Pulmonic Regurgitation

Etiology

Secondary to Pulmonary Hypertension

Idiopathic Pulmonary Arterial Hypertension (PAH)[3]

Associated with Left Heart Disease

1. Left heart failure
2. Aortic and mitral valve disease.

Associated with Lung Disease

1. Chronic obstructive lung disease
2. Interstitial lung disease
3. Obstructive sleep apnea 

Associated with Chronic Thromboembolism of Lungs

Other Disorders of the Pulmonary Vasculature

1. Sarcoidosis
2. Sickle cell disease
3. Schistosomiasis

Pulmonic Valve Disease

1. Congenital
2. Postvalvotomy (iatrogenic)
3. Endocarditis[4]
4. Carcinoid
5. Post ROSS procedure (pulmonary autograft for aortic valve disease)
6. Drugs like methysergide, pergolide, fenfluramine

Annular Enlargement

1. Pulmonary hypertension
2. Idiopathic dilation
3. Marfan syndrome
4. Post-tetralogy of Fallot (TOF) repair

Epidemiology

Pulmonary regurgitation has bimodal prevalence. The first peak appears in young individuals who underwent surgical repair of the valve 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 PR. No racial or ethnic predilection exists. The differing frequency of PR between women and men corresponds to the specific etiology resulting in 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, which is 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 (RV) 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 (PA) pressure resulting in the opening of the valve and causing the blood 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 if 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 pulmonary regurgitation. 

PR demonstrates an increase in both preload and afterload. The reverse pressure gradient from the pulmonary artery to the right ventricle (RV), which is the driver of the PR, progressively decreases throughout the diastole and accounts for the decrescendo nature of the diastolic murmur. With pulmonary 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 (CO) remains preserved during the early stages of the disease but may not normally increase with exercise and declines over time. A reduced RV ejection fraction may be an early indicator of hemodynamic compromise. There is a significant enlargement of the RV and right atrium (RA) 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, cabergoline act through 5HT2B receptors causing proliferation of valve endothelium, causing valvulopathy and PR similar to carcinoid disease.

History and Physical

History

The etiology of pulmonary regurgitation mainly determines the history. In PR 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 PR causes RV 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 PR, which often results only in incidental auscultatory findings. Patients with PR caused by infective endocarditis who develop septic pulmonary emboli and pulmonary hypertension often exhibit severe RV failure. With the disease progression, the patient may report fatigue, exertional dyspnea, abdominal fullness/bloating, and lower extremity swelling.

Post Ross procedure: Ross procedure is a pulmonary autograft placement in place of the diseased aortic valve, which is a common procedure in congenital aortic valve disease. Ross 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 post-procedurally, which can occur anytime. Another major complication of this procedure is PR, 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 post-surgical hemodynamic and electrophysiological abnormalities. Right bundle branch block, residual intra-cardiac shunts, tricuspid regurgitation, etc., cause pulmonary annular dilatation causing PR.[9]

Physical Findings

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

Auscultation[11]

• The first heart sound (S) is normal.
• P2 is not audible in patients with congenital absence of the pulmonic valve; however, this sound becomes accentuated in patients with PR secondary to pulmonary hypertension. There may be a wide splitting of S2 caused by the prolongation of RV ejection accompanying the augmented RV stroke volume.
• A systolic ejection click can be heard sometimes in the second left intercostal space, due to sudden expansion of the pulmonary artery by augmented RV stroke volume.
• An S3 and S4 originating from the right ventricle are often audible, most readily in the fourth intercostal space at the left parasternal area, and become augmented by inspiration.
• In the absence of pulmonary hypertension, the PR 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 auscultation of the peak intensity of this murmur is when the gradient between these pressures is maximal, and soon, it ends with equilibration of the pressures.
• The Graham Steell murmur: It 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.

Progression of PR[12]

As per 2014 AHA/ACC guidelines, all valvular heart diseases progress through four stages

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

Descriptions of the severity of PR appear in the section of the investigations below.

Evaluation

EKG

Commonly seen EKG findings in pulmonary 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 along with right axis deviation can be seen. These findings are secondary to RV hypertrophy.[13]

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

Echocardiography

Right ventricular dilation, along with hypertrophy, appears in two-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 PR. The absence of a wave and systolic notching of the posterior leaflet suggests pulmonary hypertension; large a wave indicate pulmonic stenosis. Doppler echocardiography is extremely accurate in detecting PR and in helping to estimate its severity.

• Mild PR - Normal right ventricular dimensions with thin (less than 10mm in length) regurgitant jet width by color doppler
• Moderate PR - Normal or dilated right ventricle with intermediate regurgitant jet width (less than 50% of pulmonic valve annulus) 
• Severe PR- Dilated right ventricle (except in acute PR) with large regurgitant jet width (greater than 50% of pulmonic valve annulus)

Angiography

In PR, 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 in assessing pulmonary artery dilation and the severity of PR.

Treatment / Management

Treatment of the primary condition is the most crucial aspect of management. 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, ACE inhibitors, and digoxin.

Patients with iatrogenic PR caused by the surgical correction of tetralogy of Fallot (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 PR following surgical correction of congenital heart defects.[14]  (B3)

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

1. Severe symptomatic PR

2. Asymptomatic severe PR with two out of four of the following conditions 

• Elevated right ventricular volume (end-diastolic vol. index more than 160 mL/m^2 or end-systolic volume index of 80 ml/m2)
• Elevated right ventricular pressure.
• Reduced exercise tolerance
• Mild to moderate systolic dysfunction of either right or left ventricle

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 conduit 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 to 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

Pulmonary regurgitation can be seen in several underlying heart and lung conditions, as noted in the etiology. Identifying the underlying cause can be the most challenging aspect and plays a critical role in the management of PR. 

Clinically it is very important to distinguish the blowing decrescendo murmur of PR from a similar murmur noticed in aortic regurgitation. PR can sometimes coexist as one of the multivalvular lesions involving mitral and aortic valves. Such cases need further investigations with echocardiography to check the severity of each lesion.

Treatment Planning

Mild PR on echocardiography will not require a follow-up unless the patient becomes symptomatic or if the initial echocardiogram showed signs of early RV dysfunction. Moderate to severe PR 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

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

In PR 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

RV enlargement leading to right-sided heart failure and sudden cardiac death are some of the major complications of severe PR. Other complications include hepatic congestion secondary to right heart failure, thromboembolic events, arrhythmias are not so uncommon with severe PR. 

Complications post pulmonic valve replacement include valve failure and infective endocarditis.[18]