ATP-Sensitive Potassium Channel Opener Diazoxide Reduces Myocardial Stunning in a Porcine Regional With Subsequent Global Ischemia Model
Background ATP-sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic opening of ATP potassium channels with diazoxide preserves myocardial function following prolonged global ischemia, making it an ideal candidat...
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| Published in | Journal of the American Heart Association Vol. 11; no. 23; p. e026304 |
|---|---|
| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
John Wiley and Sons Inc
06.12.2022
Wiley |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Background ATP-sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic opening of ATP potassium channels with diazoxide preserves myocardial function following prolonged global ischemia, making it an ideal candidate for use during cardiac surgery. We hypothesized that diazoxide would reduce myocardial stunning after regional ischemia with subsequent prolonged global ischemia, similar to the clinical situation of myocardial ischemia at the time of revascularization. Methods and Results Swine underwent left anterior descending occlusion (30 minutes), followed by 120 minutes global ischemia protected with hyperkalemic cardioplegia±diazoxide (N=6 each), every 20 minutes cardioplegia, then 60 minutes reperfusion. Cardiac output, time to wean from cardiopulmonary bypass, left ventricular (LV) function, caspase-3, and infarct size were compared. Six animals in the diazoxide group separated from bypass by 30 minutes, whereas only 4 animals in the cardioplegia group separated. Diazoxide was associated with shorter but not significant time to wean from bypass (17.5 versus 27.0 minutes;
=0.13), higher, but not significant, cardiac output during reperfusion (2.9 versus 1.5 L/min at 30 minutes;
=0.05), and significantly higher left ventricular ejection fraction at 30 minutes (42.5 versus 15.8%;
<0.01). Linear mixed regression modeling demonstrated greater left ventricular developed pressure (
<0.01) and maximum change in ventricular pressure during isovolumetric contraction (
<0.01) in the diazoxide group at 30 minutes of reperfusion. Conclusions Diazoxide reduces myocardial stunning and facilitates separation from cardiopulmonary bypass in a model that mimics the clinical setting of ongoing myocardial ischemia before revascularization. Diazoxide has the potential to reduce myocardial stunning in the clinical setting. |
|---|---|
| AbstractList | Background
ATP‐sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic opening of ATP potassium channels with diazoxide preserves myocardial function following prolonged global ischemia, making it an ideal candidate for use during cardiac surgery. We hypothesized that diazoxide would reduce myocardial stunning after regional ischemia with subsequent prolonged global ischemia, similar to the clinical situation of myocardial ischemia at the time of revascularization.
Methods and Results
Swine underwent left anterior descending occlusion (30 minutes), followed by 120 minutes global ischemia protected with hyperkalemic cardioplegia±diazoxide (N=6 each), every 20 minutes cardioplegia, then 60 minutes reperfusion. Cardiac output, time to wean from cardiopulmonary bypass, left ventricular (LV) function, caspase‐3, and infarct size were compared. Six animals in the diazoxide group separated from bypass by 30 minutes, whereas only 4 animals in the cardioplegia group separated. Diazoxide was associated with shorter but not significant time to wean from bypass (17.5 versus 27.0 minutes;
P
=0.13), higher, but not significant, cardiac output during reperfusion (2.9 versus 1.5 L/min at 30 minutes;
P
=0.05), and significantly higher left ventricular ejection fraction at 30 minutes (42.5 versus 15.8%;
P
<0.01). Linear mixed regression modeling demonstrated greater left ventricular developed pressure (
P
<0.01) and maximum change in ventricular pressure during isovolumetric contraction (
P
<0.01) in the diazoxide group at 30 minutes of reperfusion.
Conclusions
Diazoxide reduces myocardial stunning and facilitates separation from cardiopulmonary bypass in a model that mimics the clinical setting of ongoing myocardial ischemia before revascularization. Diazoxide has the potential to reduce myocardial stunning in the clinical setting. Background ATP-sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic opening of ATP potassium channels with diazoxide preserves myocardial function following prolonged global ischemia, making it an ideal candidate for use during cardiac surgery. We hypothesized that diazoxide would reduce myocardial stunning after regional ischemia with subsequent prolonged global ischemia, similar to the clinical situation of myocardial ischemia at the time of revascularization. Methods and Results Swine underwent left anterior descending occlusion (30 minutes), followed by 120 minutes global ischemia protected with hyperkalemic cardioplegia±diazoxide (N=6 each), every 20 minutes cardioplegia, then 60 minutes reperfusion. Cardiac output, time to wean from cardiopulmonary bypass, left ventricular (LV) function, caspase-3, and infarct size were compared. Six animals in the diazoxide group separated from bypass by 30 minutes, whereas only 4 animals in the cardioplegia group separated. Diazoxide was associated with shorter but not significant time to wean from bypass (17.5 versus 27.0 minutes; =0.13), higher, but not significant, cardiac output during reperfusion (2.9 versus 1.5 L/min at 30 minutes; =0.05), and significantly higher left ventricular ejection fraction at 30 minutes (42.5 versus 15.8%; <0.01). Linear mixed regression modeling demonstrated greater left ventricular developed pressure ( <0.01) and maximum change in ventricular pressure during isovolumetric contraction ( <0.01) in the diazoxide group at 30 minutes of reperfusion. Conclusions Diazoxide reduces myocardial stunning and facilitates separation from cardiopulmonary bypass in a model that mimics the clinical setting of ongoing myocardial ischemia before revascularization. Diazoxide has the potential to reduce myocardial stunning in the clinical setting. Background ATP‐sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic opening of ATP potassium channels with diazoxide preserves myocardial function following prolonged global ischemia, making it an ideal candidate for use during cardiac surgery. We hypothesized that diazoxide would reduce myocardial stunning after regional ischemia with subsequent prolonged global ischemia, similar to the clinical situation of myocardial ischemia at the time of revascularization. Methods and Results Swine underwent left anterior descending occlusion (30 minutes), followed by 120 minutes global ischemia protected with hyperkalemic cardioplegia±diazoxide (N=6 each), every 20 minutes cardioplegia, then 60 minutes reperfusion. Cardiac output, time to wean from cardiopulmonary bypass, left ventricular (LV) function, caspase‐3, and infarct size were compared. Six animals in the diazoxide group separated from bypass by 30 minutes, whereas only 4 animals in the cardioplegia group separated. Diazoxide was associated with shorter but not significant time to wean from bypass (17.5 versus 27.0 minutes; P=0.13), higher, but not significant, cardiac output during reperfusion (2.9 versus 1.5 L/min at 30 minutes; P=0.05), and significantly higher left ventricular ejection fraction at 30 minutes (42.5 versus 15.8%; P<0.01). Linear mixed regression modeling demonstrated greater left ventricular developed pressure (P<0.01) and maximum change in ventricular pressure during isovolumetric contraction (P<0.01) in the diazoxide group at 30 minutes of reperfusion. Conclusions Diazoxide reduces myocardial stunning and facilitates separation from cardiopulmonary bypass in a model that mimics the clinical setting of ongoing myocardial ischemia before revascularization. Diazoxide has the potential to reduce myocardial stunning in the clinical setting. |
| Author | Etchill, Eric Lawton, Jennifer S Cho, Brian Brady, Mary Beth Dodd-O, Jeffrey Giuliano, Katherine Meyer, Joseph M Velez, Ana K Kearney, Sean Jones, Melissa Wang, Jie |
| AuthorAffiliation | 2 Division of Cardiac Anesthesiology, Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine Baltimore MD 1 Division of Cardiac Surgery, Department of Surgery Johns Hopkins University School of Medicine Baltimore MD 3 Division of Cardiology, Department of Medicine Johns Hopkins University School of Medicine Baltimore MD |
| AuthorAffiliation_xml | – name: 1 Division of Cardiac Surgery, Department of Surgery Johns Hopkins University School of Medicine Baltimore MD – name: 2 Division of Cardiac Anesthesiology, Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine Baltimore MD – name: 3 Division of Cardiology, Department of Medicine Johns Hopkins University School of Medicine Baltimore MD |
| Author_xml | – sequence: 1 givenname: Ana K surname: Velez fullname: Velez, Ana K organization: Division of Cardiac Surgery, Department of Surgery Johns Hopkins University School of Medicine Baltimore MD – sequence: 2 givenname: Eric orcidid: 0000-0002-5381-648X surname: Etchill fullname: Etchill, Eric organization: Division of Cardiac Surgery, Department of Surgery Johns Hopkins University School of Medicine Baltimore MD – sequence: 3 givenname: Katherine orcidid: 0000-0003-2260-1854 surname: Giuliano fullname: Giuliano, Katherine organization: Division of Cardiac Surgery, Department of Surgery Johns Hopkins University School of Medicine Baltimore MD – sequence: 4 givenname: Sean surname: Kearney fullname: Kearney, Sean organization: Division of Cardiac Surgery, Department of Surgery Johns Hopkins University School of Medicine Baltimore MD – sequence: 5 givenname: Melissa surname: Jones fullname: Jones, Melissa organization: Division of Cardiac Surgery, Department of Surgery Johns Hopkins University School of Medicine Baltimore MD – sequence: 6 givenname: Jie surname: Wang fullname: Wang, Jie organization: Division of Cardiac Surgery, Department of Surgery Johns Hopkins University School of Medicine Baltimore MD – sequence: 7 givenname: Brian orcidid: 0000-0003-3594-3247 surname: Cho fullname: Cho, Brian organization: Division of Cardiac Anesthesiology, Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine Baltimore MD – sequence: 8 givenname: Mary Beth surname: Brady fullname: Brady, Mary Beth organization: Division of Cardiac Anesthesiology, Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine Baltimore MD – sequence: 9 givenname: Jeffrey surname: Dodd-O fullname: Dodd-O, Jeffrey organization: Division of Cardiac Anesthesiology, Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine Baltimore MD – sequence: 10 givenname: Joseph M orcidid: 0000-0002-9304-7101 surname: Meyer fullname: Meyer, Joseph M organization: Division of Cardiology, Department of Medicine Johns Hopkins University School of Medicine Baltimore MD – sequence: 11 givenname: Jennifer S orcidid: 0000-0002-0825-6591 surname: Lawton fullname: Lawton, Jennifer S organization: Division of Cardiac Surgery, Department of Surgery Johns Hopkins University School of Medicine Baltimore MD |
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| Keywords | swine ventricular function, left diazoxide cardiopulmonary bypass animals myocardial stunning heart arrest, induced |
| Language | English |
| License | This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
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| Notes | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-3 content type line 23 ObjectType-Review-1 For Sources of Funding and Disclosures, see page 9. This work was presented at the American Heart Association Scientific Sessions, November 13–15, 2021. |
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| Snippet | Background ATP-sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic... Background ATP‐sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic... Background ATP‐sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic... |
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| SubjectTerms | Adenosine Triphosphate Animals cardiopulmonary bypass diazoxide Diazoxide - pharmacology heart arrest, induced Ischemia KATP Channels Myocardial Ischemia - complications Myocardial Ischemia - drug therapy myocardial stunning Myocardial Stunning - etiology Myocardial Stunning - prevention & control Original Research Stroke Volume Swine Ventricular Function, Left |
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| Title | ATP-Sensitive Potassium Channel Opener Diazoxide Reduces Myocardial Stunning in a Porcine Regional With Subsequent Global Ischemia Model |
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