium affected by recent ischaemia is correctly distinguished as viable by MPI in early reperfusion, when compared to a standard histochemical technique.
[show abstract][hide abstract] ABSTRACT: Spontaneous dissection of the coronary artery is a rare cause of sudden death and myocardial infarction. We report three cases in women aged 32, 38, and 55 years. One patient was one week post partum. In one case all three coronary arteries were involved. Two patients underwent coronary artery bypass grafting and one died of acute heart failure. The epidemiology, aetiology, and clinical manifestations are briefly described. We suggest that coronary angiography should be considered in young women with acute myocardial infarction and few risk factors of atherosclerosis.