Pulmonic Regurgitation

Etiology

The causes of pulmonic regurgitation can be categorized as follows:

Secondary to Pulmonary Hypertension

• Other disorders of the pulmonary vasculature
• Chronic thromboembolism of the lungs
• Lung disease
  • Chronic obstructive lung disease
  • Interstitial lung disease
  • Obstructive sleep apnea 
• Idiopathic pulmonary arterial hypertension (PAH) [3]
  • Left heart failure
  • Aortic and mitral valve disease
• Left heart disease
  • Sarcoidosis
  • Sickle cell disease
  • Schistosomiasis

Pulmonic Valve Disease

• Congenital
• Postvalvotomy (iatrogenic)
• Endocarditis [4]
• Carcinoid
• Post-ROSS procedure (pulmonary autograft for aortic valve disease)
• Drugs like methysergide, pergolide, fenfluramine

Annular Enlargement

• Pulmonary hypertension
• Idiopathic dilation
• Marfan syndrome
• Post—tetralogy of Fallot (TOF) repair

Epidemiology

Pulmonic regurgitation has bimodal prevalence. The first peak appears in young individuals who underwent surgical valve repair for congenital heart diseases. This condition is also prevalent in the adult population with pulmonary hypertension due to various reasons. The exact prevalence is hard to predict as there is a multitude of causes for pulmonary hypertension, which in turn can lead to pulmonic regurgitation. No racial or ethnic predilection exists. The differing frequency of pulmonic regurgitation between women and men corresponds to the specific etiology of this condition.

Pathophysiology

The valve opening and closing are mainly due to the pressure changes across it. The normal anatomy of the pulmonary valve is such that it can open only in the direction of blood flow from the ventricle to the pulmonary artery. Normal pulmonary artery pressure is 15 to 28 mmHg during systole and 5 to 16 mmHg during diastole. Right ventricular pressures range from 15 to 28 mmHg during systole and 0 to 8 mmHg during diastole. During systole, the ventricular pressure increases to higher than the pulmonary artery pressure, resulting in the opening of the valve and causing the blood to flow from the ventricle to the pulmonary artery. Towards the end of the systole and the beginning of diastole, after most of the blood from the ventricle empties into the pulmonary artery, the valves close because of higher pressure inside the pulmonary artery, which pushes the valve leaflets to a closed position, preventing any leak into the ventricle. If the valve is defective or the pressure in the pulmonary artery is very high, there could be a backward leak of blood from the pulmonary artery into the right ventricle, causing pulmonic regurgitation. 

Pulmonic regurgitation demonstrates an increase in both preload and afterload. The reverse pressure gradient from the pulmonary artery to the right ventricle, which drives the pulmonic regurgitation, progressively decreases throughout the diastole and accounts for the decrescendo nature of the diastolic murmur. With pulmonic regurgitation, the end-diastolic volume of the right ventricle remains higher than normal. As the disease progresses, the right ventricular diastolic pressure and cavity size increase due to the backflow. The forward cardiac output remains preserved during the early stages of the disease but may not normally increase with exercise and declines over time. A reduced right ventricle ejection fraction may be an early indicator of hemodynamic compromise. There is a significant enlargement of the right ventricle and right atrium in advanced stages with marked elevation of the jugular venous pressure. As the diastolic pressure in the right ventricle increases with the progression of the disease, the murmur becomes shorter in duration.[5] Drugs that act through serotonergic pathways like fenfluramine or dopaminergic pathways like pergolide and cabergoline act through 5HT2B receptors, causing the proliferation of valve endothelium, causing valvulopathy and pulmonic regurgitation similar to carcinoid disease.

History and Physical

History

The etiology of pulmonic regurgitation mainly determines the history. In pulmonic regurgitation secondary to pulmonary hypertension, the clinical picture is dominated by the primary lung disease or the high pulmonary vascular resistance rather than the volume load.[5] Isolated pulmonic regurgitation causes right ventricular volume overload and may be tolerated for many years without difficulty unless it complicates. In most patients, clinical manifestations of the primary disease are severe and usually overshadow the pulmonic regurgitation, which often results only in incidental auscultatory findings. Patients with pulmonic regurgitation caused by infective endocarditis who develop septic pulmonary emboli and pulmonary hypertension often exhibit severe right ventricular failure. The patient may report fatigue, exertional dyspnea, abdominal fullness or bloating, and lower extremity swelling with the disease progression.

Post–Ross Procedure

The Ross procedure is a pulmonary autograft placement in place of the diseased aortic valve, which is a common procedure in congenital aortic valve disease. The procedure is the only aortic valve intervention that has long-term survival benefit. As per the recent American Journal of Cardiology consensus (2018), this procedure is also under consideration for selected young patients.[6] In this procedure, a pulmonary autograft replaces the aortic valve, and a pulmonary autograft replaces the pulmonic valve. Aortic regurgitation is a known complication postprocedurally, which can occur anytime. Another major complication of this procedure is pulmonic regurgitation, which can occur after 10 to 15 years of the procedure.[7][8]

Post–TOF Repair

Despite major advances in TOF repair in the past few decades, many patients experience several complications secondary to postsurgical hemodynamic and electrophysiological abnormalities. Right bundle branch block, residual intra-cardiac shunts, tricuspid regurgitation, etc, cause pulmonary annular dilatation causing pulmonic regurgitation.[9]

Physical Findings

Jugular venous distension with large V-waves (Lancisi sign) can be seen in patients with pulmonic regurgitation secondary to pulmonary hypertension if the right ventricular pressure is high enough to cause tricuspid insufficiency as well.[10]

Auscultation[11]

The following may be observed on auscultation:

• The first heart sound (S): This is normal.
• Pulmonic valve closure (P2): This is not audible in patients with congenital absence of the pulmonic valve; however, this sound becomes accentuated in patients with pulmonic regurgitation secondary to pulmonary hypertension. A wide splitting of the second heart sound (S2) may be caused by the prolongation of right ventricular ejection accompanying the augmented right ventricular stroke volume.
• Systolic ejection click: This can sometimes be heard in the second left intercostal space due to the sudden expansion of the pulmonary artery by augmented right ventricular stroke volume.
• Third and fourth heart sounds (S3 and S4): Originating from the right ventricle, these are often audible, most readily in the fourth intercostal space at the left parasternal area, and become augmented by inspiration.
• Pulmonic regurgitation murmur: In the absence of pulmonary hypertension, the pulmonic regurgitation murmur is a diamond-shaped, diastolic, low-pitched murmur that commences as soon as the pulmonary artery and the right ventricular pressures diverge (approximately 0.04 seconds after P2). The peak intensity of this murmur is ausculted when the gradient between these pressures is maximal, and soon, it ends with the pressures equilibrated.
• Graham Steell murmur: This is heard when systolic pulmonary artery pressure exceeds approximately 55 mm Hg, resulting in dilatation of the pulmonary annulus, causing a high-velocity regurgitant jet. It is a high-pitched, blowing, decrescendo murmur beginning immediately after P2, most prominent in the left 2 to 4 intercostal spaces, increases in intensity with inspiration, exhibits little change after amyl nitrite inhalation or vasopressor administration, is diminished during the Valsalva strain, and returns to baseline intensity almost immediately after the release of the Valsalva strain. [11]

Progression of Pulmonic Regurgitation[12]

As per 2014 American Heart Association (AHA) and American College of Cardiology (ACC) guidelines, all valvular heart diseases progress through 4 stages:

• Stage A: Patients at risk for pulmonic regurgitation who still have not developed it
• Stage B: Asymptomatic patients with mild or moderate pulmonic regurgitation
• Stage C: Asymptomatic patients with severe pulmonic regurgitation
• Stage D: Symptomatic patients with pulmonic regurgitation

Evaluation

Electrocardiogram

Commonly seen electrocardiogram (EKG) findings in pulmonic regurgitation in the absence of pulmonary artery hypertension (PAH) are rSR configuration in the right precordial leads, which reflects RV diastolic overload. If it is secondary to PAH, then a P-pulmonale (tall P-waves indicating right atrial enlargement), increased r to s ratio in the right precordial leads, and right axis deviation can be seen. These findings are secondary to RV hypertrophy.[13]

Both pulmonary artery and right ventricular enlargement are visible on a chest X-ray, but these signs are nonspecific. Fluoroscopy may demonstrate pronounced pulsation of the main pulmonary artery.

Echocardiography

Right ventricular dilation, along with hypertrophy, appears in 2-dimensional echocardiography in patients with pulmonary hypertension. Abnormal motion of the septum characteristic of volume overload of the right ventricle in diastole and/or septal flutter may be evident. The motion of the pulmonic valve may point to the cause of the pulmonic regurgitation. The absence of a wave and systolic notching of the posterior leaflet suggests pulmonary hypertension; large A-waves indicate pulmonic stenosis. Doppler echocardiography is extremely accurate in detecting PR and helping estimate its severity.

• Mild pulmonic regurgitation: Normal right ventricular dimensions with thin (<10 mm in length) regurgitant jet width by color Doppler
• Moderate pulmonic regurgitation: Normal or dilated right ventricle with intermediate regurgitant jet width (<50% of pulmonic valve annulus) 
• Severe pulmonic regurgitation: Dilated right ventricle (except in acute pulmonic regurgitation) with large regurgitant jet width (>50% of pulmonic valve annulus)

Angiography

In pulmonic regurgitation, opacification of the right ventricle is noticed following the injection of contrast into the pulmonary artery due to the regurgitant jet. Cardiac magnetic resonance helps assess pulmonary artery dilation and the severity of pulmonic regurgitation.

Treatment / Management

The most crucial aspect of management is treating the primary condition. For example, treating the lesion responsible for PAH, such as mitral valve regurgitation/stenosis, often improves PR. Symptomatic patients who are not surgical candidates receive management with heart failure therapy, especially diuretics, angiotensin-converting enzyme (ACE) inhibitors, and digoxin.

Patients with iatrogenic pulmonic regurgitation caused by the surgical correction of TOF might benefit from a treatment specifically directed at the pulmonary valve. In such conditions, valve replacement may be necessary, preferably with a porcine bioprosthesis or a pulmonary allograft. With recent advances, transcatheter pulmonary valve replacement is being implemented with great success in native pulmonic valve disease and pulmonic regurgitation following surgical correction of congenital heart defects.[14]  (B3)

The following are the indications for surgery:[15](B3)

• Severe symptomatic pulmonic regurgitation
• Asymptomatic severe pulmonic regurgitation with 2 out of 4 of the following conditions: 
  1. Elevated right ventricular volume (end-diastolic volume index >160 mL/m² or end-systolic volume index of 80 mL/m²)
  2. Elevated right ventricular pressure
  3. Reduced exercise tolerance
  4. Mild to moderate systolic dysfunction of either the right or left ventricle
  5. A bioprosthetic valve is preferable to a mechanical valve as long-term anticoagulation is not required and has better longevity (up to 15 years). 

Percutaneous pulmonary valve implantation is indicated in patients with dysfunctional conduits in the right ventricular outflow tract with a regurgitant prosthetic valve. This procedure involves artificial valve placement through central venous access. The success rate of this procedure is about 94% to 98%. Procedural complication rates are between 3% to 6%, among which coronary artery compression is the most important one. Another advantage of this procedure is very little hospitalization time (4-5 days), and patients will be able to go back to their work immediately post-discharge. Infective endocarditis forms the most important delayed complication.[15](B3)

Differential Diagnosis

Pulmonic regurgitation can be seen in several underlying heart and lung conditions. Identifying the underlying cause can be the most challenging aspect and plays a critical role in pulmonic regurgitation management. Clinically, distinguishing the blowing decrescendo murmur of pulmonic regurgitation from a similar murmur noticed in aortic regurgitation is very important. Pulmonic regurgitation can sometimes coexist as one of the multivalvular lesions involving mitral and aortic valves. Such cases need further investigation with echocardiography to check the severity of each lesion.

Treatment Planning

Mild pulmonic regurgitation on echocardiography will not require a follow-up unless the patient becomes symptomatic or if the initial echocardiogram showed signs of early right ventricular dysfunction. Moderate to severe pulmonic regurgitation needs regular follow-up with history, physical exam, and echocardiography to assess the disease progression and the need for surgery. As per adult congenital heart disease guidelines by AHA/ACC, patients who underwent TOF repair should have an annual check-up with a cardiologist with expertise in that area.[16]

Prognosis

The prognosis depends on the severity of pulmonic regurgitation. Most patients with pulmonic regurgitation secondary to repair for tetralogy of Fallot do well, but there could be delayed mortality, which is related to right ventricular dysfunction. If pulmonic regurgitation is mild to moderate, there is no significant reduction in survival. However, severe pulmonic regurgitation and persistently elevated RV volume may lead to RV failure propensity for arrhythmias and increased risk of cardiac death.[17]

In pulmonic regurgitation secondary to pulmonary hypertension, the time of diagnosis and duration of pulmonary hypertension play a significant role in the prognosis. Early diagnosis of pulmonary hypertension and the presence of a reversible cause for PAH carries a good prognosis.

Complications

Right ventricular enlargement leading to right-sided heart failure and sudden cardiac death are some of the major complications of severe pulmonic regurgitation. Other complications include hepatic congestion secondary to right heart failure and thromboembolic events; arrhythmias are not so uncommon with severe pulmonic regurgitation. Complications post–pulmonic valve replacement include valve failure and infective endocarditis.[18]