Aortic Regurgitation

Background

Aortic regurgitation (AR) is the diastolic flow of blood from the aorta into the left ventricle (LV). Regurgitation is due to incompetence of the aortic valve or any disturbance of the valvular apparatus (eg, leaflets, annulus of the aorta) resulting in the diastolic flow of blood into the left ventricular chamber. (See Pathophysiology and Etiology.)

Valvular abnormalities that may result in AR can be caused by the following (see Etiology, Presentation, and Workup):

Congenital causes - Bicuspid aortic valve is the most common congenital cause^[1]

Acquired causes:

• Rheumatic fever
• Infective endocarditis
• Collagen vascular diseases
• Degenerative aortic valve disease
• Traumatic
• Postsurgical (including post-transcatheter aortic valve replacement)

Abnormalities of the ascending aorta, in the absence of valve pathology, may also cause AR. Such abnormalities may occur with the following conditions:

• Longstanding, uncontrolled hypertension
• Marfan syndrome
• Idiopathic aortic dilation
• Cystic medial necrosis
• Senile aortic ectasia and dilation
• Syphilitic aortitis
• Giant cell arteritis
• Takayasu arteritis
• Ankylosing spondylitis
• Whipple disease
• Other spondyloarthropathies

Aortic regurgitation may be a chronic disease process or it may occur acutely, presenting as heart failure.^[2] The most common cause of chronic aortic regurgitation used to be rheumatic heart disease, but presently it is most commonly caused by bacterial endocarditis.^[3] In developed countries, it is caused by dilation of the ascending aorta (eg, aortic root disease, aortoannular ectasia). (See Presentation and Workup.)

Three fourths of patients with significant aortic regurgitation survive 5 years after diagnosis; half survive for 10 years. Patients with mild to moderate regurgitation survive 10 years in 80-95% of the cases. Average survival after the onset of congestive heart failure (CHF) is less than 2 years. (See Prognosis, Treatment, and Medication.)

Acute aortic regurgitation is associated with significant morbidity, which can progress from pulmonary edema to refractory heart failure and cardiogenic shock.

Patient education

The 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for valvular heart disease, including for AR, are available to the public online for free.^[4]  Additionally, educational and support organizations, such as the National Marfan Foundation and the Bicuspid Aortic Foundation, exist for many of the underlying conditions.

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Pathophysiology

Incompetent closure of the aortic valve can result from intrinsic disease of the leaflets, cusp, diseases of the aorta, or trauma. Diastolic reflux through the aortic valve can lead to left ventricular volume overload. An increase in systolic stroke volume and low diastolic aortic pressure produces an increased pulse pressure. The clinical signs of AR are caused by the forward and backward flow of blood across the aortic valve, leading to increased stroke volume.^[5]

The severity of AR is dependent on the diastolic regurgitant valve area, the diastolic pressure gradient between the aorta and LV, and the duration of diastole.

The pathophysiology of AR depends on whether the AR is acute or chronic. In acute AR, the LV does not have time to dilate in response to the volume load, whereas in chronic AR, the LV may undergo a series of adaptive (and maladaptive) changes.

Acute aortic regurgitation

Acute AR of significant severity leads to increased blood volume in the LV during diastole. The LV does not have sufficient time to dilate in response to the sudden increase in volume. As a result, LV end-diastolic pressure increases rapidly, causing an increase in pulmonary venous pressure and altering coronary flow dynamics. As pressure increases throughout the pulmonary circuit, the patient develops dyspnea and pulmonary edema. In severe cases, heart failure may develop and potentially deteriorate to cardiogenic shock. Decreased myocardial perfusion may lead to myocardial ischemia.

Early surgical intervention should be considered (particularly if AR is due to aortic dissection, in which case surgery should be performed immediately).

Chronic aortic regurgitation

Chronic AR causes gradual left ventricular volume overload that leads to a series of compensatory changes, including LV enlargement and eccentric hypertrophy. LV dilation occurs through the addition of sarcomeres in series (resulting in longer myocardial fibers), as well as through the rearrangement of myocardial fibers. As a result, the LV becomes larger and more compliant, with greater capacity to deliver a large stroke volume that can compensate for the regurgitant volume. The resulting hypertrophy is necessary to accommodate the increased wall tension and stress that result from LV dilation (Laplace law).

During the early phases of chronic AR, the LV ejection fraction (EF) is normal or even increased (due to the increased preload and the Frank-Starling mechanism). Patients may remain asymptomatic during this period. As AR progresses, LV enlargement surpasses preload reserve on the Frank-Starling curve, with the EF falling to normal and then subnormal levels. The LV end-systolic volume rises and is an indicator of progressive myocardial dysfunction.

Eventually, the LV reaches its maximal diameter and diastolic pressure begins to rise, resulting in symptoms (dyspnea) that may worsen during exercise. Increasing LV end-diastolic pressure may also lower coronary perfusion gradients, causing subendocardial and myocardial ischemia, necrosis, and apoptosis. Grossly, the LV gradually transforms from an elliptical to a spherical configuration.

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Etiology

Acute aortic regurgitation

Infective endocarditis may lead to destruction or perforation of the aortic valve leaflet. A bulky vegetation can also interfere with proper coaptation of the valve leaflets or lead to frank prolapse or disruption of a leaflet (flail leaflet).^[3]

Another cause of acute AR, chest trauma, may lead to a tear in the ascending aorta and disruption of the aortic valve support apparatus. With the development and clinical adoption of transcatheter aortic valve replacement (TAVR) techniques, post-TAVR AR has emerged as a common and potentially important cause of both acute and chronic AR.^[6] AR may also develop as a complication of left ventricular assist device (LVAD) implantation.^[7]

In acute ascending aortic dissection (type A), the retrograde proximal dissection undermines the suspensions of the aortic valve leaflets. Varying levels of aortic valve malcoaptation and prolapse occur. Prosthetic valve malfunction can also lead to AR.

Chronic aortic regurgitation

Bicuspid aortic valve is the most common congenital lesion of the human heart. Although it leads more often to progressive aortic stenosis than to AR, it is nonetheless the most common cause of isolated AR requiring aortic valve surgery. In patients with bicuspid aortic valve, an associated aortopathy may be present, resulting in aortic dilation and/or dissection that worsens the AR.^[8]  Current American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend consideration of surgical intervention when the aortic diameter reaches 5.0 cm (or 4.5 cm in patients who are undergoing cardiac surgery for reasons other than aortic enlargement).^[9]

Certain weight loss medications, such as fenfluramine and dexfenfluramine (commonly referred to as Phen-Fen), may induce degenerative valvular changes that result in chronic AR.

Rheumatic fever, a common cause of AR in the first half of the 20th century, has become less common in the United States, although it remains prevalent in some immigrant populations. Fibrotic changes cause thickening and retraction of the aortic valve leaflets, resulting in central valvular regurgitation. Leaflet fusion may occur, leading to concurrent aortic stenosis. Associated rheumatic mitral valve disease is almost always present.

Ankylosing spondylitis often causes an aortitis, which most frequently involves the aortic root, with associated AR.^[10] Further extension of the subaortic fibrotic process into the intraventricular septum may result in conduction system disease. Coronary and more distal aortic abnormalities are also seen in this condition.

Behçet disease causes cardiac complications in less than 5% of patients, but potential findings include proximal aortitis with AR, as well as coronary artery disease.^[11]

Giant cell arteritis is a systemic vasculitis that typically affects the extracranial branches of the carotid artery but may also cause aortic inflammation and AR (as well as coronary artery disease and LV dysfunction).^[12]

Rheumatoid arthritis uncommonly causes granulomatous nodules to form within the aortic valve leaflets. In rare cases, this may lead to clinical AR, although it is more commonly an incidental finding postmortem.^[13]

Systemic lupus erythematosus can cause valvular fibrosis and consequent dysfunction, including AR.^[14] Lupus is also associated with Libman-Sacks endocarditis, resulting in sterile, verrucous valvular vegetations that can cause AR.^{[15, 16]}

Takayasu arteritis, in addition to having aortic valvular (and coronary) involvement, can produce an aortitis. The aortitis may increase the risk of prosthetic valve detachment, leading some to advocate for concurrent aortic root replacement in patients undergoing valve surgery.^[17]

Whipple disease has been reported in the literature in association with AR or aortic valve endocarditis.^[18]

Connective tissue disorders that can cause significant AR include the following:

• Marfan syndrome
• Ehlers-Danlos syndrome
• Floppy aortic valve
• Aortic valve prolapse
• Sinus of Valsalva aneurysm
• Aortic annular fistula

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Epidemiology

Occurrence in the United States

Although rheumatic heart disease is overall the most common cause of AR worldwide, congenital and degenerative valve abnormalities are the most common cause in the United States, with the age of detection peaking at 40-60 years. Estimates of the prevalence of AR of any severity range from 2-30%, but only 5-10% of patients with AR have severe disease, resulting in an overall prevalence of severe AR of less than 1% in the general population.^[19]

In the Framingham study (with an original cohort of 5209 patients aged 28-62 y and an additional cohort of 5124 patients), AR of any severity was found in 13% of men and 8.5% of women.^[20] Prevalence and severity increased with age; when stratified by decades of life, AR of moderate or greater severity was seen in less than 1% of patients in all strata younger than 70 years.

International occurrence

The prevalence of AR internationally is not well known. However, the international prevalence of underlying conditions has been described elsewhere. For example, rheumatic heart disease remains highly prevalent in many Asian, Middle Eastern, and North African countries.^[21]

Race-, sex-, and age-related demographics

The prevalence of AR appears to be similar across racial populations in the United States, although internationally there is significant variation in the prevalence of predisposing conditions, such as rheumatic heart disease.^[21]

AR is seen more commonly in men than in women. In the cohort from the Framingham study, AR was found in 13% of men and 8.5% of women.^[20] The greater prevalence of AR in men may reflect, in part, the preponderance of underlying conditions, such as Marfan syndrome^[22] or bicuspid aortic valve, in males.^[23]

Chronic aortic regurgitation often begins in patients when they are in their late 50s and is documented most frequently in patients older than 80 years. In general, the prevalence and severity of AR increase with age, although severe chronic AR is uncommon before age 70 years.^[20] However, there are many exceptions to this observation. Patients with bicuspid aortic valve and, especially, those with Marfan syndrome tend to present much earlier.^{[22, 23]}

Following TAVR

TAVR has emerged as an important treatment for aortic valve disease, primarily aortic stenosis. Paravalvular AR is common after TAVR, occurring to some degree in approximately 70% of cases and being graded as moderate or severe in approximately 15%.^[6]

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Prognosis

The prognosis for patients with severe AR depends on the presence or absence of LV dysfunction and symptoms In asymptomatic patients with normal EF, the following has been found:

• Rate of progression to symptoms or LV dysfunction - Less than 6% per year
• Rate of progression to asymptomatic LV dysfunction - Less than 3.5% per year
• Rate of sudden death - Less than 0.2% per year

In asymptomatic patients with decreased EF, the rate of progression to symptoms is greater than 25% per year, while in symptomatic patients, the mortality rate is over 10% per year.

The strongest predictors of outcome are echocardiographic parameters (EF and LV end-systolic dimension), underscoring the crucial role of serial echocardiography in the management of patients with severe AR.

Exercise LV end-systolic volume index (LVESVi) may have prognostic value as an independent predictor of outcomes in in patients with asymptomatic moderate or severe AR.^[24]

Severe acute AR, if left untreated, is likely to lead to considerable morbidity and mortality from either the underlying cause (typically infective endocarditis or aortic dissection) or from hemodynamic decompensation of the LV.

Potential complications in patients with severe chronic AR include progressive LV dysfunction and dilation, congestive heart failure, myocardial ischemia, arrhythmia, and sudden death. Additional complications may arise as a result of the patient's underlying condition (such as aortic root dissection in a patient with a bicuspid aortic valve and a severely dilated aortic root).

Morbidity and mortality

Severe acute AR carries a very high short-term rate of morbidity and mortality owing to the imposition of a greatly increased regurgitant volume upon a relatively noncompliant LV. Increased LV end-diastolic pressure leads to elevated left atrial and pulmonary pressures with resulting pulmonary edema, as well as decreased coronary perfusion gradients that potentially can cause myocardial ischemia and even sudden cardiac death. In most cases, early (if not emergent) surgical intervention is warranted.

Severe chronic AR tends to follow a more gradual clinical course. This is typically characterized initially by a long, relatively asymptomatic period. However, once symptoms ensue, the patient's clinical status may deteriorate relatively rapidly. Thus, current guidelines recommend surgical intervention before symptoms develop, usually based on echocardiographic parameters.

With conservative (medical) management of severe chronic AR, the linearized yearly rates of major events have been estimated as follows^[25] :

• Death from any cause - 4.7%
• Congestive heart failure - 6.2%
• Aortic valve surgery - 14.6%

The presence of symptoms has been found to predict yearly mortality risk, as follows:

• Asymptomatic - 2.8%
• New York Heart Association (NYHA) class I - 3.0%
• NYHA class II - 6.3%
• NYHA class III-IV - 24.6%

Although these types of data suggest that a symptom-triggered approach to surgical intervention may be feasible, multiple studies have shown that, as stated earlier, the most important predictors of mortality (and of postoperative LV function) are not symptoms but 2 crucial echocardiographic parameters; specifically, LV ejection fraction and LV end-systolic dimension.

Risk of coronary artery disease

A study by Atalar et al found that in patients with rheumatic valve disease, the prevalence of AR was inversely proportional to the prevalence of significant coronary artery disease. The investigators, who conducted a retrospective analysis of more than 1000 patients with rheumatic valve disease, also found that, while the presence of coronary artery disease was particularly low in patients with AR, it was unusually high in those with aortic stenosis.^[26]

Following TAVR

Multiple studies have shown that the presence of greater than mild AR following TAVR is associated with significantly increased morbidity and mortality. Compared with patients who have no or mild AR, patients with moderate or severe AR after TAVR may have more than double the risk of mortality.^[6]

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History

Acute aortic regurgitation

The typical presentation of severe acute AR includes sudden, severe shortness of breath; rapidly developing heart failure; and chest pain if myocardial perfusion pressure is decreased or an aortic dissection is present.^[5]

Chronic aortic regurgitation

Patients with chronic AR often have a long-standing asymptomatic period that may last for several years. A compensatory tachycardia may develop to maintain a large forward stroke volume, leading to a decreased diastolic filling period. As a result, patients may be asymptomatic even with exercise. Over time, however, chronic volume overload leads to LV dysfunction as the LV dilates. Significant deterioration of LV function may begin prior to the development of symptoms in up to 25% of patients, highlighting the importance of periodic echocardiographic surveillance.

Among patients with asymptomatic LV dysfunction, more than 25% of them develop symptoms within 1 year. Once symptoms arise, cardiac function usually worsens more rapidly and mortality may exceed 10% per year.

Symptoms of severe chronic AR include the following:

Palpitations - Often described as the sensation of having forceful heart beats, due to widened pulse pressure with hyperdynamic circulation

• Uncomfortable awareness of the heartbeat
• Shortness of breath - May not worsen with exertion in the early stages due to compensatory tachycardia with shortened diastole
• Chest pain - Occurs if increased LV end-diastolic pressure compromises coronary perfusion pressure gradients
• Sudden cardiac death - This is uncommon (< 0.2% per year) in asymptomatic patients with preserved LV function

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Physical Examination

Many classical physical examination findings have been described in patients with severe chronic AR. However, these findings may be only minimally present (if at all) in patients with severe acute AR.

Acute aortic regurgitation

Cases of acute AR may be fulminant and lead to cardiogenic shock; patients who have CHF or shock associated with severe AR often appear gravely ill. Other symptoms of acute AR include the following:

• Tachycardia
• Peripheral vasoconstriction
• Cyanosis
• Pulmonary edema
• Arterial pulsus alternans; normal LV impulse

Early diastolic murmur (lower pitched and shorter than in chronic AR) may be present. An Austin-Flint murmur, which is caused by the regurgitant flow causing vibration of the mitral apparatus, is lower pitched and short in duration. The decrescendo diastolic murmur is heard best with the patient leaning forward in full expiration in a quiet room. It is one of the cardiac murmurs most commonly missed.

A murmur at the right sternal border is associated more often with aortic dissection than it is with any other cause of AR.

Chronic aortic regurgitation

Manifestations of severe chronic AR are often the result of widened pulse pressure (ie, an exaggerated difference between systolic and diastolic blood pressure) because (1) elevated stroke volume exists during systole and (2) the incompetent aortic valve allows the diastolic pressure within the aorta to fall significantly.

Diastolic pressures are often lower than 60 mm Hg, with pulse pressures often exceeding 100 mm Hg, although younger patients with more compliant vessels may have a less widened pulse pressure. Associated physical examination findings include the following:

• Becker sign - Visible systolic pulsations of the retinal arterioles
• Corrigan pulse ("water-hammer" pulse) - Abrupt distention and quick collapse on palpation of the peripheral arterial pulse
• de Musset sign - Bobbing motion of the patient's head with each heartbeat
• Hill sign - Popliteal cuff systolic blood pressure 40 mm Hg higher than brachial cuff systolic blood pressure
• Duroziez sign - Systolic murmur over the femoral artery with proximal compression of the artery, and diastolic murmur over the femoral artery with distal compression of the artery
• Müller sign - Visible systolic pulsations of the uvula
• Quincke sign - Visible pulsations of the fingernail bed with light compression of the fingernail
• Traube sign ("pistol-shot" pulse) - Booming systolic and diastolic sounds auscultated over the femoral artery

On palpation, the point of maximal impulse may be diffuse or hyperdynamic but is often displaced inferiorly and toward the axilla. Peripheral pulses are prominent or bounding. Auscultation may reveal an S₃ gallop if LV dysfunction is present.

The murmur of AR occurs in diastole, usually as a high-pitched sound that is loudest at the left sternal border. The duration of the murmur correlates better with the severity of AR than does the loudness of the murmur. A functional systolic flow murmur may also be present because of increased stroke volume, although concurrent aortic stenosis may also be present.^[5]

An Austin-Flint murmur may be present at the cardiac apex in severe AR; it is a low-pitched, mid-diastolic rumbling murmur due to blood jets from the AR striking the anterior leaflet of the mitral valve, which results in premature closure of the mitral leaflets.

In many cases, physical examination also reveals findings relating to the underlying cause of AR. For example, there may be various embolic phenomena in patients with AR due to infective endocarditis, or the patient may have skeletal features suggestive of Marfan syndrome or a spondyloarthropathy if AR is due to these conditions.

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Approach Considerations

Laboratory testing in patients with AR should be guided by the clinical scenario. For example, in patients with AR due to suspected infective endocarditis, peripheral blood counts and cultures may help to clarify the diagnosis and to identify the causative organism. Specific serologic tests may assist in the diagnosis of rheumatologic causes. Laboratory assessment of renal and hepatic function may play an important role in determining a patient's eligibility for certain vasodilator or other drug therapy.

Laboratory studies for AR may also include the following:

• Complete blood count (CBC)
• Prothrombin time (PT)/activated partial thromboplastin time (aPTT)
• Type and screen
• Electrolytes
• VDRL
• Lactate dehydrogenase

Early surgical intervention is recommended in cases of AR caused by infective endocarditis, and emergent intervention is warranted in cases caused by aortic dissection.

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Imaging for Aortic Regurgitation

Transthoracic echocardiography

Transthoracic echocardiography should be performed in all patients with suspected AR, and should be performed periodically in patients with confirmed AR of significant severity.^[27]

Echocardiography is a highly accurate test in AR, with sensitivity and specificity well in excess of 90%. In addition, echocardiographic parameters are used to determine the optimal timing of surgery in many cases.^[4] Important echocardiographic findings in AR include the following:

• Aortic valve structure and morphology - Bileaflet versus trileaflet, flail, thickening
• Presence of vegetations or nodules - May require transesophageal echocardiography in selected cases
• Severity of AR
• Color Doppler jet width
• Vena contracta width - In severe AR, the vena contracta width is usually more than 65% of the width of the LV outflow tract
• Regurgitant volume, fraction, and orifice area
• Premature closure of the mitral valve (seen in severe AR) and opening of the aortic valve (with severely elevated LV end-diastolic pressure)
• Pressure half-time - Usually less than 300-350 ms with significant AR
• Associated lesions of the aorta - Including dilation, aneurysm, dissection, or ectasia
• LV structure and function
• LV hypertrophy and dilation
• Ejection fraction (EF) and end-systolic dimension - These are key determinants of outcome; surgery is recommended if the EF is 55% or less or if the LV end-systolic dimension is more than 55 mm^[4]

Echocardiographic assessment of AR following TAVR is much more challenging because the AR is usually paravalvular and occurs in the context of acute hemodynamic changes, as well as prosthetic materials that may impair image quality. Proposed TEE criteria for identifying significant AR include a regurgitant jet extending below the LV outflow tract, multiple AR jets, holodiastolic flow reversal in the descending aorta, and circumferential extent of the jet in short axis (>10% moderate, ≥ 30% severe).^[6] Further research is needed to validate these criteria for clinical application.

Exercise treadmill testing

Exercise treadmill testing may be used to guide recommendations for surgical therapy in patients with severe chronic AR and equivocal symptoms.^[4] However, the role of stress echocardiography in patients with AR remains uncertain, and further studies may be needed before it can be recommended for routine clinical use.^[28]

Chest radiography

Standard chest radiography may show evidence of structural abnormalities (aortic dilation, prosthetic valve dislodgement, aortic valvular calcification) or functional compromise (pulmonary edema, cardiomegaly).

In acute aortic regurgitation, the following may be seen:

See the list below:

• Minimal cardiac enlargement
• Normal aortic root/arch
• Pulmonary venous pattern increased

In chronic aortic regurgitation, the following may be seen:

• Marked cardiac enlargement
• Prominent aortic root/arch
• Normal pulmonary venous pattern

Radionuclide imaging

Radionuclide imaging may provide complementary clinical information, including the AR regurgitant fraction and the LV/right ventricular (RV) stroke volume ratio. In the absence of mitral regurgitation and tricuspid regurgitation, an LV/RV stroke volume ratio of 2.5 or more denotes severe aortic regurgitation.

Demonstration of a fall in the EF with exercise is one of the most important indications for surgery in patients who are asymptomatic.

Aortic angiography

Aortic angiography, which may be performed during a cardiac catheterization procedure, may provide useful information regarding the severity of the patient's AR. Traditional angiographic grading is as follows:

• Mild (1+) - A small amount of contrast enters the LV during diastole and clears with each systole
• Moderate AR (2+) - Contrast enters the LV with each diastole, but the LV chamber is less dense than the aorta
• Moderately severe AR (3+) - The LV chamber is equal in density to the ascending aorta.
• Severe AR (4+) - Complete, dense opacification of the LV chamber occurs on the first beat, and the LV is more densely opacified than the ascending aorta

Assessment of the anatomy of the aorta and coronary ostia usually produces normal findings, except for the visible reflux of dye from the aortic root into the ventricle.

Cardiac CT scanning and magnetic resonance imaging (MRI)

Cardiac computed tomography (CT) scanning and magnetic resonance imaging (MRI) have not yet achieved widespread adoption in the management of AR, although support in the literature is increasing for the potential clinical use of these imaging techniques.^{[29, 30, 31]}

In a study that used quantitative flow measurement by cardiac MRI (CMR) with calculation of regurgitant fraction (RF) to assess aortic regurgitation (AR), Orwat et al found that TTE significantly underestimated the presence of moderate AR, compared with CMR.^[32] Overall, there was only fair agreement between CMR and TTE regarding the grading of AR (weighted κ = 0.33). The investigators indicated given that higher AR severity on echocardiography has been associated with worse patient outcome, prospective studies of the potential incremental prognostic value of CMR are warranted in this setting.^[32]

In a separate study, Harris et al noted that CMR-derived regurgitant volume was more predictive of clinical outcomes than that derived by TTE in patients with AR, whereas both imaging modalities demonstrated similar performances for patients with mitral regurgitation.^[33] Regurgitant volume greater than 50 mL on CMR identified those with AR at high risk, with 50% undergoing valve surgery, compared to 0% in those whose regurgitant volumes were 50 mL or less.

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Electrocardiography

Electrocardiographic findings are nonspecific but may include evidence of the following:

• LV hypertrophy
• Left axis deviation
• Left atrial enlargement
• LV volume overload pattern - Prominent Q waves in leads I, aVL, and V₃ to V₆ and relatively small r waves in V₁
• LV conduction defects - Typically late in the disease process

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Cardiac Catheterization

Cardiac catheterization is not always required in all patients with chronic AR but may provide extremely valuable clinical information, especially in patients who are contemplating surgery.Indications for cardiac catheterization include the following^[4] :

• Assessment of coronary anatomy prior to aortic valve surgery in patients with risk factors for coronary artery disease
• Assessment of severity of AR, LV function, or aortic root size when noninvasive tests are inconclusive or are discordant with clinical findings

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Histologic Findings

Histologic valvular findings in patients with AR depend on the AR’s cause. Patients with congenital abnormalities can usually be easily characterized noninvasively or grossly at the time of surgery or during pathologic inspection.

Aortic root dilation may be present in up to 25% of patients with AR due to bicuspid valve. Many patients with a bicuspid aortic valve have concurrent aortopathy, including connective tissue and cellular abnormalities, that predisposes these individuals to aortic dilation, aneurysm, and dissection.^[8]

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Approach Considerations

In severe acute aortic regurgitation (AR), surgical intervention is usually indicated, but the patient may be supported medically with dobutamine to augment cardiac output and shorten diastole and with sodium nitroprusside to reduce afterload in hypertensive patients.

Vasodilator therapy may be used on an inpatient or outpatient basis under conditions described in the current ACC/AHA guidelines.^[4]

All patients with an artificial heart valve should receive antibiotic prophylaxis prior to dental procedures. For antithrombotic therapy, all patients with an artificial heart valve should receive daily aspirin, and many should also receive oral anticoagulation therapy.^[4]

Although diuretics, nitrates, and digoxin are sometimes used to help control symptoms in patients with AR, not enough data in the clinical literature justify routinely recommending or discouraging these therapies. Also, no data support drug therapy of any class in patients with less than severe AR.^[4]

Intra-aortic balloon counterpulsation, which can be used to provide temporary mechanical circulatory support, is contraindicated in patients with severe AR.

Inpatient/outpatient care

Inpatient care is required for most patients with severe acute aortic regurgitation (AR), particularly patients with symptoms or evidence of hemodynamic decompensation. Patients with severe chronic AR may be followed as inpatients or outpatients, depending on the stage of their disease and severity of their symptoms and LV dysfunction.

Transfer

For patients who are hospitalized for severe AR in facilities without appropriate cardiovascular and surgical expertise, transfer may be justified to optimize clinical outcomes. For outpatients with stable but severe AR, longitudinal care by a cardiologist with appropriate expertise is recommended.

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Emergency Department Care

General requirements in emergency department care for patients with AR include the following:

• Provide adequate airway management
• Intubate when necessary
• Consider prompt surgical intervention in acute AR

Acute aortic regurgitation

Administer a positive inotrope (eg, dopamine, dobutamine) and a vasodilator (eg, nitroprusside). Administration of vasodilators may be appropriate to improve systolic function and to decrease afterload.

The administration of cardiac glycosides (eg, digoxin) for rate control may in rare cases be necessary. Avoid beta-blockers in the acute setting.

Chronic aortic regurgitation

Consider antibiotic prophylaxis for patients with endocarditis when performing procedures likely to result in bacteremia. The administration of pressors and/or vasodilators may be appropriate.

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Vasodilator Therapy

In severe chronic AR, vasodilator therapy may be used in select conditions to reduce afterload in patients with systolic hypertension, in order to minimize wall stress and optimize LV function. In normotensive patients, however, vasodilator therapy is not likely to reduce regurgitant volume (preload) significantly and thus may not be of clinical benefit.^[34]

Antibiotic Prophylaxis

The prophylactic use of antibiotics prior to dental procedures is no longer routinely recommended for all patients with AR.^[4] However, select patient groups for whom prophylactic antibiotic therapy prior to dental procedures may be reasonable include the following:

• Patients with prosthetic material in their heart - Such as an artificial valve or a valve repaired with prosthetic material
• Patients with prior infective endocarditis
• Patients who, following cardiac transplantation, have valve regurgitation due to a structurally abnormal valve
• Patients with congenital heart disease (CHD) who meet any of the following criteria: (1) cyanotic CHD that has not been repaired or has been incompletely repaired (including patients with palliative shunts and conduits); (2) repaired CHD using prosthetic material, for the first 6 months postprocedurally (ie, prior to endothelialization of the material); or (3) repaired CHD but the patient is at risk for inhibited endothelialization (ie, with residual defects at or adjacent to the site of the prosthetic material)

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Valve Surgery

Surgical treatment of AR usually requires replacement of the diseased valve with a prosthetic valve, although valve-sparing repair is increasingly possible with advances in surgical technique and technology. Such improvements have also enabled many patients, even those with severe LV dysfunction, to undergo valve surgery instead of cardiac transplantation.^{[35, 36, 37]} Salih et al recommend early surgical closure for patients with VSD and AV prolapse for better post-repair outcomes and prevention of AR progression.^[38]

In a retrospective analysis (995-2012), De Meester et al compared the prognosis of aortic valve (AV) repair to that of AV replacement (AVR) using a propensity score analysis and found similar operative mortality (2% vs 5%, respectively).^[39] However, on Kaplan-Meier survival analysis, there was a significantly better overall 9-year survival after AV repair (87%) than after AVR (60%). Cox proportional survival analysis showed that treatment selection was an independent predictor of postoperative survival.^[39] The investigators suggest these findings indicate that AVR should probably the preferred surgical intervention for correction of aortic regurgitation as feasible.

Mechanical versus bioprosthetic aortic valves

For patients undergoing aortic valve replacement, careful consideration should be given to the relative risks and benefits of mechanical versus bioprosthetic valves.

Traditionally, mechanical valves have been thought to be more durable, but they require long-term anticoagulation therapy with warfarin due to an increased risk of thrombosis. The use of bioprosthetic valves avoids the need for long-term warfarin, but they carry a greater risk of long-term deterioration and a need for reoperation.^[40]

In some cases, the choice of valve is apparent; eg, a homograft is often preferred to a mechanical valve in the setting of active infective endocarditis.

While further discussion is beyond the scope of this article, the reader is referred to the current ACC/AHA guidelines, which include major criteria for aortic valve selection, as well as recommendations for antithrombotic therapy (including aspirin for all prosthetic valve recipients along with long-term anticoagulation with warfarin for selected patients).^[4]

Transcatheter aortic valve replacement as a treatment

Transcatheter aortic valve replacement (TAVR) has emerged as an important therapy for aortic stenosis (with or without AR) and now is being evaluated for use in patients with predominantly AR. TAVR involves the implantation of a bioprosthetic aortic valve using a catheter that is inserted peripherally, typically through the femoral artery, and implanted without requiring a median sternotomy (ie, without “open heart surgery”). Initial reports are promising but further studies are needed before TAVR becomes clinically available.^[41]

TAVR as a cause

Management of AR that is the result of TAVR, typically following its use for aortic stenosis, depends on the severity and hemodynamic impact of the AR. Once a determination is made that the patient is likely to benefit from intervention, potential corrective measures (each of which carries unique risks include the following:^[6]

• Balloon postdilation - In cases of valve malapposition or underexpansion
• Snare technique - Use of a snare catheter to reposition a deeply implanted valve
• Interventional closure - Use of a vascular plug to seal a localized AR jet
• Valve-in-valve implantation - Deployment of a second prosthetic valve

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Diet and Activity

No specific dietary recommendations exist pertaining purely to AR. However, for patients with hypertension or hypervolemia (including peripheral edema or other heart failure symptoms), salt restriction may provide significant clinical benefit.

Current recommendations regarding activity in patients with AR are based mostly on expert opinion, because there is a paucity of clinical trial data, including no convincing evidence to suggest that even strenuous periodic exercise worsens LV function in patients with AR.

Patients who are asymptomatic and have a normal EF may safely participate in normal daily activities as well as mild exercise and some forms of competitive exercise. However, isometric exercise is discouraged. The short-term safety of more vigorous exercise (eg, competitive athletics) may be estimated through the use of stress testing at a comparable level of exertion, but the long-term effects of such exercise are not known.

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Long-Term Monitoring

Asymptomatic patients with severe chronic AR require ongoing clinical surveillance with periodic echocardiography. This is because significant LV dysfunction in many cases may arise even before the patient becomes symptomatic.

After the initial study, clinical evaluation and a repeat echocardiogram are recommended in 3 months. The recommended frequency of subsequent follow-up evaluations is based on the stability of the LVESD and LVEDD, as follows:

• For patients with an end-systolic dimension (ESD) below 45 mm or an end-diastolic dimension (EDD) below 60 mm and stable dimensions, clinical evaluation is recommended every 6-12 months and repeat echocardiography is recommended every 12 months
• For patients with an ESD below 45 mm or an EDD below 60 mm and increasing dimensions, clinical evaluation and repeat echocardiography are recommended in 3 months
• For patients with an ESD of 45-50 mm or an EDD of 60-70 mm and stable dimensions, clinical evaluation is recommended every 6 months and repeat echocardiography is recommended every 12 months
• For patients with an ESD of 45-50 mm or an EDD of 60-70 mm and increasing dimensions, clinical evaluation and repeat echocardiography are recommended in 3 months
• For patients with an ESD of 50-55 mm or an EDD of 70-75 mm and stable dimensions, clinical evaluation and repeat echocardiography are recommended every 6 months
• For patients with an ESD of 50-55 mm or an EDD of 70-75 mm and increasing dimensions, clinical evaluation and repeat echocardiography are recommended in 3 months
• For patients with an ESD of 55 mm or greater or an EDD of 75 mm or greater, surgery is recommended

Table 1: Frequency of Followup of Patients With Aortic Regurgitation.

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Guidelines Summary

In 2014, the AHA/ACC released a revision to its 2008 guidelines for management of patients with VHD;^[4] and ESC/EACTS issued a revision of its 2007 guidelines in 2012.^[42] The Society of Thoracic Surgeons (STS) published guidelines for the management of aortic valve disease in 2013.^[9]

The 2014 AHA/ACC guidelines classify progression of chronic aortic regurgitation (AR) into 4 stages (A to D) as follows:^[4]

• Stage A: At Risk of AR
• Stage B: Asymptomatic with progressive AR (mild to moderate) 
• Stage C: Asymptomatic with severe AR
• Stage D: Symptomatic with severe AR

Both AHA/ACC and ESC/EACTS guidelines require intervention decisions for severe valvular heart disease (VHD) should be based on an individual risk-benefit analysis. Improved prognosis should outweigh the risk of intervention and potential late consequences, particularly complications related to prosthetic valves.^{[4, 42]}

Recognizing the known limitations of the EuroSCORE (European System for  Cardiac Operative Risk Evaluation) and the STS (Society of Thoracic Surgeons) score , the AHA/ACC guidelines suggest using STS plus three additional indicators: frailty (using accepted indices), major organ system compromise not to be improved postoperatively, and procedure-specific impediment when assessing risk.^[4]

Vasodilator Therapy

The current ACC/AHA guidelines provide the following recommendations for vasodilator therapy^[4] :

• Vasodilator therapy is indicated for long-term treatment in patients who have severe chronic AR and symptoms of LV dysfunction but who are not candidates for surgery.
• Vasodilator therapy is reasonable for short-term therapy in patients with severe LV dysfunction and heart failure symptoms, in order to improve their hemodynamic profile before surgery
• Vasodilator therapy is acceptable for long-term therapy in asymptomatic patients with severe AR and LV dilation with normal EF

Under the guidelines, vasodilator therapy is not indicated for the following:

• Long-term therapy in asymptomatic patients with less than severe AR and normal EF
• Long-term therapy in asymptomatic patients with LV dysfunction who are candidates for surgery
• Long-term therapy in symptomatic patients with less than severe LV dysfunction who are candidates for surgery

The 2012 European Society of Cardiology (ESC)/European Association for Cardio-Thoracic Surgery (EACTS) guidelines recommend short-term use of vasodilators and inotropic agents to improve the condition of patients with severe heart failure before proceeding with valve surgery. In patients with severe chronic AR and heart failure, vasodilators are useful in the treatment of those who have hypertension, those in whom surgery is contraindicated, or patients whose LV dysfunction persists postoperatively.^[42]

Surgical Intervention

A comparison of surgical recommendations for aortic regurgitation is provided in the table below.

Table 2. Guidelines for Aortic Regurgitation Surgical Intervention

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In 2015, the ACC/AHA released a guideline clarification statement addressing indications for early surgical intervention for associated enlargement or aneurysm of the ascending aorta in patients with bicuspid aortic valve (BAV) with the following recommendations:^[43]

Intervention to repair or replace the aortic root (sinuses) or replace the ascending aorta is indicated in asymptomatic patients with BAV if the diameter of the aortic root or ascending aorta is ≥5.5 cm (Class I)

Iintervention to repair or replace the aortic root (sinuses) or replace the ascending aorta is reasonable in asymptomatic patients with BAV if the diameter of the aortic root or ascending aorta is ≥5.0 cm and an additional risk factor for dissection is present (eg, family history of aortic dissection or aortic growth rate ≥0.5 cm per year) or if the patient is at low surgical risk and the surgery is performed by an experienced aortic surgical team in a center with established expertise in these procedures. (Class IIa)

Replacement of the ascending aorta is reasonable in patients with BAV undergoing AVR because of severe aortic stenosis or aortic regurgitation when the diameter of the ascending aorta is >4.5 cm. (Class IIa)

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Medication Summary

Vasodilator therapy may be considered under the previously described conditions. Many classes of vasodilators have been studied, with long-term hydralazine or nifedipine therapy being associated with higher EF and less LV dilation in smaller trials. Results with enalapril and quinapril have been less consistent.^[4]

Historically, beta-blocker therapy has been discouraged in patients with severe AR because heart rate reduction could prolong diastole, thus worsening AR. However, beta-blockers have been shown to produce beneficial neuroendocrine alterations in patients with heart failure. An observational study suggested that beta-blocker therapy is associated with a significant survival benefit in patients with severe AR,^[44] spurring hope that further investigation will confirm this finding and allow its translation into a clinically meaningful recommendation.

• References

Captopril

• Dosing, Interactions, etc.

Clinical Context:  Captopril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion. It is rapidly absorbed, but bioavailability is significantly reduced with food intake. Captopril achieves a peak concentration in 1 hour and has a short half-life. The drug is cleared by the kidney; impaired renal function requires reduction of the dosage. Captopril is absorbed well orally.

Give captopril at least 1 hour before meals. If it is added to water, use it within 15 minutes. The dose can be low initially, then titrated upward as needed and as tolerated by the patient.

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Enalapril (Vasotec)

• Dosing, Interactions, etc.

Clinical Context:  Enalapril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. The drug helps to control blood pressure and proteinuria. Enalapril decreases the pulmonary-to-systemic flow ratio in the catheterization laboratory and increases systemic blood flow in patients with relatively low pulmonary vascular resistance.

Enalapril has a favorable clinical effect when administered over a long period. Because it helps to prevent potassium loss in the distal tubules, enalapril reduces the amount of oral potassium supplementation needed by the patient.

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Lisinopril (Prinivil, Zestril)

• Dosing, Interactions, etc.

Clinical Context:  Lisinopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

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Benazepril (Lotensin)

• Dosing, Interactions, etc.

Clinical Context:  Benazepril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

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Fosinopril

• Dosing, Interactions, etc.

Clinical Context:  Fosinopril is a competitive ACE inhibitor. It prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. It decreases intraglomerular pressure and glomerular protein filtration by decreasing efferent arteriolar constriction.

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Quinapril (Accupril)

• Dosing, Interactions, etc.

Clinical Context:  Quinapril is a competitive ACE inhibitor. It reduces angiotensin II levels, decreasing aldosterone secretion.

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Ramipril (Altace)

• Dosing, Interactions, etc.

Clinical Context:  Ramipril partially inhibits both tissue and circulating ACE activity, thereby reducing the formation of angiotensin II in the tissue and plasma. Ramipril has an antihypertensive effect, even in patients with low-renin hypertension.

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Class Summary

These agents are competitive inhibitors of angiotensin-converting enzyme (ACE). They reduce angiotensin II levels, decreasing aldosterone secretion.

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Losartan (Cozaar)

• Dosing, Interactions, etc.

Clinical Context:  Losartan inhibits the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking the binding of angiotensin II to receptors.

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Valsartan (Diovan)

• Dosing, Interactions, etc.

Clinical Context:  Valsartan inhibits the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking the binding of angiotensin II to receptors.

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Azilsartan (Edarbi)

• Dosing, Interactions, etc.

Clinical Context:  Azilsartan inhibits the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking the binding of angiotensin II to receptors.

• References

Candesartan (Atacand)

• Dosing, Interactions, etc.

Clinical Context:  Candesartan inhibits the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking the binding of angiotensin II to receptors.

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Eprosartan (Teveten)

• Dosing, Interactions, etc.

Clinical Context:  Eprosartan inhibits the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking the binding of angiotensin II to receptors.

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Irbesartan (Avapro)

• Dosing, Interactions, etc.

Clinical Context:  Irbesartan inhibits the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking the binding of angiotensin II to receptors.

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Olmesartan (Benicar)

• Dosing, Interactions, etc.

Clinical Context:  Olmesartan inhibits the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking the binding of angiotensin II to receptors.

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Telmisartan (Micardis)

• Dosing, Interactions, etc.

Clinical Context:  Telmisartan inhibits the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking the binding of angiotensin II to receptors.

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Class Summary

ARBs inhibit angiotensin II binding to type 1 angiotensin II receptors. These agents are also available in numerous combinations with diuretics.

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Nifedipine (Procardia, Adalat, Nifedical)

• Dosing, Interactions, etc.

Clinical Context:  Produces significant fall in arterial pressure, reduces LV volume and mass, increases EF, and delays need for AVR in asymptomatic patients with severe AR and normal LV systolic function. Effective vasodilator therapy requires adjustment of dosage to decrease arterial pressure.

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Diltiazem (Cardizem, Dilacor, Cartia XT, Tiazac)

• Dosing, Interactions, etc.

Clinical Context:  During depolarization, diltiazem inhibits calcium ions from entering slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium. It produces vasodilation but causes less reflex tachycardia than nifedipine does. Diltiazem may be useful if patients develop excessive hypotension with nifedipine.

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Amlodipine (Norvasc)

• Dosing, Interactions, etc.

Clinical Context:  Amlodipine has a longer duration of action than nifedipine or diltiazem and requires less frequent dosing. Experience with this agent in pulmonary hypertension is not as extensive as that with other agents. Amlodipine has fewer effects on conduction and infrequently causes atrioventricular (AV) block.

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Class Summary

Calcium channel blockers inhibit the movement of calcium ions across the cell membrane, depressing impulse formation (automaticity) and conduction velocity.

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Digoxin (Lanoxin)

• Dosing, Interactions, etc.

Clinical Context:  The effects of digoxin include an increase in the force and velocity of myocardial systolic contraction (positive inotropic action), a slowing of the heart rate, and a decrease in conduction velocity through the atrioventricular (AV) node (vagomimetic effect). The use of this drug in patients with heart failure has been associated with 25% reduction in the frequency of hospitalization for heart failure. However, digoxin use is not associated with a mortality benefit.

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Class Summary

The effects of digoxin include an increase in the force and velocity of myocardial systolic contraction (positive inotropic action), a slowing of the heart rate, and a decrease in conduction velocity through the atrioventricular (AV) node (vagomimetic effect). The use of this drug in patients with heart failure has been associated with 25% reduction in the frequency of hospitalization for heart failure. However, digoxin use is not associated with a mortality benefit.

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Furosemide (Lasix)

• Dosing, Interactions, etc.

Clinical Context:  Like torsemide and bumetanide, furosemide is a potent loop diuretic. Compared with all other classes of diuretics, loop diuretics have the highest efficacy in mobilizing sodium and chloride from the body, inhibiting the Na+, K+, and Cl- cotransport in the ascending limb of the loop of Henle.

Furosemide and other loop diuretics are indicated in the treatment of edema associated with CHF, cirrhosis of the liver, and renal disease, including nephrotic syndrome. They may be used alone or with other antihypertensive agents to treat hypertension.

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Bumetanide

• Dosing, Interactions, etc.

Clinical Context:  Bumetanide increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle. This agent does not appear to act in the distal renal tubule.

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Class Summary

Diuretics increase urine flow. These agents are ion-transport inhibitors that decrease the reabsorption of sodium at different sites in the nephron. Diuretics have major clinical uses in managing disorders involving abnormal fluid retention (edema) or in treating hypertension, in which their diuretic action causes decreased blood volume.

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Dobutamine (Dobutrex)

• Dosing, Interactions, etc.

Clinical Context:  Dobutamine is a synthetic direct-acting catecholamine and beta-receptor agonist. It increases cardiac contractility and output in CHF. At therapeutic doses, it is mainly an inotropic agent, while producing comparatively mild chronotropic and vasodilative effects. As compared with other sympathomimetic drugs, dobutamine does not significantly increase myocardial oxygen demands, which is its major advantage compared with other direct-acting catecholamines.

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Class Summary

These agents act directly on alpha- and beta-receptors, producing effects similar to those that occur following stimulation of sympathetic nerves or the release of the hormone epinephrine from the adrenal medulla.

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