Pulmonary Arterial Hypertension Associated with Congenital Heart Disease

Pulmonary Arterial Hypertension Associated with Congenital Heart Disease

Nils Patrick Nickel

Richard A. Lange

Christine Bui

Anitra W. Romfh


Pulmonary hypertension (PH) is a heterogeneous hemodynamic and pathophysiologic disorder, characterized by an increased mean pulmonary arterial pressure (mPAP > 20 mm Hg).1 PH can be caused by a variety of cardiovascular and respiratory conditions. The correct classification of PH is paramount because the various types differ significantly in their prognosis and clinical management. A framework focused on a hemodynamic definition in conjunction with a pathophysiologic and clinical classification helps identify patients who most likely benefit from targeted therapy.

Using the hemodynamic information, PH can be divided into three categories: precapillary, postcapillary, and combined pre- and postcapillary PH. The hemodynamic features of each category are displayed in Table 110.1. Precapillary PH shows evidence of increased pulmonary vascular resistance in the absence of increased pulmonary venous or left-sided filling pressures. Postcapillary PH is defined by elevated left-sided filling pressures and normal pulmonary vascular resistance. Combined post- and precapillary PH is present in patients with pulmonary venous congestion and elevated pulmonary vascular resistance out of proportion to the elevated pulmonary venous pressure.

The clinical classification of PH is designed to categorize clinical conditions associated with PH based on similar pathophysiologic mechanisms, clinical presentation, hemodynamic characteristics, and therapeutic management. A comprehensive and simplified version of the clinical classification of PH in children and adults is presented in Table 110.2, with PH divided into five different groups, according to underlying cause and pathophysiology. In the patient with congenital heart disease (CHD), PH may be owing to (1) pulmonary arterial hypertension (PAH, Group 1), so-called PAH-CHD, which is precapillary; (2) left heart dysfunction resulting in postcapillary PH (Group 2), as seen in valvular heart disease, congenital or acquired left heart inflow or outflow tract obstruction, cardiomyopathies, and pulmonary vein stenosis; or (3) complex cardiac conditions with PH owing to unclear or multifactorial (Group 5) such as complex congenital abnormalities in the pulmonary vasculature or single ventricle physiology.1

Because of the remarkable heterogeneity, PAH-CHD (Group 1) is further classified into clinical and anatomicphysiologic categories. PAH-CHD clinical categories include patients with simple operable and inoperable CHD, subgrouped as those with (1) Eisenmenger physiology; (2) PAH and left-to-right shunts; (3) PAH thought to be incidental to their CHD; and (4) postoperative/closed defects. The features of each of these are shown in Table 110.3. The anatomic-pathophysiologic classification of PAH-CHD differentiates between type, dimension, and direction of the shunt. The type of shunts is divided between pre-, post-tricuspid, or combined shunts and complex defects such as truncus arteriosus or transposition of the great arteries (TGA). The dimension of the shunt is defined by hemodynamic and anatomic parameters.

Epidemiology of PAH in CHD

The overall prevalence of PAH in adult patients over the entire CHD spectrum is reported to range from 3% to 10%.2 PAH is most common in patients with Eisenmenger syndrome and left-to-right shunts (ie, ventricular septal defects [VSD], atrial septal defects [ASD], and patent ductus arteriosus [PDA]). Patients with isolated pre-tricuspid defects rarely develop severe PAH. Increased blood flow, pressure, and shear stress in the pulmonary circulation over time contribute to the development of PAH in CHD. It is therefore not surprising that the prevalence of PAH increases with age.2 Furthermore, the size of the defect, gender, and genetic factors also play a role in the development of PAH in CHD patients.3 The lifetime risk for PAH after CHD repair increases over time and ranges from 4% to over 15%, depending on the cardiac defect. Based on registry data, 7% to 37% of group 1 PAH is attributable to CHD.4,5,6

Outcomes of Patients With PAH-CHD

The presence of PAH has a significant impact on survival in patients with CHD.7 However, with continuous improvements in clinical management and new therapies, outcomes in adults with PAH-CHD have improved over recent years.8 In general, the outcome of PAH-CHD is associated with the size and the anatomy of the defect. Patients with the most complex defects (TGA, complete atrioventricular septal defect, Fontan, Eisenmenger physiology) have the lowest survival rates among CHD
patients.7 The underlying CHD anatomy is also an important parameter influencing PAH-CHD outcome, and there are key differences in adaptation of the right ventricle to pulmonary vascular remodeling. Patients with congenital post-tricuspid shunts have significant alterations in pulmonary blood flow and pressure early in life that can lead to the accelerated development of pulmonary vascular disease.9 In these patients, the right ventricle is primed to sustain a higher afterload compared to other types of PAH patients, possibly owing to retention of a favorable neonatal right-heart phenotype.10 In addition, the presence of an open shunt may act as a “pop-off,” allowing decompression of the subpulmonary ventricle at the expense of cyanosis.11 This is in line with the observation that patients with isolated pre-tricuspid shunts usually develop PAH later in life, and the development of severe PAH or Eisenmenger syndrome in these patients is associated with worse survival compared to PAH that occurs with post-tricuspid or complex lesions.12 Many patients with pre-tricuspid PAH-CHD are thought to have an underlying pulmonary vascular disease process independent from the CHD.

In contrast to other forms of PAH, patients with PAH-CHD have the highest survival, with a 7-year survival rate of 67%, compared to 49% in patients with idiopathic PAH or 35% in those with connective tissue disease-associated PAH.13 These findings are consistent with other PAH cohorts.8,14


Increased blood flow and circumferential stretch are “sensed” by vascular cells and lead to activation of transcription factors and altered gene expression, resulting in vascular remodeling.15 Changes in vascular cell proliferation and migration, as well as dysregulated production of vasoactive mediators and their receptors, have been described in patients with PAH-CHD.16 Remodeling of the pulmonary circulation can result in pulmonary vasodilation, constriction, vessel obliteration, or the development of arteriovenous malformations. These structural changes are influenced by local factors, blood flow, pressure, genetics, and hepatic venous return. Angiograms in children with CHD reveal that increased pulmonary blood flow in the
absence of increased pressure or resistance is associated with enlarged proximal pulmonary arteries and veins but no signs of remodeling when compared to normal angiograms.17 In patients with increased pulmonary blood flow and increased pressure, the pulmonary arteries are enlarged and tortuous. In patients with markedly elevated pulmonary pressure and increased resistance, abrupt termination of dilated and tortuous arteries and a diminished capillary blush are observed, indicating vessel obliteration or loss. This corresponds to the finding that PAH-CHD patients with the most severe PAH show evidence of distal pulmonary artery obliteration and loss on lung biopsy.18

Many studies since the 1950s have described the histopathologic changes in PAH-CHD: intimal and medial hypertrophy, muscularization of distal pulmonary arteries, in situ thrombosis, plexiform lesions, and perivascular inflammation are common features.19 A more recent study showed that PAH-CHD lungs demonstrate the same features of pulmonary vascular remodeling as seen in patients with idiopathic PAH (muscular remodeling, extracellular matrix proliferation, plexiform lesions), independent of the underlying CHD defect. Recent and organized thrombi and perivascular inflammation are also common in both groups.20

Genetic factors are increasingly recognized as contributors to pulmonary vascular remodeling, although there is increasing evidence that the genetics of PAH-CHD differs from other forms of adult PAH. For instance, mutations in the bone-morphogenetic receptor 2 are found in 60% of patients with hereditable PAH,21 but in less than 10% of children and 15% of adults with PAH-CHD.22 Conversely, a mutation in the SOX17 (SRY-related HMG-box17) gene was identified in 7% of PAH-CHD but only in 0.4% of adult PAH patients.23 Hence, some patients with CHD are likely to be at increased risk for the development of pulmonary vascular disease in the setting of increased blood flow and shear stress.


Signs and Symptoms

The signs and symptoms of PH are nonspecific and related to progressive right ventricular dysfunction and heart failure or anatomical changes of the pulmonary circulation. The most common symptoms reported by patients with PAH-CHD are dyspnea, fatigue, light-headedness, syncope, chest pain, and hemoptysis. The pathogenesis of dyspnea in patients with PAH is multifactorial; hypoxemia, ventilation-perfusion mismatch, and reduced cardiac output likely play a role. Fatigue, light-headedness, and syncope can be direct consequences of reduced cardiac output and/or hypoxia. Additionally, patients with PAH exhibit reduced cerebrovascular reactivity to blood pCO2 levels and a blunted increase in cerebral blood flow during exercise, thus increasing the risk for syncope.24 Chest pain can be caused by myocardial ischemia of the hypertrophied and hypoperfused right ventricle or compression of the left main coronary artery by a dilated pulmonary trunk.25

Some symptoms can be caused directly by anatomical changes in the pulmonary circulation. Hemoptysis in patients with PAH-CHD can be the direct result of remodeling of the pulmonary vasculature, such as hypertrophied bronchial arteries and shunts between pulmonary arteries, veins, and bronchial circulation.26 Wheezing and hoarseness can result from massive dilation of the pulmonary arteries compressing the large airways and recurrent laryngeal nerve (Ortner syndrome). Venous congestion and hypoperfusion from right-heart failure are commonly associated with organ dysfunction such as congestive hepatopathy, renal dysfunction, and myopathy.

Physical Examination

On physical examination, signs of PAH include a right ventricular lift, a wide split S2 with a prominent pulmonic component of the second heart sound, a pansystolic murmur of tricuspid regurgitation that increases in intensity with inspiration (Carvallo sign), elevated jugular venous pressure, and lower extremity edema. Genetic syndromes are commonly associated with PAH-CHD and can have specific physical examination features, as seen in Down syndrome.

Cyanosis—the bluish discoloration of mucus membranes or skin caused by an increased amount of deoxygenated blood (usually when systemic arterial saturation <85%)—is common in PAH-CHD. Peripheral cyanosis results from low cardiac output and peripheral vasoconstriction or venous congestion. Central cyanosis is seen in patients with right-to-left shunting from severe PAH (Eisenmenger), intrapulmonary shunting, or other complex CHD without significant PAH.27 Differential cyanosis refers to cyanosis that only affects the lower extremities (ie, upper extremities are spared) and can be seen in patients with Eisenmenger syndrome owing to a large PDA. In reverse differential cyanosis—which can be seen in TGA with PDA and elevated pulmonary vascular resistance—the arms are more cyanotic than the legs.28 Hypertrophic osteoarthropathy or clubbing can be observed in patients with long-standing tissue hypoxemia and cyanosis. Clubbing is characterized by enlargement of the anteroposterior and lateral diameter of the nail owing to the proliferation of connective tissue between the nail matrix and the distal phalanx. Clubbing and cyanosis are not specific to PAH and can be seen in any cardiopulmonary disease that is associated with tissue hypoxemia.

Differential Diagnosis

The differential diagnosis for a patient with CHD and suspected PH is broad because presenting signs and symptoms are usually nonspecific. Dyspnea, fatigue, and chest pain need to be thoroughly evaluated and cardiac, pulmonary, hematologic, and metabolic causes need to be considered. Because the prevalence of PAH in patients with CHD is high, extensive hemodynamic evaluation with an echocardiogram and/or right-heart catheterization is usually recommended in these patients to determine whether symptoms are related to progressive heart failure or other underlying causes such as concomitant lung disease, liver disease, or thromboembolic disorder. If PH is suspected, alternative causes should be evaluated, such as collagen vascular diseases, HIV infection, or liver disease with portal hypertension. Echocardiography can be helpful to evaluate concomitant left heart or valvular disease. Pulmonary function testing (PFT) is recommended to rule out obstructive or restrictive lung disease. Ventilation-perfusion scanning of the lung is recommended to evaluate chronic thromboembolic disease that can be missed on contrast computed tomography (CT) scans (Algorithms 110.1 and 110.2).