Pulmonic Valvular Stenosis

Pulmonic valvular stenosis (PVS) is a form of right ventricular outflow tract obstruction (RVOTO). Stenosis may be valvular, subvalvular, or supravalvular. It is usually an isolated lesion and occurs in up to 12% of congenital heart disease (CHD).[1, 2] It is the most common cause of RVOTO.

Clinically relevant disease is typically diagnosed within the first year of life. Neonates with critical stenosis may present initially with central cyanosis at birth. Infants and children with ejection murmurs auscultated in the pulmonic region often undergo evaluation and PVS may be uncovered. PVS has been seen in the setting of well-defined congenital syndromes, most notably Holt-Oram syndrome, Noonan syndrome, and Leopard syndrome.[3, 4, 5] Eisenmenger syndrome associated with trisomy 13 also results in RVOTO in conjunction with other cardiac malformations.[6]

A large study called the Second Natural History Study of Congenital Heart Defects analyzed the treatment, quality of life, echocardiography findings, complications, exercise responses, and predisposition to endocarditis with regards to cardiac valvular disease, and pulmonary stenosis was found to be the most benign valvular lesion.[7]

According to the current ACC/AHA guidelines, PVS severity is defined by peak gradient across the pulmonic valve (PV), as follows[2] :

• Mild: < 30 mmHg

• Moderate: 30-50mmHg

• Severe: >50mmHg 

Disease course, outcomes and management are determined based on the illness severity.

Current guidelines outline the following three clinically relevant valve morphologies[2] :

• Dome-shaped pulmonic valve (PV)

• Dysplastic PV

• Uni- or bicuspid PV

Dome-shaped PV is more common, characterized by a narrow central opening with a preserved, mobile valve mechanism. Well-defined valve commissures are not present; however the structures exist in a rudimentary form. The pulmonary trunk may be dilated.[8, 9, 2]

Dysplastic PV is characterized by poorly mobile and myxomatous leaflets with no defined commissures. The pulmonary annulus and the right ventricular outflow tract (RVOT) may be narrowed as well. While uncommon, it is the typical morphology characteristic of Noonan syndrome.[8, 2]

The inheritance rate is low, although when part of Noonan syndrome it is autosomal dominant.[10] Mutations in germlines PTPN1 and RAF1 associated tetralogy of Fallot (TOF) are also associated with a uni- or bicuspid pulmonic valve, which may or may not cause an independent obstruction. Supravalvular lesions may occur in the setting of TOF, Williams syndrome, and Alagille syndrome, as well as in Noonan syndrome.[11]

During early development, the myocardial cushion begins as a matrix of endothelial cells and an outer mitochondrial layer separated by cardiac jelly. After endocardial cushion formation, the endothelial mesenchymal transformation (EMT), which are specified endothelial cells, differentiate and migrate into the cardiac jelly. Through a poorly understood process, the cardiac jelly goes through local expansion and bolus swelling, and cardiac valves are formed. The aortic and pulmonic valves develop from the outflow tract of the endocardial cushion, also believed to have neural crest cell migration from the brachial crest during development.[3]

Research suggests that the vascular endothelial growth factor (VEGF), a pleiotropic factor, is responsible for signaling the development of the endocardial cushion. Hypoxia and glucose have regulatory effects on this factor. Infants born to hyperglycemic mothers have a significant increase in cardiovascular abnormalities.[12] There has been correlation between intrapartum hypoxic events and valvular disease. Additionally, numerous signaling molecules contribute to VEGF and EMT such as the ERB-B signaling in the cardiac jelly, transforming growth factor (TGF)/cadherin, and bone morphogenetic protein (BMP)/TGF-beta.[3]

The pulmonic valve develops between the 6th and 9th week of gestation. Normally, the pulmonic valve is formed from three swellings of subendocardial tissue called the semilunar valves. These tubercles develop around the orifice of the pulmonary tree. The swellings are normally hollowed out and reshaped to form the three thin-walled cusps of the pulmonic valve. In Noonan syndrome, tissue pad overgrowth within the sinuses interferes with the normal mobility and function of the valve.

While pulmonic valvular stenosis is primarily a congenital malformation, it may also occur as part of congenital rubella syndrome. The most common etiologies of acquired are carcinoid syndrome, rheumatic fever, and homograft dysfunction.[8]

United States data

Approximately 5 out of 1000 infants are born with a congenital cardiac malformation.[3] Valvular defects are the most common type of cardiac malformation, accounting for 25% of all malformations involving the myocardium.[3] The prevalence of pulmonic valvular stenosis accounts for 7-10% of all CHD.[13]

Sixty percent of patients with Noonan syndrome are found to have some degree of pulmonic valvular stenosis.[4]

Sex- and age-related demographics

The male-to-female ratio of pulmonic valvular stenosis is approximately 1:1. There are no sex-related differences in outcomes.[14]

When pulmonic valvular stenosis is diagnosed before one year of age, it is considered a high risk group and patients must undergo close lifetime follow up, including connection to a regional CHD specialty center.[14]

Mild pulmonic valvular stenosis has a good overall prognosis and life expectancy.[7] Recent literature suggests that pulmonic valvular stenosis is associated with a five times increase in mortality, especially in individuals who have not undergone intervention.[14] There was also a higher mortality seen in patients diagnosed before age one year, suggesting more severe disease in cases detected earlier in life.

Years of stenosis can result in subendocardial hypertrophy causing significant right ventricular outflow tract obstruction (RVOTO), resulting in right ventricular pressure overload and pulmonary hypertension. As this process worsens, an asymptomatic adult becomes gradually symptomatic.[15, 16]

Patients with moderately severe-to-severe stenosis have clinically progressing disease. The survival rate for severe stenosis is 96%; however, mean follow-up over a period of 33 years suggests that 53% of patients required further intervention. Forty percent may have associated atrial or ventricular arrhythmias.[11, 15]

Morbidity/mortality

Valvular disease in general has high morbidity and mortality rates. However, isolated pulmonic valvular stenosis has been found to be the most benign.[7] In the United States, about 82,000 valvular replacements are performed per year.[3] Survival to adulthood is most common, as symptoms and extent of disease progress with time.[17]

Much of what is known about the morbidity and mortality of pulmonic valvular stenosis comes from the Natural History Study of Congenital Heart Defects and the Second Natural History Study of Congenital Heart Defects. The Natural History Study of Congenital Heart Defects included an initial cardiac catheterization and then follow up for events over an 8-year period. The Second Natural History Study of Congenital Heart Defects reported on 16-27 years of follow up from the same cohort.[7]

The studies demonstrated that adverse outcomes directly relate to the right ventricular systolic pressure gradient.[18] Mild pulmonic valvular stenosis with pressure gradient across the valve less than 50 mm Hg was found to be well tolerated clinically and subjectively.[7] Of these patients, 94% were asymptomatic, without cyanosis or congestive heart failure (CHF).[19, 20] Moderate-to-severe pulmonic valvular stenosis, with pressure gradient greater than 50 mm Hg was more often associated with decreased cardiac output, right ventricular hypertrophy, early CHF, and cyanosis. Valvotomy has been shown to improve morbidity and mortality and is indicated in severe disease.[7]

The morbidity and mortality of valvular lesions in regard to pregnancy and fetal outcomes has not been rigorously studied. Recent literature suggests there is no impact of pulmonic valvular stenosis on maternal or fetal health.[21, 14]

Complications

Complications are rare and are mostly related to post valve repair (valvulotomy vs surgical).

In the unoperated patient with mild pulmonic valvular stenosis, disease is rarely progressive, owing to the mild gradient of flow.

Moderate and severe pulmonic valvular stenosis can progress to right heart failure, secondary to hypertrophy of the RVOT over time.[8, 2]

Patients and parents of those with mild PVS should be reassured that this condition is not related to, or associated with, coronary artery disease or sudden death. There is a mild association with benign dysrhythmia.[8, 7]

If the patient is asymptomatic with mild pulmonic valvular stenosis, an annual screening examination and ECG should be scheduled. Follow up every 3-5 years may be initiated if subsequent evaluations show no change.[11] Recent European Society of Cardiology (ESC) guidelines recommend that all patients, regardless of disease severity, should be seen by a specialist at least once in their lifetime. Mild disease can be followed routinely by a generalist or by a general cardiologist.[22]

Pulmonic valvular stenosis (PVS) in adults may present as an asymptomatic systolic murmur, or they may complain of decreased exercise tolerance.

In a functional and hemodynamic study of 19 Belgian patients with isolated mild-to-moderate pulmonary valve stenosis but no previous cardiac interventions, investigators reported significant differences in the following at-rest and exertional parameters between patients and their age- and sex-matched controls[23] :

• Higher resting heart rate (P = 0.001)

• Lower peak power (P = 0.006)

• Lower peak oxygen uptake (VO2) (P = 0.011) and lower oxygen uptake efficiency slope (P = 0.007)

• Higher ventilatory equivalent for carbon dioxide (VE/VCO2) (P = 0.01)

The investigators indicated an observed linear increase in the peak pulmonary valve gradient may suggest a fixed valve area during exercise.[23] They also reported no signs of right heart functional or morphologic changes during exercise, with good ventricular performance.

For most adults with pulmonic valvular stenosis (PVS), there are no classic phenotypic findings, and disease is suspected during cardiac examination.

For suspected Noonan syndrome, phenotypes include the following:

• Facial anomalies such as low set ears and hairline, hypertelorism, micrognathia, webbed neck

• Chest deformities (pectus excavatum)

• Short stature

• Intellectual disability

Cardiac examination findings correlate with the severity of stenosis, valve pathology, and other associated cardiac lesions. Rarely, overt right heart failure is seen (unless end-stage disease).

On auscultation, the first heart sound is normal and followed by a systolic ejection click loudest over the left upper sternal border.[11, 15] The murmur decreases with inspiration; this is secondary to the premature opening of the pulmonary valve by the atrial kick into a stiff right ventricle.[2]

The second heart sound may have a wide split, especially in severe disease. This is due to delayed closing of the pulmonic valve at the end of systole. The pulmonic component of the second heart sound may be diminished in intensity, and a right sided fourth heart sound may be heard.

In more severe pulmonic valvular stenosis, a right ventricular lift with associated jugular venous distention may be appreciated, and the pulmonary ejection murmur is much louder and longer.

Myocardial infarction of hypertrophied right ventricle may occur.[9] Cyanosis may occur with right-to-left shunting at the atrial level as with a patent foramen ovale or septal defect.[15]

Laboratory evaluation usually is not helpful.

Oximetry provides information on possible right-to-left shunting in borderline cyanotic lesions or in patients with anemia but does not identify the cause of the shunt (pulmonary, interatrial, interventricular, great arterial).[15]

Although arterial blood gases (ABG) analysis usually is not needed, one notable exception is the hyperoxia test in newborns with cyanosis of undetermined origin.

Administered 100% FIO2 generally does not increase the partial pressure of oxygen to levels much greater than 100 mm Hg in patients with a cyanotic congenital heart defect.

Electrocardiography is not diagnostic, and in mild to moderate pulmonic valvular stenosis will yield normal results. In severe pulmonic valvular stenosis, right axis deviation and right ventricular hypertrophy may occur.

According to the American College of Cardiology/American Heart Association guidelines for the management of adults with congenital heart disease, cardiac catheterization is unnecessary for diagnosis and should only be utilized when percutaneous catheter intervention is considered.[2]

Chest radiography

Chest radiography may demonstrate a prominent main pulmonary artery segment but a normal heart size; however, it may also present as congestive heart failure (CHF), with cardiomegaly secondary to enlarged right atria and ventricle.

Computed tomography scanning and magnetic resonance imaging

Modalities such as computed tomography (CT) scanning and magnetic resonance imaging (MRI) can show structural cardiac abnormalities.[24, 25] They are the preferred modality when echocardiogram cannot be used.

One case report described the identification of a patient with isolated subvalvular pulmonary stenosis using whole-heart MRI.[26] This imaging tool is noninvasive and has the added benefit of creating a 3-dimensional representation of the heart and surrounding structures. Other reports have described the use of whole-heart MRI as a presurgical adjunct.[24]

Cardiac CT has been beneficial for noninvasive presurgical evaluation of someone with known coronary artery disease. The radiation exposure is minimal, and the reconstructions of a 64-slice CT can yield very accurate images of myocardium changes associated with outflow tract obstruction.[25]

Echocardiography is safer and more effective in the diagnosis of pulmonic valvular stenosis (PVS) compared with cardiac catheterization. It can determine flow gradients across the pulmonic valve, which is an indicator of disease severity.[7] Multiple views and measurements increase the accuracy. Additionally, in the parasternal short axis view, "doming" can be seen, which is evidence of a thickened pulmonic valve with restricted systolic motion.

The transthoracic approach provides valuable information about the site of obstruction and other possible congenital abnormalities.[18, 27, 28, 29] The transesophageal approach can also be used if the views are suboptimal, or if assessing for infective endocarditis.[2] Practice guidelines use echocardiography to determine definitive management in pulmonic valvular stenosis and as part of patient follow up.[30]

In a study that compared live/real-time three-dimensional transesophageal echocardiography (3D-TEE) with two-dimensional transesophageal echocardiography (2D-TEE) to determine whether there are advantages to using 3D-TEE on patients with pulmonary stenosis, investigators prospectively enrolled 16 consecutive adult patients with pulmonary stenosis and indications of TEE. They found evidence of the incremental value of using 3D-TEE instead of 2D-TEE during assessments of pulmonary stenosis, specifically in cases where special conditions cause inaccuracy in recordings of the transvalvular peak gradient. The investigators concluded that during routine echocardiographic examinations, 3D-TEE should be used as a complementary imaging tool to 2D-TEE.[31]

Most children with pulmonary stenosis do not require further evaluation beyond echocardiography.

Surgical management is the definitive treatment for pulmonic valvular stenosis (PVS). Patients with congestive heart failure may benefit from anticongestive therapy.

Interventions for pulmonic valvular stenosis include balloon dilatation, stenting, and pulmonic valve replacement.[32, 33, 34, 35]

Current guidelines recommend balloon valvuloplasty as the treatment of choice for all patients who can anatomically undergo the procedure.[22, 30] The American Heart Association (AHA) and American College of Cardiology (ACC) have established the following criteria[30] :

• Asymptomatic patients with peak doppler gradient >60 mm Hg are recommended for balloon valvotomy.

• Symptomatic patients with a peak doppler gradient >50 mm Hg and a domed pulmonic valve are recommended for balloon valvotomy.

When surgical valve repair is required, it is typically in the setting of severe stenosis along with concomitant severe pulmonary regurgitation, hypoplastic annulus, subvalvular or supravalvular stenosis, or in a patient with dysplastic valves. Additionally, it may be considered when the patient is already undergoing a concurrent cardiac surgery.

Outcomes after balloon or surgical valvulotomy are generally excellent. Stenosis usually does not recur, and right ventricular hypertrophy often regresses.[11] A 2007 study presented long-term follow-up data on 90 adult patients who had pulmonary balloon valvuloplasty. Outcome data was excellent, and the study supports the use of balloon angioplasty.[36]

Oxygen should be administered to any patient in respiratory distress. Oxygen may also assist with pulmonary artery vasodilation, thus increasing pulmonary blood flow. Use of oxygen may reduce pulmonary artery pressure in patients with a reactive pulmonary vasculature, thus increasing pulmonary blood flow.

Clinical evaluation and echocardiography will direct management. Patients presenting in extremis will need rapid stabilization, and it is recommended that transfer to a regional congenital heart disease center is initiated.[2]

Hospitalization

Intervention with either balloon angioplasty or valve repair is indicated for patients with severe or symptomatic infundibular or supravalvular pulmonic valvular stenosis (PVS). This is seen clinically with peak valve gradients more than 50 mm Hg, or for patients experiencing angina, presyncope, syncope, or exertional dyspnea. Corrective options include open heart surgery, balloon angioplasty, percutaneous stenting, percutaneous valve replacement, or percutaneous conduit placement.[11]

In infants, critical pulmonic valvular stenosis may present with near pulmonary atresia (a cyanotic lesion) with a small and often inadequate right ventricle. These patients survive because of a patent ductus arteriosus. Pulmonary valve atresia or critical pulmonic valvular stenosis with inadequate right ventricle requires a shunt (usually modified Blalock-Taussig or central shunt) after the ductus is kept patent pharmacologically with prostaglandin E1.[11] Definitive repair may not be possible if the right ventricle is hypoplastic, requiring a single ventricular palliation, such as the Fontan procedure, or a variation, such as a direct right atrial appendage to main pulmonary artery anastomosis.[17] Frequently, the main and branch pulmonary arteries require augmentation.

Patients with infundibular or supravalvular pulmonic stenosis, if severe, require operative and invasive surgical interventions.

A surgical approach is often preferred in patients with Noonan syndrome because of the degree of immobility that is often present.[37]

Patients who require such interventions should be transferred to a tertiary care center that specializes in congenital heart disease (CHD).

Postprocedure complications are rare. Infective endocarditis of the pulmonary valve is very rare. During the Second Natural History Study of Congenital Heart Defects, 592 patients with pulmonic valvular stenosis (PVS) were followed for 10,688 person-years; only one patient had an episode of bacterial endocarditis.[38] Current guidelines do not recommend for prophylaxis with antibiotics.[2]

In the unoperated, asymptomatic patient with pulmonic valvular stenosis (PVS), ACC/AHA guidelines outline the following[2] :

• Initial evaluation for all patients includes two-dimensional (2D) echocardiography, chest radiography, and electrocardiography (ECG).

• In mild pulmonic valvular stenosis, follow up exams every 5 years with 2D echocardiography and ECG are recommended.

• In moderate to severe pulmonic valvular stenosis, follow up exams every 2-5 years with 2D echocardiography are recommended.

Most patients with murmurs are given prophylaxis against infective subacute bacterial endocarditis (SBE).[39] Opinions differ about the need for SBE prophylaxis recommendations for patients with pulmonic valvular stenosis because of the extremely low incidence of endocarditis in this relatively large subpopulation.[39] Current ACC/AHA guidelines do not advise prophylaxis for pulmonic valvular stenosis.[2]