Aortic Regurgitation

Pathophysiology | Etiology | Symptoms | Physical Examination | Peripheral Signs | Diagnosis | Treatment

Introduction

Aortic regurgitation (AR) occurs when blood flows retrograde (backwards) across the aortic valve from the aorta into the left ventricle during diastole.

This abnormal backflow of blood leads to pathologic changes in the heart - remodeling - in order to maintain effective forward cardiac output.

Aortic regurgitation may occur due to damage to the aortic valve leaflets or as a result of dilation of the aortic annulus. As the disease progresses, symptoms of heart failure eventually occur. The definitive treatment is surgical aortic valve replacement; however, medical therapy can improve symptoms.

Pathophysiology – Aortic Regurgitation

The left ventricular volume loading that occurs with AR leads to pathologic changes that are highly dependent on two factors: aortic regurgitation severity and the pace of disease development.

Left ventricular chamber enlargement and hypertrophy (increased wall thickness) take place in order to maintain a normal forward cardiac output in chronic aortic regurgitation. [HTH 14e - Chapter 47: p20A] The LV dilates and hypertrophies (eccentrically) slowly over time. These changes help to maintain normal LV pressures in the setting of a significantly increased LV volume. In fact, patients with severe chronic AR may have the largest LV end-diastolic volumes produced by any cardiac disease state, without significant elevation of LV end-diastolic pressures.

However, with acute aortic regurgitation, these compensatory changes cannot take place. The intra-cardiac pressures increase quickly and heart failure — often cardiogenic shock —  may occur. The limited increase in left ventricular end diastolic volume (LVEDV) due to acute AR leads to a greatly increased left ventricular end diastolic pressure (LVEDP) and increased pulmonary artery pressure, leading to severe symptoms of left heart failure, including “flash” pulmonary edema. While acute AR is a comparatively rare condition, the prognosis is much worse than for chronic AR. [HTH 14e - Chapter 47: p24A] Acute AR can be difficult to clinically differentiate from other acute conditions, including sepsis, pneumonia, and nonvalvular hear disease. [Hamirani 2012: p1B]

As chronic aortic regurgitation worsens, regurgitant volume increases, as does stroke volume in order to maintain forward cardiac output. This results in  increased systolic pressures, reduced diastolic pressures, and widened pulse pressure. Increased stroke volume leads to a number of unusual peripheral physical examination findings, discussed below in Peripheral Signs.

The low diastolic aortic pressures can significantly affect coronary perfusion pressures, as coronary flow occurs during diastole.

Afterload (peripheral resistance) is an important factor in the degree of aortic regurgitation. All other factors being equal, increased peripheral resistance will be associated with increased regurgitation.. Thus, afterload reduction has become the mainstay of pharmacotherapy in aortic regurgitation.

Etiology – Aortic Regurgitation

Aortic regurgitation can result from abnormalities of the aortic valve leaflets or dilation of the aortic root. When the aortic leaflets are involved, a destructive process such as infective endocarditis or rheumatic valvular disease  is frequently implicated. Any disease process that leads to aortic root dilation (e.g. Marfan syndrome or aortic dissection) may cause enlargement of the aortic valve annulus; this results in failure of the leaflets to coapt (close) properly in diastole (loss of coaptation) and aortic regurgitation. Frequently, repairs to the aortic root and valve are required in these conditions.

Below is a list of etiologies for aortic regurgitation:

Aortic leaflet/cusp abnormalities

Aortic root abnormalities

Other congenital abnormalities

The most common causes of acute aortic dissection include bacterial endocarditis, aortic dissection, and blunt trauma-induced aortic valve damage. [Hamirani 2012: p1C; HTH 14e - Chapter 47: p24B]

Symptoms – Aortic Regurgitation

As chronic aortic regurgitation develops slowly over time, the left ventricle slowly undergoes compensatory remodeling, as described previously. The disease remains asymptomatic for a long period of time. The later symptoms of chronic AR are mostly due to congestive heart failure (HF).

Left heart failure results in passive elevation of pulmonary pressures with dyspnea. Physical activity may even cause transient pulmonary edema.

As increased pulmonary pressure affects the right ventricle, right heart failure can ensue.

Right heart failure symptoms include lower extremity-dependent edema and hepatic congestion. At night, when patients are recumbent, the excess extracellular fluid redistributes centrally, causing orthopnea (the need to sit up to breathe) or paroxysmal nocturnal dyspnea.

Hepatic congestion may be associated with right upper quadrant abdominal pain.

The large stroke volumes and forceful LV contractions may cause head bobbing and awareness of the peripheral pulse. Angina may occur in the absence of atherosclerotic coronary disease, as the low diastolic pressures in severe aortic regurgitation compromise coronary filling, and the left ventricular hypertrophy increases oxygen demand. Other symptoms related to low cardiac output include fatigue, weakness and, in extreme cases, cardiac cachexia.

Unlike in chronic aortic regurgitation, almost all patients with significant acute aortic regurgitation are symptomatic. Signs of acute left heart failure — including severe dyspnea, dyspnea at rest, orthopnea and paroxysmal nocturnal dyspnea (PND) — arise. Patients typically present with symptoms of low cardiac output and systemic vasoconstriction, including pallor and coolness in the distal extremities, peripheral cyanosis, and tachycardia (with a reduced peripheral pulse). [HTH 14e - Chapter 47: p25B] Hypotension, flash pulmonary edema and shock can also occur.

Physical Examination – Aortic Regurgitation

In chronic aortic regurgitation, visible cardiac and arterial pulsations are common due to the large stroke volume. The carotid pulse can commonly be seen. The point of maximal impulse (PMI)  is displaced laterally and caudally due to the LV dilation and hypertrophy that occurs. On auscultation, the typical murmur of aortic regurgitation is a soft, high-pitched, early diastolic decrescendo murmur heard best at the third intercostal space on the left, known as Erb’s Point, on end expiration with the patient sitting up and leaning forward.

This murmur may be difficult to distinguish from the Graham-Steele murmur of pulmonic insufficiency. If aortic root disease is the cause of the aortic regurgitation, the murmur will be heard best at the right upper sternal border — not at Erb’s point. As aortic regurgitation worsens, the murmur becomes shorter, as less time is needed for left ventricular and aortic pressure equalization.

In addition, a systolic ejection murmur may be present at the right upper sternal border, simply due to the large stroke volume passing through the aortic valve with each LV systolic contraction. An early diastolic rumble (the Austin-Flint murmur) may also be heard at the apex, due to the regurgitant jet striking the anterior leaflet of the mitral valve and causing it to vibrate.

A widened pulse pressure is often present due to increased stroke volume, as previously described. When heart failure develops, the pulse pressure decreases and the peripheral signs of aortic regurgitation, listed below, are lessened. A fourth heart sound (S4) may develop when LV hypertrophy becomes severe and limits diastolic filling. A third heart sound (S3) is often present, due to increased early diastolic filling into a compliant, dilated left ventricle.

Acute aortic regurgitation will cause a very short, early diastolic decrescendo murmur with the aortic and left ventricular pressures equalized quickly, as the left ventricle has not had time to dilate or hypertrophy. Because increased left ventricular filling pressure and systemic vasoconstriction limit peripheral runoff, a wide pulse pressure is not typically seen in acute aortic regurgitation. [HTH 14e - Chapter 47: p25B]

Peripheral Signs – Aortic Regurgitation

The peripheral signs of aortic regurgitation are mostly due to the increased stroke volume and wide pulse pressure seen in aortic regurgitation.

In 19th century Europe, syphilis was widespread. Syphilitic aortitis, resulting in aortic root dilation and severe aortic valve regurgitation, was quite common. With no therapy — medical or surgical — available, the disease was allowed to progress; many individuals developed congestive heart failure from aortic regurgitation. Manu physicians described various physical findings of aortic regurgitation. These were often named after the physician who described them; they are listed below. In the era of quantitative echocardiography, they remain are intellectually and historically interesting.

Many peripheral signs of aortic regurgitation have been identified and named after the physician that first described it; they are listed below. The sensitivity of these findings are low. While intellectually and historically interesting, they are not always clinically useful.

  • Corrigan’s pulse: A rapid and forceful distension of the arterial pulse with a quick collapse
  • De Musset’s sign: Bobbing of the head with each heartbeat (like a bird walking)
  • Müller’s sign: Visible pulsations of the uvula
  • Quincke’s sign: Capillary pulsations seen on light compression of the nail bed
  • Traube’s sign: Systolic and diastolic sounds heard over the femoral artery (“pistol shots”)
  • Duroziez’s sign: Gradual pressure over the femoral artery leads to a systolic and diastolic bruit
  • Hill’s sign: Popliteal systolic blood pressure exceeding brachial systolic blood pressure by 60 mm Hg or more (most sensitive sign for aortic regurgitation)
  • Shelly’s sign: Pulsation of the cervix
  • Rosenbach’s sign: Hepatic pulsations
  • Becker’s sign: Visible pulsation of the retinal arterioles
  • Gerhardt’s sign (aka Sailer’s sign): Pulsation of the spleen in the presence of splenomegaly
  • Mayne’s sign: A decrease in diastolic blood pressure of 15 mm Hg when the arm is held above the head (very nonspecific)
  • Landolfi’s sign: Systolic contraction and diastolic dilation of the pupil

In acute aortic regurgitation, peripheral signs are often absent and the murmur of aortic regurgitation is short. It be difficult to hear with aortic pressure and LV pressure (elevated in acute AR) equalizing quickly in diastole. Due to premature closure of the mitral valve, the intensity of the first heart sound may be reduced.

Diagnosis – Aortic Regurgitation

Transthoracic echocardiography (TTE) is the preferred diagnostic modality for aortic regurgitation. Almost 100% sensitive and specific for the detection of aortic regurgitation, TTE is also crucial in determining etiology and estimating severity.

Color flow Doppler echo permits direct visualization of the regurgitant jet. This is extremely important in patients with acute AR when stroke volume is compromised.

In addition to the regurgitant jet, echo examination demonstrates structural abnormalities, such as a bicuspid aortic valve or cusp prolapse. Vegetations on the aortic valve, consistent with endocarditis, may also be identified, although transesophageal echocardiography (TEE) is more sensitive. Finally, the size of the aortic root can be measured and aortic dissections identified.

Two classification systems for chronic aortic regurgitation are currently in widespread use: the ASE grading system and the ACC/AHA staging system. The ASE grading system classifies AR into three categories: mild, moderate, and severe; or four grades: grade I (mild AR), grade II (moderate AR), grade III (moderate-to-severe AR), and grade IV (severe AR). This system is based on echocardiographic findings alone, and considers: [Zoghbi 2017: p38A (Table 11), p42A]

  1. structural parameters (aortic leaflet anatomy, LV size)
  2. qualitative doppler parameters (jet width in LV outflow tract [LVOT], flow convergence, jet density, pressure half-time, and diastolic flow reversal in the descending aorta)
  3. semiquantitative parameters (vena contracta width, the ratio of jet width to LVOT, and the ratio of jet cross-sectional area [CSA] to LVOT CSA)
  4. quantitative parameters (regurgitant volume, regurgitant fraction, and effective regurgitant orifice area [EROA])

The most informative (semi)quantitative echocardiographic parameters are discussed below.

The pressure half-time index is the time it takes for the initial maximal pressure gradient in diastole to fall by 50%. In patients with mild aortic regurgitation, this fall in pressure is gradual. In severe aortic regurgitation, a rapid drop in pressure gradient occurs. A pressure half-time of greater than 500 milliseconds is consistent with mild aortic regurgitation, from 500 to 200 ms with moderate, and of less than 200 ms with severe AR. Significantly increased left ventricular end diastolic pressure (LVEDP) may lead to overestimation of the severity of aortic regurgitation by independently shortening the pressure half-time.

The vena contracta is the narrowest portion of the regurgitant flow that occurs at or immediately after (downstream of) the regurgitant orifice (in the case of AR, the aortic valve). [Zoghbi 2017: p7A] A vena contracta width (VCW) of less than 0.3 cm characterizes mild AR, while a VCW between 0.3 and 0.6 cm indicates moderate AR, and that above 0.6 cm severe AR. [Zoghbi 2017: p38A (Table 11)]

Regurgitant jet size represents the ratio of the aortic regurgitation jet width (diameter) just below the leaflets of the aortic valve to the width (diameter) of the LV outflow. Ideally, the ratio should be zero because no regurgitant jet should be present. A ratio of below 25% is mild (grade I), between 25% and 45% moderate (grade II), between 46% and 64% moderate-to-severe (grade III), and 65% and above severe (grade IV). [Zoghbi 2017: p38A (Table 11)]

Regurgitant volume (RVol) per beat, which can be calculated as the difference between the stroke volume though the affected valve and stroke volume through a competent valve (among other methods), is a measure of volume overload severity. [Zoghbi 2017: p9A] In mild (grade I) AR, RVol is less than 30 mL/beat, while it is 30-44 mL/beat in moderate (grade II) AR, 45-59 mL/beat in moderate-to-severe (grade III) AR, and 60 mL//beat and higher in severe (grade IV) AR. [Zoghbi 2017: p38A (Table 11)]

Regurgitant fraction (RF) is the percentage of the stroke volume (total left ventricular output) that returns to the left ventricle from the aorta during diastole. For example, a regurgitant fraction of 33% means that one-third of the total stroke volume returns to the LV retrograde across the AV during diastole. According to ASE Guidelines, a regurgitant fraction of less than 30% indicates mild aortic regurgitation (grade I), 30% to 39% indicates mild-to-moderate aortic regurgitation (grade II), 39% to 49% indicates moderate-to-severe AR (grade III), and 50% or greater indicates severe aortic regurgitation (grade IV). [Zoghbi 2017: p38A (Table 11)]

Effective regurgitant orifice area (EROA) is considered a fundamental measure of lesion severity. [Zoghbi 2017: p9A] An EROA of less than 0.10 cm2 indicates mild (grade I) AR. Moderate (grade II) AR is characterized by an EROA of 0.10-0.19 cm2, and moderate-to-severe (grade III) disease by an EROA of 0.20-0.29 cm2. An EROA of 0.30 cm2 or higher indicates severe (grade IV) disease. [Zoghbi 2017: p38A (Table 11)]

It is important to note that the severity of aortic regurgitation assessed using echocardiography is dependent on the hemodynamic status of the patient at the time of the evaluation — most importantly, the afterload.

Chronic aortic regurgitation is also classified according to the staging system developed by the ACC and the AHA. The 2020 ACC/AHA Guidelines divide chronic AR into four distinct categories (Stages A, B, C, and D) on the basis of valve anatomy, valve hemodynamics, LV dilation and dysfunction, and the presence or absence of symptoms. [Otto 2020: p33A (e104)]

Stage A disease (at risk of AR) comprises conditions characterized by abnormal or damaged aortic valves in the absence of abnormal valve hemodynamics and symptoms. These conditions include congenital valve anomalies, aortic valve sclerosis, diseases of the aortic sinuses or the ascending aorta, rheumatic fever or rheumatic heart disease, and infective endocarditis. [Otto 2020: p34A (e105, Table 15)]

Stage B disease (progressive AR) is anatomically characterized by mild to moderate calcification of a normal (trileaflet) aortic valve (AV), a bileaflet valve or other congenital AV anomaly, dilated aortic sinuses, rheumatic valve changes, or previous infective endocarditis. Stage B can be further subdivided into mild AR and moderate AR, based either on the hemodynamic values (jet width/LVOT, VCW, RVol, EF, and EROA) that characterize mild and moderate AR according to the ASE grading system (grade I = mild; grades II and III = moderate; see above) or based on angiographic grading (grade I = mild; grade II = moderate; see below). Despite hemodynamic abnormalities, patients with Stage B aortic regurgitation have normal LV systolic function, with normal LV volumes and only mild LV dilation. Like in Stage A and Stage C disease, no symptoms are present. [Otto 2020: p34A (e105, Table 15)]

Stage C (asymptomatic severe) aortic regurgitation is defined by hemodynamically severe AR (i.e. jet width/LVOT, VCW, RVol, EF, and EROA values consistent with ASE grade IV AR; or angiographic grade III or IV AR) in the absence of symptoms. Anatomically, it may be characterized by calcific aortic valve disease, a congenital AV anomaly, dilated aortic sinuses or ascending aorta, rheumatic valve changes, and infective endocarditis with abnormal leaflet closure or perforation. On the basis of LV dysfunction, Stage C aortic regurgitation can be further subdivided into Stage C1 (normal LV ejection fraction [LVEF] and mild to moderate LV dilation [LV end-systolic dimension below 50 mm]) and Stage C2 (LVEF 55% or lower, or severe LV dilation [LV end-systolic dimension above 50 mm or indexed LV end-systolic dimension above 25 mm/m2). Like in Stage A and B disease, symptoms are absent in Stage C aortic regurgitation, although exercise testing may be performed to confirm their absence. [Otto 2020: p34A (e105, Table 15)]

Stage D (symptomatic severe) aortic regurgitation is distinguished from Stage C disease by the presence of symptoms: exertional dyspnea, angina, or more severe symptoms of heart failure. Otherwise, it is characterized by the same anatomic features and hemodynamic severity (ASE grade IV, or angiographic grade III or IV) as Stage C aortic regurgitation. In Stage D aortic regurgitation, systolic function may be normal (LVEF >55%), or there may be mild-to-moderate (LVEF 40% to 55%) or severe LV dysfunction (LVEF <40%). [Otto 2020: p34A (e105, Table 15)]

Cardiac catheterization with aortography and hemodynamic measurements is no longer necessary in the majority of patients with aortic regurgitation because of the accuracy of TTE. Coronary angiography is indicated if surgical aortic valve replacement is planned, or if the patient has symptoms or risk factors that suggest coronary disease may be present.

With contrast aortography, aortic regurgitation can be  directly demonstrated by  contrast injection into the aortic root with diastolic reflux  of contrast into the left ventricle. Angiography can also    aortic root disease. Several factors may affect the grading of severity of aortic regurgitation during the procedure. If the catheter is positioned too close to the aortic valve, the amount of aortic regurgitation will be overestimated. The volume and rate of injection of contrast into the aortic root may affect the grading of aortic regurgitation. And, as previously mentioned, the hemodynamic parameters at the time of assessment also affect the severity of aortic regurgitation — again, mostly afterload.

The angiographic grading scale for aortic regurgitation is shown below.

  Amount LV contrast Intensity Contrast clearance
I (mild) Some contrast seen Aorta > LV Completely cleared each beat
II (moderate) Completely filled LV after many beats Aorta > LV Incomplete clearance each beat
III (mod-sev) Completely filled after several beats Aorta = LV Slow clearance
IV (severe) Completely filled after only one beat Aorta < LV Very slow clearance
 

In addition to cardiac catheterization, other diagnostic modalities such as TEE and cardiac magnetic resonance (CMR) imaging may be a useful supplement to TTE in the diagnostic process. The 2020 ACC/AHA Guidelines recommend the use of CMR, cardiac catheterization, or TEE for the assessment of left ventricular systolic function, systolic and diastolic volumes, aortic size, and AR severity in patients with moderate or severe AR and suboptimal transthoracic echocardiography (TTE) images or a discrepancy between clinical and TTE findings. [Otto 2020: p35A (e106, 4.3.1)]

In addition to its auxiliary utility in the diagnosis of aortic regurgitation, CMR can also be used to assess paravalvular leakage following transcatheter aortic valve replacement (TAVR; see the “Treatment” section below), although echocardiography is still the preferred imaging modality. The advantages of CMR include the ability to measure regurgitant volume irrespective of regurgitant jet number or morphology, the ability to measure regurgitant volume for multiple valve lesions, and the high reproducibility of measurements. [Zoghbi 2019: p5A, p17A] Current limitations of CMR include high operating costs, access to scanners, and lack of expertise applying the technique to valve disease. [Zoghbi 2019: p17B]

The ECG in patients with aortic regurgitation is non-specific and may show left ventricular hypertrophy and left atrial enlargement. In acute aortic regurgitation, sinus tachycardia due to the increased sympathetic tone may be the only abnormality on ECG. The chest radiograph is also nonspecific in aortic regurgitation. Cardiomegaly is present in patients with chronic AR. In acute AR, pulmonary edema is almost universally present. If the AR is associated with aortic dissection, the mediastinum may appear widened.

Treatment – Aortic Regurgitation

In patients with Stage A and Stage B aortic regurgitation, no specific treatment is required. These patients should be monitored yearly to assess disease progression. Antibiotic prophylaxis is recommended to prevent bacterial endocarditis.

Surgical aortic valve replacement (AVR), not repair, is the definitive treatment for aortic regurgitation. The 2020 ACC/AHA Guidelines provide the following recommendations for AVR in patients with AR:

  1. AVR is indicated (class 1 recommendation) for all patients with Stage D aortic regurgitation, all patients with Stage C2 aortic regurgitation (LVEF 55% of less), and for patients with Stage C aortic regurgitation who are undergoing surgery for another cardiac condition. [Otto 2020: p36A (e107, 4.3.3), p37A (e108, Figure 4)]
  2. AVR is reasonable (class 2a recommendation) for patients with Stage C1 aortic regurgitation (LVEF above 55% and LV end-systolic dimension above 50 mm) and for patients with Stage B aortic regurgitation that is hemodynamically moderate who are undergoing surgery for another cardiac condition. [Otto 2020: p36A (e107, 4.3.3), p37A (e108, Figure 4)]
  3. AVR may be considered (class 2b recommendation) for patients with Stage C aortic regurgitation who, on at least 3 studies showed either a progressive decrease in LVEF to the low normal range (55-60%) or a progressive increase of LV dilation to severe range (LV end-diastolic dimension greater than 65 mm). [Otto 2020: p36A (e107, 4.3.3), p37A (e108, Figure 4)]

Because of the dilation of the aortic annulus and root, a transcatheter approach to AVR (TAVR) is not typically feasible in isolated chronic aortic regurgitation, and surgical AVR (SAVR) is greatly preferred. The risks of TAVR include transcatheter valve migration and paravalvular leaks. [Otto 2020: p37B (e108, Figure 4)] The ACC/AHA Guidelines specify that TAVR should not be attempted (class 3 recommendation: harm) in patients with isolated severe AR who are candidates for SAVR and do not have a prohibitive surgical risk. [Otto 2020: p36A (e107, 4.3.3)]

The ideal time for AVR is late enough in the course of the disease to justify the risk-benefit ratio of surgery, yet early enough to prevent potential irreversible myocardial damage from occurring. The LV ejection fraction has been shown to correlate best with surgical outcome.

There is no evidence that medical therapy can reduce aortic regurgitation severity or delay disease progression. In patients with severe chronic aortic regurgitation, systolic blood pressure is typically higher than in patients without aortic regurgitation. The ACC/AHA Guidelines recommend that patients with asymptomatic (Stage B and Stage C) chronic aortic regurgitation receive vasodilators to treat hypertension. In patients with severe AR who are symptomatic and/or show left ventricular systolic dysfunction (Stages C2 and D) but are not candidates for surgery, the ACC/AHA Guidelines recommend treatment for LV dysfunction with ACE inhibitors, ARBs, and/or sacubitril/valsartan. [Otto 2020: p35B-C (e106, 4.3.2)]

References:

  1. ACC/AHA Guidelines: Valvular Heart Disease
  2. Bekeredjian R and Grayburn PA. Aortic Regurgitation. Circulation. 2005;doi:10.1161/CIRCULATIONAHA.104.488825.
  3. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine
  4. Hurst’s the Heart, 14th Edition
  5. Hamirani YS, Dietl CA, Voyles W, et al. Circulation. 2012 Aug 28;126(9):1121-6. doi: 10.1161/CIRCULATIONAHA.112.113993.
  6. Zoghbi WA, Adams D, Bonow RO, et al. J Am Soc Echocardiogr. 2017 Apr;30(4):303-371. doi: 10.1016/j.echo.2017.01.007.
  7. Zoghbi WA, Asch FM, Bruce C, et al. J Am Soc Echocardiogr. 2019 Apr;32(4):431-475. doi: 10.1016/j.echo.2019.01.003.
  8. Pettersson GB and Hussain ST. Ann Cardiothorac Surg. 2019 Nov;8(6):630-644. doi: 10.21037/acs.2019.10.05.