Background
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] :
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Mild: < 30 mmHg
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Moderate: 30-50mmHg
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Severe: >50mmHg
Disease course, outcomes and management are determined based on the illness severity.
Pathophysiology
Current guidelines outline the following three clinically relevant valve morphologies [2] :
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Dome-shaped pulmonic valve (PV)
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Dysplastic PV
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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]
Epidemiology
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]
Prognosis
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]
Patient Education
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]
