En Bloc Heart‐Lung Transplantation: Past and Present. A Systematic Review

ABSTRACT

Background

En bloc heart‐lung transplantation (HLTx) has been utilized for the past 50 years for the treatment of end‐stage heart and lung disease, with significant evolution in the field over that time. This is a systematic review of HLTx and a description of the evolution and outcomes in this patient population.

Methods

Pubmed and Embase were searched for all articles on HLTx from the time of database inception. A total of 1513 articles were screened, and after exclusion, 29 were included in this systematic review.

Results

Reported cases of HLTx were more common in the early era (before 2000), for the indications of cystic fibrosis, Eisenmenger's syndrome, and pulmonary hypertension. In the contemporary era (2000–present), patients were not as commonly transplanted for cystic fibrosis, with pulmonary hypertension and congenital heart disease comprising the majority of cases. Rates of short‐term mortality tended to be lower in more recent studies, with only recent studies reporting long‐term survival.

Discussion

HLTx has evolved substantially. In tandem with isolated heart and lung transplantation, the indications for transplant, medical therapy, and outcomes have changed over time. While HLTx is used less frequently in contemporary times compared to the early days of cardiothoracic transplantation, indications for HLTx continue to exist, and the use of HLTx will continue to be indicated. Centers with experience in HLTx should continue to report trends in patient management and outcomes, to continue to guide continued refinement in the field of HLTx.

Abbreviations

AKI

acute kidney injury

ATG

anti‐thymocyte globulin

CAV

cardiac allograft vasculopathy

CF

cystic fibrosis

ECMO

extracorporeal membrane oxygenation

ES

Eisenmenger's syndrome

HLTx

en bloc heart‐lung transplantation

ICU

intensive care unit

LOS

length of stay

PA

pulmonary artery

PGD

primary graft dysfunction

PH

pulmonary hypertension

PRISMA

preferred reporting items for systematic reviews and meta‐analyses

RIBCA

right intercostobronchial artery

1. Introduction

Over the past 60 years, the fields of heart and lung transplantation have evolved. From patient selection to surgical techniques to medical management, advances have resulted in ever‐improving outcomes for heart and lung transplant patients.

First described in 1968, combined or en bloc heart‐lung transplants (HLTx) have been utilized for the treatment of patients with end‐stage heart and lung disease [1, 2, 3]. Historically, HLTx began as the initial form of cardiothoracic transplantation, following which isolated lung transplantation emerged. Since its establishment, HLTx has been utilized for several conditions including cystic fibrosis, Eisenmenger's syndrome (ES), pulmonary hypertension (PH), and congenital malformations [3, 4, 5, 6, 7, 8]. Over the preceding decades, the use of HLTx has declined largely due to a better understanding of transplantation and advancements in medical and non‐transplant surgical therapies for various conditions including PH, ES, and cystic fibrosis (CF) [3, 4, 6]. Despite this decline, it is still utilized in specific cases and continues to be a therapeutic option for patients with end‐stage heart and lung disease. Herein, we perform a systematic review of the literature to provide an overview of the field of HLTx. This review will focus on the origins of HLTx, evolution in surgical technique, medical management, and outcomes of patients undergoing HLTx over the preceding decades.

2. Methods

2.1. Data Sources

The search strategy and structure of this systematic review was guided by the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines [9]. The literature search was performed of the PubMed and Embase databases by two authors. The dates of inclusion were from inception to the final date of the search, July 31, 2024. The following search terms were utilized individually or in combination: “En bloc, heart transplant, lung transplant, heart‐lung transplant, heart and lung transplant.” The reference lists of manuscripts selected for full‐text review were screened for additional relevant studies. This systematic review was not registered prior to the commencement of data collection.

2.2. Study Selection

The inclusion criteria for this review were manuscripts published on human patients undergoing HLTx. Exclusion criteria for this study were animal studies, review papers, editorials, case reports, published abstracts without an associated full‐length manuscript, non‐English language manuscripts, or if data was not reported regarding outcomes of patients who have received en bloc HLTx or were on a waiting list for HLTx (Table S1). Data was extracted by two authors based on prespecified outcomes. Disagreements in final study selection were resolved by deliberation until consensus was reached.

2.3. Quality Assessment

Risk of bias was assessed for the included studies using the Newcastle‐Ottawa Scale. The included studies were assessed based on the eight domains within three categories outlined by the Newcastle‐Ottawa scale. Studies were given points based on each domain which were totaled and used to determine overall quality of the manuscript. Good quality is defined as ≥3 stars in the Selection domain, ≥1 star in the comparability domain, and ≥2 star in the outcome domain. Fair quality is defined as 2 stars in the Selection domain, ≥1 star in the comparability domain, and ≥2 star in the outcome domain. Poor quality studies were defined as those that did not meet the previous criteria. The results of the quality assessment are provided in Figure S1. Three studies in the historical era and 15 in the contemporary era were determined to high quality, while nine studies in the historical era and two studies in the contemporary era were determined to be of low quality (Figure S1).

2.4. History of En Bloc Heart‐Lung Transplantation

Prior to the first successful thoracic transplants, significant efforts were made to verify the surgical principles of transplantation as well as the information regarding immunology and rejection that make transplantation today possible. Considerable work was completed by surgeons such as Demikhov, Marseille, Hardin and Kittle, and Hardy in the field of lung transplantation which set the stage for clinical transplantation and the development of HLTx [2, 10, 11, 12, 13]. Following years of animal research and experimental lung transplants, Dr. James Hardy performed the first human lung transplantation surgery on June 13, 1963, although the patient only survived 17 days owing to renal failure and infection [2, 14]. What is widely considered the first successful single lung transplantation occurred in 1983 followed by the first successful double lung transplant in 1986 by Dr. Joel Cooper at Toronto General Hospital [2, 15]. This patient survived for 7 years.

HLTx was first performed on September 15, 1968 by Dr. Cooley [1, 2]. This was done in a 2.5‐year‐old female with severe PH, although she only survived for 14 h. Other notable cases included the second HLTx performed by Dr. Lillihei in a 43‐year‐old patient and by Dr. Barnard in 1971. Similar to lung transplantation, these first cases resulted in survival of days to weeks. The first successful HLTx was reported by Reitz et al. in 1981, prior to even the first successful isolated bilateral lung transplantation, who described three cases, one of which was performed in a 45‐year‐old patient with PH, another was done in a 30‐year‐old patient with ES, and the third in a 29‐year‐old patient with transposition of the great arteries [2, 3, 16]. The peak of HTLx was in 1989 when approximately 290 transplants were performed [17, 18]. Since that time there has been a steady decline in the number of HLTx operations performed annually.

Immunosuppressive therapies contributed most significantly to the improved survival of transplant patients. Initial immunosuppressive regimens utilized medications such as methotrexate, azathioprine, and prednisone. The introduction of cyclosporine was a leap forward in the advancement of transplantation with significant improvements in the survival of cardiac transplant and HLTx patients [5, 19]. Today's immunosuppressive therapies most often include a calcineurin inhibitor with tacrolimus being utilized more frequently than cyclosporine, antimetabolites such as mycophenolate mofetil (purine analogue antagonist) or azathioprine, and corticosteroids such as prednisone [20, 21]. Preoperative induction may include Basilixumab, anti‐thymocyte globulin (ATG), or alemtuzumab [20, 21], or no induction. Postoperative management includes temporary antifungal and antiviral agents as well as lifelong preventative antibiotic therapy.

3. Results

A total of 1513 articles were initially screened. Of those, 89 were collected and underwent a full text review. Sixty manuscripts were excluded and 29 were included in this review that reported on the outcomes of patients undergoing HLTx (Figure 1, Table 1). Of the included studies, 18 were found to be of good quality and 11 of low quality (Figure S1).

FIGURE 1.

PRISMA flow diagram for the literature search and study inclusion. Visual Abstract: Summary of the use of en bloc heart‐lung transplantation in the historical and contemporary eras. Dotted lines represent the less commonly utilized intervention while the solid line represents the more common interventions.

TABLE 1.

Study descriptions.

Study name	Study type	Number of patients analyzed	Years data collected	Follow‐up period	Study populations and intervention	Indication for transplant
Historical studies
Barlow 2000	Retrospective	23	1988–1997	5 years	Patients undergoing HLTx compared to LTx	Cystic fibrosis: 22 Bronchiectasis: 2
Baudet 1996	Retrospective	18	1990–1994	22–69 Months	Patients undergoing HLTx	COPD: 9 Cystic fibrosis: 1 Pulmonary fibrosis: 8
Bolman 1991	____	23	____	2 years	Patients undergoing HLTx	PH: 9 ES: 8 Alpha 1 Antitrypsin deficiency: 3 Cystic fibrosis: 1 Bronchopulmonary dysplasia: 1 Lymphocytic interstitial pneumonitis: 1
Broukaert 2019	Retrospective	38	1991–2014	15 years	Patients undergoing HLTx or LTx	PH
Chapelier 1993	____	21	1986–1992	4 years	Patients undergoing HLTx or LTx	PH: 17 Chronic pulmonary embolism: 3 Histiocytosis X: 1
Ganesh 2005	Retrospective	93	1995–2002	4 years	Patients undergoing HLTx or LTx for cystic fibrosis	Cystic fibrosis
Jamieson 1984	Retrospective	13	1981–1983	1–2 years	Patients undergoing HLTx	PPH: 4 (30.8) ES: 9 (69.2)
Mattila 1997	____	15	1988–1996	4 years	Patients undergoing HLTx	PH: 5 ES: 5 Pulmonary embolism: 3 Emphysema with right heart failure: 2
Moffatt‐Bruce 2006	Retrospective	77	1990–2000	5 years	Patients undergoing HLTx or LTx	ES: 46 Cystic fibrosis: 14 PH: 12 Other: 5
Penketh 1987	____	7	1982–1986	3 years	Patients undergoing HLTx	Cryptogenic Fibrosing Alveolitis, cystic fibrosis, emphysema (2), sarcoidosis, histiocytosis X, bronchiectasis
Talbot 2002	Prospective	4	1996–1999	49 months	Patients undergoing HLTx with primary cardiac sarcoma	Soft tissue sarcoma: 4 (100)
Van Trigt 1996	Retrospective	5	1992–1995	5 years	Comparing patients undergoing HTx, LTx, HLTx	Redo Eisenmenger's complex: 2 (40) Cystic fibrosis: 1 (20) Sarcoidosis, cardiomyopathy: 1 (20) Congenital: 1 (20)
Contemporary studies
Becher 2020	Registry	76	1999–2015	5 years	Patients undergoing transplant for congenital heart disease	Congenital heart disease
Dimopoulos 2019	Retrospective	79	1997–2015	10 years	Patients undergoing transplant for congenital heart disease	Congenital heart disease
Elde 2024	Retrospective	271	1981–2022	10 years	Patients undergoing HLTx	Congenital 46% Cystic fibrosis 9.2% IPF 3.3% ILD 2.6% Sarcoidosis 1.8% COPD 1.1% ATD 0.7% Bronchiectasis 0.4%
Fadel 2010	Retrospective	152	1986–2008	15 years	Patients undergoing HLTx or LTx for PH	PH
Gorler 2009	Retrospective	16	1987–2007	10 years	Patients undergoing HLTx or LTx for congenital heart disease, PH	Congenital Heart Disease: 9 PH: 4 Other: 3
Guihaire 2014	Retrospective	79	1996–2006	10 years	Patients undergoing HLTx or HTx	PAH: 54 PH: 21 Other: 4
Hill 2015	Retrospective	261	1987–2012	10 years	Patients undergoing HLTx or LTx for PAH	PAH
Hjorsthoj 2020	Retrospective	57	1985–2012	15 years	Patients undergoing HLTx or LTx for Eisenmenger Syndrome	ES
Riggs 2020	Retrospective	209	1987–2018	10 years	Pediatric patients undergoing HLTx (UNOS)	Congenital heart disease with ES: 40 (19.1) Congenital heart disease without ES: 70 (33.5) PPH: 6 (2.9)
Sainathan 2023	Retrospective	172	2005–2021	3 years	Comparing outcomes for patients undergoing HLTx for PPH vs. ES	PPH: 128 (74.4) ES: 44 (25.6)
Sertic 2020	Retrospective	316	1987–2018	10 years	Patients undergoing HLTx compared to bilateral LTx for ES	ES
Shin 2022	Retrospective	246	2012–2021	3 years	Patients undergoing HLTx	WHO Group 1pHTN: 333 (67.7) ‐ Idiopathic: 190 (57.1) ‐ Sarcoidosis: 36 (10.8) ‐ Connective Tissue: 27 (8.1) ‐ Congenital: 61 (18.3) ‐ Other: 19 (5.7) WHO Group 3: 22 (4.5) WHO Group 4: 6 (1.2) WHO Group 5: 3 (0.6) Pulmonary fibrosis: 56 (11.4) Cystic fibrosis: 36 (7.3) Pneumonitis: 9 (1.8) Other: 27 (5.5)
Shudo 2018	Retrospective	49	2008–2018	6 years	Patients undergoing HLTx	IPH: 17 (35) Non‐idiopathic PH: 4 (8) Cystic fibrosis: 6 (12)
Shudo 2019	Registry	997	1987–2017	5.6 years	Patients alive after 1 year of HLTx compared to patients that died or underwent re‐transplant	Congenital heart disease: 427 (42.8) PH: 248 (24.9) Cystic fibrosis: 50 (5) Interstitial pneumonitis: (2.4)
Shudo 2023	Retrospective	201	2014–2022	4 years	Comparing waitlist times before and outcomes for patients undergoing HLTx before and after UNOS heart allocation policy	Congenital heart disease: 39 (19.4) PH: 67 (33.3) Pulmonary fibrosis: 44 (21.9) Other: 51 (25.4)
Toyoda 2008	Retrospective	49	1982–2006	10 years	Patients undergoing LTx and HLTx between group 1 (1982–1993) and 2 (1994–2006)	Idiopathic PAH: 49 (100) Group 1: 1982‐1993 Group 2: 1994‐2006 (prostaglandin E1, nitroglycerin, pneumoplegia, alemtuzumab)
Weingarten 2023	Retrospective	SCD:178 ECD: 65 Total: 243	2005–2021	5 years	Examining outcomes of patients undergoing HLTx on standard and extended donor criteria	PPH: 61 (25.1) ILD: 47 (19.3) Cardiomyopathy: 36 (14.8) ES: 29 (11.9)

Abbreviations: COPD, chronic obstructive pulmonary disease; ES, Eisenmenger Syndrome; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; UNOS, United Network for Organ Sharing.

3.1. Surgical Technique for En Bloc Heart‐Lung Transplantation

Donor procurement of the en bloc heart‐lung involves a median sternotomy. Dissection and exposure of several structures is required including the trachea, inferior and superior vena cava, azygous vein, and the ascending aorta from the main PA. Cannulas are placed in the ascending aorta and pulmonary artery in order to deliver cardioplegia and pulmonoplegia once an aortic cross clamp is placed. Once the organs are flushed, the clamp and cannulas are removed. The inferior and superior vena cava are transected. The aorta is divided at or proximal to the aortic arch. The trachea is then dissected away from the esophagus. The inferior pulmonary ligament is then divided and the lung is dissected from the pleura and pericardium superiorly until the lung is free. This is then repeated on the contralateral side. The trachea is then stapled, retaining at least 5–6 cartilaginous rings above the carina, and the bloc is removed [8].

HLTx can be performed either through a median sternotomy or a bilateral thoracosternotomy (clamshell incision) [6, 8, 22]. Early approaches to lung transplantation utilized a single tracheal anastomosis, although this was associated with tracheal ischemia and poor healing due to ligation of the tracheal artery during transplant. The blood supply to the trachea and bronchi post‐transplantation were found to arise from retrograde flow from deoxygenated blood from the lungs. The approach to isolated lung transplantation has since shifted toward bilateral bronchial anastomoses leaving a short length of donor lung bronchus to reduce the distance retrograde blood is required to flow to supply the bronchus resulting in fewer airway complications [6, 8, 23].

In contrast to the modern bronchial anastomotic technique used for lung transplantation, a single tracheal anastomosis is still commonly used in HLTx, although both approaches can be utilized [6]. The great vessel anastomoses are largely similar to those performed in a typical heart transplantation. The recipient's heart and lungs are dissected out individually or en bloc. The donor organs are placed in the chest with the lungs passed into the pleural spaces through pericardiotomies. The tracheal anastomosis is performed first, followed by the inferior vena cava, superior vena cava, and finally the ascending aorta [8]. Care must be taken to avoid injury to the phrenic nerves intraoperatively. The phrenic nerves are at risk during HLTx given its proximity to the pulmonary hilum and extensive dissection in this area. Phrenic nerve pedicles must be left intact after recipient organ explant to ensure diaphragmatic function postoperatively. In patients with previous thoracic operations, adhesions may make it difficult to identify the phrenic nerves. Dissection in this area requires care to avoid injuring the phrenic nerves prior to identification. The avoidance of metal instruments while cauterizing in this area, relying on plastic instruments instead, reduces the risk of inadvertent injury to the phrenic nerve by conduction of the electrical current from the cautery to surrounding structures.

Cases of en bloc heart‐single lung transplantation have been performed in the past as well. In these cases, the PA, pulmonary veins, and bronchus are removed from the side that is to be transplanted. The heart is explanted by cutting the right atrium, PA, and aorta. The heart and lung are removed. The donor heart and lung are brought into the field and the lung placed in the pleural space. The left atrial anastomosis is performed first, with the remaining anastomoses performed in any order [22].

3.1.1. Rates of Heart‐Lung Transplantation

The International Society for Heart and Lung Transplantation publishes reports of international rates of transplantation. In the adult patient population, rates of HLTx declined from a peak in the 1990s of 200–225 cases per year to approximately 50 per year since 2013. From 2010 to 2018, at least one HLTx was reported from 87 centers making up 33.7% of the total number of centers in the registry, with the majority performing an average of one case per year [18]. The indications for transplant did not change considerably with PH being the most common indication. Median survival improved over time, being 3.7 years from 1992 to 2001, 5.5 years from 2002 to 2009, and 6.5 years from 2010 to 2017 [18]. In pediatric patients, the proportion of HLTx have declined over time. From 1992 to 2000, HLTx accounted for 59.9% of transplants, while lung transplants made up the remaining 40.1%. From 2001 to 2009 HLTx declined to 42.6% and was down to 19.1% between 2010 and 2018 [17].

3.2. Historical Outcomes

3.2.1. Indication for Transplantation

Eleven studies in this review included patients undergoing HLTx prior to 2000 [7, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33]. The published studies during the historical era were limited to small sample sizes ranging from 4 to 93 patients among the included studies, although the majority were limited to <30 patients. The most common indications for HLTx in studies published during the historical era included CF (133 patients), ES (68), and PH (47) [7, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33].

3.2.2. Mortality

Waitlist mortality for patient awaiting HLTx was reported in one study at 41.9% [26]. In‐hospital mortality following HLTx was reported in five studies with mortality rates ranging from 4% to 26.6% [7, 25, 27, 28, 32]. 30‐day mortality after HLTx was reported in two studies and was found to be 0% and 15.4% [24, 27]. At 1 year, eight studies reported mortality rates for HLTx patients between 13% and 33.3% [7, 24, 25, 28, 29, 30, 32, 33]. 3‐year mortality following HLTx from five studies ranged from 14.3% to 27.8% [24, 25, 29, 30, 33]. 5‐year mortality after HLTx ranged from 25% to 53% in four studies [24, 25, 29, 30]. Longer‐term outcomes past 5 years were not reported in any of the early studies. Overall, short‐term mortality rates after HLTx were low in most studies with a marked increase after 5 years of follow‐up and limited long‐term follow‐up (Table 2).

TABLE 2.

Mortality rates.

Study name	Waitlist (%)	In‐hospital (%)	30 days (%)	1 year (%)	3 years (%)	5 years (%)	10 years (%)	Other (%)
Historical studies
Barlow 2000	—	—	(0)	(14)	(18)	(35)	—	—
Baudet 1996	—	3 (16.6)	—	(22.2)	(27.8)	(53.1)	—	—
Bolman 1991	—	1 (4)	—	(15)	—	—	—	2 years (26)
Broukaert 2019	—	9 (23.7)	—	(18)	—	(26)	(39)	15 years (52)
Chapelier 1993	—	3 (14.3)	—	(19)	—	—	—	4 years (56)
Ganesh 2005	101/241 (41.9)	—	—	—	—	—	—	4 years (49)
Jamieson 1984	—	1 (7.7)	2 (15.4)	—	—	—	—	—
Mattila 1997	—	4 (26.6)	—	5 (33.3)	—	—	—	—
Moffatt‐Bruce 2006	—	—	—	(13)	(26)	(34)	—	—
Penketh 1987	—	—	—	1 (14.3)	1 (14.3)	—	—	—
Talbot 2002	—	—	—	1 (25)	1 (25)	1 (25)	—	—
Van Trigt 1996	—	—	—	—	—	—	—	2 (40)—3 weeks for 1, unspecified time for other
Contemporary studies
Becher 2020	21 (27.6)	—	—	20 (37.0)	22 (40.7)	25 (46.3)	—	—
Dimoupoulos 2019	—	—	(19)	(30.4)	—	(38.2)	(54.8)	—
Elde 2024	—	—	(10)	(19)	—	(45)	(66)	—
Fadel 2010	—	(21.7)	—	(30)	—	(50)	(61)	20 years (80)
Gorler 2009	—	—	2 (12.5)	—	—	—	—	—
Guihaire 2014	—	—	—	—	—	(49)	(57)	—
Riggs 2020	(42)	—	—	(30)	—	—	(75)	—
Sainathan 2023	—	—	17 (9.9)	25 (14.5)	62 (36.0)	—	—	—
Sertic 2020	—	84 (26.6)	—	(32)	—	(52.7)	(69.5)	—
Shin 2022	80 (14.4)	—	—	(15.9–16.2)	—	—	—	—
Shudo 2018	—	—	2 (4)	5 (10)	—	—	—	—
Shudo 2019 (graft survival)	—	—	(18.7)	(33.4)	—	—	—	—
Shudo 2023	61 (16.5)	21 (10.4)	—	—	—	—	—	—
Toyoda 2008	—	—	—	(39)	—	(60)	(67)	15 years (77) 20 years (81)
Weingarten 2023	—	—	SCD: (10.9) ECD: (3.2)	SCD: (21.7) ECD: (13.3)	—	SCD: (45.4) ECD: (41.9)	—	—

3.2.3. Morbidity

Rates of primary graft dysfunction (PGD) were directly reported in two studies. Rates of PGD varied from 0.0 to 23.8% (Table 3) [30, 34].

TABLE 3.

Morbidity rates.

Study name	Primary graft dysfunction (%)	Rejection (%)	Stroke (%)	Major bleeding (%)	Obliterative bronchiolitis (%)	ICU LOS (IQR or ±SD) days	Hospital LOS (IQR or ±SD) days	AKI (%)	Postop ECMO (%)	Recurrent heart or lung failure/ required repeat transplant
Historical studies
Barlow 2000	—	5 years (79)	—	1 (4.3)	—	—	38 ± 34	3 (13)	—	—
Baudet 1996	—	11 (61.1)	—	3 (16.7)	5 (33)	—	—	—	—	—
Bolman 1991	—	—	—	—	5 (23)	—	—	—	1 (4.3)	—
Broukaert 2019	5 (23.8)	Death Due to Rejection 2 (5.3)	—	12 (31.6)	—	Median (min–max) 16 (7–89)	Median (min–max) 38 (14–132)	—	0	—
Chapelier 1993	—	6 (33)	—	—	6 (28.6)	—	—	—	—	1 (4.8)
Jamieson 1984	—	5 (38.5)	—	5	—	—	Range 38–85	—	—	1 (7.7)
Mattila 1997	—	4 (26.7)	—	—	—	—	—	1 (6.7)	—	—
Moffatt‐Bruce 2006	—	5 years (60)	—	—	5 years 48%	15 ± 33	—	—	—	—
Penketh 1987	—	1 (14.3)	—	1 (14.3)	—	—	—	—	—	—
Talbot 2002	0 (0)	—	—	1 (25)	2 (50)	—	65 (only 1 patient reported)	—	—	1 (25)
Van Trigt 1996	—	—	—	1 (20)	—	—	—	—	—	—
Contemporary studies
Elde 2024  Early  Modern  Overall	19/82 (23)	23 (16) 12 (22) 35 (18)	7/82 (8.5)	4 (2.8) 0 (0) 4 (2)	61 (41) 38 (33) 99 (38)	13 (5–27)	23 (16–40) 23 (14–55) 23 (15–43)	—	11 (13.4)	—
Fadel 2010	48 (46.2)	Death from cardiac rejection 5/152 (3.3)	—	—	10 years (35)	—	—	—	—	—
Guihaire 2014	1 (5)	Acute graft rejection 63 (80)	—	—	6 (7.6)	—	—	—	—	—
Riggs 2020	—	—	—	—	—	—	—	—	15 (7.2)	—
Sainathan 2023	—	33 (19.2)	7 (4.1)	—	—	—	19.5–27.5 (28–31)	37 (21.5)	25 (14.5)	—
Sertic 2020	24 (14.0)	BOS 120 (51.9)	—	—	45 (26.3)	—	23 (19–26)	—	—	1 (0.4)
Shin 2022	—		52 (21.1)	—	—	—	—	—	61 (24.8)	—
Shudo 2018	2 (13.3)	Acute 3 (20) Chronic 8 (26.7)	—	—	—	—	33.8 (12–47)	10 (20)	1 (2)	—
Shudo 2019	—	—	—	—	—	—	—	—	—	—
Shudo 2023	—	—	14 (7.0)	—	—	—	Pre‐period: 52.7 ± 57.4 Post‐period: 50.7 ± 54.0	57 (28.4)	56 (27.9)	—
Weingarten 2023	—	SCD: 51 (28.7) ECD: 17 (26.6)	SCD: 8 (4.6) ECD: 3 (4.7)	—	—	—	SCD: 25 (16–51) ECD: 36.5 (17–63.5)	SCD: 44 (26.2) ECD: 18 (30.0)	SCD: 8 (13.6) ECD: 8 (18.2)	—

Abbreviations: BOS, bronchiolitis obliterans syndrome; ECD, extended criteria donor; SCD, standard criteria donor.

Rates of rejection were reported in eight studies. Rates of rejection ranged from a low of 5.3% when defined as “death due to rejection” and were as high as 79% at 5 years [7, 24, 25, 27, 28, 29, 33].

Rates of postoperative major bleeding were reported in five studies. Rates of major bleeding ranged from 2.8% to 25% [24, 25, 30, 31, 35] (Table 3).

Rates of obliterative bronchiolitis were reported in six studies with rates ranging from 23% to 50% [7, 25, 29, 30, 32, 35] (Table 3).

Intensive care unit (ICU) length of stay (LOS) was only reported in two studies in the early cohort, with ICU LOS being 26 ± 10.9 days for patients without obliterative bronchiolitis and 37.6 ± 20.5 days in those with obliterative bronchiolitis in the study by Baudet et al., while ICU LOS was 40 days in the study by Jamieson et al. [25, 27]. Hospital LOS was also reported in only two ranging from 38 ± 34 days to 65 days, although the latter was only reported for a single patient [24, 30] (Table 3).

Rates of acute kidney injury (AKI) were reported in two studies from early cohorts and ranged from 6.7% to 13% [24, 28] (Table 3).

Requirement of postoperative extracorporeal membrane oxygenation (ECMO) was 4.3% in a single study [32], although ECMO was rarely utilized prior to 2000 (Table 3).

Recurrent heart or lung failure, or required repeat transplantation ranged from 4.8% to 25% in three studies [7, 27, 30] (Table 3).

3.3. Contemporary Outcomes

3.3.1. Indication for Transplantation

Eighteen studies reported outcomes of patients, a majority of whom had their transplant after the year 2000 [23, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50]. Included studies in the contemporary cohort included much larger studies than in the early cohort, ranging from 16 to 997 patients. The most common reported indications during this time included PH with 1110 patients, CHD with 826, ES with 170, and CF with 82 patients reported [23, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50].

3.3.2. Mortality

Waitlist mortality in the four studies that reported it ranged from 14.4% to 42% [36, 42, 45, 46]. In‐hospital mortality was reported in four studies and ranged from 10.4% to 26% [34, 38, 44, 46]. 30% mortality was reported in seven studies. 30‐day mortality ranged from 4% to 19% [23, 35, 37, 40, 47, 49]. 1‐year mortality was reported in 13 studies and ranged from 10% to 39% [23, 34, 35, 36, 38, 42, 43, 44, 45, 47, 48, 49]. 3‐year mortality was only available from two studies, which had mortality rates of 36.0%–40.7% [36, 43]. 5‐year mortality was obtained from nine studies. Mortality at 5‐year follow‐up ranged from 26% to 60% [34, 35, 36, 37, 38, 39, 44, 48, 49]. In contrast to the early cohort, long‐term mortality at greater than 5 years was provided in multiple studies. From eight studies, 10 year or later mortality rate ranged from 39% to 75% [34, 35, 37, 38, 39, 42, 44, 48]. Longer‐term outcomes were reported with 15‐year mortality ranging from 52% to 77% and 20‐year mortality ranging from 80% to 81%, in two studies each [34, 38, 48] (Table 2).

Weingarten compared the mortality of patients who received transplantation from donors who met standard criteria versus those who met extended criteria. Criteria were related to both donor and organ specific criteria including age, donor past medical history, organ cold ischemia time, and organ function with either one or both organs meeting standard or extended criteria. Rates of mortality in the recipients were 10.9% for standard criteria donors, 10.8% for extended criteria heart only, 9.1% for extended criteria lungs only, and 3.2% for both organs meeting extended criteria at 30 days (p = 0.34). At 1 year rates of mortality in the recipients were 21.7% for standard criteria donors, 17.3% for extended criteria heart only, 17.2% for extended criteria lungs only, and 13.3% for both organs meeting extended criteria (p = 0.39). At 5 years, rates of mortality in the recipients were 45.4% for standard criteria donors, 43.9% for extended criteria heart only, 34.2% for extended criteria lungs only, and 41.9% for both organs meeting extended criteria (p = 0.43) [49].

3.3.3. Morbidity

PGD rates were directly reported in five studies. Rates of PGD varied widely from 5% up to 46.2% [23, 35, 38, 39, 44] (Table 3).

Rates of rejection were reported in seven studies and similarly to the historical cohort, ranged from 3.3% when defined as “death due to cardiac rejection” with a high of 80% [23, 35, 38, 39, 43, 44].

Rates of stroke were reported in five studies with stroke rates ranging from 4.1% to 21.1% [35, 43, 45, 46, 49]. Major bleeding was only reported in two studies. The rates of bleeding were considerably different with one study reporting 0% incidence of major bleeding [35] and the other identifying 31.6% incidence of major bleeding [34] (Table 3).

Incidence of obliterative bronchiolitis were reported in four studies in the contemporary cohort [35, 38, 39, 44]. Rates of obliterative bronchiolitis ranged from 7.6% to 33%, with the higher rates being reported in studies with follow‐up times up to 10 years (Table 3).

ICU length of stay was reported in one study with an average length of stay of 13 days [35]. Overall hospital length of stay ranged from 23 to 57.4 days in a total of six studies [23, 34, 35, 44, 46, 49]. Rates of acute kidney injury were similar across studies with rates of 20%–30% [23, 43, 46, 49]. Rates of required postoperative ECMO were reported in eight studies with rates ranging from 0% to 27.9% [23, 34, 35, 42, 43, 45, 46, 49] (Table 3).

4. Discussion

Since the first cases of HLTx were performed, the field has changed drastically in some respects, with others remaining relatively unchanged. The indications for HLTx have undoubtedly changed over time. In the early era, this review identified pulmonary hypertension, ES, and cystic fibrosis as the most commonly reported indications for HLTx. While ES and some congenital heart conditions remain indications for transplant today, the management of cystic fibrosis and pulmonary hypertension, previously common indications for HLTx, have changed significantly (Visual Abstract).

With improved medical therapy, fewer cystic fibrosis patients are being referred for transplantation, often later in life, and are now being managed with double lung transplantation. Similarly, PAH therapies have improved in recent years, and in patients requiring transplantation, lung transplantation has become the preferred intervention instead of combined HLTx as was traditionally the case. This is due to the findings that right ventricular function may recover following isolated lung transplantation and that double lung transplantation results in comparable or improved outcomes in many patients with PAH. Additionally, double lung transplantation allows for use of the heart for transplantation in another patient, rather than using both organs in a single patient [51]. Improvements in outcomes may also be related to improvements in ECMO technology and understanding with appropriate patients receiving ECMO prior to lung transplantation more commonly in the contemporary era [23, 34, 35, 42, 43, 45, 46, 49]. Although, the most commonly reported contemporary indications for HLTx continued to be pulmonary hypertension and congenital heart disease making up the largest portions of patients treated with HLTx in the reported literature. Interestingly, among patients with septal defects and Eisenmenger Syndrome, the type of septal defect is associated with differing outcomes depending on the type of transplant. Sertic et al. found that among 442 adults with Eisenmenger Syndrome who underwent thoracic transplantation, those with atrial septal defects had improved outcomes following double lung transplantation, while patients with ventricular septal defects had improved outcomes following HLTx. Identification of these findings has helped to guide the utilization of donor organs and optimal selection of transplantation procedures for patients [44]. This is also in the context of differing selection criteria for HLTx compared to isolated lung transplantation with patients and donors for HLTx tending to be younger than in lung transplantation and with stringent size matching requirements [18, 23, 35, 45, 52].

An important concept in the early years of HLTx that has decreased in popularity over time is the Domino Transplant. This was initially performed in patients with cystic fibrosis, where the heart and lungs would be transplanted in the cystic fibrosis patient, and that patient's normal heart would be transplanted into a subsequent recipient requiring a heart. Given the aforementioned improvements in medical management of cystic fibrosis and the increased use of isolated lung transplantation, domino transplants in this patient population have been infrequently utilized in recent years [3].

The surgical technique involved in HLTx has remained largely consistent over time. While in the realm of lung transplantation, a significant advance in surgical technique and patient outcomes in terms of airway complications was the shift from a single tracheal anastomosis to bilateral bronchial anastomoses, this has not been the case with HLTx with the single tracheal anastomosis commonly being performed. While bronchiolitis obliterans syndrome continues to be a concern in HLTx, coronary allograft vasculopathy (CAV) has been demonstrated to occur less frequently following HLTx compared to heart transplantation alone. This has been hypothesized to be due to the protection of the coronary vasculature by the lungs, resulting in slower rates of CAV development [29, 39].

One of the greatest contributors to improvements in the outcomes following HLTX, and solid organ transplantation in general, has been the postoperative medical therapy of these patients. The field of immunosuppression has evolved immensely since the early days of solid organ transplantation. Early immunosuppressive agents utilized in this field included methotrexate, azathioprine, and prednisone. While steroids are still commonly utilized in thoracic transplantation, the adoption of calcineurin inhibitors, initially cyclosporine A followed by tacrolimus, and purine analogue antagonists, such as mycophenolate mofetil, have become the standard therapies [5, 19, 20, 21]. Preoperative management including induction agents such as basiliximab, ATG, and alemtuzumab have also contributed to the reduction in rates of T‐Cell mediated early rejection and mortality following transplantation [53, 54, 55].

While the frequency of HLTx has declined in favor of medical therapy or isolated heart or lung transplantation, HLTx remains a valuable tool for selected patients. Even with improved medical therapy for pulmonary arterial hypertension and advancements in congenital cardiac surgery, a subset of these patients will continue to progress to end‐stage organ failure requiring HLTx. It is likely that HLTx will continue to be utilized for the foreseeable future, given the inability to manage patients with ES or some forms of congenital heart disease with medical therapy or isolated organ transplantation. Furthermore, there have been recent advances that have the potential to increase the donor pool for HLTx, such as recently reported cases of donation after cardiac death donors being used for HLTx, often utilizing normothermic regional perfusion or ex vivo organ perfusion [56, 57, 58, 59].

Given the reduce frequency of these procedures, it may be beneficial to refer patients to centers with high volumes and greater experience in HLTx for workup and transplantation, rather than performing small numbers of these procedures at a large number of centers, to ensure optimal outcomes for these patients which require complex surgical treatment and postoperative management. However, this has not been definitively proven and future studies investigating outcomes of programs based on volume may help to guide referrals of patients for HLTx. It is important to continue to highlight research in this field as the evolving indications, medical therapies, and outcomes of HLTx will continue to guide the management of these patients in the future.

4.1. Limitations

There are limitations to this review. Details regarding HLTx were not provided independently of single heart or lung transplantation in several manuscripts resulting in their exclusion from this study. There was overlap in some of the reported cohorts as there have been multiple uses of the same registries, although the population of interest and periods were often different resulting in some variability in patient inclusion and provided justification for the inclusion of those studies. Additionally, overlap occurred in timing of procedures between the “Historical” and “Contemporary” eras with some of the Contemporary publications including a subset of patients from before the year 2000, confounding some of the differences identified between the two cohorts.

5. Conclusions

HLTx has evolved greatly over the preceding decades. In conjunction with isolated heart and lung transplantation, the indications for transplant, medical therapy, and outcomes have evolved over time. As our understanding of end‐stage heart and lung disease have evolved, our management of these patients has been refined and become more targeted. While HLTx is used less frequently in contemporary times compared to the early days of cardiothoracic transplantation, indications for HLTx continue to be prevalent and as will the use of HLTx given the ongoing need in a variety of patients. Centers with experience in the field of HLTx should report trends in patient management and outcomes moving forward in order to guide the field of HLTx.

Author Contributions

Study design, literature search, data collection, data analysis, data interpretation, generation of figures, writing of the manuscript, approval of final manuscript: Ryaan EL‐Andari, Nicholas M. Fialka, Abrar Alam, and Isha Khonde. Study design, data interpretation, writing and proofreading the manuscript, approval of final manuscript: Jason Weatherald, Kieran Halloran, and Jayan Nagendran.

Disclosure

The authors have nothing to report.

Consent

The authors confirm that patient consent is not applicable to this article as it is a review of the literature.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: Search strategy summary.

Figure S1: Assessment of quality of included manuscripts based on the Newcastle‐Ottawa Scale.

EL‐Andari R., Fialka N. M., Alam A., et al. “En Bloc Heart‐Lung Transplantation: Past and Present. A Systematic Review.” Clinical Transplantation 39, no. 8 (2025): 39, e70270. 10.1111/ctr.70270

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study. The data underlying this article are available in the article and its supplementary material.