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 . 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 .
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 . In this context, the Organ Care System
(Transmedics, OCS) is used at our center . 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
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
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
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).
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.
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
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 -
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 , 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 , the main causes of 30-day
mortality are acute rejection and multiorgan failure. Publication
of data  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.  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  with an incidence of 50-60% after 5 years
post-transplantation . 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 . 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
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.
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