Pulmonic valvular stenosis (PVS) is described as lesions that collectively are associated with obstruction to the right ventricular outflow tract. Stenosis may be valvular, subvalvular, or supravalvular. Isolated pulmonary stenosis is considered to be a rare congenital abnormality.[1] It is the most common cause of congenital outflow tract obstruction, resulting in decreased flow from the right ventricle to the pulmonary arteries.[2] Isolated right ventricular outflow tract obstruction is pulmonic valvular stenosis in 80% of cases.[3]
Pulmonic valvular disease is clinically detected at different stages of life. The more severe the obstruction, the earlier the valvular abnormality is typically detected. Pulmonic valvular stenosis is most often associated with the failure of the valvular leaflets to fuse and less commonly is caused by dysplastic thickening of the valves.[4]
Neonates with critical stenosis typically present with central cyanosis at birth. Infants and children with ejection murmurs auscultated in the pulmonic area are often evaluated, and stenosis is discovered during this period. Symptoms of pulmonic stenosis have been observed to progress with time.[5] Adults present with symptoms of congestive heart failure (CHF) and right ventricular outflow obstruction that is progressive in nature.[6] Many of these congenital valvular malformations occur in the setting of well-defined syndromes. Examples of such syndromes involving stenosis of the pulmonic valves are Holt-Oram syndrome, Noonan syndrome, and Leopard syndrome.[5, 7] Eisenmenger syndrome associated with trisomy 13 also results in pulmonary outflow tract obstruction; however, often, other cardiac malformations are involved as well.[8]
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.[9]
Supravalvular, valvular, and subvalvular lesions are associated with pulmonic valvular stenosis. Lesions vary in severity, from with simple valvular hypertrophy to complete outflow obstruction and atresia.[6] The trileaflet pulmonic valve ranges from thickened or partially fused commissures to an imperforate valve.
Most cases of pulmonic valvular stenosis are congenital. Often times, the valvular abnormality is associated with syndromes such as Noonan syndrome and Leopard syndrome. The inheritance pattern of pulmonic valvular stenosis is poorly understood, although these syndromes display an autosomal dominant pattern. Rarely, pulmonic stenosis is associated with recessively transmitted conditions such as Laurence-Moon-Biedl syndrome. Mutations in germlines PTPN1 and RAF1 have been associated with these valvular abnormalities.[10] Supravalvular lesion may occur in the setting of tetralogy of Fallot, Williams syndrome, Alagille syndrome, as well as Noonan syndrome.[6]
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.[5]
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 3-fold increase in cardiovascular abnormalities. 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 BMP/TGF-beta.[5]
The pulmonic valve develops between the 6th and 9th week of gestation. Normally, the pulmonic valve is formed from 3 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 3 thin-walled cusps of the pulmonary valve. In Noonan syndrome, tissue pad overgrowth within the sinuses interferes with the normal mobility and function of the valve.
Failure to develop normally can result in the following malformations: fusion of 2 of the cusps, 3 leaflets that are thickened and partially fused at the commissures, or a single cone-shaped valve.
In the congenital rubella syndrome, supravalvular pulmonic and pulmonary artery branch stenoses are frequently present. Acquired valvular disease is rare. The most common etiologies are carcinoid syndrome, rheumatic fever, and homograft dysfunction.[4]
Years of stenosis can result in subendocardial hypertrophy causing significant outflow obstruction and resulting in right ventricular pressure overload and pulmonary hypertension. As this process worsens, the asymptomatic adult becomes gradually symptomatic.[11, 12]
Approximately 5 out of 1000 infants are born with a congenital cardiac malformation.[5] Cardiac malformation is the most common congenital abnormality. Among cardiac malformations, valvular defects are the most common subtype, accounting for 25% of all malformations involving the myocardium.[5] Prevalence of pulmonary stenosis is 8-12% of all congenital heart defects.
Isolated pulmonic valvular stenosis with intact ventricular septum is the second most common congenital cardiac defect. Pulmonic valvular stenosis may occur in as many as 30% of all patients who have other congenital heart defects.
Sixty percent of patients with Noonan syndrome are found to have some degree of pulmonic valvular stenosis.[7]
The male-to-female ratio of pulmonic valvular stenosis is approximately 1:1.
Pulmonic valvular stenosis most commonly presents in newborns. It can be asymptomatic for years.
Mild pulmonic valvular stenosis has a good overall prognosis. Life expectancy approaches that of someone without valvular disease.[9]
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 suggest that 53% of patients had required further intervention. Forty percent may have atrial or ventricular arrhythmias.[6, 11]
Following balloon or surgical valvulotomy, outcome generally is excellent. After interventions to relieve the stenosis, stenosis usually does not recur and right ventricular hypertrophy often regresses.[6] A 2007 study presented long-term follow-up data on 90 adult patients who had pulmonary balloon valvuloplasty. In this cohort, outcome data were excellent; this study supports the use of balloon angioplasty in these patients, even if there is an associated tricuspid regurgitant lesion or infundibular stenosis.[13]
Valvular disease in general has high morbidity and mortality rates. Isolated pulmonic valvular disease has been found to be the most benign.[9] In the United States, about 82,000 valvular replacements are performed per year.[5] Survival to adulthood is most common, as symptoms and extent of disease progress with time.[2]
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.[9]
The studies demonstrated that adverse outcomes directly relate to the right ventricular systolic pressure gradient.[14] Mild pulmonic valvular stenosis with pressure gradient across the valve less than 50 mm Hg was found to be well tolerated clinically and subjectively.[9] Of these patients, 94% were asymptomatic, without cyanosis or congestive heart failure.[15, 16] Moderate-to-severe pulmonic valvular stenosis, with pressure gradient greater than 50 mm Hg is more often associated with decreased cardiac output, right ventricular hypertrophy, early congestive heart failure (CHF), and cyanosis. Valvulotomy has been shown to improve morbidity and mortality and is indicated with these gradients.[9]
The morbidity and mortality of valvular lesions in regards to pregnancy and fetal outcomes has not been rigorously studied. A case-control study of 17 patients suggested that there is no adverse impact on either the mother or the fetus.[17]
Complications of pulmonic valvular stenosis may include the following:
Patients and parents of those with mild pulmonic valvular stenosis 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.[4, 9]
The disease is progressive, and isolated mild pulmonic valvular stenosis may not cause symptoms until age 40 years or older.[6]
If the patient is asymptomatic with mild pulmonic valvular stenosis, annual screening examination and ECG should be scheduled. Follow up every 3-5 years may be initiated if subsequent evaluations show no change.[6]
Adults presenting with symptoms of progressive outflow tract obstruction due to pulmonic valvular disease were most likely born with some congenital malformation that was not diagnosed as a child.[4]
Signs of pulmonic valvular stenosis include the following:
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[18] :
The investigators indicated an observed linear increase in the peak pulmonary valve gradient may suggest a fixed valve area during exercise.[18] They also reported no signs of right heart functional or morphologic changes during exercise, with good ventricular performance.
Physical examination findings correlate with the severity of right ventricular outflow obstruction.
The first heart sound is normal and followed by a systolic ejection click. The systolic ejection click is variable with respiration and louder on expiration. It is loudest over the left upper sternal border.[1, 6] The murmur of pulmonic stenosis is of the systolic ejection type and is best heard at the second left intercostal space.[11] Patients with dysplastic valves may not have a systolic ejection click. If the valve is pliant, a systolic ejection click is often heard.
The second heart sound is split. 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.
Systolic ejection murmur (crescendo-decrescendo), grade 2-5/6, is audible at the left upper sternal border, transmitting into the back and posterior lung fields. The murmur is heard best in the first to third intercostal spaces.[3, 6] The murmur usually does not radiate to the left sternal boarder.
The severity of valvular disease is related directly to the intensity and duration of the murmur. When severe, murmur extends into diastole (beyond the second heart sound).
Severe pulmonic valvular stenosis is associated with tricuspid insufficiency and may be associated with elevated central venous pressure, hepatosplenomegaly, a pulsatile liver, jugular venous pulsations, and hepatojugular reflux. Hepatosplenomegaly may develop in cases of CHF.
Significant pulmonic stenosis is characterized by a prominent jugular venous a wave and a right ventricular lift
Myocardial infarction of hypertrophied right ventricle may occur.[19]
Cyanosis may occur with right-to-left shunting at the atrial level as with a patent foramen ovale or septal defect.[11]
Pulmonic valvular stenosis primarily results from a maldevelopment of the pulmonic valve tissue and the distal portion of the bulbus cordis. One maldevelopment is characterized by fusion of leaflet commissures, resulting in a domed appearance to the valve. Other etiologies result in dysplastic valves, which do not open and close normally.[19]
Coexisting cardiac malformations (eg, ventricular septal defect, atrial septal defect, patent ductus arteriosus) may complicate the anatomy, physiology, and clinical picture.
Aberrant flow patterns in utero may be associated, in part, with maldevelopment of the pulmonary valve.
Rubella embryopathy may cause pulmonic valvular stenosis.
Family history is a mild risk factor.[20]
Cases have been reported in the setting of congenital syndromes such as Mayer-Rokitansky-Kuster-Hauser syndrome.[21]
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).[11]
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.
Chest radiography may demonstrate a prominent main pulmonary artery segment but a normal heart size.
Pulmonary vascular markings are usually normal but may be decreased in severe pulmonic valvular stenosis. In severe valvular pulmonary stenosis, CHF presents as cardiomegaly with right ventricular and right atrial enlargement.
ECG reflects the degree of right ventricular involvement.
Right axis deviation and right ventricular hypertrophy are seen in moderate valvular pulmonary stenosis.
Degree of right ventricular hypertrophy correlates with the severity of pulmonic valvular stenosis.
Tall R wave in V1 more than 10 mm suggests severe stenosis.
Incidences of arrhythmias are increased in patients with pulmonic valvular stenosis.[4, 22]
The transthoracic approach provides valuable information about the site of obstruction and other possible congenital abnormalities.[14, 23, 24, 25]
Valve surface area is not used to determine the severity of stenosis. Rather, the peak gradient across the pulmonic valve is used as an indicator of disease severity.[9] Doppler studies can accurately determine velocity of flow across the valve. The gradient is calculated from 4 times the peak systolic velocity squared: Pressure gradient = 4 X velocity squared
Multiple views and measurements increase the accuracy of the predicted peak systolic pressure gradient.
A thickened pulmonic valve with restricted systolic motion, called doming, in the parasternal short axis view is apparent.
Frequently, the main pulmonary artery is dilated distal to the stenotic orifice.
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 (PS), investigators prospectively enrolled 16 consecutive adult patients with PS and indications of TEE. They found evidence of the incremental value of using 3D-TEE instead of 2D-TEE during assessments of PS, 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.[26]
Most children with pulmonary stenosis do not require further evaluation beyond echocardiography.
Modalities such as MRI and CT can show structural cardiac abnormalities.[27, 28]
One case report described the identification of a patient with isolated subvalvular pulmonary stenosis using whole-heart MRI.[29] 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.[27]
Cardiac CT has been beneficial for noninvasive presurgical evaluation of someone with known coronary artery disease. The radiation exposure is minimal with cardiac CT, and the reconstructions of a 64-slice CT can yield very accurate images of myocardium changes associated with outflow tract obstruction.[28]
Catheterization assesses the morphology of the right ventricle, pulmonary outflow tract, degree of tricuspid regurgitant flow, and pulmonary arteries. The technique for angioplasty was described in 1982.[30] This procedure is not indicated for mild pulmonic valvular stenosis, but it is essential in severe stenosis.
Cardiac catheterization is indicated when pulmonary stenosis is not adequately evaluated by echocardiography. When the peak systolic gradient is more than 36 mm Hg, then balloon valvuloplasty may be indicated.[11] Cardiac catheterization with balloon valvuloplasty is indicated if the gradient is more than 50 mm Hg.[4]
Patients with echocardiographic evidence of significant pulmonic valvular stenosis (>50 mm Hg) should undergo diagnostic and therapeutic cardiac catheterization. Percutaneous balloon dilatation, stenting, and pulmonic valve replacement[31] are increasingly being performed with high success rates.[32, 33, 34]
Findings from a retrospective Chinese study appear to indicate similar immediate and long-term results between single-balloon valvuloplasty in children and Inoue balloon valvuloplasty in adults with isolated pulmonary valve stenosis.[35] In the pediatric group (n=38), the right ventricular pulmonary artery systolic gradient decreased from a baseline of 52.79 +/- 35.08 mmHg to a postprocedure 22.55 +/- 12.92 mmHg (P< 0.001); in the adult group (n=42), the baseline gradient of 94.79 +/- 42.19 mmHg decreased to 34.02 +/- 15.00 mmHg (P< 0.001) following the Inoue balloon pulmonary valvuloplasty. At a median follow-up of 15 years, the investigators found no significant differences in gradients for both groups relative to those at 1-month follow-up.[35]
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.[36]
If the patient has a large left-to-right shunt, such as patent ductus arteriosus or ventricular septal defect, and is in respiratory distress, diuresis is effective in reducing the cyanosis secondary to pulmonary edema.
Oxygen should be administered to any cyanotic patient in respiratory distress. Use of oxygen may reduce pulmonary artery pressure in patients with a reactive pulmonary vasculature, thus increasing pulmonary blood flow.
Management depends on the degree of stenosis. Therefore, clinical evaluation as well as imaging is will direct management. Cardiology or cardiothoracic consultation is needed if imaging studies indicate right outflow tract obstruction.
Note the following:
During the Second Natural History Study of Congenital Heart Defects, 592 patients with pulmonic valvular stenosis were followed for 10,688 person-years; only one patient had an episode of bacterial endocarditis.[37]
Pulmonic valvular stenosis is not specifically mentioned in the 2007 American Heart Association (AHA) guidelines for antibiotic prophylaxis to prevent bacterial endocarditis. This guideline recommends prophylaxis for endocarditis in the 6 months following repair of a congenital heart defect. Additionally, prophylaxis is required for lifetime for individuals who have prosthetic valves.[38]
Intervention with either balloon angioplasty or valve repair is indicated for patients with peak valve gradients more than 50 mm Hg or for patients with angina, syncope, exertional dyspnea, or presyncope. Corrective options include open heart surgery, balloon angioplasty, percutaneous stenting, percutaneous valve replacement, or percutaneous conduit placement.[6]
Galal et al reported on the case of a pregnant patient with severe pulmonary valve stenosis and exertional dyspnea who underwent balloon dilation using sole echocardiographic guidance to protect the baby from radiation. The primary technical difficulty occurred during catheter advancement across the right ventricular outflow tract into the pulmonary valve, which was overcome by using a wedge balloon catheter over a percutaneous transluminal coronary angioplasty wire. The investigators concluded that pulmonary balloon valvuloplasty can be performed safely using sole transthoracic echocardiography guidance without fluoroscopy.[39]
Patients with severe or symptomatic infundibular or supravalvular pulmonary stenosis require surgical intervention.[6]
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.[6] 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.[2] Frequently, the main and branch pulmonary arteries require augmentation.
Consult with a pediatric cardiologist and with an intensivist.
Patients with symptomatic pulmonic valvular stenosis should be transferred to a tertiary care center offering pediatric cardiology and pediatric cardiothoracic surgery.
Most patients with murmurs are given prophylaxis against infective subacute bacterial endocarditis (SBE).[38] 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.[38]
For patients older than 6 months with a gradient less than 40 mm Hg at the time of diagnosis, follow-up care can safely be performed at intervals of 2 years or more.
No medications are useful in isolated pulmonic valvular stenosis.
Patients with CHF may benefit from anticongestive therapy.
Patients with cyanosis may benefit from oxygen and prostaglandin E1. Patients with cyanosis from a large right-to-left shunt require a definitive surgical procedure.
Clinical Context: Used to maintain patency of ductus arteriosus when cyanotic lesion (critical pulmonary stenosis/atresia) or interrupted aortic arch presents in newborns. More effective in premature infants than in mature patients.
This agent is used as a smooth muscle relaxer. In cases of severe congenital pulmonic valvular stenosis, this agent is used to keep ductus arteriosus open until surgical repair is coordinated. It is used as temporizing measure.[6]