Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.729462
Title: Post-cardiac arrest myocardial dysfunction
Author: Taghavi, Fouad John
ISNI:       0000 0004 6494 756X
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2017
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Abstract:
One of the major medical advances of the twentieth century is the development of cardiac transplantation. Cardiac transplantation is the definitive treatment for end-stage heart disease. Cardiac transplantation relies on organs procured from Brain Dead Donors (DBD). Donation after Circulatory Death (DCD) organs are being increasingly used for renal, liver and lung transplantation. Hearts from DCD donors have not been utilized as there is a fear that they will have sustained irreversible myocardial injury post cardiac arrest. We have a limited understanding of Post cardiac arrest myocardial depression due to the lack of a good physiological model of the disease. Objective: To develop a model of in-vivo cardiac arrest and resuscitation in order to characterize the biology of the associated myocardial dysfunction and test potential therapeutic strategies. Methods and Results: We developed a rodent model of post arrest myocardial depression (DCD model) using extracorporeal membrane oxygenation for resuscitation, followed by invasive haemodynamic measurements. In isolated cardiomyocytes, we assessed mechanical load and Ca2+-induced Ca2+ release (CICR) simultaneously using the microcarbon fiber technique and observed reduced function and myofilament calcium sensitivity in the post arrest group. Additionally, in contrast with findings from Langendorff models of ischemia-reperfusion, there is a marked augmentation of CICR in isolated cells. This increase in calcium serves to maintain contraction in the face of myofilament dysfunction and, it seems to be mediated by autophosphorylation of calcium-calmodulin protein kinase II (CAMKII). It is further dependent on ryanodine receptor calcium but not PKA leading us to speculate that it is triggered by adrenergic activation but maintained by CAMKII. Finally, activation of aldehyde-dehydrogenase II by the small molecule Alda-1 dramatically improved whole animal and cellular contractile performance after arrest, and restored CICR to close to normal levels. Conclusions: Cardiac arrest and reperfusion lead to calcium cardiac memory, which support cardiomyocyte contractility in the face of post arrest myofilament calcium sensitivity. Alda-1 mitigates these effects and improves outcome.
Supervisor: Drinkhill, Mark ; Homer-Vanniasinkam, Shervanthi ; Large, Stephen Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.729462  DOI: Not available
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