The Experts below are selected from a list of 48 Experts worldwide ranked by ideXlab platform
David J. Chambers - One of the best experts on this subject based on the ideXlab platform.
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esmolol cardioplegia the cellular mechanism of diastolic arrest
Cardiovascular Research, 2010Co-Authors: Hazem B Fallouh, Sonya C Bardswell, David J. Chambers, Linda M Mclatchie, Michael J Shattock, Jonathan C KentishAbstract:Aims Esmolol, an ultra-short-acting β-blocker, acts as a Cardioplegic Agent at millimolar concentrations. We investigated the mechanism by which esmolol induces diastolic ventricular arrest. Methods and results In unpaced Langendorff-perfused rat hearts, esmolol (0.03–3 mmol/L) had a profound negative inotropic effect resulting in diastolic arrest at 1 mmol/L and above. This inhibition of contraction was maintained during ventricular pacing. At 3 mmol/L, esmolol also abolished action potential conduction. To determine the cellular mechanism for the negative inotropism, we measured contraction (sarcomere shortening) and the calcium transient (fura-2 fluorescence ratio; Catr) in electrically-stimulated rat ventricular myocytes at 23 and 34°C. The decrease in contraction (by 72% at 23°C, from 0.16 ± 0.01 to 0.04 ± 0.01 µm, P < 0.001) was similar to that of isolated hearts and was caused by a large decrease in Catr (from 0.13 ± 0.02 to 0.07 ± 0.02, P < 0.001). There was no additional effect on myofilament Ca2+ sensitivity. Esmolol's effects on contraction and Catr were not shared or altered by the β-blocker, atenolol (1 mmol/L). Sarcoplasmic reticulum inhibition with thapsigargin did not alter the inhibitory effects of esmolol. Whole-cell voltage-clamp experiments revealed that esmolol inhibited the L-type calcium current ( I Ca,L) and the fast sodium current ( I Na), with IC50 values of 0.45 ± 0.05 and 0.17 ± 0.025 mmol/L, respectively. Conclusion Esmolol at millimolar concentrations causes diastolic ventricular arrest by two mechanisms: at 1 mmol/L (and below), the pronounced negative inotropic effect is due largely to inhibition of L-type Ca2+ channels; additionally, higher concentrations prevent action potential conduction, probably due to the inhibition of fast Na+ channels.
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targeting for cardioplegia arresting Agents and their safety
Current Opinion in Pharmacology, 2009Co-Authors: Hazem B Fallouh, Jonathan C Kentish, David J. ChambersAbstract:Elective temporary cardiac arrest (cardioplegia) is often required during cardiac surgery. In the 1970 s, the development of hyperkalaemic Cardioplegic solutions revolutionised cardiac surgery by offering effective chemically-induced cardiac arrest and myocardial protection during global ischaemia. Despite remaining the most widely-used Cardioplegic technique, hyperkalaemia can have detrimental effects due to the Na and Ca loading of the cardiac cell induced by depolarisation of the cell membrane. Efforts over the last two decades to establish better Cardioplegic Agents have mainly remained limited to animal experiments. The failure of these approaches to progress to clinical trials may be due to a lack of clear criteria that a Cardioplegic Agent should meet at a cellular level and, more importantly, at a system level. In this review we attempt to define the criteria for the optimal Cardioplegic Agent. We also assess the suitability and clinical potential of previously-studied Cardioplegic Agents and suggest cellular targets, particularly those involved in cardiac excitation-contraction coupling, that may prove to be attractive options for the development of new Cardioplegic drugs. Finally, we propose a multicellular target approach using a combination of pharmacological Agents in order to offer better Cardioplegic solutions.
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myocardial protection the efficacy of an ultra short acting β blocker esmolol as a Cardioplegic Agent
The Journal of Thoracic and Cardiovascular Surgery, 2001Co-Authors: Ryuzo Bessho, David J. ChambersAbstract:Abstract Objective: During myocardial revascularization, some surgeons (particularly in the United Kingdom) use intermittent crossclamping with fibrillation as an alternative to cardioplegia. We recently showed that intermittent crossclamping with fibrillation has an intrinsic protection equivalent to that of cardioplegia. In this study we hypothesized that arrest, rather than fibrillation, during intermittent crossclamping may be beneficial. Because esmolol, an ultra-short-acting β-blocker, is known to attenuate myocardial ischemia-reperfusion injury, we compared the protective effect of esmolol arrest with that of intermittent crossclamping with fibrillation and conventional cardioplegia (St Thomas' Hospital solution). Methods: Isolated rat hearts were Langendorff perfused at either constant flow (14 mL/min) or constant pressure (75 mm Hg) with oxygenated Krebs-Henseleit bicarbonate buffer (37°C), and left ventricular developed pressure was assessed. In study 1 (constant flow perfusion) 8 groups (n = 6 hearts per group) were studied: (1) 40 minutes of global ischemia; (2) 2 minutes of St Thomas' Hospital infusion and 40 minutes of ischemia; (3) multidose (every 10 minutes) infusions of St Thomas' Hospital solution during 40 minutes of ischemia; (4) 2 minutes of esmolol infusion and 40 minutes of ischemia; (5) multidose (every 10 minutes) esmolol infusions during 40 minutes of ischemia; (6) continuous infusion of esmolol for 40 minutes during coronary perfusion; (7) intermittent (4 × 10 minutes) ischemia with ventricular fibrillation; and (8) intermittent (4 × 10 minutes) ischemia preceded by intermittent esmolol administration. All protocols were followed by 60 minutes of reperfusion. Further experiments (study 2) examined the esmolol administration method in hearts perfused by constant pressure. Results: An optimal arresting dose of 1.0 mmol/L esmolol was established. In study 1 recovery of left ventricular developed pressure (expressed as percentage of preischemic value) was 7% ± 4%, 28% ± 8%, 70% ± 5%, 8% ± 1%, 90% ± 4%, 65% ± 3%, 71% ± 5%, and 76% ± 5% in groups 1 to 8, respectively. Intermittent esmolol arrest with global ischemia provided equivalent myocardial protection to intermittent crossclamping with fibrillation, continuous esmolol perfusion, and multidose St Thomas' Hospital solution. Surprisingly, multidose esmolol infusion was more protective than all other treatments. In further experiments (study 2) optimal recovery was obtained with multiple esmolol infusions (by constant flow or constant pressure), but continuous esmolol infusion (at constant flow) was less effective than constant pressure infusion. Conclusions: Intermittent arrest with esmolol did not enhance protection of intermittent crossclamping with fibrillation; however, multiple esmolol infusions during global ischemia provided improved protection. Administration (constant flow or constant pressure) of arresting solutions influenced outcome only during continuous infusion. Multidose esmolol arrest may be a beneficial alternative to intermittent crossclamping with fibrillation or conventional cardioplegia. J Thorac Cardiovasc Surg 2001;122:993-1003
George Matalanis - One of the best experts on this subject based on the ideXlab platform.
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custodiol versus blood cardioplegia in complex cardiac operations an australian experience
European Journal of Cardio-Thoracic Surgery, 2013Co-Authors: Fabiano Viana, William Y Shi, Philip A R Hayward, Marco E Larobina, Frank Liskaser, George MatalanisAbstract:OBJECTIVES: A single or dual-dose strategy for myocardial protection is attractive in long operations, in avoiding the need to interrupt the procedure to re-administer cardioplegia. We hypothesized that a single administration of Bretschneider histidine–tryptophan–ketoglutarate (HTK) crystalloid solution (Custodiol) offers myocardial protection comparable with repeated tepid blood cardioplegia. METHODS: We reviewed a prospectively compiled single-centre database containing all adult cardiac procedures performed from January 2005 to January 2011. Preoperative demographic and investigative data, operative variables and postoperative (30-day) mortality and morbidity were compared between the Custodiol and blood cardioplegia groups. The study primary endpoints were 30-day mortality, return to the operating theatre, myocardial infarction, stroke, postoperative requirement for an intra-aortic balloon pump, new renal failure, prolonged ventilation and re-admission to hospital within 30 days. Propensity score matching was performed to correct for any bias that may have been associated with the usage of Custodiol. RESULTS: A total of 1900 cardiac surgical procedures were identified of which 126 (7%) utilized Custodiol and 1774 (93%) used blood cardioplegia as the primary Cardioplegic Agent. After propensity-score matching, we were able to match 71 Custodiol cases one-to-one to those receiving blood cardioplegia. There were no statistically significant differences noted for any of the endpoints studied after propensity-score matching. In particular, the proportion of mortality (blood cardioplegia: 1 vs. Custodiol 4%, P= 0.63) any mortality/ morbidity (blood cardioplegia: 35 vs. Custodiol: 39% P= 0.46) was similar between the groups. CONCLUSIONS: The use of Custodiol is convenient, simple and at least as safe as tepid blood cardioplegia for myocardial protection in complex cardiac operations. A randomized prospective comparison of myocardial protection strategies is warranted.
Hazem B Fallouh - One of the best experts on this subject based on the ideXlab platform.
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esmolol cardioplegia the cellular mechanism of diastolic arrest
Cardiovascular Research, 2010Co-Authors: Hazem B Fallouh, Sonya C Bardswell, David J. Chambers, Linda M Mclatchie, Michael J Shattock, Jonathan C KentishAbstract:Aims Esmolol, an ultra-short-acting β-blocker, acts as a Cardioplegic Agent at millimolar concentrations. We investigated the mechanism by which esmolol induces diastolic ventricular arrest. Methods and results In unpaced Langendorff-perfused rat hearts, esmolol (0.03–3 mmol/L) had a profound negative inotropic effect resulting in diastolic arrest at 1 mmol/L and above. This inhibition of contraction was maintained during ventricular pacing. At 3 mmol/L, esmolol also abolished action potential conduction. To determine the cellular mechanism for the negative inotropism, we measured contraction (sarcomere shortening) and the calcium transient (fura-2 fluorescence ratio; Catr) in electrically-stimulated rat ventricular myocytes at 23 and 34°C. The decrease in contraction (by 72% at 23°C, from 0.16 ± 0.01 to 0.04 ± 0.01 µm, P < 0.001) was similar to that of isolated hearts and was caused by a large decrease in Catr (from 0.13 ± 0.02 to 0.07 ± 0.02, P < 0.001). There was no additional effect on myofilament Ca2+ sensitivity. Esmolol's effects on contraction and Catr were not shared or altered by the β-blocker, atenolol (1 mmol/L). Sarcoplasmic reticulum inhibition with thapsigargin did not alter the inhibitory effects of esmolol. Whole-cell voltage-clamp experiments revealed that esmolol inhibited the L-type calcium current ( I Ca,L) and the fast sodium current ( I Na), with IC50 values of 0.45 ± 0.05 and 0.17 ± 0.025 mmol/L, respectively. Conclusion Esmolol at millimolar concentrations causes diastolic ventricular arrest by two mechanisms: at 1 mmol/L (and below), the pronounced negative inotropic effect is due largely to inhibition of L-type Ca2+ channels; additionally, higher concentrations prevent action potential conduction, probably due to the inhibition of fast Na+ channels.
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targeting for cardioplegia arresting Agents and their safety
Current Opinion in Pharmacology, 2009Co-Authors: Hazem B Fallouh, Jonathan C Kentish, David J. ChambersAbstract:Elective temporary cardiac arrest (cardioplegia) is often required during cardiac surgery. In the 1970 s, the development of hyperkalaemic Cardioplegic solutions revolutionised cardiac surgery by offering effective chemically-induced cardiac arrest and myocardial protection during global ischaemia. Despite remaining the most widely-used Cardioplegic technique, hyperkalaemia can have detrimental effects due to the Na and Ca loading of the cardiac cell induced by depolarisation of the cell membrane. Efforts over the last two decades to establish better Cardioplegic Agents have mainly remained limited to animal experiments. The failure of these approaches to progress to clinical trials may be due to a lack of clear criteria that a Cardioplegic Agent should meet at a cellular level and, more importantly, at a system level. In this review we attempt to define the criteria for the optimal Cardioplegic Agent. We also assess the suitability and clinical potential of previously-studied Cardioplegic Agents and suggest cellular targets, particularly those involved in cardiac excitation-contraction coupling, that may prove to be attractive options for the development of new Cardioplegic drugs. Finally, we propose a multicellular target approach using a combination of pharmacological Agents in order to offer better Cardioplegic solutions.
Jonathan C Kentish - One of the best experts on this subject based on the ideXlab platform.
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esmolol cardioplegia the cellular mechanism of diastolic arrest
Cardiovascular Research, 2010Co-Authors: Hazem B Fallouh, Sonya C Bardswell, David J. Chambers, Linda M Mclatchie, Michael J Shattock, Jonathan C KentishAbstract:Aims Esmolol, an ultra-short-acting β-blocker, acts as a Cardioplegic Agent at millimolar concentrations. We investigated the mechanism by which esmolol induces diastolic ventricular arrest. Methods and results In unpaced Langendorff-perfused rat hearts, esmolol (0.03–3 mmol/L) had a profound negative inotropic effect resulting in diastolic arrest at 1 mmol/L and above. This inhibition of contraction was maintained during ventricular pacing. At 3 mmol/L, esmolol also abolished action potential conduction. To determine the cellular mechanism for the negative inotropism, we measured contraction (sarcomere shortening) and the calcium transient (fura-2 fluorescence ratio; Catr) in electrically-stimulated rat ventricular myocytes at 23 and 34°C. The decrease in contraction (by 72% at 23°C, from 0.16 ± 0.01 to 0.04 ± 0.01 µm, P < 0.001) was similar to that of isolated hearts and was caused by a large decrease in Catr (from 0.13 ± 0.02 to 0.07 ± 0.02, P < 0.001). There was no additional effect on myofilament Ca2+ sensitivity. Esmolol's effects on contraction and Catr were not shared or altered by the β-blocker, atenolol (1 mmol/L). Sarcoplasmic reticulum inhibition with thapsigargin did not alter the inhibitory effects of esmolol. Whole-cell voltage-clamp experiments revealed that esmolol inhibited the L-type calcium current ( I Ca,L) and the fast sodium current ( I Na), with IC50 values of 0.45 ± 0.05 and 0.17 ± 0.025 mmol/L, respectively. Conclusion Esmolol at millimolar concentrations causes diastolic ventricular arrest by two mechanisms: at 1 mmol/L (and below), the pronounced negative inotropic effect is due largely to inhibition of L-type Ca2+ channels; additionally, higher concentrations prevent action potential conduction, probably due to the inhibition of fast Na+ channels.
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targeting for cardioplegia arresting Agents and their safety
Current Opinion in Pharmacology, 2009Co-Authors: Hazem B Fallouh, Jonathan C Kentish, David J. ChambersAbstract:Elective temporary cardiac arrest (cardioplegia) is often required during cardiac surgery. In the 1970 s, the development of hyperkalaemic Cardioplegic solutions revolutionised cardiac surgery by offering effective chemically-induced cardiac arrest and myocardial protection during global ischaemia. Despite remaining the most widely-used Cardioplegic technique, hyperkalaemia can have detrimental effects due to the Na and Ca loading of the cardiac cell induced by depolarisation of the cell membrane. Efforts over the last two decades to establish better Cardioplegic Agents have mainly remained limited to animal experiments. The failure of these approaches to progress to clinical trials may be due to a lack of clear criteria that a Cardioplegic Agent should meet at a cellular level and, more importantly, at a system level. In this review we attempt to define the criteria for the optimal Cardioplegic Agent. We also assess the suitability and clinical potential of previously-studied Cardioplegic Agents and suggest cellular targets, particularly those involved in cardiac excitation-contraction coupling, that may prove to be attractive options for the development of new Cardioplegic drugs. Finally, we propose a multicellular target approach using a combination of pharmacological Agents in order to offer better Cardioplegic solutions.
Fabiano Viana - One of the best experts on this subject based on the ideXlab platform.
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custodiol versus blood cardioplegia in complex cardiac operations an australian experience
European Journal of Cardio-Thoracic Surgery, 2013Co-Authors: Fabiano Viana, William Y Shi, Philip A R Hayward, Marco E Larobina, Frank Liskaser, George MatalanisAbstract:OBJECTIVES: A single or dual-dose strategy for myocardial protection is attractive in long operations, in avoiding the need to interrupt the procedure to re-administer cardioplegia. We hypothesized that a single administration of Bretschneider histidine–tryptophan–ketoglutarate (HTK) crystalloid solution (Custodiol) offers myocardial protection comparable with repeated tepid blood cardioplegia. METHODS: We reviewed a prospectively compiled single-centre database containing all adult cardiac procedures performed from January 2005 to January 2011. Preoperative demographic and investigative data, operative variables and postoperative (30-day) mortality and morbidity were compared between the Custodiol and blood cardioplegia groups. The study primary endpoints were 30-day mortality, return to the operating theatre, myocardial infarction, stroke, postoperative requirement for an intra-aortic balloon pump, new renal failure, prolonged ventilation and re-admission to hospital within 30 days. Propensity score matching was performed to correct for any bias that may have been associated with the usage of Custodiol. RESULTS: A total of 1900 cardiac surgical procedures were identified of which 126 (7%) utilized Custodiol and 1774 (93%) used blood cardioplegia as the primary Cardioplegic Agent. After propensity-score matching, we were able to match 71 Custodiol cases one-to-one to those receiving blood cardioplegia. There were no statistically significant differences noted for any of the endpoints studied after propensity-score matching. In particular, the proportion of mortality (blood cardioplegia: 1 vs. Custodiol 4%, P= 0.63) any mortality/ morbidity (blood cardioplegia: 35 vs. Custodiol: 39% P= 0.46) was similar between the groups. CONCLUSIONS: The use of Custodiol is convenient, simple and at least as safe as tepid blood cardioplegia for myocardial protection in complex cardiac operations. A randomized prospective comparison of myocardial protection strategies is warranted.