Pulmonic regurgitation overview

# Overview
Pulmonic regurgitation (PR) is a condition where the pulmonary valve is not strong enough to prevent backflow into the right ventricle.  Nearly all individuals have physiologic (trace-to-mild) pulmonic regurgitation and the incidence increases with advancing age.  Hence, there is a backward flow of blood from the pulmonary artery, through the pulmonary valve, and into the right ventricle of the heart during diastole.
PVR may be classified according to the pulmonary valve morphology and severity of the disease. However, in a small percentage of patients, it is a normal finding. PVR may share overlapping symptoms with certain other conditions such as aortic regurgitation, tricuspid re gurgitation, left to right shunting, right ventricular cardiomyopathy, pulmonary hypertension, infective endocarditis, carcinoid heart disease, syphilis and Marfan syndrome.
The main pathophysiologic mechanism for pulmonary regurgitation includes the backflow of blood into the right ventricle resulting in ventricular overload and ventricular remodeling. Complications that may result from pulmonary regurgitation include progressive right ventricular dilatation, heart failure, tricuspid regurgitation, ventricular arrhythmias, and sudden cardiac death.
The diagnosis of pulmonic regugitation may include detailed history, and physical examination. Certain diagnostic tests such as echocardiography and cardiac MRI may help confirm the diagnosis. The mainstay of treatment for PR may include medical therapy for mild to moderate cases and pulmonary valve replacement in severe cases. Medical therapy may include use of diuretics and ACE inhibitors in patients with right ventricular dysfunction.
Lifelong follow up may be required among patients with PR to monitor pulmonary valve morphology and to assess right ventricular function.

# Historical perspective
Pulmonic regurgitation murmur was first described as Graham-Steell murmur by Dr. Graham Steel in 1888. Before that  The pulmonary valve and its function of allowing blood to the lungs for nourishment was first described by Hippocrates. Ibn Nafis then described the pulmonary circulation. Mondino drew a sketch of the pulmonic valve. In 1888 an early blowing diastolic murmur due to pulmonary hypertension was described by Graham-steel, known as Graham-steel murmur. Techniques were then developed to diagnose pulmonary valve regurgitation via the dye method and cardiac catheterization.

# Classification
Pulmonary valve regurgitation (PR) may be classified according to etiology of the regurgitant flow, severity of the disease and chronicity. Based on the etiology of the regurgitant flow, PR may be classified into primary and secondary/ functional types. The severity of the disease may classify into mild, moderate, and severe disease. New York Heart Association's (NYHA) functional classification helps to gauge the severity of the heart failure which is a complication of PR. The severity of PR can be assessed by utilizing the American Heart Association and American College of Cardiology (AHA/ACC) staging of valvular heart disease (VHD).

# Pathophysiology
Pulmonary valve is located at the junction of the right ventricular outflow tract and pulmonary artery. Three equal-sized, semilunar cusps or leaflets make up the pulmonary valve. Pulmonary valve opens during right ventricular systole and closes during right ventricular diastole. Pulmonary regurgitation (PR) may be caused by an acquired alteration in the valvular morphology, idiopathic dilatation of the pulmonary artery (IDPA), pulmonic valve ring dilatation,  congenital absence or malformation of the valve, and increasing regurgitation causing right ventricular volume overload. The pathophysiologic mechanism of pulmonic regurgitation includes right ventricular overload resulting in the right ventricular remodeling and progressive decline in function. The rate of decline in right ventricular systolic function is affected by associated conditions such as peripheral pulmonary artery stenosis and pulmonary hypertension which further increase the severity of pulmonary regurgitation. Among patients with severe PR, the gene expression pattern of GRK2 and 2-adrenoceptor (molecular markers of cardiac dysfunction) has been reported to be altered. Isolated PR is uncommon and is usually demonstrated with other valvular abnormalities or in certain conditions. Conditions associated include TOF, rheumatic heart disease and syphilis. On gross pathology vegetative lesions on the pulmonic valve leaflets may be observed among patients with acquired alteration in the valvular leaflet morphology.

# Causes
A small percentage of pulmonic regurgitation is normal and occasionally can be heard in thin subjects. The most common causes of PR are following repair of tetralogy of Fallot and pulmonary stenosis.

# Differential Diagnosis
Pulmonic regurgitation (PR) must be differentiated from other diseases that cause blowing decrescendo murmur such as aortic regurgitation. The diseases which may present with overlapping symptoms as pulmonic regurgitation may include aortic regurgitation, tricuspid regurgitation, left to right shunting, right ventricular cardiomyopathy, pulmonary hypertension, infective endocarditis, carcinoid heart disease, syphilis and marfan syndrome.

# Epidemiology and demograpics
The prevalence of mild PR among patients with normal anatomy of the pulmonary valve is 40% to 78%. Among patients born with congenital heart disease, 20% of patients have associated abnormalities of the pulmonary valve or the right ventricular outlet obstruction. The incidence and prevalence of PR increases with age. 24% of the deaths due to valvular heart disease are attributed to tricuspid valve and pulmonic valve abnormalities combined. There is one study supporting the increased prevalence of PR among women. In developing countries Pulmonary hypertension (PAH) is primarily due to rheumatic heart disease (RHD) which is rare in developed countries. PAH is a major cause of secondary PR.

# Risk factors
MOst potent risk factors for the development of pulmonic regurgitation may include pulmonary hypertension, surgical repair of teratology of Fallot, and congenital heart diseases. Less common but important risk factors include endocarditis, left sided heart disease, previous Ross procedure, collagen vascular disease, and malignancies involving the main pulmonary artery.

# Screening
There are no specific screening recommendations for patients with pulmonary regurgitation (PR). However, patients on an increased risk of developing PR secondary to conditions such as repair of Tetralogy of Fallot (TOF), pulmonary atresia or truncus arteriosus may be evaluated by routine echocardiography, ECG or MRI to assess right ventricular size and status of pulmonary valve. A study recommends considering ADAMTS19 genetic testing among all patients with multiple semilunar valve abnormalities. The key diagnostic tests that may be used for screening of PAH (a major risk factor for PR) may include doppler transthoracic echocardiography, DLCO, BNP, NT-pro-BNP, serum urate levels, and ECG.

# Natural history, complications and prognosis
The majority of patients with mild pulmonary regurgitation (PR) are asymptomatic and have a benign course, not progressing to chronic PR. Patients tolerate severe chronic PR for a long period of time and begin to develop symptoms when the right ventricle function begins to decline. Chronic severe PR leads to progressive dilation and systolic dysfunction of the right ventricle resulting in symptoms. The severity of PR after TOF repair can increase over time and patients may develop symptoms from an early age. Complications that may result from PR  include progressive right ventricular dilatation, heart failure, tricuspid regurgitation, ventricular arrhythmias, and sudden cardiac death. The prognosis of pulmonic regurgitation depends on the severity of the condition, etiology, and associated complications. Symptomatic patients are treated with pulmonary valve replacement (PVR) and have a good prognosis.

# Diagnosis
The diagnosis of pulmonic regurgitation may include detailed history, physical examination and diagnostic tests such as EKG, echocardiography, chest x ray and cardiac MRI.

## History and symptoms
The history and clinical presentation of pulmonary regurgitation (PR) vary with the cause of the regurgitation and right ventricular dysfunction. The patient may present with a history related to the primary cause of PR. Isolated pulmonary regurgitation is usually asymptomatic. However, patients with chronic PR may present with symptoms of heart failure such as dyspnea on exertion, fatigue, ankle edema, hemoptysis, nocturnal cough and palpitations. Smoking or intravenous drug use (recreational) history are important to assess the cause fo PR.

## Physical examination
Physical examination findings of pulmonary regurgitation (PR) includes a well-appearing patient. On neck exam, increased JVP, prominent "a" wave, "v" wave in the neck may be observed. Precordial (cardiac) exam may reveal a palpable apical impulse (lift or heave) is usually present at the left lower sternal border because of right ventricular dilation. On auscultation, it may be associated with wide splitting of S2 with right sided S3 accentuated with respiration. Murmur of pulmonic regurgitation may vary depending on the underlying cause. Pedal edema and hepatomegaly demonstrate right heart failure.

## Electrocardiogram
EKG findings among patients wit chronic Pulmonic regurgitation (PR) may be non-specific. Ventricular tachycardia is demonstrated on EKG among patients with PR and RV dilatation. Patients may develop atrial flutter/fibrillation after years of PR development. Among patients with tetralogy of Fallot (TOF), increased QRS duration with widened QRS complex reflects the severity of PR and right ventricular dilation predisposes the patients to develop malignant arrythmias.

## Chest X-ray
Chest x ray may not be required for the diagnosis of pulmonic regurgitation (PR). However, lateral and PA view of chest radiograph may help determining the right ventricular enlargement. Right atrial enlargement may also be seen among patients with concomitant tricuspid regurgitation. On plain chest Xray PR may be characterized by right ventricular enlargement, prominent pulmonary trunk, features of tricuspid regurgitation (TR), and of congestive heart failure (CHF).

## Echocardiography
Echocardiography is the initial test that may be used to assess pulmonary valve morphology, RVOT anatomy, and to identify the presence and quantify the severity of pulmonary regurgitation (PR). Different modes of echocardiography may be used to improve the accuracy of findings and assess the severity of the disease which include doppler|color flow doppler, continuous wave doppler, pulsed doppler, spectral doppler and exercise echocardiography. The severity of PR can be assessed by observing color pulmonic valve morphology, flow PR jet size and density, and regurgitant Fraction (RF) via doppler echocardiography.

## Cardiac MRI
Cardiac magnetic resonance(CMR) is a gold standard for assessment of morphology of the pulmonary valve, for quantification of the severity of the regurgitation and the RV systolic function. CMR is useful in quantification of the regurgitant volume and the regurgitant fraction of PR by using sequences called velocity- encoded phase-contrast images. CMR is useful for evaluating pulmonary regurgitant fraction, RV end-diastolic and end-systolic volume and RV ejection fraction. CMR is the diagnostic modality preferred to determine the requirement of re-intervention among patients with repaired tetralogy of Fallot and to assess the ventricular function and dimensions.

## Pulmonary angiography
Pulmonary angiography may play a role among patients with TOF repair having pulmonary regurgitation.

# Treatment
Treatment of pulmonic regurgitation may include medical therapy, surgical therapy and regular follow up.

## Medical therapy
Treatment of pulmonic regurgitation may be divided into medical and surgical treatment. Medical management of pulmonic regurgitation may include use of diuretics in patients with RV dysfunction. ACE inhibitors and beta blockers may be used to reverse neurohormonal activation and improve symptoms. Antibiotic prophylaxis may be indicated in certain conditions such as patients with cyanotic heart disease, prosthetic heart valves, rheumatic heart disease, and patients previously having sustained bacterial endocarditis. Among patients with carcinoid heart disease subcutaneously administered octreotide in 24 divided doses (501500 g/day) provides symptomatic and biochemical benefit.

## Surgical therapy
Surgical management of pulmonic regurgitation may include pulmonary valve replacement (PVR). The major indications for PVR may include symptomatic patients with arrythmias or NYHA class higher than II, an ejection fraction of less than 40% when assessed with CMR, patients with progressive right ventricular regurgitation(right ventricular end- diastolic volume 160 mL/m2 or end-systolic volume 82 mL/m2 on CMR), moderate to severe tricuspid valve regurgitation, resulting from annular dilatation, patients at risk of developing arrythmias and with prolonged QRS duration.(total QRS duration 180 msec, or QRS duration increase >3.5 msec per year and severe pulmonic regurgitation among patients with another cardiac lesion that requires operative intervention. Timing of pulmonary valve replacement is not well defined. However timely intervention is advised before the onset of RV dysfunction. Pulmonary valve replacement (PVR) by surgical and percutaneous approach is the definitive treatment for the management of chronic PR and has proven to improve RV function, New York Heart Association Functional Class status, quality of life, and reduce risk for development of RV tachyarrhythmias and sudden cardiac death. Among patients with arrhythmias, intraoperative electrophysiological mapping with cryoablation during pulmonary valve replacement has demonstrated promising results.

## Follow up
Follow up of the patients with pulmonic regurgitation requires regular echocardiographic monitoring after PVR. Oral anticoagulation among patients with bioprosthetic valves is recommended only when other indications such as atrial arrhythmia or prior thromboembolic event are present. Upon surveillance among patients with PR monitoring right ventricular dilatation and its sequelae holds more significance than the regurgitation itself.