Primary graft dysfunction after heart transplantation: a thorn amongst the roses

Singh, Sanjeet Singh Avtaar; Dalzell, Jonathan R.; Berry, Colin; Al‐Attar, Nawwar

doi:10.1007/s10741-019-09794-1

Cited by 86 publications

(72 citation statements)

References 209 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The primary outcome measurements are typically myocardial IS and cardiac function following ischemia and reperfusion ( 5 ). DAMPs and IRI are investigated less intensively in HTx ( 72 ). However, targeting DAMPs, was studied in kidney, liver and lung transplantation, aiming for a reduction of primary graft dysfunction and rejection ( 73 – 76 ).…”

Section: Damage-associated Molecular Patterns Related To Myocardial Imentioning

confidence: 99%

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

et al. 2020

View full text Add to dashboard Cite

In the setting of myocardial infarction (MI), ischemia reperfusion injury (IRI) occurs due to occlusion (ischemia) and subsequent re-establishment of blood flow (reperfusion) of a coronary artery. A similar phenomenon is observed in heart transplantation (HTx) when, after cold storage, the donor heart is connected to the recipient’s circulation. Although reperfusion is essential for the survival of cardiomyocytes, it paradoxically leads to additional myocardial damage in experimental MI and HTx models. Damage (or danger)-associated molecular patterns (DAMPs) are endogenous molecules released after cellular damage or stress such as myocardial IRI. DAMPs activate pattern recognition receptors (PRRs), and set in motion a complex signaling cascade resulting in the release of cytokines and a profound inflammatory reaction. This inflammatory response is thought to function as a double-edged sword. Although it enables removal of cell debris and promotes wound healing, DAMP mediated signalling can also exacerbate the inflammatory state in a disproportional matter, thereby leading to additional tissue damage. Upon MI, this leads to expansion of the infarcted area and deterioration of cardiac function in preclinical models. Eventually this culminates in adverse myocardial remodeling; a process that leads to increased myocardial fibrosis, gradual further loss of cardiomyocytes, left ventricular dilation and heart failure. Upon HTx, DAMPs aggravate ischemic damage, which results in more pronounced reperfusion injury that impacts cardiac function and increases the occurrence of primary graft dysfunction and graft rejection via cytokine release, cardiac edema, enhanced myocardial/endothelial damage and allograft fibrosis. Therapies targeting DAMPs or PRRs have predominantly been investigated in experimental models and are potentially cardioprotective. To date, however, none of these interventions have reached the clinical arena. In this review we summarize the current evidence of involvement of DAMPs and PRRs in the inflammatory response after MI and HTx. Furthermore, we will discuss various current therapeutic approaches targeting this complex interplay and provide possible reasons why clinical translation still fails.

show abstract

Section: Damage-associated Molecular Patterns Related To Myocardial Imentioning

confidence: 99%

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Heart transplantation (HT) is the treatment of choice for carefully selected patients with advanced or end-stage heart failure [1], with a median survival around 12 years. Among the different factors that may influence the prognosis of HT [2], cold ischemia time (CIT) has been associated with primary graft failure and mortality [3] and is one of the most important risk factors for early graft dysfunction [4]. However, there is still uncertainty regarding the CIT cutoff value that might have relevant clinical implications.…”

Section: Introductionmentioning

confidence: 99%

Cold ischemia >4 hours increases heart transplantation mortality. An analysis of the Spanish heart transplantation registry

Valero‐Masa

González‐Vílchez

Almenar‐Bonet

et al. 2020

International Journal of Cardiology

View full text Add to dashboard Cite

Background: Cold ischemia time (CIT) has been associated to heart transplantation (HT) prognosis. However, there is still uncertainty regarding the CIT cutoff value that might have relevant clinical implications. Methods: We analyzed all adults that received a first HT during the period 2008-2018. CITwas defined as the time between the cross-clamp of the donor aorta and the reperfusion of the heart. Primary outcome was 1month mortality. Results: We included 2629 patients, mean agewas 53.3±12.1 years and 655 (24.9%) were female. Mean CIT was 202 ± 67 min (minimum 20 min, maximum 600 min). One-month mortality per CIT quartile was 9, 12, 13, and 19%. One-year mortality per CIT quartile was 16, 19, 21, and 28%. CIT was an independent predictor of 1-month mortality, but only in the last quartile of CIT >246 min (odds ratio 2.1, 95% confidence interval 1.49-3.08, p < .001). We found no relevant differences in CIT during the study period. However, the impact of CIT in 1-month and 1-year mortality decreased with time (p value for the distribution of ischemic time by year 0.01), particularly during the last 5 years. Conclusions: Although the impact of CIT in HT prognosis seems to be decreasing in the last years, CIT in the last quartile (> 246 min) is associated with 1-month and 1-year mortality. Our findings suggest the need to limit HT with CIT N> 246 min or to use different myocardial preservation systems if the expected CIT is> 4 h.

show abstract

“…In DCD there will inevitably be WI as organ perfusion can be severely reduced before the formal diagnosis of circulatory arrest, and during the period of circulatory arrest. Prolonged time to flush organs in situ, remove them from the donor and place them on ice has been demonstrated to contribute to graft failure [100][101][102], and WI time has been shown to more harmful than CI time on a minute-for-minute basis [103]. For DCD donors the current critical practice of a 'stand-off' period (typically 5 min) after cessation of circulation before circulatory death can be confirmed and the organs are retrieved, also makes periods of WI hard to circumvent.…”

Section: Pharmacological Strategies Targeted To Mitochondria During Transplantationmentioning

confidence: 99%

Mitochondria as Therapeutic Targets in Transplantation

Saeb‐Parsy

Martin

Summers

et al. 2021

Trends in Molecular Medicine

View full text Add to dashboard Cite

Advances in surgical procedures, technology, and immune suppression have transformed organ transplantation. However, the metabolic changes that occur during organ retrieval, storage, and implantation have been relatively neglected since the developments many decades ago of cold storage organ preservation solutions. In this review we discuss how the metabolic changes that occur within the organ during transplantation, particularly those associated with mitochondria, may contribute to the outcome. We show how a better understanding of these processes can lead to changes in surgical practice and the development of new drug classes to improve the function and longevity of transplanted grafts, while increasing the pool of organs available for transplantation. Organ Preservation during TransplantationDevelopment of organ transplantation has transformed lives [1-10]. Initially using organs from living donors, its success led to a demand for organs from deceased donors, and thus a need for prolonged periods of extracorporeal storage to allow transport to the recipient center [1,2]. In situ flushing of donor organs with cold University of Wisconsin solution has become the most widely used procedure for organ preservation [1,2]. This approach is thought to protect the organ by slowing metabolism through cooling, providing osmotic support that stops cell rupture following disruption of ionic gradients as the ATP:ADP ratio falls, and reducing the ischemia-reperfusion (IR) injury that occurs upon transplantation of the graft (see Glossary) into the recipient [11,12]. Although emerging technologies allow preservation of some organs under normothermic and/or normoxemic conditions [13,14], rapid cooling at the onset of ischemia remains the mainstay of organ preservation, enabling the heart, kidney, and liver to be stored for up to~4 h, >24 h, and >12 h, respectively (Box 1). The precise duration depends on the quality of the organ, with organs from young, healthy donors being better able to tolerate longer periods of cold ischemia. Despite its widespread use and importance for transplantation, our understanding of why cold storage is protective is incomplete, and our understanding of the critical metabolic and mitochondrial changes that occur during organ retrieval, storage, and implantation in the recipient has lagged behind technical and immunological advances.Recently there has been greater understanding of how mitochondrial metabolism contributes to cell damage in general [15][16][17][18][19], and to poor outcome in transplantation in particular [20][21][22][23][24]. We discuss the mitochondrial and metabolic changes that contribute to tissue damage during transplantation and consider how to target these pathways therapeutically.

show abstract

Primary graft dysfunction after heart transplantation: a thorn amongst the roses

Cited by 86 publications

References 209 publications

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

Cold ischemia >4 hours increases heart transplantation mortality. An analysis of the Spanish heart transplantation registry

Mitochondria as Therapeutic Targets in Transplantation

Contact Info

Product

Resources

About