When the “Most Precious Gift Ever” Fails Early On.

Published:March 03, 2023DOI:
      Heart transplantation offers the best long-term outcome for patients with advanced heart failure [1]. In the current issue of the Journal of Cardiothoracic and Vascular Anesthesia, Aljure et al. highlight the perioperative management of these complex cohort of patients [1].
      Compared to the large number of organ recipients, the number of donors is dramatically limited. Therefore, to increase the number of potential donors, “extended criteria” for donor selection such as advanced age, dependence on inotropic support, reduced left ventricular ejection fraction, and diabetes have been added to increase the potential donor pool [2]. However, this strategy clearly contributes to the risk of primary graft failure, a condition categorized by the International Society of Heart and Lung transplantation (ISHLT) in 2014 as mild, moderate or severe [3]. The cumulative incidence of primary graft failure is 20.5%, and is associated with 30-day mortality of up to 39% [4].
      The mechanisms underlying primary graft failure are manifold. The duration of allograft ischemia plays a pivotal role but is also critically impacted by donor age [5]. Ischemia and reperfusion injury results in a complex inflammatory process. At the cellular level, the formation of radical oxygen species and damaging proteins leads to cellular injury. At the microvascular level, the combination of increased immune cell attraction, cellular and interstitial edema formation, and activation of the coagulation cascade merges into a reduction in nutritive capillary blood flow, which can ultimately lead to a microvascular obstruction, resulting in a no-reflow phenomenon [6, 7]. In heart transplantation, unlike other organ transplants, ischemia and reperfusion injury is aggravated by the generally elevated inflammatory state of the recipient being induced by cardiopulmonary bypass. In addition to these primarily innate immune responses, the cardiac allograft is adversely altered by the homeostatic and metabolic state of the donor [6, 7].
      The functional correlate of the myocardium in this complex process is myocardial stunning, a disturbance in both systolic and diastolic myocardial function. Myocardial stunning has been well studied in the context of reperfusion after percutaneous coronary interventions and in fibrinolytic therapy after myocardial ischemia and infarction [8]. In this context, the myocardium of senescent animals has been found to be more susceptible to myocardial stunning than that of young animals [9]. The present data provide convincing evidence that recovery of stunned myocardium is not just a matter of hours but takes weeks, even after short periods of ischemia [8, 9]. [Figure 1.] In this context, it is evident that in moderate primary graft failure, stimulating the heart with high-dose vasopressor therapy is not optimal. Instead, prolonged reperfusion in a non-ejecting/unloaded state by early initiation of extracorporeal membrane oxygenation is increasingly advocated as a first-line strategy [3, 10]. However, prolonged reperfusion using extracorporeal membrane oxygenation carries the risks of peripheral vessel complications, hemorrhage, and pulmonary congestion [11]. Optimal outcome with this invasive strategy is not guaranteed.
      Figure 1
      Figure 1Myocardial ischemia and timing of myocardial stunning
      From reference (9): Panza JA, Chrzanowski L, Bonow RO. Myocardial Viability Assessment Before Surgical Revascularization in Ischemic Cardiomyopathy: JACC Review Topic of the Week. J Am Coll Cardiol. 2021 Sep 7;78(10):1068-1077. doi: 10.1016/j.jacc.2021.07.004. PMID: 34474740
      What are the strategies for the future? One promising approach is the use ex-vivo organ care systems which are designed to provide oxygen and nutrients during transport of donor-after brain-deaths hearts. Harvested and warm perfused allografts could overcome the negative consequences of prolonged transport times and the otherwise potentially fatal after-effects of conventional static cold storage [12]. The promising preliminary retrospective data derived from single-center experiences remain to be confirmed in larger randomized, prospective, multicenter trials and registry studies.
      Another possible strategy is rigorous and careful scoring using risk models for early graft failure and mortality. Organs should only be accepted for transplantation for a defined candidate under conditions where the risk of moderate primary graft failure is low. Appropriate tools are already available. Despite the obvious need to match blood groups, predicting a perfect organ match involves many more aspects than size- and gender-related items, which are well addressed by the ISHLT Predicted Heart Mass Match Calculator. The RADIAL risk score, introduced in 2011, includes six multivariate risk factors for primary graft failure [13]. The United Network of Organ Sharing scoring system (UNOS score) is used to predict 1-year mortality and considers more parameters of allograft function [14]. The preoperative risk stratification score (RSS) is similar to the UNOS score but is supplemented by advanced categorization of donor and recipient conditions and duration of ischemia [14]. Further risk assessment systems for short and intermediate outcomes, applied to a large European single-center database, have recently been found to provide reliable support for risk-adapted organ allocation [15]. However, the dynamics of technical development and the change in administrative regulations in the complex environment of heart transplantation requires continuous validation and development of these sophisticated risk assessment tools.
      A donor heart is the most precious gift which can be provided to a person with end-stage heart failure. We should take the utmost care to ensure that this gift brings new quality of life to the recipient.
      Declaration of interests
      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      1. Aljure OD, Derek T, Loebe M, et al. How would we treat our own heart transplantation surgery: A perioperative look. Journal of Cardiothoracic and Vascular Anesthesia (2023), doi: JCVA article
      2. Tong CKW, Khush KK. New Approaches to Donor Selection and Preparation in Heart Transplantation. Curr Treat Options Cardio Med. 2021;23:28.
      3. Kobashigawa J, Zuckermann A, Macdonald P, et al. Report from a consensus conference on primary graft dysfunction after cardiac transplantation. J Heart Lung Transplant. 2014;33:327-40.
      4. Buchan TA, Moayedi Y, Truby LK, et al. Incidence and impact of primary graft dysfunction in adult heart transplant recipients: A systematic review and meta-analysis. J Heart Lung Transplant. 2021;40:642-651.
      5. Lund LH, Khush KK, Cherikh WS, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Heart Transplantation Report-2017; Focus Theme: Allograft ischemic time. J Heart Lung Transplant. 2017;36:1037-1046.
      6. Toldo S, Quader M, Salloum FN, et al. Targeting the Innate Immune Response to Improve Cardiac Graft Recovery after Heart Transplantation: Implications for the Donation after Cardiac Death. Int J Mol Sci. 2016;17:958.
      7. Krezdorn N, Tasigiorgos S, Wo L, et al. Tissue conservation for transplantation. Innov Surg Sci. 2017;2:171-187.
      8. Heusch G. Myocardial stunning and hibernation revisited. Nat Rev Cardiol. 2021;18:522-536.
      9. Panza JA, Chrzanowski L, Bonow RO. Myocardial Viability Assessment Before Surgical Revascularization in Ischemic Cardiomyopathy: JACC Review Topic of the Week. J Am Coll Cardiol. 2021;78:1068-1077.
      10. Hull TD, Crowley JC, Villavicencio MA, et al. Primary graft dysfunction in heart transplantation: How to recognize it, when to institute extracorporeal membrane oxygenation, and outcomes. JTCVS Open. 2021;8:128-133.
      11. Morshuis M, Erdoes G, Koster A, et al. We Enter the Bridge and Start to Run Out of Time. J Cardiothorac Vasc Anesth. 2022;36:1251-1253.
      12. Bryner BS, Schroder JN, Milano CA. Heart transplant advances: Ex vivo organ-preservation systems. JTCVS Open. 2021;8:123-127.
      13. Segovia J, Cosío MD, Barceló JM, et al. RADIAL: a novel primary graft failure risk score in heart transplantation. J Heart Lung Transplant. 2011;30:644-51.
      14. Zheng S, Tang H, Zheng Z, et al. Validation of existing risk scores for mortality prediction after a heart transplant in a Chinese population. Interact Cardiovasc Thorac Surg. 2022;34:909-918.
      15. Schramm R, Zittermann A, Fuchs U, et al. Donor-recipient risk assessment tools in heart transplant recipients: the Bad Oeynhausen experience. ESC Heart Fail. 2021;8:4843-4851.

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      • How Would We Treat Our Own Heart Transplantation Surgery: A perioperative look
        Journal of Cardiothoracic and Vascular Anesthesia
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          Heart failure is a disease affecting 6.2 million adults in the United States, resulting in morbidity and mortality in the short and long term. While options such as mechanical circulatory support and transplantation are considered a solution when medical management is not sufficient, heart transplantation (HTX) is regarded as the better option with a lower incidence of multiorgan failure. A limiting step for heart transplantation is the inadequate donor pool so options like donation after circulatory death and xenotransplantation have emerged as alternatives.
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