- Email: [email protected]
Primary graft dysfunction after heart transplantation: What are we fighting for?
http://www.jhltonline.org
EDITORIAL
Primary graft dysfunction after heart transplantation: What are we fighting for? Michael Zakliczynski, MD From the Department of Cardiac, Vascular and Endovascular Surgery and Transplantology, Medical University of Silesia in Katowice, Silesian Centre for Heart Diseases, Zabrze, Poland
One may say that the reconnaissance-by-combat approach, the barbarian technique “popularized” by the Red Army during the Second World War, applies to almost all aspects of heart transplantation, but for me it is an especially accurate description of our attempts to explain and manage the problem of primary graft dysfunction (PGD). Despite efforts to explain PGD at the molecular level,1,2 it remains a “black box” that cannot be recognized in any other way. PGD’s definition is based on the source and means that are necessary in its management.3 Despite this limitation, in this issue of the journal, Sabatino and colleagues clearly prove that this definition is accurate.4 PGD is a sum of all unavoidable misfortunes and unexpected events that may occur during transplantation with regard to donor, recipient and organ preservation issues. However, there are known and statistically provable risk factors, such as older age of donor and/or recipient, high pulmonary vascular resistance, prolonged ischemic time, etc. More detailed analyses of our recipient populations may allow us to identify more distinctive risk factors, such as the greater likelihood of an immunologic background of PGD in African Americans5; however, most risk factors involve borderline quality of the transplanted organ, aggravated biologic status of the recipient and sub-optimal logistics of graft procurement.6,7 The question is not how to avoid them, but rather how to manage them and how to set the limits. The ISHLT registry clearly shows a sharply decreasing quality of heart donors (represented by their age) in Europe in contrast to North America.8 Sabatino et al show that pushing the limit of donor age each year becomes necessary to maintain the volume of transplants at a satisfactory level. As a result, the population of high-risk donors is overrepresented and the decision to properly allocate available organs has become a dilemma. The authors show that matching high-risk donors with high-risk recipients is not the best option, but this alarming level of risk may still E-mail address: [email protected]
be more acceptable, both by physician and patient, than moderately increased cumulative risk in high-risk donor/low-risk recipient combinations. The authors accurately identify the main limitation of their analysis, which is the low number of patients transplanted after bridging by mechanical circulatory support (MCS). Considering current trends, it is easy to suggest that patients with implantable left ventricular assist devices (LVADs) will comprise the majority of heart transplant recipients worldwide in the near future. This group of patients brings to account a history of at least 1 additional sternotomy and a burden of all complications typical for MCS, which are often the direct indication for the urgent transplantation. However, a benefit can also be anticipated—the problem of high pulmonary vascular resistance may be overcome in these individuals.9,10 The use of amiodarone as a potential risk factor for PGD in patients awaiting heart transplantation seems to be the biggest current controversy in the field. A review of the literature reveals the full range of perspectives with authors describing: the dose-dependent influence of amiodarone on PGD occurrence11; the negative impact on 1-year survival but with no significant increase in PGD number12; the lack of any interference with early survival13; and the beneficial effect of chronic amiodarone intake due to suppression of early atrial fibrillation after heart transplantation.14 The best illustration of this uncertainty can be seen in 2 metaanalyses prepared by the same authors over a 1-year interval, where the earlier study supports the deleterious effect of amiodarone on early survival15 and the more recent one rejects this view.16 However, the potential ways of linking amiodarone with PGD are numerous and most of them are easily explainable, so the recommendation to avoid this drug when possible, or to reduce its dose to the minimum before transplantation, should be strongly considered. Apart from the direct suppressive effect of amiodarone on the graft and especially its sinus node, the possible interactions with the first doses of immunosuppressive drugs, thyroid gland
1053-2498/$ - see front matter r 2017 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2017.09.025
2
The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]
dysfunction resulting in thyrotoxicosis or hypothyroidism, lung complications requiring prolonged ventilation, and even the higher rate of re-operations due to bleeding have been described in the literature.17–19 Heart transplantation remains a high-risk procedure, with an early death rate that would be hardly acceptable in another area of cardiac surgery. PGD remains the main cause of early death after the procedure. Our goal is to improve our results but the landscape of heart transplantation is changing irreversibly. We cannot reverse the direction of these changes but that does not mean we have to observe them passively. I am convinced it is time to develop an individualized method of matching donor and recipient to neutralize their risks rather than multiply them, and to test this method in a prospective fashion. Consequently, the prioritization of matches with the lowest risk of PGD should be reflected in the allocation system. With this approach we will not be doomed to solve our dilemmas using reconnaissance by combat.
Disclosure statement The author has no conflicts of interest to disclose.
References 1. Aharinejad S, Schäfer R, Krenn K, et al. Donor myocardial HIF-1alpha is an independent predictor of cardiac allograft dysfunction: a 7-year prospective, exploratory study. Am J Transplant 2007;7:2012-9. 2. Yang X, Wu X, Wu K, et al. Correlation of serum- and glucocorticoidregulated kinase 1 expression with ischemia-reperfusion injury after heart transplantation. Pediatr Transplant 2015;19:196-205. 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. Sabatino M, Vitale G, Manfredini V, et al. Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: epidemiology, risk factors, and outcomes [e-pub ahead of print]. J Heart Lung Transplant http://dx.doi.org/10.1016/j.healun.2017.02. 014, accessed October 24, 2017. 5. Morris AA, Kalogeropoulos AP, Zhao L, et al. Race and ethnic differences in the epidemiology and risk factors for graft failure after heart transplantation. J Heart Lung Transplant 2015;34:825-31.
6. Singh TP, Almond CS, Semigran MJ, et al. Risk prediction for early inhospital mortality following heart transplantation in the United States. Circ Heart Fail 2012;5:259-66. 7. 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. 8. Lund LH, Edwards LB, Dipchand AI, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-third adult heart transplantation report—2016; Focus theme: Primary diagnostic indications for transplant. J Heart Lung Transplant 2016;35: 1158-69. 9. Mikus E, Stepanenko A, Krabatsch T, et al. Reversibility of fixed pulmonary hypertension in left ventricular assist device support recipients. Eur J Cardiothorac Surg 2011;40:971-7. 10. Atluri P, Fairman AS, MacArthur JW, et al. Continuous flow left ventricular assist device implant significantly improves pulmonary hypertension, right ventricular contractility, and tricuspid valve competence. J Card Surg 2013;28:770-5. 11. Wright M, Takeda K, Mauro C, et al. Dose-dependent association between amiodarone and severe primary graft dysfunction in orthotopic heart transplantation [e-pub ahead of print]. J Heart Lung Transplant http://dx.doi.org/10.1016/j.healun.2017.05.025, accessed October 24, 2017. 12. Cooper LB, Mentz RJ, Edwards LB, et al. Amiodarone use in patients listed for heart transplant is associated with increased 1-year post-transplant mortality. J Heart Lung Transplant 2017;36: 202-10. 13. Chelimsky-Fallick C, Middlekauff HR, et al. Amiodarone therapy does not compromise subsequent heart transplantation. J Am Coll Cardiol 1992;20:1556-61. 14. Rivinius R, Helmschrott M, Ruhparwar A, et al. Comparison of posttransplant outcomes in patients with no, acute, or chronic amiodarone use before heart transplantation. Drug Des Devel Ther 2017;11: 1827-37. 15. Baker WL, Jennings DL. Pre-cardiac transplant amiodarone use increases postoperative mortality: a meta-analysis. Ann Pharmacother 2016;50:514-5. 16. Jennings DL, Baker WL. Pre-cardiac transplant amiodarone use is not associated with postoperative mortality: an updated meta-analysis. Int J Cardiol 2017;236:345-7. 17. Jennings DL, Martinez B, Montalvo S, et al. Impact of preimplant amiodarone exposure on outcomes in cardiac transplant recipients. Heart Fail Rev 2015;20:573-8. 18. Siccama R, Balk AH, de Herder WW, et al. Amiodarone therapy before heart transplantation as a predictor of thyroid dysfunction after transplantation. J Heart Lung Transplant 2003;22:857-61. 19. Blomberg PJ, Feingold AD, Denofrio D, et al. Comparison of survival and other complications after heart transplantation in patients taking amiodarone before surgery versus those not taking amiodarone. Am J Cardiol 2004;93:379-81.
EDITORIAL
Primary graft dysfunction after heart transplantation: What are we fighting for? Michael Zakliczynski, MD From the Department of Cardiac, Vascular and Endovascular Surgery and Transplantology, Medical University of Silesia in Katowice, Silesian Centre for Heart Diseases, Zabrze, Poland
One may say that the reconnaissance-by-combat approach, the barbarian technique “popularized” by the Red Army during the Second World War, applies to almost all aspects of heart transplantation, but for me it is an especially accurate description of our attempts to explain and manage the problem of primary graft dysfunction (PGD). Despite efforts to explain PGD at the molecular level,1,2 it remains a “black box” that cannot be recognized in any other way. PGD’s definition is based on the source and means that are necessary in its management.3 Despite this limitation, in this issue of the journal, Sabatino and colleagues clearly prove that this definition is accurate.4 PGD is a sum of all unavoidable misfortunes and unexpected events that may occur during transplantation with regard to donor, recipient and organ preservation issues. However, there are known and statistically provable risk factors, such as older age of donor and/or recipient, high pulmonary vascular resistance, prolonged ischemic time, etc. More detailed analyses of our recipient populations may allow us to identify more distinctive risk factors, such as the greater likelihood of an immunologic background of PGD in African Americans5; however, most risk factors involve borderline quality of the transplanted organ, aggravated biologic status of the recipient and sub-optimal logistics of graft procurement.6,7 The question is not how to avoid them, but rather how to manage them and how to set the limits. The ISHLT registry clearly shows a sharply decreasing quality of heart donors (represented by their age) in Europe in contrast to North America.8 Sabatino et al show that pushing the limit of donor age each year becomes necessary to maintain the volume of transplants at a satisfactory level. As a result, the population of high-risk donors is overrepresented and the decision to properly allocate available organs has become a dilemma. The authors show that matching high-risk donors with high-risk recipients is not the best option, but this alarming level of risk may still E-mail address: [email protected]
be more acceptable, both by physician and patient, than moderately increased cumulative risk in high-risk donor/low-risk recipient combinations. The authors accurately identify the main limitation of their analysis, which is the low number of patients transplanted after bridging by mechanical circulatory support (MCS). Considering current trends, it is easy to suggest that patients with implantable left ventricular assist devices (LVADs) will comprise the majority of heart transplant recipients worldwide in the near future. This group of patients brings to account a history of at least 1 additional sternotomy and a burden of all complications typical for MCS, which are often the direct indication for the urgent transplantation. However, a benefit can also be anticipated—the problem of high pulmonary vascular resistance may be overcome in these individuals.9,10 The use of amiodarone as a potential risk factor for PGD in patients awaiting heart transplantation seems to be the biggest current controversy in the field. A review of the literature reveals the full range of perspectives with authors describing: the dose-dependent influence of amiodarone on PGD occurrence11; the negative impact on 1-year survival but with no significant increase in PGD number12; the lack of any interference with early survival13; and the beneficial effect of chronic amiodarone intake due to suppression of early atrial fibrillation after heart transplantation.14 The best illustration of this uncertainty can be seen in 2 metaanalyses prepared by the same authors over a 1-year interval, where the earlier study supports the deleterious effect of amiodarone on early survival15 and the more recent one rejects this view.16 However, the potential ways of linking amiodarone with PGD are numerous and most of them are easily explainable, so the recommendation to avoid this drug when possible, or to reduce its dose to the minimum before transplantation, should be strongly considered. Apart from the direct suppressive effect of amiodarone on the graft and especially its sinus node, the possible interactions with the first doses of immunosuppressive drugs, thyroid gland
1053-2498/$ - see front matter r 2017 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2017.09.025
2
The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]
dysfunction resulting in thyrotoxicosis or hypothyroidism, lung complications requiring prolonged ventilation, and even the higher rate of re-operations due to bleeding have been described in the literature.17–19 Heart transplantation remains a high-risk procedure, with an early death rate that would be hardly acceptable in another area of cardiac surgery. PGD remains the main cause of early death after the procedure. Our goal is to improve our results but the landscape of heart transplantation is changing irreversibly. We cannot reverse the direction of these changes but that does not mean we have to observe them passively. I am convinced it is time to develop an individualized method of matching donor and recipient to neutralize their risks rather than multiply them, and to test this method in a prospective fashion. Consequently, the prioritization of matches with the lowest risk of PGD should be reflected in the allocation system. With this approach we will not be doomed to solve our dilemmas using reconnaissance by combat.
Disclosure statement The author has no conflicts of interest to disclose.
References 1. Aharinejad S, Schäfer R, Krenn K, et al. Donor myocardial HIF-1alpha is an independent predictor of cardiac allograft dysfunction: a 7-year prospective, exploratory study. Am J Transplant 2007;7:2012-9. 2. Yang X, Wu X, Wu K, et al. Correlation of serum- and glucocorticoidregulated kinase 1 expression with ischemia-reperfusion injury after heart transplantation. Pediatr Transplant 2015;19:196-205. 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. Sabatino M, Vitale G, Manfredini V, et al. Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: epidemiology, risk factors, and outcomes [e-pub ahead of print]. J Heart Lung Transplant http://dx.doi.org/10.1016/j.healun.2017.02. 014, accessed October 24, 2017. 5. Morris AA, Kalogeropoulos AP, Zhao L, et al. Race and ethnic differences in the epidemiology and risk factors for graft failure after heart transplantation. J Heart Lung Transplant 2015;34:825-31.
6. Singh TP, Almond CS, Semigran MJ, et al. Risk prediction for early inhospital mortality following heart transplantation in the United States. Circ Heart Fail 2012;5:259-66. 7. 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. 8. Lund LH, Edwards LB, Dipchand AI, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-third adult heart transplantation report—2016; Focus theme: Primary diagnostic indications for transplant. J Heart Lung Transplant 2016;35: 1158-69. 9. Mikus E, Stepanenko A, Krabatsch T, et al. Reversibility of fixed pulmonary hypertension in left ventricular assist device support recipients. Eur J Cardiothorac Surg 2011;40:971-7. 10. Atluri P, Fairman AS, MacArthur JW, et al. Continuous flow left ventricular assist device implant significantly improves pulmonary hypertension, right ventricular contractility, and tricuspid valve competence. J Card Surg 2013;28:770-5. 11. Wright M, Takeda K, Mauro C, et al. Dose-dependent association between amiodarone and severe primary graft dysfunction in orthotopic heart transplantation [e-pub ahead of print]. J Heart Lung Transplant http://dx.doi.org/10.1016/j.healun.2017.05.025, accessed October 24, 2017. 12. Cooper LB, Mentz RJ, Edwards LB, et al. Amiodarone use in patients listed for heart transplant is associated with increased 1-year post-transplant mortality. J Heart Lung Transplant 2017;36: 202-10. 13. Chelimsky-Fallick C, Middlekauff HR, et al. Amiodarone therapy does not compromise subsequent heart transplantation. J Am Coll Cardiol 1992;20:1556-61. 14. Rivinius R, Helmschrott M, Ruhparwar A, et al. Comparison of posttransplant outcomes in patients with no, acute, or chronic amiodarone use before heart transplantation. Drug Des Devel Ther 2017;11: 1827-37. 15. Baker WL, Jennings DL. Pre-cardiac transplant amiodarone use increases postoperative mortality: a meta-analysis. Ann Pharmacother 2016;50:514-5. 16. Jennings DL, Baker WL. Pre-cardiac transplant amiodarone use is not associated with postoperative mortality: an updated meta-analysis. Int J Cardiol 2017;236:345-7. 17. Jennings DL, Martinez B, Montalvo S, et al. Impact of preimplant amiodarone exposure on outcomes in cardiac transplant recipients. Heart Fail Rev 2015;20:573-8. 18. Siccama R, Balk AH, de Herder WW, et al. Amiodarone therapy before heart transplantation as a predictor of thyroid dysfunction after transplantation. J Heart Lung Transplant 2003;22:857-61. 19. Blomberg PJ, Feingold AD, Denofrio D, et al. Comparison of survival and other complications after heart transplantation in patients taking amiodarone before surgery versus those not taking amiodarone. Am J Cardiol 2004;93:379-81.