Primary Graft Dysfunction After Isolated Heart Transplantation　― Incidence, Risk Factors, and Clinical Implications Based on a Single-Center Experience ―

Abstract

Background: Since the international consensus on primary graft dysfunction (PGD) following heart transplantation (HT) was reported in 2014, few clinical studies have been reported. We aimed to analyze the incidence, predictive factors, and clinical implications of PGD following the International Society of Heart and Lung Transplant criteria in a single center.

Methods and Results: This study enrolled 570 consecutive adult patients undergoing isolated HT between November 1992 and December 2017. Under a new set of criteria, PGD-left ventricle (PGD-LV) occurred in 35 patients (6.1%; mild, n=1 [0.2%]; moderate, n=14 [2.5%]; severe, n=20 [3.5%]), whereas PGD-right ventricle (PGD-RV) occurred in 3 (0.5%). Multivariable analysis demonstrated that preoperative admission (odds ratio [OR] 4.20; 95% confidence interval [CI] 1.24–14.26; P=0.021), preoperative extracorporeal membrane oxygenation (OR 4.03; 95% CI 1.75–9.26; P=0.001), and prolonged total ischemic time (OR 1.09; 95% CI 1.02–1.15; P=0.006) were significant predictors of moderate to severe PGD-LV. Moderate to severe PGD-LV was an independent and significant risk factor for early death (OR 55.64; 95% CI 11.65–265.73; P<0.001), with its effects extending up to 3 months after HT.

Conclusions: Moderate to severe PGD-LV, as defined by the new guidelines, is an important predictor of early mortality, with effects extending up to 3 months after HT. Efforts to reduce the occurrence of moderate to severe PGD-LV may lead to better outcomes.

Since the first successful human heart transplant in 1967,¹ heart transplantation (HT) remains the gold standard treatment for eligible patients with end-stage heart failure.^2,3 Despite remarkable improvements in HT outcomes over decades with advances in medicine and surgical techniques, primary graft dysfunction (PGD), the most common cause of early mortality after HT, remains unresolved.^2,4,5 The reported incidence of PGD ranges from 2.3% to 28.2%, suggesting that different diagnostic criteria have been used by individual centers or study cohorts; thus, different outcomes were inevitable.^6–12 To address this issue, standardized diagnostic criteria and treatment protocols were urgently required.

A consensus document on PGD discussed at the 33rd annual International Society of Heart and Lung Transplant (ISHLT) meeting in 2013 was published in 2014.⁵ It should be note that a time frame limited to the first 24 h after HT and a severity grading system were mentioned in the diagnostic criteria. Through these standardized diagnostic criteria, it was expected that less disparity in results could be achieved. Subsequently, a few validation studies have demonstrated the clinical relevance of the new criteria for PGD.^13–15

The aim of this study was to validate the new guidelines and report the outcomes of a single-center experience. In this study we identified and classified PGD according to the criteria and then evaluated the incidence, predictive factors, and clinical implications of PGD.

Methods

Patient Population and Data Collection

All consecutive patients who received orthotopic HT between November 1992 and December 2017 in Asan Medical Center were reviewed, and adult patients who underwent isolated HT were enrolled in the present study. Pediatric patients aged <17 years or patients who underwent multiorgan transplants were excluded. Clinical data were retrieved from the Korean Organ Transplantation Registry (KOTRY) and the institutional cardiac surgery database, and a retrospective review of the medical records was performed to obtain supplementary information. In particular, data on variables indispensable for the definition of PGD, such as hemodynamic parameters, administered dosage of inotropes, and left ventricle ejection fraction (LVEF) within 24 h after HT, were retrieved.

This study was approved by the Asan Medical Center Institutional Ethics Committee/Review Board (Study no. 2017-0140) and conforms to the ethical guidelines of the Declaration of Helsinki. Because of the retrospective nature of the study, the requirement for informed consent was waived.

Organ Procurement and Operative Technique

All allograft hearts were donated after brain death. During harvest, myocardial protection of the donor heart was secured by infusion of 2,000 or 3,000 mL histidine-tryptophan-ketoglutarate solution (Custodial^® HTK; Essential Pharmaceuticals, Newtown, PA, USA) at 4℃ through an aortic root cannula. The harvested heart was rinsed and preserved with the same solution. The standard method of preparation for recipients was similar to that for other conventional open-heart surgeries: a median full sternotomy approach, arterial cannulation at the distal ascending aorta, and bicaval cannulation at the superior and inferior venae cavae (SVC and IVC, respectively) for cardiopulmonary bypass (CPB). Recently, instead of direct IVC cannulation, an open IVC anastomotic technique has been primarily used. Here, a long venous cannula is inserted into the IVC through the femoral vein with vacuum-assisted venous drainage. Recipient cardiectomy was performed upon arrival of the donor heart. Before 1999, the implantation was performed using the standard biatrial technique; after 1999, the bicaval technique has generally been used. The current anastomosis sequence begins with the left atrium (LA), followed by the ascending aorta, IVC, main pulmonary artery, and SVC anastomoses. After completion of the LA and ascending aorta anastomoses, the aortic cross-clamp (ACC) is removed for reperfusion of the heart allograft. Anastomoses of the remaining great vessels are performed with the heart beating if the sinus node function of the heart allograft has been restored. A pair of atrial and/or ventricular temporary pacing wires, chest tubes, and a pericardial soft drain (Hemovac Evacuator; Zimmer, Warsaw, IN, USA) are placed. The methods of heart procurement and implantation have been described in detail previously.^16–19

Postoperative Management and Follow-up

All patients were transferred to the intensive care unit (ICU) after surgery. Norepinephrine and dobutamine were usually administered to achieve appropriate vital signs. If the demand for inotropes continued to increase, a small amount of vasopressin was administered. Milrinone was often administered when pulmonary arterial pressure or systemic vascular resistance was elevated. To modulate heart rate, temporary pacing or isoproterenol was used. All vital signs had to be satisfactory under the condition of sufficient intravascular volume status, represented by a central venous pressure of ≥10 mmHg. Based on these conditions, the expected urine output was at least 100 mL/h during the first 24 h. After confirming alert consciousness, patients were gradually withdrawn from the mechanical ventilator and the endotracheal tubes were generally removed within 24 h.

Clinical follow-up was performed at the outpatient clinic without referral to other hospitals. Information for the final follow-up was obtained using the social security death index and/or a review of medical records.

Immunosuppression Protocol

Prior to June 1999, the induction therapy comprised cyclosporine (3–5 mg/kg) and azathioprine (2–3 mg/kg). In June 1999, anti-interleukin-2 receptor monoclonal antibody (basiliximab) and mycophenolate mofetil (Cellcept; Roche Laboratories, Nutley, NJ, USA) were introduced in the induction therapy protocols. Before January 2007, the maintenance therapy protocol consisted of a triple-drug combination of cyclosporine, mycophenolate mofetil replacing azathioprine, and corticosteroids. Recently, tacrolimus has been used instead of cyclosporine. A bolus of 500 mg methylprednisolone was administered immediately before ACC release. The initial postoperative dose of prednisone for maintenance therapy was 1 mg/kg/day, tapering to 0.25 mg/kg/day at 1 month and to 0.1 mg/kg/day at 1 year. If possible, prednisone was discontinued at 1 year after HT. Details of the changes in the immunosuppression regimen have been described previously.^16–20

Definitions and Study Endpoints

The definition of PGD followed the new diagnostic criteria adopted at the ISHLT consensus conference.⁵ Secondary graft dysfunction (SGD) was defined as recipients receiving mechanical circulatory support (MCS) because of discernible causes as suggested in the criteria. Because PGD of moderate or greater severity was considered clinically significant,^3,4,13–15 the present study focused on the analysis of moderate to severe PGD. Early death and urgent retransplantation were the main outcome measures. Early mortality was defined as death within 30 days after HT. The definition of urgent retransplantation was transplantation reperformed during the same hospitalization after the first HT. It is indisputable that PGD is an independent, and the strongest, factor for early death, as reported in many studies.^{4–8,10–15} Therefore, we analyzed the effects of PGD on late death as well as early mortality. Late death was defined as all deaths except early deaths during the follow-up period.

Statistical Analyses

Continuous variables are expressed as the mean±SD or as the median with interquartile range (IQR), depending on their distribution in the study population. Categorical variables are reported as numbers and percentages. Student’s t-tests for continuous variables and Chi-squared or Fisher’s exact tests for categorical variables were used to compare independent groups. Logistic regression was used to analyze predictive factors, and all variables with P<0.20 in the univariable analysis were subject to the multivariable analysis. Survival data were analyzed using the Kaplan-Meier method, and a Cox proportional hazards regression model was used to analyze the contributions of variables to the outcomes. Two-sided P<0.05 was considered significant. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 19.0 (IBM Corp., Armonk, NY, USA).

Results

Population Data

In all, 662 consecutive patients underwent orthotopic HT between November 1992 and December 2017. After excluding pediatric (n=73) and multiorgan transplant (n=19) patients, 570 adult patients undergoing isolated HT were enrolled in the present study. The mean age of the recipients was 46.7±13.7 years, and 28.9% were women. The baseline and operative profiles of the patients are presented in Table 1.

Table 1. Patient Baseline and Operative Profiles (n=570)

Age (years)	46.7±13.7
Age ≥60 years	109 (19.1)
Female sex	165 (28.9)
Diabetes	82 (14.4)
Hypertension	83 (14.6)
Chronic kidney disease	47 (8.2)
Cerebrovascular accident	33 (5.8)
COPD	9 (1.6)
Previous cardiac surgery	91 (16.0)
Total bilirubin (mg/dL)	1.9±2.5
eGFR (mL/min/1.73 m2)	74.8±26.2
Causes for heart transplantation
Dilated cardiomyopathy	357 (62.6)
Ischemic cardiomyopathy	79 (13.9)
Hypertrophic cardiomyopathy	33 (5.8)
Valvular cardiomyopathy	25 (4.4)
Restrictive cardiomyopathy	15 (2.6)
Miscellaneous	61 (10.7)
Preoperative echocardiographic findings
Significant tricuspid regurgitation (Grade ≥3)	234 (41.4)
Systemic pulmonary arterial pressure (mmHg)	41.0±16.1
Significant pulmonary hypertension (≥50 mmHg)	165 (29.0)
Preoperative clinical conditions
Preoperative admission	386 (67.8)
Preoperative inotropic support	372 (65.3)
Preoperative ICU care	75 (13.2)
Preoperative ventilator support	57 (10.0)
Preoperative ECMO support	52 (9.1)
Donor profiles
Age (years)	33.8±11.0
Age ≥30 years	353 (61.9)
Female sex	119 (20.9)
Operative profiles
Female donor (male recipient)	50 (8.8)
Male donor (female recipient)	95 (16.7)
TIT (min)	151.1±59.5
TIT ≥180 min	178 (31.2)
TIT ≥240 min	64 (11.2)

Values are given as the mean±SD or as n (%). COPD, chronic obstructive pulmonary disease; ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; ICU, intensive care unit; TIT, total ischemic time.

Early Outcomes and PGD

Of 570 patients, 38 (6.7%) were classified as PGD according to the guidelines. Among 35 patients (6.1%) with PGD-left ventricle (PGD-LV), 1 was classified as mild, 14 as moderate, and 20 as severe, accounting for 2.9%, 40%, and 57.1%, respectively, of patients manifesting the LV type. PGD-right ventricle (PGD-RV) occurred in 3 patients (0.5%): 2 were managed with inotropic support, whereas 1 required extracorporeal membrane oxygenation (ECMO) support. Of 2 patients classified as having SGD, 1 required ECMO immediately after surgery because of excessive bleeding and the other was supported by ECMO 3 days after HT because of RV failure resulting from severe pulmonary hypertension (Table 2).

Table 2. Early Postoperative Outcomes (n=570)

PGD	38 (6.7)
PGD-LV	35 (6.1)
Mild	1 (0.2)
Moderate	14 (2.5)
Severe	20 (3.5)
PGD-RV	3 (0.5)
Secondary graft dysfunction	2 (0.4)
Early death (within 30 days)	10 (1.8)
Urgent retransplantation	5 (0.9)
Exploration for bleeding	50 (8.8)
New-onset dialysis	44 (7.7)
Mechanical circulatory support	29 (5.1)
IABP	5 (0.9)
ECMO	24 (4.2)
Length of ICU stay (days)	9.0±12.7
Length of postoperative hospital stay (days)	34.5±20.0

Values are given as the mean±SD or as n (%). ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; ICU, intensive care unit; LV, left ventricle; PGD, primary graft dysfunction; RV, right ventricle.

Urgent retransplantation was performed in 5 patients (0.9%), all because of PGD: 4 patients had severe PGD-LV and 1 had PGD-RV. Ten patients (1.8%) died within 30 days after HT because of sepsis (n=4 patients), multiorgan failure (MOF; n=3), brain hemorrhage (n=2), and aggravated pneumonia (n=1). Of these 10 patients, 7 were classified as PGD. Early mortality was significantly higher in patients with than without PGD (18.4% vs. 0.6%; odds ratio [OR] 39.82; P<0.001). In addition to early mortality, bleeding requiring exploration (26.3% vs.7.5%; OR 4.39; P=0.001) and new-onset dialysis (36.9% vs. 5.6%; OR 9.76; P<0.001) also occurred more frequently in patients with PGD. Patients with PGD had a longer ICU length of stay than patients without PGD (18.0±16.2 vs. 8.4±12.2 days; P=0.001).

Focusing on the severity of PGD-LV, the frequency of early mortality was 0%, 14.3%, and 25% in cases of mild, moderate, and severe PGD-LV, respectively. Although the number of patients in each severity group was so small that no statistically significant differences were found, early mortality tended to increase with PGD severity. Similar results were observed for exploration for bleeding and new-onset dialysis (Table 3).

Table 3. Early Outcomes According to Severity

	No PGD (n=532)	PGD
		Mild (n=1)	Moderate (n=14)	Severe (n=20)
Early death (within 30 days)	3 (0.6)	0	2 (14.3)	5 (25)
Urgent re-transplantation	0	0	0	4 (20)
Exploration for bleeding	40 (7.5)	0	1 (7.1)	9 (45)
New-onset dialysis	30 (5.6)	0	4 (28.6)	9 (45)
Mechanical circulatory support
IABP	0	0	5	0
ECMO	0	0	1	20
Length of stay (days)
ICU stay	8.4±12.2	5	8.5 [7–13.3]	16 [11–29]
Postoperative hospital stay	33.8±16.8	30	30 [29.3–32.8]	33 [23.8–54.3]

Values are given as the mean±SD, median [interquartile range], or n (%). Abbreviations as in Table 2.

Analyses of Risk Factors for Moderate to Severe PGD-LV

The predictive factors of moderate to severe PGD-LV identified in univariable analysis were chronic kidney disease, previous cardiac surgery, elevated total bilirubin level, preoperative admission, preoperative ICU care, preoperative ventilator support, preoperative ECMO support, and prolonged total ischemic time (TIT). Multivariable analysis demonstrated that preoperative admission, preoperative ECMO support, and prolonged TIT were significant risk factors for moderate to severe PGD-LV (Table 4).

Table 4. Risk Factors for Moderate to Severe Primary Graft Dysfunction of the Left Ventricle

	Univariable analysis			Multivariable analysis
	OR	95% CI	P value	OR	95% CI	P value
Age >60 years	0.44	0.13–1.48	0.19
Chronic kidney disease	2.59	1.01–6.61	0.047
Previous cardiac surgery	2.34	1.08–5.08	0.031
Total bilirubin	1.11	1.02–1.21	0.012
Preoperative admission	5.24	1.58–17.37	0.007	4.20	1.24–14.26	0.021
Preoperative inotropic support	1.79	0.79–4.02	0.16
Preoperative ICU care	4.73	2.26–9.93	<0.001
Preoperative ventilator support	4.34	1.96–9.61	<0.001
Preoperative ECMO support	4.90	2.20–10.93	<0.001	4.03	1.75–9.26	0.001
TIT (for 10-min increments)	1.08	1.02–1.14	0.010	1.09	1.02–1.15	0.006

CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.

Receiver operating characteristic (ROC) curve analysis was used to assess the best predicted value of TIT for moderate to severe PGD-LV. A TIT cut-off value of 152.5 min had 67.6% sensitivity and 62.7% specificity (area under the curve [AUC] 0.62; 95% confidence interval [CI] 0.52–0.73). In all, 223 patients had a TIT >152.5 min. Of these, 25 (11.2%) were classified as PGD; among patients with a TIT <152.5 min, the incidence of PGD was 3.2% (11/347; OR 3.24; 95% CI 1.62–6.49; P=0.001).

Effects of Moderate to Severe PGD-LV on Early Mortality

Recipient age, total bilirubin, preoperative mechanical ventilator support, preoperative ECMO support, and moderate to severe PGD-LV were factors affecting the occurrence of early death in univariable analysis. Multivariable analysis showed that recipient age (OR 1.10; 95% CI 1.02–1.19; P=0.015), total bilirubin (OR 1.17; 95% CI 1.02–1.34; P=0.030), and moderate to severe PGD-LV (OR 55.64; 95% CI 11.65–265.73; P<0.001) were independently associated with an increased risk of early death.

Long-Term Outcomes and Effects of Moderate to Severe PGD-LV on Late Death

Follow-up was completed for 99.8% (569/570) of patients. During a median follow-up of 72.5 months (IQR 35–122 months), overall death occurred in 136 patients, consisting of 10 early deaths and 126 late deaths. Five patients underwent urgent retransplantation, and 7 underwent late retransplantation. The overall 1-, 5-, and 10-year survival rates were 93.7±1.0%, 84.1±1.6%, and 75.4±2.2%, respectively. There were statistically significant differences in survival rates according to the occurrence of PGD (P<0.001). The 1- and 5-year survival rates of patients with PGD were 72.5±7.5% and 58.5±8.8%, respectively, compared with 95.1±0.9% and 85.9±1.6%, respectively, in patients without PGD (Figure 1A).

Figure 1.

Overall mortality according to the development of (A) primary graft dysfunction (PGD) and (B) landmark analysis excluding in-hospital deaths occurring within 3 months after heart transplantation.

The risk factors associated with late death are shown in Table 5, in which moderate to severe PGD is presented as an independent risk factor for late death. However, the landmark analysis showed that PGD-related death extended up to 3 months after HT based on the survival curve of patients with PGD declining sharply up to 3 months after surgery, followed by a slower decline (Figure 1A). In multivariable analysis, the risk factors for late death after 3 months were preoperative diabetes and preoperative ICU care. Moderate to severe PGD-LV was excluded in univariable analysis (Table 6). No significant differences in survival rates were observed between patients with and without PGD in the survival analysis 3 months after HT (Figure 1B).

Table 5. Analysis of Risk Factors for Late Death

	Univariable analysis			Multivariable analysis
	HR	95% CI	P value	OR	95% CI	P value
Age	1.02	1.00–1.033	0.011	1.02	1.00–1.03	0.033
Sex	0.68	0.44–1.04	0.076
Diabetes	2.22	1.42–3.46	<0.001	2.04	1.26–3.31	0.004
Chronic kidney disease	1.84	0.92–3.67	0.085
Total bilirubin	1.07	1.00–1.15	0.061	1.08	1.01–1.16	0.020
Preoperative admission	1.31	0.90–1.90	0.16
Preoperative inotropic support	1.39	0.96–2.01	0.080
Preoperative ICU care	2.34	1.42–3.86	0.001
Preoperative ECMO support	1.76	0.88–3.51	0.11
Donor age	1.01	1.00–1.031	0.13
Total ischemic time >240 min	1.67	1.00–2.81	0.052	1.79	1.06–3.28	0.029
Moderate to severe PGD-LV	1.99	0.97–4.08	0.061	2.24	1.08–4.64	0.030

HR, hazard ratio; PGD-LV, left ventricular primary graft dysfunction. Other abbreviations as in Tables 1,4.

Table 6. Landmark Analysis of Risk Factors for Late Death After 3 Months

	Univariable analysis			Multivariable analysis
	HR	95% CI	P value	HR	95% CI	P value
Age	1.02	1.00–1.03	0.016
Sex	0.65	0.42–1.02	0.061	0.66	0.42–1.04	0.073
Diabetes	2.29	1.45–3.62	<0.001	2.50	1.57–3.97	<0.001
Chronic kidney disease	1.79	0.86–3.72	0.12
Preoperative ICU care	1.94	1.12–3.37	0.019	2.09	1.20–3.65	0.009
Preoperative inotropic support	1.31	0.90–1.90	0.16
Donor age	1.02	1.00–1.03	0.11
Total ischemic time >240 min	1.67	0.98–2.86	0.059	1.91	1.12–3.28	0.018
Moderate to severe PGD-LV	1.57	0.69–3.57	0.29

Abbreviations as in Tables 1,4,5.

Treatment of Moderate to Severe PGD-LV

Of 34 patients classified as having moderate to severe PGD-LV, 26 were supported by MCS: 21 by ECMO and 5 by intra-aortic balloon pump (IABP). Eight patients did not require MCS despite high-dose inotropes. Of 20 patients with severe PGD-LV, 12 were successfully weaned from ECMO, 4 could not be weaned from ECMO and subsequently died, and 4 received retransplantation. Ultimately, 6 patients died in hospital. Of 14 patients with moderate PGD-LV, 1 required ECMO 24 h after HT and was successfully weaned. Five patients received IABP. Two of 8 patients who did not require MCS support died of sepsis within 30 days (Figure 2).

Figure 2.

Results of treatment in patients with moderate to severe primary graft dysfunction-left ventricle (PGD-LV). EMCO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; MCS, mechanical circulatory support.

Discussion

Since publication of the consensus document on PGD in 2014, only a few studies have been reported. Therefore, we sought to verify the clinical relevance of the new guidelines.

The mean recipient and donor age reported in the 36th Adult Heart Transplantation Registry report published by the ISHLT registry (for 2010–June 2018; n=481 heart transplant centers located primarily in North America and Europe) was 55 and 35 years, respectively; this is older than the mean recipient and donor age in other countries in Asia, as well as in the present study.^2,21 The reason for the older recipient age in Western countries is that the number of patients with heart failure leading to HT has increased, and advances in medicine and devices allow these patients to survive longer. Consequently, there is a lack of donors compared with recipients, leading to extended criteria for donors, including an older age than before. These trends are occurring worldwide, and Asia is no exception. Although, contemporarily, there is a difference in the age of recipients and donors according to the region, the age of both is increasing in Asia.^21,22

Also, in the present study, dilated cardiomyopathy (62.6%) accounted for an overwhelming proportion of causes of HT, followed by ischemic cardiomyopathy (13.9%), which is the leading cause of HT in Western countries. This means that the etiology of end-stage heart failure differs fundamentally among regions.² Recently, a trend for an increase in the number of patients with heart failure caused by ischemic heart disease has been observed in South Korea, as well as in other countries in Asia; thus, it is estimated that several baseline characteristics including the causes of HT, the mean recipient and donor age will change.²²

Incidence of PGD

In the present study, the overall incidence of PGD (6.7%) was within the range of figures reported previous studies. Moreover, the incidence of the different categories of PGD severity did not deviate from prevailing reports that mild PGD-LV is rare.^13–15 However, compared with studies using the new criteria, generalization of the results had not been achieved. It had been believed that the wide range of PGD incidence was caused by the lack of a standardized definition; however, the incidence of PGD still shows considerable variability depending on individual study cohorts despite the use of the same guidelines.

Patient selection was considered the most fundamental reason for variability in the incidence of PGD, and this is associated with special circumstances, such as the late introduction of ECMO in Asan Medical Center. Because there was no ECMO before 2006, patients who would now undergo HT with ECMO support would have been naturally excluded because they would have died before transplantation. Before 2006, there were not many transplants (23.7%; 135/570), and few cases of PGD (incidence 3.0% before 2006 vs. 8.6% from 2006 to 2017). Thereafter, the incidence of PGD increased as the number of HTs increased with recipients supported by ECMO prior to surgery. The annual PGD incidence has steadily increase, with the rate of 8.7% recorded in 2017 being the highest yet observed.

Different treatment approaches may be another presumable cause of the variable rates of PGD incidence. DePasquale et al noted different treatment approaches for individual centers, with different thresholds for various high-dose inotropes and MCS.²³ In particular, with a time frame limited to 24 h after HT, the severity of PGD in patients manifesting equivocal severity between mild to moderate or moderate to severe grades may be classified differently depending on the treatment policies of each center.

Risk Factors

Preoperative ECMO MCS as a bridge to transplantation (BTT) in patients with clinical and hemodynamic exacerbations can provide stabilized and controlled circumstances before HT.²⁴ Despite its important role, MCS is well known as one of the most significant risk factors for PGD.^{4–6,11–15,25–31} In the present study, 9.1% of patients overall underwent preoperative ECMO as a BTT, whereas previous studies have reported up to 50% of recipients receiving preoperative MCS.^2,6,11,13,15 In the center, the number of patients undergoing preoperative ECMO has gradually increased; in the last year of the study period, 30% of patients underwent preoperative ECMO. Under the current trends, identifying and inhibiting the mechanism of the occurrence of PGD by MCS would be an ultimate solution because it is not feasible to exclude the use of preoperative MCS. The pathophysiology of PGD induced by preoperative MCS is not obvious, although it may be associated with vasoplegia caused by activation of the systemic inflammatory response.^5,29 Further studies at the molecular or cellular level are needed so that the systemic inflammatory response can be inhibited or the vasoplegia resolved.

The first problem to be surmounted in our strategy is to avoid ECMO because the outcomes are worse than those for other types of MCS. Recipients with ECMO at the time of transplantation are usually in a critical condition, with hemodynamic collapse or profound biventricular dysfunction. In addition, they often present evidence of MOF and sepsis, which are associated with worse outcomes.^32–34 ECMO and extracorporeal left ventricular assist devices (LVADs) are associated with PGD, whereas implantable LVADs have been shown to have a relatively low risk of PGD without diminishing post-transplantation survival.^28–30,34 Therefore, changing to implantable LVADs is recommended in candidates in whom ECMO has been stabilized.^3,30 Consequently, most patients requiring MCS mainly receive LVAD, whereas fewer than 1% of patients undergo ECMO at the time of transplantion.² In Asan Medical Center, the first case of implantable LVAD was performed in 2015, and no patients received an LVAD as a BTT during the study period. However, preoperative LVAD support is expected to increase because social insurance coverage for LVAD has been available in South Korea since 2018 and the number of LVADs has continued to increase.

Because the development of PGD is multifactorial, the coexistence of donor and recipient risk factors can increase the incidence of PGD.^5,12,14,27 Therefore, for patients with MCS before HT, further optimization is needed to reduce the occurrence of PGD. If the preoperative status of recipients is not modifiable, donor- or procedural-related factors must be adjusted. That is, meticulous allocation is important for high-risk recipients.

Prolonged TIT Static cold storage (SCS) has dominated clinical cardiac preservation because of the logistical difficulties of the perfusion system, although hypothermic machine perfusion showed superior results in comparison studies with SCS.^35–40 Cold ischemic time (CIT), which is a major component of the pathology in SCS, is the main factor that can modulate TIT and can lead to PGD because of the inevitable accompanying processes, such as cardioplegic arrest, cold storage, and subsequent reperfusion injuries.^39,40 The most obvious way to reduce CIT is to reduce the transport time of the donor heart. However, this is not feasible because reducing CIT by limiting the geographical areas in which donor hearts are sourced can exacerbate the problem of donor shortages. To address the issue, various preservation solutions have been studied to extend the preservation time. However, no consensus on the optimal preservation solution has yet been reached,^41–43 and CIT remains limited to 4–6 h with current technology.^37,39 We used additional strategies, including supplemental cardioplegia and a modified anastomosis technique to overcome the problem. Supplemental cardioplegia, administered at the time of implantation, was added in an attempt to reduce reperfusion damage. We infused normothermic blood cardioplegia during implantation; however, because of the relatively small number of cases, more data are required. In addition, we tried to minimize the warm ischemic time (WIT) by releasing ACC immediately after completion of the LA and ascending aorta anastomoses, whereas ACC release was previously performed after complete allograft anastomosis. This modified technique contributed to a significant reduction in WIT and, consequently, TIT.⁴⁴

Recently, the most remarkable advancement in the field of preservation techniques has been the Organ Care System (OCS; TransMedics, Andover, MA, USA), the only clinical platform for ex vivo heart perfusion.⁴⁵ The OCS is an innovative method to extend the preservation (out-of-body) time to at least 8 h, which allows a significant reduction in CIT and subsequent damage and expands the potential geographical area for organ procurement. Furthermore, assessment of extended criteria for donor hearts, such as reduced LVEF, left ventricular hypertrophy, previous donor cardiac arrest, and unknown coronary artery disease status, may be possible based on increased lactate levels.^45,46 As such, although studies continue to propose methods to minimize ischemic time and subsequent injuries, further advances are still required in this field still.

Clinical Effects of Moderate to Severe PGD-LV

The early mortality rate in patients with moderate to severe PGD-LV (20.6%) differed significantly from that in patients without PGD (0.6%; P<0.001). The results of the present analysis confirmed the strong effect of moderate to severe PGD-LV on early death.^{3–8,11–15,23,26,27,30} These results also showed that PGD-related death extended up to 3 months after HT. Landmark analysis showed no significant difference in survival rates in patients with or without moderate to severe PGD-LV, consistent with other validation studies.^5,14,15 Therefore, moderate to severe PGD-LV no longer appeared to affect late mortality in patients who recovered from this condition and its concomitant complications.

Treatments for Severe PGD

Although prevention of PGD is the ultimate goal, it is also important to properly manage and treat PGD. MCS is the only effective treatment for severe PGD, with ECMO being the preferred type of MCS.^{25,28,31,47–49} Moreover, expeditious determination is necessary during the immediate postoperative period. There should be no hesitation in implementing MCS.^5,28,48–50 We actively implemented ECMO within 24 h after HT in patients with refractory left, right, or biventricular failure despite high doses of inotropes. However, ECMO was usually implemented after the transfer of patients to the ICU and showed relatively higher early mortality than in other studies in which ECMO was inserted simultaneously with CPB weaning.⁴⁹ This suggests the need for a more aggressive and prompt implementation of ECMO.

Study Limitations

This study has inherent limitations of retrospective observational studies. The study reported outcomes based on a single-center experience, which may limit the generalization of its findings. The present study did not reflect the recent introduction of LVADs, and there were limited clinical data to analyze the results of endeavors to reduce the incidence of PGD, such as supplemental cardioplegia and a modified anastomosis sequence. In addition, the consensus report on PGD recommends an autopsy for all patients who died from PGD, but unfortunately there are cultural taboos surrounding autopsies in Korea. Therefore, tremendous efforts to address all these limitations are required in further studies on PGD.

Conclusions

In conclusion, moderate to severe PGD-LV, as defined by the new guidelines, was the strongest independent predictor of early mortality, and its effects extended up to 3 months after HT. Therefore, it is important to avoid risk factors to reduce the incidence of PGD; moreover, early detection and immediate appropriate treatment are important to improve the outcomes of HT.

Sources of Funding

This research was supported by grants from the Research of Korea Centers for Disease Control and Prevention (Code 2014-ER6301-00, 2014-ER6301-01, 2014-ER6301-02, 2017-ER6301-00, 2017-ER6301-01, 2017-ER6301-02).

Disclosures

None declared.

IRB Information

This study was approved by the Asan Medical Center Institutional Ethics Committee/Review Board (Study no. 2017-0140).

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