Aortic Regurgitation
Roger Byrne
Dermot Phelan
I. INTRODUCTION. Aortic regurgitation (AR), despite being one of the more common forms of valvular heart disease, remains clinically challenging with regard to accurate assessment of severity and management. When closed, the normal three leaflets of the aortic valve (AV) overlap their neighbors by 2 to 3 mm, forming a tight seal against backflow of blood despite substantial diastolic pressure in the aorta. However, disruption of either the valve leaflets or the surrounding aortic root may cause leaflet malcoaptation, leading to AR.
The etiology and clinical presentation of acute AR differ significantly from those of chronic AR. Acute AR is challenging to diagnose by both physical examination and echocardiography and so requires a high index of suspicion and understanding of the specific clinical and imaging characteristics.
Chronic severe AR leads to both volume and pressure overload of the left ventricle (LV), leading to compensatory ventricular dilation and eccentric hypertrophy before finally resulting in systolic dysfunction that may not be reversible.
Surgical AV replacement (AVR) remains the only effective treatment option for the majority of patients with severe AR. Medical therapy has limited effect, and AV repair is suitable only for a small number of patients. Timing of surgery in chronic AR requires weighing the risks/benefits of surgery versus watchful waiting, while trying to avoid irreversible systolic dysfunction.
Advanced echocardiographic imaging utilizing three-dimensional (3D) imaging and two-dimensional (2D) strain imaging may improve diagnostic accuracy and identify patients who may benefit from early intervention. Multimodality imaging, including cardiac magnetic resonance (CMR) imaging and cardiac computed tomography (CCT), is increasingly being utilized in the assessment of AR.
II. ETIOLOGY
The etiologies of AR may be divided into two main categories: primary (valvular leaflet abnormalities) and secondary (aortic root abnormalities) (Fig. 2.1). Common primary causes include congenital abnormalities of the valve leaflets, such as a bicuspid aortic valve (BAV), and acquired valvular lesions, such as degenerative/calcific changes, endocarditis, or rheumatic disease. Common secondary causes leading to dilation of the aortic root include degenerative changes usually related to age, atherosclerosis, or long-standing hypertension, and genetic aortopathies such as Marfan syndrome or Loeys-Dietz syndrome. Additionally, there are mixed primary and secondary etiologies that result in AR by multiple mechanisms; these include aortic dissection and blunt chest trauma.
Clinically, the causes of AR may also be divided into pathologies that result in either chronic or acute AR (Table 2.1).
 FIGURE 2.1 Comparison of the anatomy of normal and abnormal aortic valves that lead to severe aortic regurgitation. A: Normal aortic valve. A cephalad view of a normal aortic valve from a young adult is shown. The size of the cusps and the distance between each of the commissures are roughly equal. B: Regurgitation secondary to dilated aortic root and bicuspid aortic valve. The excised valve shows a bicuspid aortic valve with the larger conjoint cusp shown on the right side. There is mild thickening of the free edge without calcification. C: Regurgitation secondary to healed endocarditis. A semilunar valve cusp shows a large central perforation as a sequela of infective endocarditis. D: Trileaflet aortic valve with regurgitation. A trileaflet aortic valve shows marked thickening and retraction of cusps. The cusp retraction by fibrous tissue results in failure of coaptation at the center of the valve. The fusion in two of the three commissures also results in valve stenosis. Abundant Lambl excrescences are present at the free edge of the cusp on the right. (Courtesy of Drs. E. Rene Rodriguez and Carmela D. Tan at www.e-heart.org.) |
III. PATHOPHYSIOLOGY
A. Chronic aortic regurgitation
The primary hemodynamic effect of AR is an increase in LV end-diastolic volume (preload) due to leaking of blood from the aorta back into the LV during diastole. Increased LV end-diastolic volume (LVEDV) results in increased wall tension. In AR, the sum of the regurgitant volume and the normal forward stroke volume (SV) is ejected forward into the high-pressure aorta during systole. The increase in the ejected forward SV causes systolic hypertension (increased afterload), and together with the decrease in diastolic pressure (owing to the drop in the aortic diastolic pressure) results in the classic finding of a wide pulse pressure. Conversely, in mitral regurgitation (MR),
the regurgitant SV flows retrogradely into the low-pressure left atrial (LA) chamber; therefore, MR is characterized by volume overload only, whereas AR is characterized by both volume and pressure overload. The Law of Laplace states that wall tension is proportionate to pressure times radius and inversely proportionate to wall thickness, and so, to maintain normal wall tension, compensatory eccentric hypertrophy occurs. The ratio of ventricular wall thickness to cavity radius is maintained in order to keep wall stress near normal despite the larger LVEDV.
the regurgitant SV flows retrogradely into the low-pressure left atrial (LA) chamber; therefore, MR is characterized by volume overload only, whereas AR is characterized by both volume and pressure overload. The Law of Laplace states that wall tension is proportionate to pressure times radius and inversely proportionate to wall thickness, and so, to maintain normal wall tension, compensatory eccentric hypertrophy occurs. The ratio of ventricular wall thickness to cavity radius is maintained in order to keep wall stress near normal despite the larger LVEDV.
TABLE 2.1 Etiologies of Aortic Regurgitation | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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In the majority of patients with AR, the disease course is chronic, characterized by slowly progressive LV adaptation via chamber dilation and eccentric hypertrophy. Eventually, the myocytes reach maximum sarcomeric elongation so that further volume increases result in reduced contractility (Frank-Starling mechanism). A concurrent, progressive reduction in LV compliance, as a result of interstitial fibrosis, leads to a chronic decompensated state.
Oxygen supply/demand mismatch resulting in the symptom of angina may occur because of (1) decreased aortic diastolic pressure and elevated left ventricular end-diastolic pressure (LVEDP), resulting in decreased coronary perfusion pressure, (2) shorter diastolic time as a result of reflex tachycardia, and (3) reduced coronary blood flow reserve in the hypertrophied myocardium.
LV distention may induce mitral annular dilation with resultant functional MR, further increasing the LA pressure and pulmonary capillary wedge pressure (PCWP), which may eventually increase pulmonary artery pressures and ultimately compromise right ventricular function.
The end result of chronic volume overload is eccentric hypertrophy, chamber enlargement (increase in end-systolic and diastolic volumes), increased LVEDP, and a progressive decrease in left ventricular ejection fraction (LVEF) and cardiac output (CO).
B. Acute aortic regurgitation
The sudden volume overload into a noncompliant, nondilated LV seen in acute AR causes an acute rise in LVEDP, subsequently increasing the LA and PCWP, causing pulmonary edema.
The acute afterload increase, resulting from the combination of elevated blood pressure and increased wall stress, leads to an acute decrease in SV and LVEF, causing hypotension and cardiogenic shock. A compensatory reflex tachycardia helps maintain CO.
Diastolic pressure between the LV and aorta equilibrates rapidly because of the acute rise in LVEDP and drop in aortic diastolic pressure. The drop in the diastolic gradient between the aorta and LVEDP (i.e., the myocardial perfusion pressure) may cause subendocardial hypoperfusion and myocardial ischemia. This rapid equilibration also results in (1) a short early diastolic murmur of AR that rapidly becomes quiet on auscultation, and (2) early diastolic preclosure of the mitral valve, and later diastolic MR (owing to severely elevated LVEDP). Acute AR may therefore be difficult to appreciate both by auscultation and by color and spectral Doppler echocardiography. Because the LV does not have time to dilate (which would increase the SV), classic physical findings of chronic AR such as a wide pulse pressure and a displaced point of maximum impulse are not present. In addition, rapid LV distention may dilate the mitral annulus, causing functional MR, further increasing the LA pressure and PCWP. Acute AR is usually a hemodynamic emergency, and urgent diagnosis and rapid intervention can be lifesaving. A known history of aortic aneurysm, Marfan disease, or BAV may point toward the diagnosis.
IV. GENETICS
The most common congenital cardiac anomaly is a BAV, which is seen in 0.5% to 2% of the population. Even individuals with a normal tricuspid AV in families with BAV disease that have associated genes such as NOTCH1 may be at risk for AV calcification or thoracic aorta aneurysm. This may lead to mixed AV disease through sclerosis and aortic root dilation.
Genetic aortopathies should be suspected in young patients with AR as a result of aortic root dilation. The most common of these is Marfan syndrome (autosomal dominant), a connective tissue disorder with a characteristic phenotypic expression defined by the revised Ghent criteria. Cardiovascular features include dilation of the aortic root at the level of the sinuses of Valsalva, aortic regurgitation and MR, and mitral valve prolapse. FNB1 mutations are identified in over two thirds of cases. TGFBR2 mutations have also been identified in patients with Marfan-like phenotypes. Patients with FBN1 mutations were found to have more extensive skeletal involvement, whereas patients with TGFBR2 mutations had more severe aortic phenotypes. Marfan syndrome patients also may exhibit findings such as ectopia lentis (lens dislocation) and dolichostenomelia (long limbs) that are not seen in Loeys-Dietz syndrome.
Loeys-Dietz syndrome (autosomal dominant) has a continuum of presentations that generally include both vascular and skeletal. It is caused by mutations in the TGFBR1, TGFBR2, SMAD3, TGFB2, or TGFB3 genes. Patients have widely spaced eyes and a bifid uvula not seen in vascular (or cardiac valvular) type Ehlers-Danlos syndrome.
Ehlers-Danlos syndrome vascular type (autosomal dominant) is attributable to a mutation in COL3A1. Midsize arteries are usually involved, with arterial rupture being the most common cause of sudden death. Valvular complications emerge during adulthood. Ehlers-Danlos cardiac valvular type is a very rare variant and relatively mild on the spectrum of clinical phenotypes resulting from COLIA2 mutations.
Finally, 91 patients with lone AR were studied by human leukocyte antigen (HLA) typing for HLA-B27 (an immunogenic marker present in 8% of the world’s white population associated with seronegative spondyloarthropathies). HLA-B27 was found to be present in 88% of the male patients with AR and severe conduction system disease.
V. NATURAL HISTORY
A. Chronic aortic regurgitation
Chronic AR has a variable progression, but in the majority of patients, the disease course is chronic and slowly progressive.
Bonow et al. studied 104 asymptomatic patients with severe AR and normal LVEF. The rate of attrition (defined as death, symptoms, or asymptomatic LV dysfunction) was <5% per year over a 11-year follow-up. The rate of sudden death was only 0.4%
per year. At 11 years, 58% of patients remained asymptomatic with normal LV systolic function. Borer et al. (Circulation 1998;97:525) found similar results in 104 different patients monitored for a mean of 7.3 years. The rate of attrition was 6.2% per year and was predicted by the change in LVEF, or LVEF adjusted for wall stress from rest to exercise. At 5 years, 75% of patients remained free of death, symptoms, or LV dysfunction.
per year. At 11 years, 58% of patients remained asymptomatic with normal LV systolic function. Borer et al. (Circulation 1998;97:525) found similar results in 104 different patients monitored for a mean of 7.3 years. The rate of attrition was 6.2% per year and was predicted by the change in LVEF, or LVEF adjusted for wall stress from rest to exercise. At 5 years, 75% of patients remained free of death, symptoms, or LV dysfunction.
Dujardin et al. (Circulation 1999;99:1851) investigated the fate of 246 patients with moderately severe or severe AR with a mean follow-up time of 7 years. Unlike the two prior studies, these patients were not all asymptomatic with normal LV systolic function. The 10-year mortality rate was 34%, with independent predictors of survival being age, functional class, comorbidity index, atrial fibrillation, LV end-systolic diameter, and LVEF. Patients with greater New York Heart Association (NYHA) functional class or LV end-diastolic diameter (LVEDD) >25 mm/m2 had an adverse prognosis. Taken together, these studies indicate that asymptomatic patients with normal LV function generally have a favorable prognosis and that decline in LVEF on serial follow-up may identify patients who will require surgical intervention.
In asymptomatic patients with normal LV function and compensated severe AR, the progression rate to symptoms is <6% per year, and the progression to LV dysfunction is 3.5% per year. Risk of sudden death is very low in asymptomatic patients (<0.2% per year). Once LV dysfunction develops, symptoms will likely occur within 3 years (>25% per year); once symptoms develop, the rate of mortality increases to >10% per year.
B. Acute aortic regurgitation
Acute severe AR is generally a surgical emergency, with outcomes dependent on the underlying substrate, etiology, and early management.
VI. CLINICAL MANIFESTATIONS
A. Chronic aortic regurgitation
Chronic AR is usually well tolerated, and patients are frequently diagnosed on routine clinical examination prior to the development of any symptoms. The development of symptoms is generally due to pulmonary congestion and decreased CO. Initial symptoms include dyspnea on exertion and a decrease in exercise tolerance. Later, symptoms of orthopnea and paroxysmal nocturnal dyspnea usually occur as LV systolic function begins to decline. Angina (also nocturnal angina) may uncommonly occur regardless of obstructive coronary artery disease owing to decreased myocardial perfusion pressure causing subendocardial ischemia, as described earlier.
B. Acute aortic regurgitation
Acute AR presents with symptoms and signs of sudden hemodynamic instability (dyspnea, syncope, altered mental status) or frank cardiogenic shock. Concomitant chest pain should raise the suspicion of aortic dissection as part of the differential diagnosis for cardiogenic shock.
VII. PHYSICAL DIAGNOSIS
A. Chronic aortic regurgitation
1. Peripheral pulse examination
AR is characterized by a hyperdynamic pulse and wide pulse pressure as a result of a brisk systolic upstroke (caused by increase in LV SV) followed by a rapid diastolic collapse (caused by reversal of flow in the aorta). It is best appreciated by raising the arm abruptly and feeling the radial pulse. This hyperdynamic pulse was thought to result in the many classic eponymous signs of AR (Table 2.2); however, a 2003 review by Babu et al. of the peer-reviewed literature found only four signs with sufficient original literature for review, and overall, there was little published evidence to support their usefulness in AR. It is important to note that the signs of a hyperdynamic circulation are not specific to AR and can be seen in other conditions associated with a hyperdynamic circulation (anemia, thyrotoxicosis,
beriberi, large arteriovenous fistula, and patent ductus arteriosus). A bisferiens (twice-beating) carotid arterial pulse may also occur in severe AR. Paradoxically in decompensated AR, the pulse pressure narrows because of a decreasing LV systolic function and forward SV.
beriberi, large arteriovenous fistula, and patent ductus arteriosus). A bisferiens (twice-beating) carotid arterial pulse may also occur in severe AR. Paradoxically in decompensated AR, the pulse pressure narrows because of a decreasing LV systolic function and forward SV.
TABLE 2.2 Eponymous Physical Signs Historically Associated with a Hyperdynamic Pulse in Chronic Aortic Regurgitation | ||||||||||||||||||||||||||||||||||
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2. Palpation
In severe AR, the apical impulse may be diffuse, laterally and caudally displaced (owing to eccentric hypertrophy of the LV), sustained, and hyperdynamic. A diastolic thrill may be felt in the second left intercostal space, and if there is a large increase in SV, a systolic thrill may be present because of the increased aortic flow.
3. Auscultation
a. Heart sounds
S1: may be soft, early, and less forceful owing to preclosure of the mitral valve as a result of elevated LVEDP. Generally, a soft S1 is associated with an elevated LVEDP.
S2: is soft (A2 may be reduced owing to poor coaptation, P2 may be normal but obscured by the diastolic murmur), narrowly split, or paradoxically split because of protracted ejection time.
S3: may be present owing to increased early diastolic filling into a noncompliant LV. If present, suggests LV volume overload/decreased LV systolic function.
S4: may be present owing to atrial contraction into a noncompliant, hypertrophied LV.
Ejection click: may be present related to abrupt opening of a bicuspid AV.
b. Murmurs
The classic murmur of chronic AR is a “blowing,” high-frequency/pitched, decrescendo, early diastolic murmur starting immediately after A2, best heard at the left sternal border (third and fourth intercostal space), and radiating toward the apex. If soft, the murmur is augmented by (1) using the diaphragm of the stethoscope, (2) sitting the patient forward (brings the base of the heart close to the chest wall), (3) expiration (increased flow through the left heart), (4) bilateral isometric handgrip for 20 to 30 seconds (increased peripheral resistance), (5) squatting (increased peripheral resistance and venous return), (6) inflating bilateral arm blood pressure cuffs above systolic pressure (increased peripheral resistance), and (7) administering a vasopressor (increased peripheral resistance).
The severity of AR is generally proportional to the duration of the murmur except in mild chronic AR and late very severe AR (where other signs of very severe AR should be present). Classically, a diastolic murmur radiating to the right sternal border indicates aortic dilation with secondary AR, and at the left sternal border indicates a primary valvular AR. Increased forward flow across the valve results in a short ejection systolic murmur at the base of the heart radiating to the neck.
Rarely, a low-pitched, mitral stenosis-like murmur (Austin Flint murmur), which is a mid-to-late diastolic rumble at the apex, often with presystolic accentuation, may occur. In this scenario, the diastolic jet of AR strikes the anterior mitral valve, impeding opening, and results in functional mitral stenosis. There may also be a coexisting murmur of aortic stenosis if mixed AV disease exists.
B. Acute aortic regurgitation
The physical examination of acute severe AR differs significantly from that of chronic severe AR (Table 2.3). The primary clinical feature is usually cardiogenic shock. Other notable features include:
1. Peripheral pulse examination
The typical chronic AR signs of a hyperdynamic circulation may be absent in acute AR. If aortic dissection is suspected, the blood pressure should be measured in all four extremities.
2. Palpation
The apical impulse is typically nondisplaced because the LV has not had time to dilate.
3. Auscultation
a. Heart sounds
S1: is soft or absent owing to early preclosure of mitral valve.
A2: is often soft.
P2: is increased secondary to postcapillary pulmonary hypertension.
S3: is common and reflects cardiac decompensation.
TABLE 2.3 Comparison of Selected Clinical and Hemodynamic Findings in Severe Chronic versus Acute Aortic Regurgitation (AR) | ||||||||||||||||||||||||||||||||||||||||||
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b. Murmurs
There is a low-pitched, quiet, and short early diastolic murmur owing to rapid equilibration of the LV and aortic diastolic pressures limiting the volume and duration of AR. There may not be any audible murmur in very severe acute AR.
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