ABSTRACT
Background
Ex situ heart perfusion (ESHP) allows longer preservation times and provides the opportunity to assess cardiac function. The goal of our study was to evaluate the impact of the treatment of beating heart in normothermic ESHP based on ECMO technology on post‐transplant graft function in an animal model.
Methods
Ten healthy male adult domestic pigs weighting 90–95 kg were selected to donate hearts n = 5 donors for prolonged (24 h) normothermic ESHP based on ECMO technology and n = 5 recipients. Perfusion system consisted of ECMO oxygenator, centrifugal pump, tubing and integrated ultrafiltration device. Baseline echocardiographic and hemodynamic parameters, along with coronary angiography, were evaluated before each heart explantation, during ex situ perfusion, and prior to transplantation. Following 24 h of ESHP, orthotopic heart transplants were performed utilizing the bicaval technique during 4 posttransplant hours. Outcomes of interest were the change in lactate, ischemic time, perfusion time, hemodynamic evaluation of the heart, and morphologic changes after heart transplantation.
Results
Heart harvesting, continuous ESHP for 24 h followed by orthotopic transplantation was performed. The mean duration was 1440 ± 80 min. Echocardiographic evaluation of the heart during ex vivo perfusion revealed a normal trend of Tissue Doppler Imaging (TDI) parameters. The mean left ventricular ejection fraction after heart transplantation was 48% (±0.7), cardiac output and cardiac index after transplantation was 6.0 L/min (±0.7) and 3.1 (±0.2) l/min/m2, respectively. For over 4 h post‐transplant, there was no evidence of graft dysfunction.
Conclusions
This study demonstrates that hearts without prior DBD/DCD exposure or cold ischemic injury are able to recover and maintain functional viability following 24 h of ex‐situ heart perfusion.
Keywords: 24 h, ECMO, ex‐situ normothermic perfusion, heart transplantation
Normothermic ESHP allows longer preservation times and provides the opportunity to assess cardiac function. Five porcine models were selected for heart harvesting, continuous ESHP for 24 h followed by orthotopic transplantation. ESHP based on ECMO technology in a non‐working model of the heart offers a safe and efficient preservation of the isolated organ.
1. Background
It is well recognized that the quality of donor hearts and the donor heart ischemic time are the key determinants of success of transplantation [1]. Cold ischemic time for the heart is limited to 4–6 h; longer ischemic times might increase the risk of post‐transplant adverse events and the risk of primary graft dysfunction. Geographical limitations in donor–recipient matching lead to underutilization of donor hearts [2, 3]. Analyses of large data sets have shown that success of heart transplant is impacted by the quality of the donor heart, procurement, preservation, graft storage, the complexity of the operation, ischemic time, and recipient comorbidities [4].
According to the Organ Preservation Alliance, almost two‐thirds of US donor hearts go untransplanted, largely due to preservation limits on assessment and matching. The preservation limits also mean that those who receive grafts often get suboptimal matching [5].
Normothermic ex‐situ heart perfusion (ESHP) allows for a longer organ preservation time and provides the opportunity to assess cardiac function, viability, and metabolism.
The current clinically available Organ Care System (OCS) relies on metabolic findings, mainly lactate concentration during perfusion to determine if the heart is suitable for transplant, limiting the ability to predict post‐transplant functional recovery [6]. Reported the “end of perfusion” lactate concentration of less than 5 mmol/L was the most powerful predictor of post‐transplantation graft failure (63% sensitivity, 93% specificity) in 30‐day outcomes [4]. But nowadays, the increasing donor after cardiac death (DCD) donation process makes it very challenging to rely only on the final lactate concentration, and even on its venous–arterial difference as a parameter of heart metabolism [7, 8]. In this context, the need for the functional, alongside the metabolic assessment of the ex situ perfused hearts to determine the eligibility of the heart for safe transplantation is warranted [9].
The goal of our study was to evaluate the impact of the treatment of beating heart in normothermic ESHP based on ECMO technology on post‐transplant graft function in an animal model.
Our study sought to provide proof of concept by investigating the impact of ECMO‐based ex‐situ normothermic perfusion for beating heart preservation on post‐transplant graft performance in an animal model.
2. Methods
2.1. Perfusion System Setup
The primary components of the perfusion ECMO circuit were: oxygenator, centrifugal pump, 3/8 in. tubing (Xenios AG, a Fresenius Medical Care company, Heilbronn, Germany) connected to special closed integrated reservoir (made in our institution), a room air flow generator (made in our institution), and a flow meter (Xenios AG, a Fresenius Medical Care company, Heilbronn, Germany). The ultrafiltration device (Xenios AG, a Fresenius Medical Care company, Heilbronn, Germany) was connected to the system. The centrifugal pump flow of the ESHP system was adjusted to maintain the mean aortic pressure between 60 and 70 mmHg and blood flow between 500 and 800 mL/min. Aortic root pressure was measured via a pressure transducer connected to a stopcock on the aortic cannula.
Blood from the coronary sinus was collected into the integrated reservoir via gravity drainage. Perfusate temperature was managed with the heater‐cooler of the ECMO system. The hearts were perfused for 24 h, and then arrested with normothermic blood cardioplegia and transplanted to recipient animals.
2.2. Perfusate Preparation
The ESHP system was primed with blood from the donor pig and diluted to achieve a mean hematocrit of 22% (2% standard deviation, hereafter SD), making a total volume of approximately 1 L. The oxygenator facilitated gas exchange using 0.1–0.9 L per minute (L/min) of atmospheric air flow. Its integrated heat exchanger was used to keep the perfusate at normothermic 36°C temperature. The system was then de‐aired and circulation started at a low flow. A one‐way valve within 3/8 arterial line was incorporated to return line to maintain aortic root pressure and prevent backflow and risk of coronary air embolism from left ventricle. Pharmacological support was provided via controlled on‐demand infusion of epinephrine, glucose, insulin, sodium nitroprussid, and sodium bicarbonate. Hemoglobin and glucose were checked every 30 min during ESHP. Similarly, the perfusate was maintained at a normal range of pH = 7.4 (SD 0.1).
Active zero balance ultrafiltration with Sterofundin as a plasma substitution solution was used to maintain the hematocrit and electrolytes in the target normal range. Calcium was normalized to 0.80 mmol/L, and the pH was adjusted with NaHCO3 as needed.
2.3. Experimental Design
The study employed 10 healthy male adult domestic pigs, weighing 90–95 kg. In the D/R combination, the donor (D) and recipient (R) pigs had matching blood types and similar immunologic characteristics. Hearts of five animals were harvested and underwent ESHP for 24 h. Heart perfusion was performed using modified ECMO technology. After 24 h of ex‐situ perfusion the donor hearts were transplanted using the bicaval technique of five recipient animals. After transplantation the recipient animals were weaned from cardiopulmonary bypass, monitored, and treated for four hours. The four‐hour observation period was chosen in accordance with institutional protocols, which identify this timeframe as capturing the most clinically significant early post‐transplant events. After four hours, the final assessment of the transplanted grafts was performed by echocardiography and pulmonary artery catheter. Design of the experiment is presented in Figure 1. Animals were treated following the Principles of Laboratory Animal Care prepared for Medical Research and the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources. The study was approved by the National Research Cardiac Surgery Center's Animal Care and Use Committee (Protocol No 2022/01–121).
FIGURE 1.
Simplified schema of the experimental design and protocol. [Color figure can be viewed at wileyonlinelibrary.com]
2.4. Donor Procedure
2.4.1. Anesthesia and Monitoring
Prior to surgery, food was withheld from each pig for 24 h and water for 12 h. Following induction, each pig was intubated with an endotracheal tube and mechanically ventilated. Thiopental sodium (10–15 mg/kg), administered through an angiocatheter, and isoflurane (0.5%–4%) was used to maintain the general anesthesia.
2.4.2. Surgical Procedure
A median sternotomy was performed, and the pericardium was opened. Anticoagulation was achieved with IV injection of 300 international units/kg of heparin to obtain an activated clotting time greater than 480 s. A double‐outlet needle was inserted in the ascending aorta and secured with a 4–0 polypropylene purse‐string suture. Through it, 500 mL of the normothermic oxygenated blood was collected and used for the blood component of short‐acting blood cardioplegia solution. 1000 mL of blood was collected as priming solution for the normothermic ESHP system, followed by aorta cross clamping and cardioplegic solution administration. After complete arrest, the heart was dissected and prepared for ESHP.
2.5. Heart Harvesting and Preparation
After the collection of baseline measurements, a single dose of normothermic blood cardioplegia (10–15 mL/kg., 36°C) mixed in a ratio of four parts donor blood to one part crystalloid was delivered. The heart was then excised and stored approximately 15–20 min while preparing to be connected to the normothermic ESHP system (Figure 2). In the ESHP system, oxygenated blood was perfused by a centrifugal pump into the aorta (retrograde fashion), perfusing the coronary arteries. The venous return from the coronary sinus was ejected through the pulmonary artery cannula only, and coronary blood flow (CBF) was monitored, as well as blood gases. The heart was oriented in the ESHP system so that the aorta was facing upward with the posterior aspect of the heart resting on a pad, which is part of our custom integrated blood reservoir. The left ventricle was passively vented with the soft silicone samp tube via one of the pulmonary vein orifices.
FIGURE 2.
The scheme and picture of portable ex situ perfusion system (our development) 1‐integrated box reservoir for a donor heart placement, 2‐oxygenator, 3‐centrifugal pump, 4‐gas exchange using atmosphere airflow and lines connecting all components. [Color figure can be viewed at wileyonlinelibrary.com]
2.6. Recipient Procedure
Preparation, anesthesia and monitoring were performed as in the donor animals. After median sternotomy, heart and great vessels were exposed and the superior and inferior vena cava were encircled. Standard bicaval cardiopulmonary bypass (CPB) was initiated. For heart implant, we used a standard bicaval anastomotic technique in sequence: left atrium, pulmonary artery, ascending aorta, inferior vena cava and superior vena cava. Myocardial protection was achieved by administering 500 mL of a 4:1 mixture of blood/crystalloid and delivered at 36°C every 20 min. Before removal of the aortic cross clamp, 500 mg of methylprednisolone was administered. Weaning from CPB was deemed successful if the animal maintained a mean systolic arterial pressure of 60 mmHg for 4 h after the discontinuation of CPB. A vasoactive infusion of dobutamine (5 μg/kg/min) and norepinephrine (0.1 μg/kg/min) was used to facilitate weaning from cardiopulmonary bypass. Hemodynamics and biventricular functional assessments were performed at 4 h postreperfusion, following which, the experiment was terminated.
2.7. Experimental Measurements
2.7.1. Myocardial Function
Parameters such as pH, lactate level, pO2, pCO2, hemoglobin, hematocrit, oxygen saturation, lactate, and electrolytes (ABL 800, Flex, Radiometer, Denmark), IL‐1, IL‐6, IL‐10 were measured and recorded. Coronary vascular resistance (CVR) and myocardial oxygen consumption (MVO2) were evaluated.
Global cardiac function in vivo was evaluated by cardiac output measurement using the pulmonary artery catheter and thermodilution technique (Swan‐Ganz catheter, Edwards Lifesciences, Irvine, CA).
2.7.2. Cardiac Echocardiography
Epicardial echocardiography was performed using a standard transthoracic echocardiographic probe (Philips Epiq, Netherlands) during in vivo and ex‐situ periods. During the ESHP period, tissue Doppler parameters were measured.
2.7.3. Coronary Angiography
Coronary angiography (CAG) was performed at the cardiac catheterization laboratory with standard hemodynamic monitoring and radiographic capabilities. The C‐arm angulation was adjusted to reach a comprehensive angiographic acquisition of the coronary arteries. (Figure 3).
FIGURE 3.
Coronary angiography (CAG findings: Normal, without spasm or malperfusion.) [Color figure can be viewed at wileyonlinelibrary.com]
The lowest possible volume of a low‐concentration, nonionic, water‐soluble, iodinated radiographic contrast medium (Omnipaque; GE Healthcare) was used.
The primary outcome of this study was the number of hearts successfully transplanted after 24 h of normothermic ESHP. Criteria of successful transplantation were defined as: weaning from CPB without or minimal doses of vasopressor (≤ 0.1 μg/kg/min Norepinephrine) and/or inotrope (≤ 5 μg/kg/min Dobutamine) support for the following 4 consecutive hours. Secondary outcomes included CVR during ESHP, lactate concentration, weight gain, hemodynamic parameters prior to heart excision from the donor animal and after separation from CPB in the recipient animal, and histologic injury scores.
2.8. Statistical Analysis
Categorical variables were expressed as group percentages, and continuous variables were expressed as mean ± standard deviation or median with IQR depending on overall distribution. Normally distributed continuous variables were compared using repeated‐measures analysis of variance or paired t‐test where appropriate (Minitab 15), and reported as mean ± standard deviation. A p‐value < 0.05 was considered statistically significant.
3. Results
Continuous ESHP for 24 h followed by orthotopic transplantation was performed in five animals. The animal characteristics, myocardial function markers, physiologic parameters, and electrolyte status before ESHP and after HTx are summarized in Table 1.
TABLE 1.
Characteristics and measurement of myocardial function, physiologic parameters, and electrolyte status before ESHP and after heart transplantation.
| Demographics | n = 5 (in vivo before perfusion) | n = 5 (in vivo after HTx) |
|---|---|---|
| Mean (SD) | Mean (SD) | |
| Body weight (kg) | 95 (5.6) | 92 (3.1) |
| BSA (m2) | 6.7 (0.3) | 6.3 (0.2) |
| Heart weight (g) | 308.4 (84) | 407 (71) |
| Myocardial function indices | ||
| Indexed myocardial Oxygen consumption (MVO2) (mL O2/min/100 g) | 5.4 (1.3) | 4.1 (1.4) |
| Cardiac output (l/min) | 5.8 (0.8) | 6.0 (0.7) |
| Cardiac index (l/min/m2) | 3.2 (0.4) | 3.1 (0.2) |
| CBF (mL/min) | 390 (0.06) | 410 (0.1) |
| MAP (mmHg) | 73 (14.6) | 81 (11.1) |
| Left ventricular ejection fraction | 59% (3) | 48% (0.7) |
| Physiologic parameters | ||
| Arterial lactates (mmol/L) | 1.34 (0.59) | 2.4 (0.2) |
| Hemoglobin (g/dL) | 10.9 (1.22) | 11.1 (1.3) |
| Glucose (mg/dL) | 7.7 (2.01) | 6.5 (3.1) |
| Temperature (°C) | 36.5 (0.2) | 36.6 (0.1) |
| pH | 7.45 (0.08) | 7.41 (0.02) |
| Electrolyte status | ||
| Ca2 + (mmoL/L) | 1.35 (0.07) | 1.4 (0.03) |
| K+ (mEq/L) | 3.91 (0.7) | 3.5 (0.9) |
| Na+ (mEq/L) | 143.4 (3.96) | 144.3 (2.1) |
| HCO3 − (mmoL/L) | 27.3 (1.79) | 25.2 (1.2) |
Note: CBF (mL/min); MAP (mmHg).
The mean ischemic time prior to starting ESHP was 21.2 ± 3.3 min, the duration of ex‐situ perfusion was 1440 ± 80 min, and the restoration of heart rhythm occurred at the average of 2.5 ± 2.2 min following the initiation of ex‐situ reperfusion. Coronary blood flow, mean arterial pressure (MAP), and heart rate were in normal range and presented in Figure 4.
FIGURE 4.
(A) Ex situ heart perfusion data and (B) CBF (mL/min), heart rate (beats a minute), AP (mmHg) of the pig hearts every hour of ex situ perfusion. All data are shown as mean ± SD. [Color figure can be viewed at wileyonlinelibrary.com]
Through all 24 h of ESHP, hearts maintained good function, evaluated by echocardiography (Figure 5). The mean left ventricular ejection fraction after heart transplantation was 48% (±0.7).
FIGURE 5.
The mean TDI parameters trend during ex situ perfusion (1‐donor, 2–20 min after ex situ perfusion, 3‐after four hour ex situ perfusion, 4‐ before ending of ex situ perfusion, 5‐ after heart transplantation) and histological characteristics. S1LV – myocardial velocity associated with isovolumic contraction of left ventricle; S1RV – myocardial velocity associated with isovolumic contraction of right ventricle. [Color figure can be viewed at wileyonlinelibrary.com]
For over 4 h post‐transplant, there was no evidence of graft dysfunction. On the contrary, the hemodynamic evaluation showed good cardiac function with the mean cardiac output and cardiac index measured with Swan‐Ganz catheter shortly after heart transplantation of 6.0 L/min (±0.7) and 3.1 (±0.2) l/min/m2, respectively.
Histological evaluation of the myocardium after the 24 h ex vivo perfusion followed by heart transplantation demonstrated slight dystrophic changes of cardiomyocytes of the myocardium of the left ventricle, right ventricle, and interventricular septum (Figure 6).
FIGURE 6.
Histological and MRI picture (T1, T2 regimes Siemens Magnetom Avanto 1.5 Tesla). Histological characteristics (semi thin slice of left ventricular myocardium, right ventricular myocardium and interventricular septum ×200 has demonstrated myocardium with dystrophic changes in cardiomyocytes of varying severity, serous endomyocarditis) after 24 h ex situ perfusion system and MRI picture. [Color figure can be viewed at wileyonlinelibrary.com]
All five transplanted hearts showed stable perfusion, biochemical characteristics during 24 h ESHP, transplantation, 4 h post‐transplant and a normal MRI (Late Gadolinium Enhancement) picture (preserved myocardial structure, perfusion and contractility, and absence of ischemic damage) (Figure 6). During ESHP the hearts showed a mean weight gain of 24% ± 9%, indicating variable but moderate myocardial edema. A slight increase of interleukins (IL—1, IL—6, IL—8 and TNF) was observed during the ex‐situ heart perfusion (Figure 7).
FIGURE 7.
The mean parameters of interleukins A‐IL‐1α, B‐6, C‐8, D‐TNF‐a trends (1‐donor, 2‐priming volume, 3–20 min after ex situ perfusion, 4‐two hour ex situ perfusion, 5‐after four hour ex situ perfusion, 6‐before ending of ex situ perfusion). [Color figure can be viewed at wileyonlinelibrary.com]
4. Discussion
In our study, we used a group of healthy pigs without neurological determination of death to avoid myocardial dysfunction and damage, and to focus on the impact of the extracorporeal circuit on the heart without a confounder, such as temperature/ischemia–reperfusion injury and hormonal imbalance. In addition, we avoided using cold crystalloid cardioplegic solution to be able to focus on ESHP‐related alterations only.
Johnson et al. reported extended viability of hearts in ESHP to a minimum of 24 h with the use of hemofiltration, indicating that failure of the perfused heart is caused by factors accumulating in the perfusate which can be removed by hemofiltration [10]. Significant edema leading to primary graft failure during the run may also play a role in the functional decline of the heart. Edema formation can impair diastolic relaxation and lead to capillary vasculature collapse, causing impairment of myocardial perfusion during ESHP [11, 12]. Reported edema formation has been significantly lower with blood‐based perfusate [13]. In our study, hearts were perfused for 24 h, substantially longer than in most previous studies [14, 15, 16]. Under these prolonged conditions, we observed a mean weight gain of 24% ± 9%, which is consistent with moderate myocardial edema expected during extended perfusion periods. Although weight gain for such prolonged ex situ perfusion is not validated in the current literature to the best of our knowledge. The concept of ultrafiltration effectiveness was successfully utilized in clinical practice, showing that hearts can be successfully transplanted after a prolonged period of ex‐situ perfusion [17]. Use of warm blood cardioplegia and conditioning of the donor hearts was found to be safe in distant procurement and preservation of donor hearts in the OCS used for graft transportations in clinical practice [18]. Another underlying reason for edema formation during ESHP may be the induction of an inflammatory response triggered by blood exposure to the extracorporeal circuit. The latter condition may be cured with hemofiltration or the use of adsorbents during ESHP. Results of our animal study do show that the use of warm blood cardioplegia during heart procurement, use of hemofiltration during the ex‐situ heart perfusion can minimize the formation of edema in the perfused heart.
Our study of beating heart in normothermic ESHP based on ECMO technology is a non‐working model of heart perfusion. Hatami et al. observed significantly better preservation of function in those hearts perfused in semi‐physiologic heart chamber pressures working mode [19]. The mechanism for such cardioprotective effect has not yet been determined. The functional assessment of the donor heart during ESHP in both modes is restricted due to lack of specific tools. Moreover, regardless of the perfusion mode, the ex‐situ perfused hearts developed similar significant edema during preservation, which may also hinder organ assessment. Echocardiography is one of the well‐known non‐invasive devices for heart function assessment. Its role in ESHP conditions is unknown due to the unrevealed physiological determinants. Correlation of Tissue Doppler Imaging (TDI) in the setting of ESHP with excellent myocardial performance after transplantation demonstrates a promising perspective. The local wall velocities are not the result of local function, as segments are moved by the action of neighboring myocardial segments. Thus, the velocity differences and velocity gradient are the main measures of regional contraction and might become the most important employment in the ESHP assessment process. The TDI mechanism for superior functional preservation of hearts perfused in working mode has not yet been determined and is under investigation by our group. Left ventricular TDI gradually decreased during ESHP, with full return to baseline levels after transplantation. This parameter remained stable for 4 h post‐transplant before elective termination. Thus, normothermic ESHP based on ECMO technology in a non‐working model of the heart offers a safe and efficient preservation of isolated organ. The mechanisms related to the excellent functional preservation of the heart are under investigation by our group. However, the cardioprotective effect on the myocardium might be impacted by the exclusion of cold crystalloid cardioplegia, which might cause damage and might have an impact on blood circulation at the ESHP device. We observed a stable heart rate without large variations throughout the ESHP period. For the full duration of NESHP, all hearts were maintained within adequate physiologic blood flow, ensuring appropriate oxygen delivery. No increase in aortic root MAP and coronary resistance was observed.
Our study was limited by 24 h ESHP, which does not fully investigate the limits of the system in terms of how long it can sustain the heart to remain viable and transplantable. There was no DCD/DBD/cold ischemic insult of the donor heart. We aimed to prove the concept and secure the experiment from the influence of other variables. Importantly, these findings should not be interpreted as evidence that 24‐h ex‐situ perfusion enables routine clinical heart preservation or transplantation. Rather, the results reflect the recovery potential of non‐injured hearts under controlled experimental conditions. Further studies incorporating DBD and DCD models, including clinically relevant ischemic insults, are required to determine the translational applicability of prolonged ex‐situ perfusion strategies.
5. Conclusion
This study demonstrates that hearts without prior DBD/DCD exposure or cold ischemic injury are able to recover and maintain functional viability following 24 h of ex‐situ heart perfusion. Prolonged (24 h) heart preservation was feasible with the use of ECMO technology. Real‐time heart function assessment was possible. ECMO technology‐based ex‐situ heart perfusion might have a promising role in improving the quality of donor hearts, especially with longer expected ex‐situ heart perfusion times.
Author Contributions
Z. N. concept/design, data analysis, interpretation; R. K. data collection; T. L. data analysis/interpretation, critical revision of article; L. F. data collection; A. M. data collection, data analysis/interpretation; Y. Z. data analysis/interpretation; B. I. data analysis, interpretation; R. S. critical revision of article, interpretation; Y.P. critical revision of article, approval of article.
Conflicts of Interest
The authors declare no conflicts of interest.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.