Трехлетние результаты перфузии аллотрансплантата ex vivo при трансплантации сердца: сравнение кардиоплегического раствора Кустодиол с тепловой кровяной кардиоплегией и кондиционированием

Резюме

Система транспортировки органов (Organ Care System, OCS) была разработана для более продолжительного и надежного хранения органов ex vivo. В настоящей статье представлены 3-летние результаты работы нашего центра по трансплантации органов у пациентов, у которых использовали стандартную кардиоплегию раствором Кустодиол, по сравнению с тепловой кровяной кардиоплегией.

Материал и методы. С мая 2014 г. по сентябрь 2017 г. 43 пациента, перенесших трансплантацию сердца на базе одного института, были рандомизированы по группам в зависимости от способа проведения кардиоплегии. В 1-й группе (n=13) для остановки донорского сердца перед изъятием и имплантацией использовали стандартную кардиоплегию раствором Кустодиол, во 2-й группе (n=30) с той же целью использовали тепловую кровяную кардиоплегию и кондиционирование. Была проведена оценка выживаемости, отсутствия васкулопатии аллотранс-плантата сердца (CAV), любого пролеченного отторжения трансплантата (ATR), нефатальных больших сердечно-сосудистых нежелательных явлений (NF-MACE) за 3 года. 

Результаты. Демографические характеристики реципиентов в каждой группе были сходными. 3-летняя частота выживаемости между группами статистически не различалась (77% в группе Кустодиола vs 67% в группе кровяной кардиоплегии и кондиционирования, p=0,5). Отсутствовала разница в отношении показателей CAV, ATR и NF-MACE. Среднее время перфузии ex vivo составило 282,5±86,7 мин в группе кровяной кардиоплегии по сравнению с 247,4±88,4 мин в группе стандартной кардиоплегии (p=0,87).

Заключение. Исходы трансплантации сердца после хранения донорского сердца с помощью системы для транспортировки органов в растворе Кустодиол или посредством тепловой кровяной кардиоплегии и кондиционирования свидетельствуют о том, что это многообещающие подходы, ассоциирующиеся со сходными промежуточными результатами.

Ключевые слова:трансплантация сердца, перфузия сердца ex vivo, кровяная кардиоплегия

Финансирование. Исследование было поддержано Министерством образования и науки Республики Казахстан (грант № AP05135095).
Конфликт интересов. Авторы заявляют об отсутствии конфликта интересов.
Для цитирования: Пя Ю.В., Калиев Р.Б., Бекбоссынова М.С., Лесбеков Т.Д., Бекбоссынов С.Т., Капышев Т.С., Нурмыхаметова Ж.А., Новикова С.П., Смагулов Н.К., Фаизов Л.Р., Куанышбек А.С., Андосова С.А., Мырзахметова Г.Ш., Турганбаева Г.М. Трехлетние результаты перфузии аллотрансплантата ex vivo при трансплантации сердца: сравнение кардиоплегического раствора Кустодиол с тепловой кровяной кардиоплегией и кондиционированием // Клиническая и экспериментальная хирургия. Журнал имени академика Б.В. Петровского. 2020. Т. 8, № 3. С. 27-31. DOI: https://doi.org/10.33029/2308-1198-2020-8-3-27-31 (англ.)

Heart transplantation is an established therapy for patients with end-stage heart failure (HF). Heart transplantation remains the final option only after all measures has not been successful in improving the degree of HF. Due to the growing number of patients with advanced HF and, at the same time, the stagnating number of available donor hearts, heart transplantation remains an option only for a limited number of patients. In spite of improvements in options for mechanical circulatory support in recent years, heart transplantation remains the approach most likely to improve survival and quality of life in patients with end stage heart failure [1]. Success in heart transplant depends on the quality of the donor heart, procurement, preservation and storage of the graft, the complexity of the operation and duration of graft ischemia [2].

In 2012, we initiated the first heart transplant program in Kazakhstan. Alongside initiatives to increase the donor pool, we sought ways to improve patient outcomes to mitigate the realities of a small donor pool and the long distances over which donor hearts are transported in our country [3]. In this context, the Organ Care System (Transmedics, OCS) is used at our center [4]. The OCS also allows for ex situ assessment of viability of donor hearts. The results of the PROCEED II study demonstrated a significant reduction in cold ischemic time for the OCS relative to standard cold storage donor preservation. The standard approach for donor heart harvesting is to use of custodiol cardiolplegic solution for arresting the heart, followed by reanimation of the heart in the OCS. Comparison of custodiol vs warm blood cardioplegia and conditioning of donor hearts during transportation with the organ care system.

In this report we evaluate the 3-year results following Custodiol versus warm blood cardioplegia and conditioning in patients after heart transplantation.

Material and methods

Participants

Between 2014 and 2017, 43 patients with heart failure underwent heart transplantation at our single center, and we used the OCS for donor heart preservation in all cases. Eligible recipients were at least 18 years of age and had to be on the heart-transplant waiting list. Of these, we arrested the donor heart before explant and before implant using blood cardioplegia and conditioning (BC group) in 30 cases and in 13 cases, we used standard Custodiol solution for cardioplegia (standard care group SC). The study received approval through the responsible ethics committee at our institution and all patients provided written informed consent to be part of this study and to allow their data to be used for the analysis. Endpoints included 3-year outcomes including survival, freedom from CAV (as defined by stenosis ≥30% by angiography), freedom from non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke), and freedom from any-treated rejection, acute cellular rejection, and antibody-mediated rejection.

Data analysis

Results were expressed as mean and standard deviation or median and interquartile range (continuous variables), and counts with percentages (categorical variables). Outcome measures used were allcause mortality using Kaplan-Meier survival curves. Statistical analyses were performed using STATA version 12 (StataCorp, Texas, US).

Results

Recipient and donor population

The donor and recipient characteristics and risk factors are shown in tab. 1. In the recipient group, the median age is slightly higher in the standard care group compared to the blood cardioplegia group. Other prognostic risk factors at baseline are similar between the two groups, including gender, body mass index and proportion of patients who were on a ventricular assist device at the time of transplant.

Table 1. The donor and recipient characteristics and risk factors

Note. Data are expressed as mean + standard deviation, unless otherwise noted; CVA - cerebrovascular accident; LVEF - left ventricular ejection fraction; BMI - body mass index; NICM - non-ischaemic cardiomyopathy; UNOS - United Network for Organ Sharing; VAD - ventricular assist device.

OCS data

Ischemic times and perfusion times of donor hearts in the OCS are shown in fig. 1. Mean (±stadard deviation) total ischemic time was 75.2 (±22) min in the blood cardioplegia group compared to 82.9 (±8.4) min in the standard care group. Mean ex vivo perfusion time was 282.5±86.7 min in the blood cardioplegia group compared to 247.4±88.4 min in the standard care group (p=0.87).

Fig. 1. Mean ischemic and perfusion time (minutes) of donor hearts in the OCS (p>0.05 for all comparison of BC versus SC group)

All donor hearts had stable perfusion and biochemical characteristics in the OCS and measures were similar between the two groups (fig. 2). Tissue Myocardial Doppler data at follow-up time were similar between the BC and SC groups, except for LVEF 60.2±3.21 vs 54.5±7.5 (p=0.01) respectively (tab. 2).

Fig. 2. Mean changes in perfusion measures in OCS Heart

Table 2.Tissue Myocardial Doppler data at follow-up time

Note. Data are expressed as mean ± standard deviation; TMD - tissue myocardial Doppler; S1LV - myocardial velocity associated with isovolumic contraction of left ventricle; S1RV - myocardial velocity associated with isovolumic contraction of right ventricle; LVEF - left ventricular ejection fraction.

Survival and graft failure

The total follow-up time was 3 patient-years. Overall, BC and SC group 10 vs 3 recipients died during follow-up period, resulting in 36 and 23% overall mortality. The mortality for the first month was 100% for both groups. The major causes for late mortality were: multiorgan failure (5 vs 2) and acute rejection (4 vs 1) and stroke in 1 patient in BC group. The overall 3-year survival of heart transplantation in BC and SC group were respectively 67 vs 77% (fig. 3). There were no difference in 3-year survival (p=0.5), freedom from CAV (p=0.9), freedom from non-fatal major adverse cardiac events (p=0.7), and freedom from any-treated rejection (p=0.7), acute cellular rejection (p=0.61), and antibody-mediated rejection (p=0.61) and the same cause of death (tab. 3).

Fig. 3. Kaplan-Meier survival estimates for patients in comparison (Blood cardioplegia and conditioning versus standard Custodiol group)

Table 3. Patient survival and freedom from adverse events

Note. CAV (as defined by stenosis ≥30% by angiography); NF-MACE - from non-fatal major adverse cardiac events; ATR - any-treated rejection; ACR - acute cellular rejection; AMR - antibody-mediated rejection.

Discussion

The preservation of a donor heart before transplantation for a longer period remains an unsolved problem in cardiac surgery. This is very important especially in the countries with low density of population and large distance between the organ procurement to the transplantation site. Organ procurement system might be of utmost importance in this situation. The effects of temporal changes in donor heart preservation in comparing of blood cardioplegia and conditioning versus Custodiol to survival after heart transplantation were analyzed in a single-center experience over a period of 3 years, firstly. Significant and clinically relevant changes were seen in the previous publication [4], show mean ex vivo heart perfusion ending concentration of IL-6 and IL-8 were significantly lower in the blood cardioplegia group compared to the standard care group. The use of blood cardioplegia and conditioning could be a safe method for myocardial protection in distant procurement and preservation of donor hearts in the OCS. ISHLT registry indicate [5], the main causes of 30-day mortality are acute rejection and multiorgan failure. Publication of data [6] showed that acute rejection was responsible for 9.4% of 30-day mortality after adult heart transplantation. Death from acute rejection may be reduced by improving rejection surveillance and appropriate treatment. McGiffin et al. [7] reported cardiac allograft vasculopathy as the causes of late mortality. Cardiac allograft vasculopathy, which is characterized by diffuse and multifocal heterogeneous myointimal hyperplasia, is reported as the most common cause of late mortality [8] with an incidence of 50-60% after 5 years post-transplantation [9]. More half success in heart transplantation survival depends on the quality of the donor heart, procurement, preservation and storage of the graft, the complexity of the operation and duration of graft ischemia.

The OCS has been used to prolong out-of-body time in some cases, expanding possibilities for organ procurement from distant sites [10]. This is an important consideration for centers such as which are forced to reckon with long transport distances and increasing rates of mechanical assist devices and fully artificial mechanical support device use in donor recipients.

Blood cardioplegia could provide near-physiologic conditions (oxygenated environment, normo-thermic) and could result in favorable patient outcomes. Adoption of this method of myocardial protection might be indicated to control early morbidity, particularly when poor donor organs are used in high-risk transplant recipients.

In our small cohort, the patient outcomes - survival and incidence of serious cardiac-related adverse events at 3-year post implant - were acceptable and demonstrate the feasibility of blood cardioplegia use with the preservation of a donor heart before transplantation for a longer period in OCS.

Our analysis has several limitations. This is a single center report. Lack of randomization and a difference of sample size are another limitations, and additional studies, ideally with randomized controlled design, are needed to evaluate the impact of procurement technique and conditioning of the donor heart during transportation might have on outcomes, especially with long ex vivo times during long distance transportation

Our results show that 3-year survival has no statistically differences between groups. We believe that transplant volume and the accumulation of our surgical experiences may correct for the expected worsening survival when higher risk transplantation is performed. A better understanding of transplant-related death may improve survival.

References 

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2.    Monteagudo Vela M., Garcia Saez D., Simon A.R. Current approaches in retrieval and heart preservation. Ann Cardiothorac Surg. 2018; 7 (1): 67-74.

3.    Pya Y., Bekbossynova M., Jetybayeva S., et al. Initial 3-year outcomes with left ventricular assist devices in a country with a nascent heart transplantation program. ESC Heart Fail. 2016; 3 (1): 26-34.

4.    Kaliyev R., Lesbekov T., Bekbossynov S. et al. Comparison of Custodiol vs blood cardioplegia and conditioning of donor hearts during transportation with the organ care system. J Card Surg. 2019; 34 (10): 969-75.

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6.    Hosenpud J.D., Bennett L.E., Keck B.M., Boucek M.M., Novick R.J. The Registry of the International Society for Heart and Lung Transplantation: eighteenth official report-2001. J Heart Lung Transplant. 2001; 20: 805-15.

7.    McGiffin D.C., Kirklin J.K., Naftel D.C., Bourge R.C. Competing outcomes after heart transplantation: a comparison of eras and outcomes. J Heart Lung Transplant. 1997; 16: 190-8.

8.    Gallo P., Agozzino L., Angelini A., Arbustini E., Bartoloni G., Bernucci P., et al. Causes of late failure after heart transplantation: a ten-year survey. J Heart Lung Transplant. 1997; 16: 1113-21.

9.    Uretsky B.F., Murali S., Reddy P.S., Rabin B., Lee A., Griffith B.P., et al. Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone. Circulation. 1987; 76: 827-34.

10.    Stamp N.L., Shah A., Vincent V., et al. Successful heart transplant after ten hours out-of-body time using the TransMedics Organ Care System. Heart Lung Circ. 2015; 24: 611-3.