Double Lung and Heart-Lung Transplantation for Congenital Heart Disease with Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension

Abstract

Patients with pulmonary hypertension who develop concomitant refractory end-stage lung disease and/or chronic end-stage heart disease should undergo evaluation to determine if they are candidates for double lung (DLTx) or heart-lung transplantation (HLTx). Pulmonary hypertension is the indication for approximately 4.5% of total lung transplants. The most common indication for HLTx is complex congenital heart disease (CHD) with Eisenmenger syndrome. HLTx is also indicated in patients with idiopathic pulmonary arterial hypertension and severe right ventricular (RV) failure. Patients with pulmonary hypertension represent a heterogenous group not only in terms of mechanism leading to the development of pulmonary hypertension but also regarding the presence and degree of right and/or left ventricular dysfunction. The choice between double lung transplant (DLTx) and HLTx is based on the etiology, clinical presentation, and other factors. In this chapter, we will discuss the treatment of patients with CHD with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension, including the surgical option of DLTx and HLTx.

1. Introduction

Pulmonary hypertension (PH) affects 1% of the world population, up to 10% of individuals older than 65 years, and at least 50% of patients with heart failure (HF) [1]. Right-sided heart catheterization is used to diagnose PH and it is defined as a mean pulmonary arterial pressure (mPAP) of ≥25 mmHg. Precapillary PH is present when pulmonary artery wedge pressure (PAWP) is ≤15 mmHg or pulmonary vascular resistance (PVR) is ≥3 Wood units. Post-capillary PH is present when PAWP is >15 mmHg (Figure 1) [1]. As shown in Table 1, pulmonary hypertension is classified into five groups: pulmonary arterial hypertension (PAH), secondary to left-heart disease, secondary to lung disease and/or hypoxia, secondary to pulmonary artery obstructions, and multifactorial. PAH is further divided into idiopathic, heritable, drug- and toxin-induced, associated with various conditions including congenital heart disease (CHD), PAH in long-term responders to calcium channel blockers, with venous and/or capillary involvement, and of the newborn [1]. Regardless of the cause, patients with PAH have deteriorating symptoms, poor long-term prognosis, and increased mortality. This chapter will discuss the use of double lung transplant (DLTx) and heart-lung transplant (HLTx) to treat end-stage idiopathic and congenital heart disease-associated PAH unresponsive to maximal medical treatment.

Figure 1.

Diagnostic algorithm for pulmonary arterial hypertension. PAWP: pulmonary arterial wedge pressure, PVR: pulmonary vascular resistance.

Groups	Prevalence
Group 1 – Pulmonary arterial hypertension	Rare
1.1 Idiopathic; 1.2 Heritable; 1.3 Drug- or toxin-induced; 1.4 Associated with certain conditions; Including congenital heart diseases
Group 2 – PH associated with left heart disease	Very common
2.1 Left ventricular systolic dysfunction; 2.2 Left ventricular diastolic dysfunction; 2.3 Valvular disease; 2.4 Outflow tract obstruction and congenital cardiomyopathies
Group 3 – PH associated with lung disease and/or hypoxia	Common
3.1 Chronic obstructive pulmonary disease; 3.2 Interstitial lung disease
Group 4 – PH associated with pulmonary artery obstruction	Rare
Group 5 – PH with unclear and/or multifactorial mechanisms	Rare
5.1 Hematologic disorders; 5.2 Systemic disorders; 5.3 Metabolic disorders; 5.4 Others

Table 1.

Classification of pulmonary hypertension (PH).

2. Etiopathogenesis

Idiopathic PAH (IPAH) is a diagnosis of exclusion and accounts for 39–46% of all PAH cases [1]. PAH associated with congenital heart disease can lead to Eisenmenger syndrome (ES), defined as PH at systemic level with a reversed or bidirectional shunt at aortopulmonary, ventricular, or atrial level [2]. Large tertiary CHD cohorts still report ES in 1% to 5.6% of patients [3]. It usually develops in patients with untreated (large atrial or ventricular septal defects) or complex (univentricular hearts) congenital heart defects, as well as surgically created extracardiac left-to-right shunts. The continued development of the field of congenital cardiac surgery has allowed early diagnosis and timely repair of simple defects and thus reduction of ES, particularly in high-income countries. However, ES is still present as a consequence of complex cardiac anatomy, as well as unrepaired defects in low- and middle-income countries. Patients with persistent shunts initially have increased pulmonary blood flow, which eventually leads to pulmonary microvasculature remodeling and pulmonary blood flow obstruction.

3. Histopathology

Patients with PAH undergo loss and obstructive remodeling of the pulmonary vascular bed (Figure 2) [1]. The pathological process involves endothelial dysfunction, intimal hyperplasia and fibrosis, smooth muscle proliferation and medial hypertrophy, adventitial proliferation, and in-situ thrombosis. Continued arterial blood flow obstruction provokes further remodeling and formation of end-stage characteristic plexiform arteriopathy. Eventually, chronic cases of both diseases cause right ventricle (RV) hypertrophy and right atrium dilatation, which convert these chambers from low-pressure to high-pressure spaces. Eventually, the RV also starts to dilate in order to maintain stroke volume and ensues RV dysfunction.

Figure 2.

Histologic changes in PH in different branches of the pulmonary artery.

4. Clinical presentation and diagnosis

Early-stage PH usually presents with nonspecific symptoms such as exertional and at-rest dyspnea, fatigue, chest pressure, or syncope. Late-stage PH is characterized by progressive RV dysfunction that presents with dilated jugular veins, hepatomegaly, ascites, and lower extremity edema. At cardiac auscultation, a pronounced pulmonic component of the second heart sound (P2) and a systolic murmur over the left para-sternal border can be heard if tricuspid regurgitation is present. Eisenmenger syndrome patients also have a variable clinical presentation that depends on the underlying cardiac defect and associated end-organ complications.

Useful imaging tests include electrocardiogram, chest X-ray, and echocardiogram. Electrocardiogram-specific signs include P pulmonale, R wave to S ratio > 1 in the V1 lead, and right ventricular strain and an S1Q3T3 pattern can sometimes be observed. Chest radiogram can show right atrial enlargement and dilated pulmonary arteries. Echocardiography can help determine the size and function of right-heart chambers, as well as congenital or acquired heart defects.

Right-heart catheterization should be performed in all cases to confirm the diagnosis. Performing vasoreactivity testing during right-heart catheterization is recommended as it allows the identification of patients with a good response to calcium channel blockers.

A ventilation-perfusion scan is obligatory to exclude PH secondary to pulmonary artery obstructions in patients with no left heart or lung disease. Additional tests that can aid in the diagnosis and further characterization of the disease include pulmonary function tests, high-resolution and contrast-enhanced computed tomography, pulmonary angiography, cardiac magnetic resonance imaging, and polysomnography.

5. Prognosis

A baseline systemic evaluation is important for predicting patients’ prognosis as it determines initial therapy. Additionally, response to treatment should be evaluated. Useful markers for initial and follow-up assessment include the World Health Organization functional class (I to IV), hemodynamic variables, and echocardiographic parameters. Hemodynamic variables include mPAP, PVR, mean right atrial pressure, cardiac index, mixed venous oxygen saturation, systolic blood pressure, and exercise tolerance [4]. Echocardiographic characteristics that should be assessed include the presence of pericardial effusion or right atrial area in end-systole >18 cm². Elevated brain natriuretic peptide may indicate right ventricular overload and increased uric acid levels may indicate tissue hypoxia secondary to venous congestion in patients with PAH [4].

PAH patients are considered low clinical risk when they have a 6-min walk distance greater than 440 m, peak VO2 > 15 mL/min/kg, and a cardiac index >2.5 L/min/m² [4]. Of note, pulmonary risk stratification for patients with ES is very limited when compared to IPAH, as they represent very different diseases and the information available for IPAH cannot be extrapolated for ES.

Reported survival rates for PAH are between 68 and 93% at 1 year and 39–77% at 3 years [1]. The long-term prognosis for ES remains unfavorable with survival rates of 74–81% at 5 years and 57% at 10 years. The higher survival rate reported for patients with ES compared to IPAH may be due to ES patients having a slower disease progression and potentially higher plasticity of cardiac myocytes earlier in life, which may lead to a better adaptation of the right ventricle to increased afterload [5, 6, 7]. Nonetheless, untreated ES patients continue to have a significantly limited life expectancy, particularly when the underlying heart defects are complex. The current leading causes of death are heart failure, infections, sudden cardiac death, thromboembolism, hemorrhage, and perioperative complications [8]. Studies have associated several risk factors with higher mortality in ES patients. Diller et al. report functional class, presence of heart failure signs, history of clinical arrhythmia, QRS duration and QTc interval, and lower serum albumin and potassium levels as important predictors of mortality [9]. Kempny et al. also found higher mortality associated with age, the presence of a pre-tricuspid shunt, lower oxygen saturation at rest, absence of sinus rhythm or arrhythmias, and presence of pericardial effusion [10]. Moceri et al. created a composite score based on the strongest echocardiographic predictors of outcome which included tricuspid annular plane systolic excursion <15 mm, ratio of right ventricular effective systolic to diastolic duration ≥1.5, right atrium area ≥ 25 cm², and ratio of right atrium to left atrial area ≥ 1.5 [11].

6. Treatment

6.1 Medical treatment

Patients with IPAH and positive response to vasoreactivity testing should be treated with calcium-channel blockers. For non-responders, PAH-specific drugs (Table 2) that target the endothelin, nitric oxide, or prostacyclin pathways should be considered, as these pathways are associated with abnormal proliferation and contraction of the smooth muscle cells of the pulmonary arteries in patients with PAH [12]. Endothelin receptor antagonists include bosental, ambrisentan, and macitentan. Phosphodiesterase-5 (PDE-5) inhibitors, such as sildenafil and tadalafil, and the soluble guanylate cyclase stimulator, riociguat, act on the nitric oxide pathway. Prostacyclin analogs include epoprostenol, treprostinil, and iloprost, while selexipag is an oral prostacyclin IP receptor agonist [13]. These medications can be used alone or in combination. Dual combination therapy with a PDE-5 inhibitor and an endothelin-receptor antagonist is the most widely utilized regimen, particularly in patients with low or intermediate risk. The goal of medical treatment is achieving a low clinical risk, which as mentioned previously, is defined as a 6-min walk distance greater than 440 m, peak VO₂ > 15 mL/min/kg, and cardiac index >2.5 L/min/m² [4]. When the treatment response is inadequate despite maximal medical therapy, referral for transplant evaluation should be considered.

Mechanism of action	Drug name	Administration route
Endothelin-receptor antagonists	Bosentan; Ambrisentan; Macitentan	Oral; Oral; Oral
Phosphodiesterase type 5 inhibitors	Sildenafil; Tadalafil	Oral; Oral
Guanylate cyclase stimulator	Riociguat	Oral
Prostacyclin analogs	Epoprostenol; Iloprost; Treprostinil; Beraprost	Intravenous; Inhaled; Subcutaneous or intravenous; Oral
Prostaglandin I2 receptor agonists	Selexipag	Oral

Table 2.

Approved drug for treatment of pulmonary arterial hypertension.

6.2 Surgical treatment

The 2019 International Heart and Lung Transplantation Registry reports IPAH as an indication of more than 1800 lung transplants and non-IPAH PH to almost 1000 lung transplants from January 1995 to June 2018, representing 4.5% of total lung transplants [14]. Among all lung transplant indications, IPAH has the highest perioperative mortality [15]. Despite being clinically complex patients, the discussion of double lung (DLTx) (Figures 3 and 4) or heart-lung transplantation (HLTx) should be initiated early in cases of end-stage cardiopulmonary disease secondary to PH.

Figure 3.

Surgical incision for double lung and heart-lung transplant.

Figure 4.

Anatomy of double lung transplant.

A systematic review and meta-analysis evaluated short-term and long-term outcomes of patients with end-stage cardiopulmonary disease of different etiologies after DLTx vs. after HLTx, and found no significant differences between DLTx and HLTx patients in 1-, 3-, 5-, and 10-year survival rates [16].

In patients with PAH, DLTx is preferred over single lung transplant [17]. DLTx can be considered in patients with PH and recoverable ventricular function, as a rapid reduction in pulmonary resistance after DLTx frequently results in improved right ventricular function [16]. Hadebank et al. reported a significant decrease in right ventricular systolic pressure and end-diastolic diameter after DLTx [18]. Nevertheless, patients with postoperative LV failure after DLTx are more susceptible to pulmonary venous congestion and early graft failure. Early after DLTx for severe PH, the LV may be unable to handle normalized LV preload [19]. The Hannover group reported successful bridges to recovery in patients with PH with the use of awake venoarterial extracorporeal membrane oxygenation [19]. Complex ES remains the main indication for HLTx in PAH [20].

Most studies report similar short and long-term outcomes of patients with progressive end-stage PH after DLTx and HLTx [16, 21, 22, 23, 24]. However, other studies report different post-transplant survival rates [25, 26]. An important outcome predictor of both procedures is the degree of preoperative right ventricular dysfunction. For successful DLTx, authors propose that patients should have a left ventricular ejection fraction between 32 and 55% and right ventricular ejection fraction between 10 and 25% [20, 22, 27, 28]. In most patients with pulmonary arterial hypertension and preserved left ventricular (LV) function, there is no advantage to HLTx compared with isolated DLTx, even in the presence of limited right ventricular dysfunction. However, great disparity continues to exist among centers regarding the lowest acceptable right and LV ejection fraction for DLTx, particularly among patients with IPAH, and some centers prefer combined HLTx if severe dysfunction exists. Disadvantages of HLTx, however, include exposure of the recipient to risks of both graft coronary artery vasculopathy and chronic lung allograft dysfunction. The availability of new medical therapies for patients with pulmonary arterial hypertension and congenital heart disease with Eisenmenger syndrome has also reduced the need for HLTx. The total number of adult procedures reported has declined from a peak of over 200 per year in the late 1980s and early 1990s to fewer than 60 per year for the last several years, compared with an increasing number of single and DLTx [14].

Hill et al. found that despite a similar adjusted overall survival, critically ill patients hospitalized with IPAH in the ICU had better outcomes after HLTx than after DLTx [25]. Although several studies have reported higher in-hospital mortality after HLTx than after DLTx, the difference was not significant [24]. An important indicator of quality of early graft function is the time on postoperative ventilation [24]. Notably, the waiting list times for HLTx are shorter than for DLTx [29].

Life-threatening complications of DLTx and HLTx include dehiscence after tracheal or bronchial anastomosis and infection. Fadel et al. report that the incidence of complications was similar for patients undergoing DLTx and HLTx for PH [30].

Currently, both DLTx and HLTx are adequate options for end-stage IPAH and ES, but HLTx is needed for patients with complex congenital heart disease or severe ventricular dysfunction [31]. Further studies are necessary to compare the outcomes of both procedures for these two specific indications, including randomized controlled trials if feasible.