Pulmonic Valvular Stenosis

Background

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 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]

NextPathophysiology

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]

PreviousNextEpidemiologyFrequencyUnited States

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]

Mortality/Morbidity

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.[13] 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.[14, 15] 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.[16]

Sex

The male-to-female ratio of pulmonic valvular stenosis is approximately 1:1.

Age

Pulmonic valvular stenosis most commonly presents in newborns. It can be asymptomatic for years.

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Pulmonic Stenosis

Background

Pulmonic stenosis (PS) refers to a dynamic or fixed anatomic obstruction to flow from the right ventricle (RV) to the pulmonary arterial vasculature. Although most commonly diagnosed and treated in the pediatric population, individuals with complex congenital heart disease and more severe forms of isolated PS are surviving into adulthood and require ongoing assessment and cardiovascular care.

NextPathophysiology

PS can be due to isolated valvular (90%), subvalvular, or peripheral (supravalvular) obstruction, or it may be found in association with more complicated congenital heart disorders. The characteristics of the various types of PS are described in this section.[1]

Valvular pulmonic stenosis

Isolated valvular PS comprises approximately 10% of all congenital heart disease. Typically, the valve commisures are partially fused and the 3 leaflets are thin and pliant, resulting in a conical or dome-shaped structure with a narrowed central orifice. Poststenotic pulmonary artery dilatation may occur owing to "jet-effect" hemodynamics.

Alternatively, approximately 10-15% of individuals with valvar PS have dysplastic pulmonic valves. These valves have irregularly shaped, thickened leaflets, with little, if any, commissural fusion, and they exhibit variably reduced mobility. The leaflets are composed of myxomatous tissue, which may extend to the vessel wall. The valve annulus is usually small, and the supravalvular area of the pulmonary trunk is usually hypoplastic. Poststenotic dilatation of the pulmonary artery is uncommon. Approximately two thirds of patients with Noonan syndrome have PS due to dysplastic valves.

A bicuspid valve is found in as many as 90% of patients with tetralogy of Fallot, whereas it is rare in individuals with isolated valvar PS.

With severe valvular PS, subvalvular right ventricular hypertrophy can cause infundibular narrowing and contribute to the right ventricular outflow obstruction. This often regresses after correction of valvular stenosis.

With severe PS and decreased right ventricular chamber compliance, cyanosis can occur from right-to-left shunting if a concomitant patent foramen ovale, atrial septal defect, or ventricular septal defect is present.

Subvalvular pulmonic stenosis

Subvalvular PS occurs as a narrowing of the infundibular or subinfundibular region, often with a normal pulmonic valve. This condition is present in individuals with tetralogy of Fallot and can also be associated with a ventricular septal defect (VSD).

Double-chambered right ventricle is a rare condition associated with fibromuscular narrowing of the right ventricular outflow tract with right ventricular outflow obstruction at the subvalvular level.

Peripheral pulmonary stenosis

Peripheral pulmonary stenosis (PPS) can cause obstruction at the level of the main pulmonary artery, at its bifurcation, or at the more distal branches. PPS may occur at a single level, but multiple sites of obstruction are more common. PPS may be associated with other congenital heart anomalies such as valvular PS, atrial septal defect (ASD), VSD, or patent ductus arteriosus (PDA); 20% of the patients with tetralogy of Fallot have associated PPS.

Functional or physiologic PPS is a common cause of a systolic murmur in infants. It occurs in both premature and full-term infants; with time, the pulmonary artery grows, and the murmur usually disappears within a few months.

Poststenotic dilatation occurs with discrete segmental stenosis but is absent if the stenotic segment is long or if the pulmonary artery is diffusely hypoplastic.

PPS is associated with various inherited and acquired conditions including rubella and the Alagille, cutaneous laxa, Noonan, Ehlers-Danlos, and Williams syndromes.

PreviousNextEpidemiologyFrequencyUnited States

PS is a common form of congenital heart disease that occasionally is diagnosed for the first time in adulthood. Isolated valvular PS comprises approximately 10% of all congenital heart disease.

Mortality/Morbidity

Except for critical stenosis in neonates, survival is the rule in congenital PS.

The long-term course of patients with mild PS is indistinguishable from that of the unaffected population. Mild PS does not tend to progress in severity; rather, pulmonic valve orifice size usually increases with body growth. However, untreated severe PS may result in outflow obstruction that progresses over a period of years; 60% of patients with severe PS require intervention within 10 years of diagnosis.

Sex

A slight female predominance exists.

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Pulmonic Regurgitation

Background

The pulmonic valve is normally a thin tricuspid structure that prevents blood from regurgitating into the right ventricle once ejected into the low-pressure pulmonary circulation. Pulmonic regurgitation refers to retrograde flow from the pulmonary artery into the right ventricle during diastole. Physiologic (trace-to-mild) pulmonic regurgitation is present in nearly all individuals, particularly in those with advanced age. However, pathologic conditions that produce excessive and clinically significant regurgitation can result in impairment of right ventricular function and eventual clinical manifestations of right-sided volume overload and heart failure. Often, pulmonic regurgitation is not the primary process but a finding secondary to an underlying process such as pulmonary hypertension or dilated cardiomyopathy.

NextPathophysiology

Incompetence of the pulmonic valve occurs by 1 of 3 basic pathologic processes: dilatation of the pulmonic valve ring, acquired alteration of pulmonic valve leaflet morphology, or congenital absence or malformation of the valve.

PreviousNextEpidemiologyFrequencyUnited States

Physiologic pulmonic regurgitation is present in nearly all individuals and is a normal echocardiographic finding. Pulmonic regurgitation detected by physical examination is not a normal finding in healthy adults. Congenital pulmonic regurgitation and congenital absence of the pulmonic valve are rare conditions.

International

No difference in international incidence is known.

Mortality/Morbidity

The morbidity and mortality rates associated with pulmonic regurgitation vary considerably, depending on the underlying etiology.

Race

No racial or ethnic predilection exists.

Sex

Differing frequency of pulmonic regurgitation between men and women corresponds to the specific etiology resulting in pulmonic regurgitation.

Age

Except for congenital absence of the pulmonic valve, which is more likely to cause right-sided ventricular decompensation early in life, the age at which clinical symptoms of pulmonic regurgitation occur is variable and is primarily related to the underlying process causing the pulmonic regurgitation.

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