Autologous mitochondrial transplantation for cardiogenic shock in pediatric patients following ischemia-reperfusion injury

Guariento, Alvise; Piekarski, Breanna; Doulamis, Ilias P.; Blitzer, David; Ferraro, Alessandra M.; Harrild, David M.; Zurakowski, David; Nido, Pedro J. del; McCully, James D.; Emani, Sitaram M.

doi:10.1016/j.jtcvs.2020.10.151

Cited by 99 publications

(62 citation statements)

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“…Patients subjected to mitochondrial transplantation were more likely to successfully wean from ECMO and exhibited better ventricular strain magnitude at the time of initial decannulation (23.0% vs. 16.8%, P = 0.03) and lower overall occurrence of cardiovascular events (20% vs. 79%, P < 0.01) compared to the control group. Kaplan-Meier curves and Cox regression analysis models showed a higher composite estimated risk of cardiovascular events in the control group (hazard ratio, 4.6; 95% confidence interval, 1.0-20.9; P < 0.04) [50].…”

Section: Human Studiesmentioning

confidence: 88%

Mitochondrial transplantation therapy for ischemia reperfusion injury: a systematic review of animal and human studies

et al. 2021

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Background Mitochondria are essential organelles that provide energy for cellular functions, participate in cellular signaling and growth, and facilitate cell death. Based on their multifactorial roles, mitochondria are also critical in the progression of critical illnesses. Transplantation of mitochondria has been reported as a potential promising approach to treat critical illnesses, particularly ischemia reperfusion injury (IRI). However, a systematic review of the relevant literature has not been conducted to date. Here, we systematically reviewed the animal and human studies relevant to IRI to summarize the evidence for mitochondrial transplantation. Methods We searched MEDLINE, the Cochrane library, and Embase and performed a systematic review of mitochondrial transplantation for IRI in both preclinical and clinical studies. We developed a search strategy using a combination of keywords and Medical Subject Heading/Emtree terms. Studies including cell-mediated transfer of mitochondria as a transfer method were excluded. Data were extracted to a tailored template, and data synthesis was descriptive because the data were not suitable for meta-analysis. Results Overall, we identified 20 animal studies and two human studies. Among animal studies, 14 (70%) studies focused on either brain or heart IRI. Both autograft and allograft mitochondrial transplantation were used in 17 (85%) animal studies. The designs of the animal studies were heterogeneous in terms of the route of administration, timing of transplantation, and dosage used. Twelve (60%) studies were performed in a blinded manner. All animal studies reported that mitochondrial transplantation markedly mitigated IRI in the target tissues, but there was variation in biological biomarkers and pathological changes. The human studies were conducted with a single-arm, unblinded design, in which autologous mitochondrial transplantation was applied to pediatric patients who required extracorporeal membrane oxygenation (ECMO) for IRI–associated myocardial dysfunction after cardiac surgery. Conclusion The evidence gathered from our systematic review supports the potential beneficial effects of mitochondrial transplantation after IRI, but its clinical translation remains limited. Further investigations are thus required to explore the mechanisms of action and patient outcomes in critical settings after mitochondrial transplantation. Systematic review registration The study was registered at UMIN under the registration number UMIN000043347.

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Section: Human Studiesmentioning

confidence: 88%

Mitochondrial transplantation therapy for ischemia reperfusion injury: a systematic review of animal and human studies

et al. 2021

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“…Pacak et al and Kesner et al have shown that mitochondrial transfer occurs through actin-mediated endocytosis and requires intact cellular heparin sulfate proteoglycans and outer mitochondrial membranes [ 22 , 50 ], but it remains a mystery as to how mitochondria escape Ca 2+ -induced permeability transition pore opening when traveling via vasculature to CM [ 48 , 49 , 51 , 52 ]. Considering that mitochondrial transplantation is currently under clinical trial in pediatric patients undergoing extracorporeal membrane oxygenation (ECMO) following myocardial IRI [ 27 , 28 ], it is imperative that studies confirm these mechanisms in vivo and solve the vasculature mystery. Nonetheless, in human clinical trials, transplants have significantly improved cardiac function, reduced the number of adverse cardiovascular events, and helped successfully wean pediatric patients off of ECMO to improve survival [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…Considering that mitochondrial transplantation is currently under clinical trial in pediatric patients undergoing extracorporeal membrane oxygenation (ECMO) following myocardial IRI [ 27 , 28 ], it is imperative that studies confirm these mechanisms in vivo and solve the vasculature mystery. Nonetheless, in human clinical trials, transplants have significantly improved cardiac function, reduced the number of adverse cardiovascular events, and helped successfully wean pediatric patients off of ECMO to improve survival [ 28 ]. In addition to myocardial IRI, mitochondrial transfer/transplantation is being studied in the treatment of heart failure [ 53 ], diabetes-exacerbated IRI [ 47 ], acute limb ischemia [ 54 ], ischemic lung injury [ 55 ], and Alzheimer’s disease [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

“…This incorporation of healthy donor mitochondria leads to improved cellular and cardiac function by increasing myocardial respiration and ATP production [ 20 , 24 ], upregulating expression of cardioprotective cytokines and mitochondrial proteins involved in respiration [ 24 ], and by replacing damaged mitochondrial (mt)DNA [ 22 ] to ultimately limit ischemic damage and improve cardiac function [ 25 , 26 ]. In clinical trials, mitochondrial transplantations offer an emerging therapeutic tool in the treatment of cardiomyopathy following ischemia-reperfusion injury (IRI) [ 26 , 27 , 28 ]. Here, we apply this technique to understand the role of mitochondria in developmentally programmed heart disease.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Transfer Improves Cardiomyocyte Bioenergetics and Viability in Male Rats Exposed to Pregestational Diabetes

Louwagie

Larsen

Wachal

et al. 2021

IJMS

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Offspring born to diabetic or obese mothers have a higher lifetime risk of heart disease. Previously, we found that rat offspring exposed to late-gestational diabetes mellitus (LGDM) and maternal high-fat (HF) diet develop mitochondrial dysfunction, impaired cardiomyocyte bioenergetics, and cardiac dysfunction at birth and again during aging. Here, we compared echocardiography, cardiomyocyte bioenergetics, oxidative damage, and mitochondria-mediated cell death among control, pregestational diabetes mellitus (PGDM)-exposed, HF-diet-exposed, and combination-exposed newborn offspring. We hypothesized that PGDM exposure, similar to LGDM, causes mitochondrial dysfunction to play a central, pathogenic role in neonatal cardiomyopathy. We found that PGDM-exposed offspring, similar to LGDM-exposed offspring, have cardiac dysfunction at birth, but their isolated cardiomyocytes have seemingly less bioenergetics impairment. This finding was due to confounding by impaired viability related to poorer ATP generation, more lipid peroxidation, and faster apoptosis under metabolic stress. To mechanistically isolate and test the role of mitochondria, we transferred mitochondria from normal rat myocardium to control and exposed neonatal rat cardiomyocytes. As expected, transfer provides a respiratory boost to cardiomyocytes from all groups. They also reduce apoptosis in PGDM-exposed males, but not in females. Findings highlight sex-specific differences in mitochondria-mediated mechanisms of developmentally programmed heart disease and underscore potential caveats of therapeutic mitochondrial transfer.

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“…Guariento and colleagues 1 describe a pilot clinical trial of a conceptually innovative form of regenerative therapyautologous mitochondrial transplantation (MT)-in ischemia-reperfusion injury. This approach extends an earlier report from this group describing the first inhuman use of autogenous MT in extracorporeal membrane oxygenation-dependent patients.…”

mentioning

confidence: 99%

Commentary: Autologous mitochondrial transplantation: An exciting innovation that needs evidence of efficacy

Barron

Coles

2021

The Journal of Thoracic and Cardiovascular Surgery

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Autologous mitochondrial transplantation for cardiogenic shock in pediatric patients following ischemia-reperfusion injury

Cited by 99 publications

References 29 publications

Mitochondrial transplantation therapy for ischemia reperfusion injury: a systematic review of animal and human studies

Mitochondrial transplantation therapy for ischemia reperfusion injury: a systematic review of animal and human studies

Mitochondrial Transfer Improves Cardiomyocyte Bioenergetics and Viability in Male Rats Exposed to Pregestational Diabetes

Commentary: Autologous mitochondrial transplantation: An exciting innovation that needs evidence of efficacy

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