Definition
Pulmonary hypertension (PH) is broadly defined as mean pulmonary arterial pressure (mPAP) ≥25 mmHg. This definition is broad, perhaps by design, to capture almost all patients with elevated pulmonary vascular resistance (PVR), particularly those with pulmonary arterial hypertension (PAH). However, such a definition may incorrectly diagnose patients with PH despite having normal PVR, especially those with congenital heart disease (CHD) and left-to-right shunting, or it may not capture PH for those with non-pulsatile pulmonary circulation. Furthermore, recent evidence suggests that the risk of mortality in patients with elevated pulmonary arterial pressure (PAP) is incremental and is not necessarily restricted to patients with mPAP ≥25 mmHg.¹ The World Symposium on Pulmonary Hypertension Task Force has recently proposed a redefinition to include patients with mPAP >20 mmHg and PVR ≥3 Wood units.² Therefore, these factors should be considered when determining therapeutic strategy, especially in patients with CHD.

Prevalence
Recent administrative data from the population of Denmark reported significantly higher cumulative incidence of PH among adults (ages 18-70 years) with CHD (7.2%) compared with the general population (0.4%).³ However, diagnosis of PH in adults with CHD using administrative data is not precise. In addition to limitations of administrative data to capture true disease states, diagnosis of PH in adults with CHD using echocardiography is often inaccurate and almost always requires invasive cardiac catheterization, which is not routinely performed in asymptomatic patients in clinical practice. Examples include patients with pulmonary stenosis in whom echocardiography-derived right ventricular (RV) systolic pressure estimation from tricuspid-regurgitation jet-velocity is not reflective of PAP, to those with single ventricle palliated with the Fontan circulation that lacks a sub-pulmonic ventricle or sub-pulmonic atrioventricular valve. Nevertheless, a significant proportion of adults with CHD have PH that ranges from mild elevation in PAP or PVR to Eisenmenger syndrome.

A Note on Eisenmenger Syndrome
Victor Eisenmenger first described the phenomenon of bi-directional shunting across a defect.⁴ Paul Wood later elegantly described different forms of PH and observed significant differences among patients with pre- tricuspid versus post-tricuspid shunts.⁵ Patients with atrial septal defect (ASD), the most common form of pre-tricuspid shunt, typically live with a left-to-right shunt unless they develop PAH (or increase in PVR), which rarely develops in childhood. Contrast them to patients with ventricular septal defects (VSDs), the most common form of post-tricuspid shunt, who develop PH much earlier in life. Thus, unlike pre-tricuspid shunts, post-tricuspid shunts are likely directly implicated in the development of PH. For this review, the term Eisenmenger phenomenon is used to describe PH with bi-directional shunting across a cardiac defect, whereas Eisenmenger syndrome is used to describe PH in patients with post-tricuspid shunts and bi-directional shunting across the defect.

Suggested Clinical Approach to PH in Adults With CHD
In addition to following the usual guidelines of managing PH in patients without CHD, certain concepts are important to highlight when approaching the adult with CHD and suspected PH.

1. PH in the Presence of Pre-Tricuspid Shunts
Examples include patients with large ASD, partial anomalous pulmonary venous return, or coronary sinus defect. Most patients do not develop PH nor Eisenmenger phenomenon. It is important to note that such lesions may coexist and/or exacerbate PH in patients with PAH and need to be considered when formulating the management plan.

• Example 1. A 28-year-old woman who was previously healthy presented with progressive shortness of breath, New York Heart Association functional class (NYHA FC) III. She was found to have a dilated RV with elevated estimated PAP on the echocardiogram and was referred for management of PH. Figure 1 demonstrates echocardiographic and magnetic resonance imaging (MRI) of totally anomalous pulmonary venous return via a large vertical vein and cor triatriatum leading to large left-to-right shunt (with calculated Qp:Qs of 4.0). Despite elevated estimated PAP on echocardiogram, we did not feel a cardiac catheterization was necessary because the patient had significant left-to-right shunting that argued against significant PH. The patient eventually underwent complete repair with resection of the cor triatriatum membrane, ligation of the decompressing vertical vein, and tricuspid valve annuloplasty. Postoperatively, mPAP was 21 mmHg. A follow-up echocardiogram 4 months after surgery is shown in Figure 1D. In this example, a large shunt may lead to incorrect diagnosis of PH based on echocardiogram due to presence of high pulmonary blood flow.

Figure 1

• Example 2. A 53-year-old woman presented with syncope and was found to have exertional desaturation, NYHA FC III. A transthoracic echocardiogram showed PAP estimate of at least 68 mmHg (53 mmHg + RA pressure estimate of 15 mmHg) and a large secundum-type ASD (with additional smaller secundum ASD posteriorly) with left-to-right shunting (Figure 2). Cardiac catheterization showed PAP of 99/30 mmHg (mean 56 mmHg) with a calculated Qp:Qs of 1.3. She was started on pulmonary vasodilators consisting of macitentan and tadalafil. Subsequent cardiac catheterization performed 6 months later showed unchanged PAP of 89/24 mmHg (mean 50 mmHg) but significant increase in the shunt fraction with a Qp:Qs of 2.8. The patient was presented at the Adult CHD Multidisciplinary Meeting, and she subsequently underwent closure of the larger ASD; the smaller ASD was left open. The patient reported significant improvement (from NYHA FC III to NYHA FC I), and her diuretic was stopped. However, she was continued on pulmonary vasodilators and follows up at our Adult CHD center. The case highlights the stark difference in management of patients with pre-tricuspid shunts compared with patients with Eisenmenger syndrome, particularly the need for a multidisciplinary team with experience in managing such patients. It is important to note that the decision to close an ASD in patients with PAH (often leaving a fenestration or in this rare case a residual separate smaller ASD) is complex and requires significant deliberation and gathering of data at multiple time-points.

Figure 2

2. PAH in the Presence of Post-Tricuspid Shunts
Post-tricuspid shunts lead to increased flow and pressure to the pulmonary vasculature up to systemic pressure levels, leading to a more rapid progression of abnormal pulmonary vascular remodeling, often early in childhood.⁶ Examples include non-restrictive VSDs (Figure 3), aortopulmonary window, and patent ductus arteriosus. The optimal treatment would be to correct the anatomic defect earlier in life prior to irreversible vascular remodeling and development of Eisenmenger syndrome. For patients with Eisenmenger syndrome, the only definitive treatment is lung transplant with shunt closure or heart-lung transplantation. Medical therapies with oral pulmonary vasoactive drugs (endothelin receptor antagonists, phosphodiesterase-5 inhibitors, or prostacyclin analogs) have been shown to improve functional capacity and quality of life in patients with Eisenmenger syndrome but have not shown definitive survival benefit.⁶ Intravenous therapies are relatively contraindicated in patients with Eisenmenger syndrome because chronic indwelling venous catheters put them at risk of paradoxical embolism in the setting of right-to-left shunting. The need for intravenous or subcutaneous therapy is decreasing with the advent of newer oral agents. However, despite the progress in management of patients with CHD, patients with Eisenmenger syndrome have a 13-fold increased risk of mortality compared with the general population.⁷ A recent analysis of 1,098 patients with Eisenmenger syndrome identified factors associated with higher risk of mortality:⁸

• Increased age
• Pre-tricuspid shunts
• Presence of pericardial effusion
• Lower oxygen saturation at rest
• Absence of normal sinus rhythm

The authors explain that the development of Eisenmenger phenomenon (and pressure loading of the RV) in patients with pre-tricuspid shunts occurs later in life (if ever), which does not allow time for adaptations that may occur earlier in life in patients with post-tricuspid shunts. We also note that a pre-tricuspid shunt leads to long-standing volume loading of the RV, which may render it incapable of tolerating the addition of pressure load if PAH ensues. Alternatively, a Berkson's bias may explain this finding: Given that the majority of these patients has ASD, the presence of an interatrial shunt may allow patients with severe PAH to present only at a later stage of their disease by preventing excessive elevation of RA pressure and subsequent development of atrial arrhythmia (which is a known strong predictor of adverse outcomes in this population). Therefore, patients with pre-tricuspid shunts in this and other cohorts may have been "too sick."

Figure 3

3. Segmental PH
In 2013, the World Pulmonary Hypertension Symposium added a new classification labeled segmental PH described as "PH in one or more lobes of one or both lungs." It overlaps histologically with WHO Groups 1 and 4. Due to the uncertainty of the pathophysiology and its response to PAH therapies, it is included under WHO Group 5.⁹ Examples of CHD lesions that predispose to segmental PH (which develops due to asymmetric lung perfusion from systemic to pulmonary shunts) include complex tetralogy of Fallot with major aortopulmonary collateral arteries, complex pulmonary atresia, or surgical aortopulmonary shunts. There are significant differences in cardiopulmonary physiology in various types of segmental PH. Therefore, evaluation and management of segmental PH should be performed at tertiary centers with expertise in both CHD and PH.

4. Multifactorial PH in Adults With CHD
Examples include patients with atrioventricular canal defects and Down syndrome, patients with Shone syndrome and intracardiac shunting, patients who underwent late repair of post-tricuspid lesions, and the many patients in adulthood who develop obstructive sleep apnea or other risk factors for PH. In practice, a large proportion of adults with CHD and PH will have more than one original or persistent lesion that have contributed to the development of PH later in life. It is important to account for these different factors to allow accurate diagnosis and management.

References

1. Maron BA, Hess E, Maddox TM, et al. Association of Borderline Pulmonary Hypertension With Mortality and Hospitalization in a Large Patient Cohort: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program. Circulation 2016;133:1240-8.
2. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019;53:1801913.
3. Schwartz SS, Madsen N, Laursen HB, Hirsch R, Olsen MS. Incidence and Mortality of Adults With Pulmonary Hypertension and Congenital Heart Disease. Am J Cardiol 2018;121:1610-6.
4. Eisenmenger V. Die angeborenen Defecte der Kammerscheidewand des Herzens. Z Klin Med 1897;32:1-28.
5. Wood P. Pulmonary hypertension with special reference to the vasoconstrictive factor. Br Heart J 1958;20:557-70.
6. Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:1494-563.
7. Diller GP, Kempny A, Alonso-Gonzalez R, et al. Survival Prospects and Circumstances of Death in Contemporary Adult Congenital Heart Disease Patients Under Follow-Up at a Large Tertiary Centre. Circulation 2015;132:2118-25.
8. Kempny A, Hjortshøj CS, Gu H, et al. Predictors of Death in Contemporary Adult Patients With Eisenmenger Syndrome: A Multicenter Study. Circulation 2017;135:1432-40.
9. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62:D34-41.

Keywords: Eisenmenger Complex, Phosphodiesterase 5 Inhibitors, Ductus Arteriosus, Patent, Pulmonary Atresia, Epoprostenol, Scimitar Syndrome, Endothelin Receptor Antagonists, Heart-Lung Transplantation, Cor Triatriatum, Tricuspid Valve Insufficiency, Tricuspid Valve, Pulmonary Circulation, Risk Factors, Vasodilator Agents, Embolism, Paradoxical, Down Syndrome, Diuretics, Blood Pressure, Arterial Pressure, Coronary Sinus, Quality of Life, World Health Organization, Tetralogy of Fallot, Sulfonamides, Heart Septal Defects, Heart Septal Defects, Ventricular, Pyrimidines, Hypertension, Pulmonary, Pulmonary Valve Stenosis, Echocardiography, Vascular Resistance, Cardiac Catheterization, Syncope, Sleep Apnea, Obstructive, Magnetic Resonance Imaging, Patient Care Team, Dyspnea, Arteries

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