| 1. |
- Axelsson, Birger, 1957-, et al.
(författare)
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Effects of Combined Milrinone and Levosimendan Treatment on Systolic and Diastolic Function During Postischemic Myocardial Dysfunction in a Porcine Model
- 2016
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Ingår i: Journal of Cardiovascular Pharmacology and Therapeutics. - Thousand Oaks, USA : Sage Publications. - 1074-2484 .- 1940-4034. ; 21:5, s. 495-503
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Tidskriftsartikel (refereegranskat)abstract
- It is not known whether there are positive or negative interactions on ventricular function when a calcium-sensitizing inotrope is added to a phosphodiesterase inhibitor in the clinical setting of acute left ventricular (LV) dysfunction. We hypothesized that when levosimendan is added to milrinone treatment, there will be synergetic inotropic and lusitropic effects. This was tested in an anesthetized porcine postischemic global LV injury model, where ventricular pressures and volumes (conductance volumetry) were measured. A global ischemic injury was induced by repetitive left main stem coronary artery occlusions. Load-independent indices of LV function were assessed before and after ventricular injury, after milrinone treatment, and finally after addition of levosimendan to the milrinone treatment. Nonparametric, within-group comparisons were made. The protocol was completed in 12 pigs, 7 of which received the inotrope treatment and 5 of which served as controls. Milrinone led to positive lusitropic effects seen by improvement in tau after myocardial stunning. The addition of levosimendan to milrinone further increased lusitropic state. The latter effect could however not be attributed solely to levosimendan, since lusitropic state also improved spontaneously in time-matched controls at the same rate during the corresponding period. When levosimendan was added to milrinone infusion, there was no increase in systolic function (preload recruitable stroke work) compared to milrinone treatment alone. We conclude that in this model of postischemic LV dysfunction, there appears to be no clear improvement in systolic or diastolic function after addition of levosimendan to established milrinone treatment but also no negative effects of levosimendan in this context.
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| 2. |
- Hennekens, C. H., et al.
(författare)
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The CHARM program: study design leads to findings of clinical and public health importance
- 2007
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Ingår i: J Cardiovasc Pharmacol Ther. - : SAGE Publications. - 1074-2484. ; 12:2, s. 124-6
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Tidskriftsartikel (refereegranskat)abstract
- In large-scale randomized trials and their meta-analyses, beta-adrenergic blockers and angiotensin-converting enzyme inhibitors provide statistically significant and clinically important additive mortality and morbidity benefits in the treatment of heart failure. The CHARM trials were designed to test whether the angiotensin-receptor blocker candesartan would provide statistically significant and clinically important additive mortality and morbidity benefits to patients with heart failure as an alternative or in addition to angiotensin-converting enzyme inhibitors. CHARM demonstrated that an angiotensin-receptor blocker at a proven dose is an effective and safe therapy as an alternative or in addition to angiotensin-converting enzyme inhibitors in patients with heart failure, 55% of whom were receiving beta-adrenergic blockers. These benefits include reductions in cardiovascular mortality rate as well as in hospitalization for heart failure. Such patients have a 50% mortality rate at 5 years, and heart failure is the leading cause of hospitalization for patients 65 years of age and older.
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| 3. |
- Karlsson, Lars O, 1975, et al.
(författare)
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Cyclosporine A, 2.5 mg/kg, Does Not Reduce Myocardial Infarct Size in a Porcine Model of Ischemia and Reperfusion
- 2012
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Ingår i: Journal of cardiovascular pharmacology and therapeutics. - : SAGE Publications. - 1940-4034 .- 1074-2484. ; 17:2, s. 159-63
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In recent years, cyclosporine A (CsA) has emerged as a promising therapy to limit myocardial ischemic-reperfusion injury, presumably by inhibiting the opening of the mitochondrial permeability transition pore. Results from different large animal models are conflicting, however, with failure to prove beneficial effects of 10 mg/kg CsA administered at reperfusion. Recently, a small clinical study using a bolus of 2.5 mg/kg CsA showed promising but not unequivocal results. The aim of the present study was to estimate the magnitude of a possible infarct reduction with the use of the latter regimen in a closed-chest porcine model for ischemia and reperfusion. Materials and METHODS: Pigs underwent catheterization with balloon occlusion of the left descending coronary artery for 40 minutes, followed by reperfusion for 4 hours. They were randomized to receive an intravenous bolus 7 minutes before reperfusion of either 2.5 mg/kg CsA (n = 12) or saline (control, n = 11). Hearts were stained to quantify area at risk and infarct size. RESULTS: Throughout the experiment, there were no differences between the groups in baseline characteristics or hemodynamic variables. CsA treatment did not reduce infarct size as a proportion of area at risk compared with control (51% +/- 6% and 54% +/- 6%, respectively, P = .75). CONCLUSION: In a closed-chest porcine model for myocardial ischemia and reperfusion injury, 2.5 mg/kg CsA administered before reperfusion did not reduce infarct size.
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| 4. |
- Karlsson, Lars O., et al.
(författare)
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Cyclosporine does not reduce myocardial infarct size in a porcine ischemia-reperfusion model.
- 2010
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Ingår i: Journal of Cardiovascular Pharmacology and Therapeutics. - : Sage Publications. - 1074-2484 .- 1940-4034. ; 15:2, s. 182-9
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Tidskriftsartikel (refereegranskat)abstract
- Cyclosporine A (CsA) has been shown to protect against myocardial ischemia and reperfusion (I/R) injury in small animal models. The aim of the current study was to evaluate the effects of CsA on myocardial I/R injury in a porcine model. Pigs were randomized between CsA (10mg/kg; n = 12) or placebo (n = 15) and anesthetized with either isoflurane (phase I) or pentobarbital (phase II). By catheterization, the left descending coronary artery was occluded for 45 minutes, followed by reperfusion for 2 hours. Hearts were stained to quantify area at risk (AAR) and infarct size (IS). Myocardial biopsies were obtained for terminal dUTP nick end labeling and immunoblot analysis of proapoptotic proteins (apoptosis-inducing factor [AIF], BCL2/adenovirus E1B 19-kd interacting protein 3 [BNIP-3], and active caspase-3). Cyclosporine A did not reduce IS/AAR compared with placebo (49% vs 41%, respectively; P = .21). Pigs anesthetized with isoflurane had lower IS/AAR than pigs anesthetized with pentobarbital (39% vs 51%, respectively; P = .03). This reduction in IS/AAR seemed to be attenuated by CsA. Apoptosis-inducing factor protein expression was higher after CsA administration than after placebo (P = .02). Thus, CsA did not protect against I/R injury in this porcine model. The data suggest a possible deleterious interaction of CsA and isoflurane.
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| 5. |
- Muessig, JM, et al.
(författare)
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A Model of Blood Component-Heart Interaction in Cardiac Ischemia-Reperfusion Injury using a Langendorff-Based Ex Vivo Assay
- 2020
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Ingår i: Journal of cardiovascular pharmacology and therapeutics. - : SAGE Publications. - 1940-4034 .- 1074-2484. ; 25:2, s. 164-173
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Tidskriftsartikel (refereegranskat)abstract
- Myocardial infarction is one of the leading causes of morbidity and mortality worldwide. Cellular interactions of red blood cells (RBCs) and platelets with endothelial cells and cardiomyocytes play a crucial role in cardiac ischemia/reperfusion (I/R) injury. However, addressing the specific impact of such cell-to-cell interactions in commonly employed in vivo models of cardiac I/R injury is challenging due to overlap of neuronal, hormonal, and immunological pathways. This study aimed to refine a Langendorff-based ex vivo transfer model to evaluate the impact of specific blood components on cardiac I/R injury. Material and methods: Murine whole blood, defined murine blood components (RBCs, platelet-rich plasma [PRP], and platelet-poor plasma [PPP], respectively) as well as human RBCs were loaded to the coronary system of isolated murine hearts in a Langendorff system before initiating global ischemia for 40 minutes. Following 60 minutes of reperfusion with Krebs Henseleit Buffer, left ventricular function and coronary flow were assessed. Infarct size was determined by specific histological staining following 120 minutes of reperfusion. Results: Loading of murine whole blood to the coronary system of isolated murine hearts at the beginning of 40 minutes of global ischemia improved left ventricular function after 60 minutes of reperfusion and reduced the infarct size in comparison to buffer-treated controls. Similarly, isolated murine RBCs, PRP, and PPP mediated a protective effect in the cardiac I/R model. Furthermore, human RBCs showed a comparable protective capacity as murine RBCs. Conclusion: This Langendorff-based transfer model of cardiac I/R injury is a feasible, time-, and cost-effective model to evaluate the impact of blood components on myocardial infarction. The presented method facilitates loading of blood components of genetically modified mice to murine hearts of a different mouse strain, thus complementing time- and cost-intensive chimeric models and contributing to the development of novel targeted therapies.
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| 6. |
- Verouhis, D, et al.
(författare)
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Ticagrelor Does Not Protect Against Endothelial Ischemia-Reperfusion Injury in Patients With Coronary Artery Disease
- 2021
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Ingår i: Journal of cardiovascular pharmacology and therapeutics. - : SAGE Publications. - 1940-4034 .- 1074-2484. ; 26:3, s. 253-259
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Tidskriftsartikel (refereegranskat)abstract
- Ticagrelor is a recommended P2Y12 receptor inhibitor after acute coronary syndrome (ACS). Its superiority has been suggested to rely on pleiotropic effects beyond platelet inhibition. Experimental studies indicate that ticagrelor may protect from ischemia-reperfusion injury but no data are available from such studies on patients. This study aimed to determine if chronic ticagrelor treatment protects against endothelial ischemia-reperfusion injury in patients with a previous ACS. Methods: Patients with a previous ACS were studied with flow mediated dilatation of the left brachial artery to determine the degree of endothelial ischemia-reperfusion injury before and after discontinuation of ticagrelor treatment, which had been continuous since 1 year. Each patient underwent 3 identical examinations. The first examination (Visit A) was at the end of ticagrelor treatment and the following 2 (Visit B and C) were after cessation of this treatment with an interval of 2 to 4 weeks. Results: Ischemia and reperfusion induced significant impairment of endothelial function at all 3 occasions (absolute decline in flow mediated dilatation 3.0% ± 0.7 at Visit A ( P < 0.001), 1.9% ± 0.9 at Visit B ( P < 0.05) and 1.9% ± 0.4 at Visit C ( P < 0.0001)). However, there was no difference in the degree of endothelial ischemia-reperfusion injury or baseline endothelial function between the visits. Conclusion: Chronic ticagrelor treatment in patients 1 year after an ACS does not protect against endothelial ischaemia-reperfusion injury. Nor is it associated with better basal endothelial function compared to after discontinuation of treatment.
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