Pulmonary Hypertension in Congenital Heart Disease: A Scientific Statement from the American Heart Association

Background: scientific statement on pulmonary hypertension associated with congenital heart disease

Pulmonary hypertension associated with congenital heart disease is a known cause of pulmonary hypertension. Advancements have led more children with congenital heart disease to survive to adulthood, but many develop additional cardiac complications such as pulmonary hypertension. Despite increases in prevalence and survival, there is a lack of definitive medical evidence for managing patients with this type of pulmonary hypertension.

• Patients are often underrepresented or excluded from clinical studies.
• Treatment strategies are often based on experience of clinician, findings from smaller studies or unmatched retrospective data instead of an individual’s structural or hemodynamic issues.

Dunbar Ivy, MD, Chief of Pediatric Cardiology and co-director of the Heart Institute at Children’s Hospital Colorado, is one of the preeminent experts in pediatric pulmonary hypertension treatment and research. The Pediatric Pulmonary Hypertension Program at Children’s Colorado was the first multidisciplinary program in the U.S. and is one of the top programs in the nation.

Dr. Ivy and other specialists from across the nation were part of the writing group that authored the American Heart Association’s (AHA) scientific statement on pulmonary hypertension associated with congenital heart disease.

Classification of pulmonary hypertension associated with congenital heart disease

Classification now includes congenital cardiac lesions important in pediatric pulmonary hypertension. Four WSPH pathogenetic groups include forms of pulmonary hypertension associated with congenital heart disease, including:

• Group 1: pulmonary arterial hypertension (PAH)
  • Eisenmenger syndrome
  • PAH-congenital heart disease with left to right shunt
  • PAH with small defect
  • PAH after congenital hear disease correction
• Group 2: pulmonary hypertension due to left heart disease
  • Pulmonary vein stenosis
  • Systolic or diastolic ventricular dysfunction
  • Left heart obstructive disease (such as hypoplastic left heart syndrome)
• Group 4: pulmonary hypertension with pulmonary artery obstructions
  • Congenital pulmonary artery stenosis (such as tetralogy of Fallot)
• Group 5: pulmonary hypertension with unclear/multifactorial mechanisms, including complex congenital heart disease 
  • Single ventricle
  • Segmental pulmonary hypertension

In the future, classifications could include recognition that patients may fit in more than one group or characteristics could change over time from original classification.

The group noted:

• Many pediatric patients have multiple reasons for pulmonary hypertension while at the same time have features of different pulmonary hypertension groups such as patients with Down syndrome with PAH-congenital heart disease.
  • Biomarkers could help understand the reason for pulmonary hypertension in children with Down syndrome.
• Future genetic studies will improve understanding of role of molecular pathways and potential overlap with physiologically-induced mechanisms.

Screening and diagnosing pulmonary hypertension-congenital heart disease

Clinical presentation, initial testing

Subtle pulmonary hypertension symptoms can lead to delayed diagnosis of PAH-congenital heart disease.

Common symptoms in infants include:

• Poor feeding
• Tachypnea
• Tachycardia
• Poor growth
• Shortness of breath

Possible physical signs include:

• Loud split-second heart sound
• Gallop
• Holosystolic murmur of tricuspid regurgitation
• Later signs of right-sided heart failure:
  • Edema of the face, hands, ankles
  • Hepatomegaly

Radiographic findings:

• Clues to degree of shunting
  • Congested vasculature common in large left-to-right intracardiac shunts
  • Oligemia in patients with restricted blood flow
• Do not always correlate with disease severity
  • Most children with pulmonary hypertension will have evidence of right ventricular hypertrophy on electrocardiogram

Transthoracic echocardiography

Techniques include:

• Conventional imaging
• 2-dimensional anatomy assessment
• Hemodynamics through Doppler echocardiography
• Qualitative, quantitative evaluation of RV, left ventricular function
• Advanced imaging
• Evaluate right-sided heart size, function
• Myocardial mechanics
• Estimate ratio of RV to pulmonary arterial coupling

Cross-sectional imaging

Cross-sectional imaging plays a key role in consensus statements on caring for adult and pediatric patients with pulmonary hypertension.

• Computed tomography (CT) and magnetic resonance imaging (MRI) offer a simultaneous view of structures in all three dimensions to helps describe complex congenital heart disease.
• MRI angiography can identify extracardiac lesions.
• MRI phase-contrast imaging can be used to calculate hemodynamic data, direction of intracardiac shunting, degree of shunting and identify physiological sequelae.
• Each method has advantages and disadvantages.

Cardiac catheterization

Right- and left-sided heart catheterization is considered the gold standard for hemodynamic measuring in patients with congenital heart disease and advanced pulmonary vascular disease. Acute vasoreactivity testing during catheterization has been used to help strategize post-operative treatment for pulmonary hypertension.

The group noted that there is a lack of evidence to support the reliability of these tests, as well as approaches including duct occlusion, fenestration occlusion and ratios of pulmonary artery to systemic artery diastolic pressure used to determine operability in certain patients.

Treating pulmonary hypertension associated with congenital heart disease

Since death and transplantation rarely occurs in childhood, surrogate markers have been to help predict therapy response. More research is needed to better understand the limitations of surrogates compared to clinically meaningful outcomes to determine therapy response.

Pharmacotherapy

Pharmaceutical treatment is common in the management of pulmonary hypertension–congenital heart disease. Specific treatment examples include:

• Treat to close - lowering pulmonary vascular resistance (PVR) to aid safe repair
• Treat after repair of defect(s)
• Improve quality of life in patients with Eisenmenger syndrome
• Further lower pulmonary artery pressures and PVR in patients with pulmonary hypertensive vascular disease and Fontan circulations to improve forward pulmonary artery flow

Three classes of drugs are available for targeted pulmonary hypertension therapy:

• Phosphodiesterase-5 inhibitors
  • Commonly used: sildenafil and tadalafil
  • Improves hemodynamics, exercise capacity in patients with PAH–congenital heart disease and Eisenmenger syndrome
• Endothelin receptor antagonists (ERAs)
  • Endothelin-1 shown to be potent mediator of vascular constriction
  • Bosentan, ambrisentan, macitentan shown to improve hemodynamics in patients with congenital heart disease, Eisenmenger syndrome
  • Larger studies needed
• Prostacyclins

Nursing considerations

Advance practice professionals, nurses and specialty pharmacies are critical to therapeutic success of these patients, especially with use of multidrug therapies and parenteral prostacyclins.

Surgical considerations

• Surgical repair of patients with PAH–congenital heart disease and biventricular circulations
• Surgical repair/palliation of PAH–congenital heart disease and univentricular circulations
• Palliation of PAH–congenital heart disease through pulmonary-to-systemic (reversed Potts shunt) shunt creation

Lung transplantation

Transplantation evaluation is appropriate for patients with:

• Severe PAH–congenital heart disease after repair
• Lack of response to medical therapy
• Eisenmenger syndrome (list only after comparing expected survival with and without transplant)
• PAH with progressive right-sided heart failure and associated end-organ injury considered eligible in World Health Organization functional class IIIb and IV (after discussion of end stage goals)

Double-lung transplantation

• Most common for patients with congenital heart disease and end-stage pulmonary hypertension
• Improved organ use compared to heart-lung transplant

Heart-lung transplantation

• Occurring less due to success of double-lung transplant and aggressive treatment of early RV dysfunction
• Best option for:
  • Eisenmenger syndrome combined with severely compromised RV or left ventricular function
  • Complex pulmonary hypertension–congenital heart disease and associated pulmonary vein stenosis

Transplantation outcomes

Patients with PAH have:

• Similar 5- and 10-year survival rates to recipients with other pathogeneses
• Significantly better 1-year survival than recipients with primary lung disease

Social determinants of health in PAH–congenital heart disease

Findings from studies on social determinants of health for this population include:

• Significant racial variability in incidence of subtypes, survival in children
• Better survival, longer length of stay for black neonates admitted for congenital heart disease care

Potential precipitants of inequality among patients with PAH include:

• Association between people of color, lower socioeconomic status with higher incidence of cardiovascular death
• 42% of U.S. population made up of underrepresented races, ethnicities (2020)
• Early diagnosis, early treatment key factors for PAH survival
• Socioeconomic, geographic barriers to safe, advanced medical care

Prognosis for patients with pulmonary hypertension–congenital heart disease

Registry studies are currently being conducted on prognosis for pediatric patients with pulmonary hypertension.

Conclusions: ongoing pulmonary hypertension-congenital heart disease research needed

There have been many advancements in the management of patients with pulmonary hypertension-congenital heart disease, but there are also many opportunities to improve patient care.

More research is needed to better understand the cause and pathophysiology within the many pulmonary hypertension-congenital heart disease subgroups and develop targeted drug therapies and effective treatment. This work will require ongoing and dedicated multidisciplinary collaboration.