The Commonalities and Differences in Mitochondrial Dysfunction Between ex vivo and in vivo Myocardial Global Ischemia Rat Heart Models: Implications for Donation After Circulatory Death Research

Quader, Mohammed; Akande, Oluwatoyin; Toldo, Stefano; Cholyway, Renee; Kang, Le; Lesnefsky, Edward J.; Chen, Qun

doi:10.3389/fphys.2020.00681

Cited by 11 publications

(11 citation statements)

References 49 publications

(96 reference statements)

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“…Besides, hypoxic pulmonary vasoconstriction following asphyxiation results in right ventricular dilatation and more damage to hearts compared with exsanguination (3,31). To induce asphyxiation, Quader et al terminated the ventilation support following paralyzing skeletal muscles with muscle relaxants (32,33), while Tolboom et al chose to transect the diaphragm (12,13). Asphyxiation can also be induced by tracheal clamping or by median sternotomy and opening the pleurae (14,(16)(17)(18).…”

Section: Discussionmentioning

confidence: 99%

A Novel Rat Model of Cardiac Donation After Circulatory Death Combined With Normothermic ex situ Heart Perfusion

Xue

Xiao

et al. 2021

Front. Cardiovasc. Med.

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Background: In heart transplantation, the adoption of hearts from donation after circulatory death (DCD) is considered to be a promising approach to expanding the donor pool. Normothermic ex situ heart perfusion (ESHP) is emerging as a novel preservation strategy for DCD hearts. Therefore, pre-clinical animal models of ESHP are essential to address some key issues before efficient clinical translation. We aim to develop a novel, reproducible, and economical rat model of DCD protocol combined with normothermic ESHP.Methods: Circulatory death of the anesthetized rats in the DCD group was declared when systolic blood pressure below 30 mmHg or asystole was observed after asphyxiation. Additional 15 min of standoff period was allowed to elapse. After perfusion of cold cardioplegia, the DCD hearts were excised and perfused with allogenic blood-based perfusate at constant flow for 90 min in the normothermic ESHP system. Functional assessment and blood gas analysis were performed every 30 min during ESHP. The alteration of DCD hearts submitted to different durations of ESHP (30, 60, and 90 min) in oxidative stress, apoptosis, tissue energy state, inflammatory response, histopathology, cell swelling, and myocardial infarction during ESHP was evaluated. Rats in the non-DCD group were treated similarly but not exposed to warm ischemia and preserved by the normothermic ESHP system for 90 min.Results: The DCD hearts showed compromised function at the beginning of ESHP and recovered over time, while non-DCD hearts presented better cardiac function during ESHP. The alteration of DCD hearts in oxidative stress, apoptosis, tissue energy state, histopathological changes, cell swelling, and inflammatory response didn't differ among different durations of ESHP. At the end of 90-min ESHP, DCD, and non-DCD hearts presented similarly in apoptosis, oxidative stress, inflammatory response, myocardial infarction, and histopathological changes. Moreover, the DCD hearts had lower energy storage and more evident cell swelling compared to the non-DCD hearts.Conclusion: We established a reproducible, clinically relevant, and economical rat model of DCD protocol combined with normothermic ESHP, where the DCD hearts can maintain a stable state during 90-min ESHP.

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Section: Discussionmentioning

confidence: 99%

A Novel Rat Model of Cardiac Donation After Circulatory Death Combined With Normothermic ex situ Heart Perfusion

Xue

Xiao

et al. 2021

Front. Cardiovasc. Med.

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“…In contrast, no pre-mortem interventions are allowed in DCD hearts due to socio-ethical reasons [38]. Since warm ischemia is inevitable with the DCD process, damage to mitochondria is already established in these hearts [19]. A recent study showed that mitochondrial transplantation decreased cardiac injury in rabbit hearts following in vivo ischemia-reperfusion injury by improving mitochondrial function [39].…”

Section: Plos Onementioning

confidence: 99%

“…Most of the knowledge on the series of events and on the extent of damage to the mitochondria in the ischemic or reperfused hearts comes from exvivo ischemia studies [15][16][17][18]. A recent study showed that the DCD process (in vivo ischemia) leads to mitochondrial dysfunction similar to the ex vivo studies but with distinct differences [19]. In this study we will address the changes in mitochondrial and cardiac function from DCD hearts subjected to different periods of in vivo ischemia and in vitro reperfusion.…”

Section: Introductionmentioning

confidence: 98%

Ischemia and reperfusion injury to mitochondria and cardiac function in donation after circulatory death hearts- an experimental study

et al. 2020

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The ultimate treatment for patients with end-stage heart failure is heart transplantation. The number of donor hearts which are primarily procured from donation after brain death (DBD) donors is limited, but donation after circulatory death (DCD) donor hearts can increase the heart donor pool. However, ischemia and reperfusion injuries associated with the DCD process causes myocardial damage, limiting the use of DCD hearts in transplantation. Addressing this problem is critical in the exploration of DCD hearts as suitable donor hearts for transplantation. In this study, rat hearts were procured following the control beating-heart donor (CBD) or DCD donation process. Changes in mitochondria and cardiac function from DCD hearts subjected to 25 or 35 minutes of ischemia followed by 60 minutes of reperfusion were compared to CBD hearts. Following ischemia, rates of oxidative phosphorylation and calcium retention capacity were progressively impaired in DCD hearts compared to CBD hearts. Reperfusion caused additional mitochondrial dysfunction in DCD hearts. Developed pressure, inotropy and lusitropy, were significantly reduced in DCD hearts compared to CBD hearts. We, therefore, suggest that interventional strategies targeted before the onset of ischemia and at reperfusion could protect mitochondria, thus potentially making DCD hearts suitable for heart transplantation.

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“…Furthermore, not all protocols employ the same definition of the start of warm ischemia. For example, some measure cardiac asystole by electrocardiogram ( 11 ) while others define the beginning of ischemia when the peak systolic pressure drops below 30 mmHg or asystole ( 12 , 13 ), or when the blood pressure was non-pulsatile or the mean arterial pressure less than 30 mmHg ( 14 , 17 ). As such, strict comparison among varying pre-clinical models requires careful interpretation, but when possible, it may aid in advancing our understanding of the pathophysiologic processes involved.…”

Section: Introductionmentioning

confidence: 99%

“…The consideration of this pre-ischemic phase and the simulation of the DCD process in a donor is receiving more and more attention in the field, and several in-situ rat models have recently been developed (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). However, no standard protocol is available; for example, initiation of the DCD process can be simulated in different ways; by simply terminating the ventilatory support (14,15,17), by terminating ventilatory support in combination with a tracheal clamp (12,13), with or without the addition of respiratory muscle paralysis (11,16), or by the transection of the diaphragm (19,20). Furthermore, not all protocols employ the same definition of the start of warm ischemia.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Experimental Rat Models in Donation After Circulatory Death (DCD): in-situ vs. ex-situ Ischemia

Arnold

Méndez-Carmona

Wyss

et al. 2021

Front. Cardiovasc. Med.

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Introduction: Donation after circulatory death (DCD) could substantially improve donor heart availability. However, warm ischemia prior to procurement is of particular concern for cardiac graft quality. We describe a rat model of DCD with in-situ ischemia in order to characterize the physiologic changes during the withdrawal period before graft procurement, to determine effects of cardioplegic graft storage, and to evaluate the post-ischemic cardiac recovery in comparison with an established ex-situ ischemia model.Methods: Following general anesthesia in male, Wistar rats (404 ± 24 g, n = 25), withdrawal of life-sustaining therapy was simulated by diaphragm transection. Hearts underwent no ischemia or 27 min in-situ ischemia and were explanted. Ex situ, hearts were subjected to a cardioplegic flush and 15 min cold storage or not, and 60 min reperfusion. Cardiac recovery was determined and compared to published results of an entirely ex-situ ischemia model (n = 18).Results: In donors, hearts were subjected to hypoxia and hemodynamic changes, as well as increased levels of circulating catecholamines and free fatty acids prior to circulatory arrest. Post-ischemic contractile recovery was significantly lower in the in-situ ischemia model compared to the ex-situ model, and the addition of cardioplegic storage improved developed pressure-heart rate product, but not cardiac output.Conclusion: The in-situ model provides insight into conditions to which the heart is exposed before procurement. Compared to an entirely ex-situ ischemia model, hearts of the in-situ model demonstrated a lower post-ischemic functional recovery, potentially due to systemic changes prior to ischemia, which are partially abrogated by cardioplegic graft storage.

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The Commonalities and Differences in Mitochondrial Dysfunction Between ex vivo and in vivo Myocardial Global Ischemia Rat Heart Models: Implications for Donation After Circulatory Death Research

Cited by 11 publications

References 49 publications

A Novel Rat Model of Cardiac Donation After Circulatory Death Combined With Normothermic ex situ Heart Perfusion

A Novel Rat Model of Cardiac Donation After Circulatory Death Combined With Normothermic ex situ Heart Perfusion

Ischemia and reperfusion injury to mitochondria and cardiac function in donation after circulatory death hearts- an experimental study

Comparison of Experimental Rat Models in Donation After Circulatory Death (DCD): in-situ vs. ex-situ Ischemia

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