Chapter 31. Pathophysiology of Aortic Valve Disease

The aortic valve (AV) is a semilunar valve positioned at the end of the left ventricular outflow tract (LVOT) between the left ventricle and aorta. Proper functioning of this valve is critical in maintaining efficient cardiac function. This chapter explores the anatomical and physiologic properties of the AV.

Embryologic development of the AV is closely associated with development of the LVOT. In the primary heart tube, blood travels from the primitive ventricle into the bulbous cordis and out the aortic roots. The midportion of the bulbous cordis, the conus cordis, develops into the outflow tracts of the ventricles. The distal portion of the bulbous cordis, the truncus arteriosus (TA), develops into the proximal portion of the aorta and pulmonary arteries. During the fifth week of development, pairs of opposing swellings appear in the conus cordis and TA (Fig. 31-1). These conotruncal, or bulbar, ridges grow toward each other and fuse to form the aorticopulmonary (AP) septum. The AP septum divides the conus cordis into the left and right ventricular outflow tracts and the TA into the ascending aorta and pulmonary trunk.

When partitioning of the TA is nearly completed, the AV begins to develop from three swellings of subendocardial tissue (see Fig. 31-1). Two swellings arising from the fused truncal ridges develop into the right and left AV leaflets. A third dorsal swelling develops into the posterior leaflet. These swellings are reshaped and hollowed out to form the three thin-walled cusps of the fully developed AV. The pulmonary valve develops in a similar manner.

The AV separates the terminal portion of the LVOT from the aorta. The normal AV consists of three semilunar leaflets or cusps projecting outward and upward into the lumen of the ascending aorta (Fig. 31-2). The space between the free edge of each leaflet and the points of attachment to the aorta comprise the sinuses of Valsalva. Because the coronary arteries arise from two of the three sinuses, the sinuses and the respective leaflets are named the right coronary, left coronary, and posterior (noncoronary) sinuses and leaflets. The ostia of coronary arteries arise from the upper part of the sinuses, with the ostium of the left coronary artery positioned slightly higher than the ostium of the right. The leaflets are separated from one another at the aorta by the right-left, right-posterior, and left-posterior commissures (Fig. 31-3). The area adjacent to the left-posterior commissure is the fibrous continuity, which interconnects the aorta and the mitral valve annulus. The area beneath this commissure is the aortomitral curtain, which is an important anatomical landmark for root enlargement procedures. The posterior leaflet attaches above the posterior diverticulum of the LVOT and opposes the right atrial wall. The right-posterior commissure is positioned directly above the penetrating atrioventricular bundle and membranous septum. The right-left commissure opposes the posterior commissure of the pulmonary valve and the two associated aortic cusps oppose the right ventricular infundibulum. The lateral part of the left coronary sinus is the only part of the AV that is not closely related to another cardiac chamber and is in direct relationship with the free pericardial space.

The AV leaflets meet centrally along a line of coaptation, at the center of which are the thickened nodules of Arantius. Because of the semilunar shape of the leaflets, the AV does not have a true annulus in the traditional sense of a ringlike attachment. Instead, the leaflets have semilunar attachments along a hollow cylinder or cuff of tissue interconnecting the left ventricular (LV) chamber and the proximal aorta (Fig. 31-4).1 The distal border of the cuff is the sinotubular junction, which is defined by imaginary lines connecting the commissures. The proximal border is the ventriculoarterial (VA) junction, which has both hemodynamic and anatomic parts. The hemodynamic VA junction is marked by the semilunar attachments of the leaflets, whereas, the anatomic VA junction is marked by the circular attachment of the proximal aorta and the muscular and membranous ventricular septums.

The valve leaflets consist of three layers of endothelially invested connective tissue of distinctly different density and composition. There is no demarcation between the outer layers of the aortic and ventricular sides of the leaflets and outer layers of the corresponding aortic and ventricular walls; that is, leaflet endothelial cells form a continuum with aortic and ventricular endothelial cells (Fig. 31-5).2,3 Endothelial cells of both the aortic and ventricular surfaces of the AV are arranged circumferentially. Beneath the endothelium, there are extensions of the aortic intima and ventricular endocardium, termed the arterialis and ventricularis, respectively. The next layer is the lamina fibrosa, which is composed of dense collagen mostly in a circumferential pattern. Because of the thickness and density of this layer, it is the strongest layer and important for bearing the stress of diastolic pressure. The middle layer, referred to as the spongiosa, forms the core of the leaflets at their bases. It is made of loose connective tissue consisting of water and glycosaminoglycans with sparse fibers and cellularity. The semifluid nature of this layer gives the leaflet considerable plasticity.

The AV passively opens and closes in response to pressure differences between the left ventricle and aorta during the cardiac cycle. Pressure generated from ventricular contraction leads to valve opening, and the subsequent relatively higher pressure of the aorta leads to valve closure. The mechanical properties of the AV allow it to open with minimal transvalvular gradient and close completely with minimal flow reversal.

Opening

Pressure differences between the aorta and the ventricle coupled with compliance of the aortic root cause aortic root dilation and constriction during the cardiac cycle. This dynamic motion of the root plays an important role in opening and closure of the AV. During late diastole, as blood fills the ventricle, a 12% expansion of the aortic root occurs 20 to 40 msec before AV opening.4,5 The leaflets begin to open as a result of root dilation even before any generation of positive pressure from ventricular contraction. Root dilation alone opens the leaflets about 20%.6 As pressure rises in the LVOT, tension across the leaflets produced from root dilation lessens. As pressure continues to rise, the pressure difference across the leaflets is minimal, and no tension is present within the leaflet.4 This loss of tension allows the aortic root to further dilate and allows the valve to open rapidly at the beginning of ejection. Under normal circumstances, the AV presents little or no obstruction to flow because the specific gravity of the leaflets is equal to that of blood.7 These mechanisms permit rapid opening of the valve and minimal resistance to ejection.8

Closure

Closure of the AV is an elegant mechanism, which has interested investigators since the time of Leonardo da Vinci.9 A principal theory involved in closure is vortex theory, which recognizes the importance of the sinuses of Valsalva in valve closure.10 As ejection occurs, blood creates small eddy currents or vortices along the aortic wall. At the end of ejection and before valve closure, these vortices fill the sinuses and balloon the leaflets away from the aortic wall toward the aortic axis. After the pressure difference across the open AV equalizes, a small flow reversal forces the leaflets completely closed. Apposition of the valve leaflets occurs briskly and the ensuing second heart sound occurs after complete closure of the AV. Upon closing, the elastic leaflets stretch and recoil to generate compression and expansion of blood. The subsequent pressure changes produce the second heart sound; the sound is not produced by physical apposition of the valve leaflets.11

Aortic stenosis (AS) is incomplete opening of the AV, which restricts blood flow out of the left ventricle during systole.

Prevalence and Etiology

In developed countries, AS is the most prevalent valvular heart disease in adults. Observational echocardiography studies demonstrate that 2% of people 65 years of age or older have isolated calcific AS, whereas 29% exhibit age-related AV sclerosis without stenosis.12 AS is more common in men and prevalence increases with age. In patients aged 65 to 75 years, 75 to 85 years, and greater than 85 years, the prevalence of AS is 1.3, 2.4, and 4%, respectively.13 The most common causes of AS are acquired degenerative disease, bicuspid AV, and rheumatic heart disease.

Acquired Aortic Stenosis

The most common cause of AS is degenerative calcification of the AV, which typically occurs in septuagenarians and octogenarians. Progressive calcification, initially along the flexion lines at the leaflet bases, leads to immobilization of the cusps. The characteristic pathologic findings are discrete, focal lesions on the aortic side of the leaflets that can extend deep into the aortic annulus. The deposits may involve the sinuses of Valsalva and the ascending aorta. Although long considered to be the result of years of mechanical stress on an otherwise normal valve, it is now understood that the mechanical stress leads to proliferative and inflammatory changes, with lipid accumulation, upregulation of angiotensin-converting enzyme (ACE) activity, and infiltration of macrophages and T lymphocytes in a process similar to atherosclerosis.13–18 The risk factors for the development of calcific AS are also similar to those for atherosclerosis and include elevated serum levels of low-density lipoprotein (LDL) cholesterol, diabetes, smoking, and hypertension.13 Therefore, coronary artery disease is commonly present in patients with AS. Age-related AV sclerosis is associated with an increased risk of cardiovascular death and myocardial infarction (MI).

Calcific AS is also observed in a number of other conditions, including Paget's disease of bone and end-stage renal disease.19 Ochronosis with alkaptonuria is another rare cause of AS, which also can cause a rare greenish discoloration of the AV.20

Bicuspid Aortic Stenosis

A calcified bicuspid AV represents the most common form of congenital AS. Bicuspid AVs are present in approximately 2% of the general population. Gradual calcification of the bicuspid AV results in significant stenosis most often in the fifth and sixth decades of life, earlier in unicommissural than in bicuspid valves and earlier in men than women. The abnormal architecture of the unicommissural or bicuspid AV induces turbulent flow, which injures the leaflets and leads to fibrosis, increased rigidity, leaflet calcification, and narrowing of the AV orifice.21 Bicuspid valves are often associated with dilatation of the ascending aorta related to accelerated degeneration of the aortic media that in some cases may progress to aneurysm formation. Recent work suggests that a DNA transcriptional error in the gene encoding endothelial nitric oxide synthetase may be implicated in the genetic abnormality that leads to bicuspid AV.22 It appears that the microfibrils within the AV and the aortic root are defective in structure in patients with bicuspid AV disease. This leads to a decrease in mechanical support for the valve, thereby contributing to accelerated "wear and tear," and hence degenerative changes in the valve matrix.

Rheumatic Aortic Stenosis

In Western countries, rheumatic AS represents the least common form of AS in adults.23 Rheumatic AS is rarely an isolated disease and usually occurs in conjunction with mitral valve stenosis.24 Rheumatic AS is characterized by diffuse fibrous leaflet thickening with fusion, to a variable extent, of one or more commissures. The early stage of rheumatic AS is characterized by edema, lymphocytic infiltration, and revascularization of the leaflets, whereas the later stages are characterized by thickening, commissural fusion, and scarred leaflet edges.25

Pathophysiology

In adults with calcific disease, the AV slowly thickens over time. Early, it causes little hemodynamic disturbance as the valve area is reduced from the normal 3 to 4 cm2 to 1.5 to 2 cm2.13 Past this point, hemodynamically significant obstruction of LV outflow develops with a concomitant increase in LV pressure and lengthening of the LV ejection time. The elevated LV pressure increases wall stress. Wall stress is normalized by increased wall thickness and LV hypertrophy (LVH). As it hypertrophies, the left ventricle becomes less compliant and LV end-diastolic pressure (LVEDP) increases without chamber dilatation. This reflects diastolic dysfunction and the ventricle becomes increasingly dependent on atrial systole for filling.26 Hence, if a patient develops an atrial arrhythmia, he or she can rapidly decompensate.

Although adaptive, the concentric hypertrophy that develops has adverse consequences. LVH, increased systolic pressure, and prolonged ejection time all contribute to an increase in myocardial oxygen consumption. Increased diastolic pressure increases endocardial compression of the coronary arteries, reducing coronary flow reserve (or maximal coronary flow).27 Prolonged ejection also results in decreased time in diastole and therefore reduced myocardial perfusion time. The increased demand of the hypertrophied ventricle and decreased delivery capacity can yield subendocardial ischemia with activity. This can result in angina and LV dysfunction. LVH also makes the heart more susceptible to ischemic injury. Severe LVH is only partly reversed by AV replacement (AVR) and is associated with decreased long-term survival even after initially successful surgery.28

In late stages of severe AS, the left ventricle decompensates with resulting dilated cardiomyopathy and heart failure. Cardiac output (CO) declines and the pulmonary artery pressure rises, leading to pulmonary hypertension.

Myocardial hypertrophy in patients with AS is characterized by increased gene expression for collagen I and II, and fibronectin that is associated with activation of the renin-angiotensin system.22 Reduction in renin-angiotensin parallels regression of hypertrophy after AVR.29 Experimental studies have indicated a role of apoptotic mechanisms in the progression to LVH and heart failure in patients with AS.30 For 50% of patients who present with symptoms of congestive heart failure (CHF), mean survival is less than 1 year.31

Hemodynamics

The severity of AS can be assessed by measuring the AV orifice area (AVA), mean pressure gradient, and peak jet velocity. AVA is calculated by using CO, heart rate (HR), systolic ejection period (SEP), and mean pressure gradient in the Gorlin formula, which describes the fundamental relationships linking the area of an orifice to the flow and pressure drop across the orifice. The Gorlin formula is:

CO can be measured using the Fick or thermodilution technique. SEP is the time from AV opening to closure. The normal AVA is 2.6 to 3.5 cm2 in adults. Valve areas of less than 1.0 cm2 represent severe AS. In low-output states, the Gorlin formula may systematically predict smaller valve areas than are actually present. Several reports also indicate that the AVA from the Gorlin formula increases with increases in CO.32

In patients with AS, the transvalvular pressure gradient can be measured by simultaneous catheter pressure measurements in the left ventricle and proximal aorta. The peak-to-peak gradient, measured as the difference between peak LV pressure and peak aortic pressure, is used commonly to quantify the valve gradient.

Invasive measurements of AS severity have been largely replaced by echocardiographic measurements, which are currently the clinical standard. The Doppler acquired jet velocity is converted to a gradient using the Bernoulli equation, which is:

Gradient = 4 × (velocity)2

Transesophageal echocardiography (TEE) is an alternative method for assessment of AVA that uses planimetry of the systolic short-axis view of the AV (Fig. 31-6).33 Planimetry of the valve area is challenging because the valve orifice is a complex, three-dimensional shape, and area measurements assume the valve orifice lies entirely within the image plane.

Clinical Presentation

Symptoms

The cardinal symptoms of AS are angina pectoris, syncope, and symptoms of CHF (dyspnea, orthopnea, and paroxysmal nocturnal dyspnea).34 Although the mechanisms of angina and heart failure are well understood, the mechanism of syncope is less clear. A common theory is that the augmented stroke volume that usually accompanies exercise is limited by the narrowed outflow orifice. With exercise-induced reduction in peripheral arterial resistance, blood pressure drops, leading to cerebral hypoperfusion and syncope.35 Syncope also may be the result of dysfunction of baroreceptor mechanisms and a vasodepressor response to the increased LV systolic pressure during exercise. Besides these cardinal symptoms, patients also commonly present with more subtle symptoms, such as fatigue, decreased exercise tolerance, and dyspnea on exertion.36

Another rare presentation of AS is gastrointestinal bleeding secondary to angiodysplasia occurring predominantly in the right colon as well as the small bowel or stomach. This complication arises from shear-stress–induced platelet aggregation with reduction in high-molecular-weight multimers of von Willebrand factor and increases in proteolytic subunit fragments. These abnormalities correlate with the severity of AS and are correctable by AVR.37 Other late manifestations of severe AS include atrial fibrillation and pulmonary hypertension. Infective endocarditis can occur in younger patients with AS; it is less common in elderly patients with a severely calcified valve.

Patients who develop severe AS have a long period of asymptomatic progression in which morbidity and mortality is relatively low (Fig. 31-7). Sudden death from AS before the onset of symptoms is estimated to be approximately 1% per year.38 With the onset of symptoms, survival is dramatically reduced without surgical intervention. Of the 35% of patients who present with angina, 50% survive for 5 years. Of the 15% who present with syncope, 50% survive for 3 years, and mean survival for those who present with CHF is 2 years.34

Signs

AS is frequently first diagnosed before symptom onset by auscultation of a murmur on physical exam. Classically, AS causes a systolic crescendo-decrescendo murmur, heard loudest at the right upper sternal border. Another sign of AS is a delayed second heart sound (S2) because of prolongation of the systolic ejection time. S2 also may be single when the aortic component is absent, and if the aortic component is audible, this may give rise to a paradoxical splitting of S2.

The classic pulsus parvus (small pulse) is a sign of severe AS or decompensated AS and occurs when stroke volume and systolic and pulse pressures fall. A wide pulse pressure is also characteristic of AS. Prolongation of the ejection phase with slow rise in the arterial pressure also gives rise to the pulsus tardus (late pulse). Pulsus parvus et tardus is diagnosed by palpation.

LVH is evident as a sustained apical thrust or heave. This sign is present only when failure occurs because until failure occurs, the hypertrophy is not accompanied by dilatation, and the apical impulse is not displaced. Conversely, absence of an apical thrust (except in muscular patients, or those with emphysema or adiposity) suggests mild or moderate AS. Other physical findings of significant AS include a prominent atrial kick and prominence of the jugular venous a wave secondary to decreased right ventricular compliance caused by right ventricular hypertrophy.39

Electrocardiogram

Most patients with severe AS present with QRS complex or ST-T interval abnormalities reflecting LVH. Patients with a higher gradient are more likely to show a "strain" or "systolic overload" pattern. The conduction abnormalities may result from septal trauma secondary to high intramyocardial tension from hypoxic damage to the conducting fibers or from extension of valvular calcifications into the fibrous septum.

Roentgenogram

The roentgenographic characteristics of compensated AS include concentric hypertrophy of the left ventricle without cardiomegaly, poststenotic dilatation of the aorta, and calcification of the valve cusps. With decompensation, there is cardiomegaly in the posteroanterior projection and pulmonary venous congestion. It is important to recognize that a routine chest x-ray may be within normal limits in patients with hemodynamically compensated AS. The rounding of the lower-left heart border may be subtle, the poststenotic aortic dilatation may be equivocal, and the valvular calcification may be invisible on the posteroanterior view. Of equal importance, the presence of cardiomegaly in a normotensive patient with isolated AS indicates decompensated AS.

Echocardiography

Echocardiography is the diagnostic tool of choice for confirming the diagnosis of AS and quantification of disease severity. Echocardiography is used to define: (1) the severity and etiology of AS; (2) coexisting valvular abnormalities; and (3) cardiac chamber size and function.

The development of diastolic dysfunction in patients with AS can lead to symptom development, and may increase late mortality after AVR.28,40 Hence, the quantification of diastolic dysfunction is important in the assessment of AS. LV filling pressures can be assessed by combining transmitral flow velocity and annular velocity obtained at the level of the mitral annulus with tissue Doppler (E/E').41 In patients with normal LV function (LVF), stress echocardiography is used to determine if symptom development during exercise is due to diastolic dysfunction.42 Diastolic dysfunction in patients with normal LVF may cause exercise intolerance for several reasons: (1) elevated LV diastolic and pulmonary venous pressures increase the work of breathing and cause dyspnea; (2) patients with LVH exhibit a limited ability to use the Frank-Starling mechanism during exercise, resulting in a decrease in CO during exercise; and (3) elevated LV diastolic and pulmonary venous pressures result in abnormalities in the diastolic properties of the ventricle.

When AS is suspected, an initial Doppler echocardiogram can confirm the diagnosis and assess the severity. Periodic re-examination, every 5 years for mild AS, every 2 years for moderate AS, and annually for severe AS, is recommended to identify worsening stenosis, LV dysfunction, LVH, and mitral regurgitation.43 Although AS is best understood as a disease continuum, severity can be graded by echocardiographic evaluation of hemodynamics. The current guidelines use definitions based on the AVA, mean pressure gradient, and peak jet velocity (Table 31-1).

Exercise Testing

Traditionally, severe AS has been regarded as a relative contraindication to exercise testing. Exercise testing should be avoided in symptomatic patients with AS as well. Recent studies have indicated that quantitative exercise Doppler echocardiography can be performed safely in asymptomatic patients and may be useful for identifying patients who at higher risk of becoming symptomatic and/or requiring AVR. Several studies have shown that asymptomatic patients with severe AS who become symptomatic on exercise stress testing, have a higher rate of cardiac death or progression to AVR.44,45 Dobutamine stress echocardiography is occasionally used in severe AS, specifically to assess contractile reserve in patients with moderate to severe AS with a low AV gradient and depressed LVF.46,47

Cardiac Catheterization

Although Doppler echocardiography is well validated, cardiac catheterization remains the gold standard for measuring the transvalvular gradient. Because coronary artery disease is common in patients with AS, coronary angiography is usually performed in patients with severe AS to assess coronary anatomy and evaluate the need for combined AVR and myocardial revascularization. Right-sided heart catheterization is also used to calculate the AVA based on the Gorlin equation, as described earlier. Cardiac catheterization can also provide an assessment of ejection fraction (EF) through ventriculography and also may provide information about the presence or absence of other valve lesions.

Computed Tomography

Computed tomography (CT) can be used to assess progression of AS. Electrocardiographically gated multidetector row CT has shown high accuracy and reproducibility in quantifying AV calcification and its progression48 and estimating AVA by planimetry.49 The quantification of calcification may develop into clinical applications with respect to the prognostic relevance of AV sclerosis, as well as the problem of calcification of bioprostheses after surgery.

Magnetic Resonance Imaging

Cardiac magnetic resonance imaging (MRI) has emerged as an alternative noninvasive imaging modality for AS.50 Similar to echocardiography, cardiac MRI records images throughout the cardiac cycle. Cardiac MRI uses a range of pulse sequences to assess structural heart disease. The steady-state free precession (SSFP) cine pulse sequence is commonly used in cardiac MRI and provides detailed images of AV leaflet number, leaflet thickening, valve calcification, and commissural fusion. This sequence is also useful for assessing the effects of AS, including LVH and LVF.51 MRI is useful when acoustic windows in the echocardiogram are poor or there are discordant imaging and catheterization results.52,53 MRI has also been used to demonstrate improvement in LVF, myocardial metabolism, and diastolic function, as well as reduced hypertrophy after AVR for AS.54

Management

Symptomatic Patients

There is no effective medical therapy for AS. Given the biologic similarity of the calcific lesions of AS to atherosclerosis, there has been substantial effort to investigate the role of lipid-lowering agents in slowing the progression of AS, but to date prospective randomized trials have not found any benefit.55,56 Prophylactic antibiotics are recommended before any dental or surgical procedures as a prevention strategy for endocarditis.43 Management of CHF from AS has traditionally consisted of diuretics and ionotropes. Beta-blockers are avoided as reduced inotropy may lead to decreased CO in an overloaded ventricle. Classically, vasodilators are avoided in AS because their administration can lead to hypotension, syncope, and reduced coronary perfusion.

Percutaneous balloon valvuloplasty (valvotomy) is effective in congenital AS, but in adults the valve tends to re-stenose, and the procedure has no effect on long-term mortality.17 Currently, valvuloplasty is recommended only as a possible bridge to surgical intervention or a palliative measure.43 AV repair for AS has yielded poor results compared with AVR.57

The definitive treatment for severe AS is AVR, and onset of symptoms is the primary indication for AVR. As the risk of asymptomatic severe AS is perceived to be low, symptom onset remains the primary indication. Survival after successful AVR is reduced in younger patients but mimics that of the normal population in older patients.28,58,59

Percutaneous AVR represents a novel, less invasive approach to the treatment of AS. This approach has been applied successfully in high-risk patients with severe symptomatic AS who were not deemed candidates for conventional surgery.60

Asymptomatic Patients

AVR in asymptomatic patients is currently controversial. Current guidelines recommend AVR for patients with symptomatic AS, for patients with asymptomatic moderate or severe AS who also require coronary revascularization or surgery of the aorta, and for patients with severe AS and reduced EF.43 As AVR has become a safer procedure and technology for assessing disease severity has improved, it is likely that an identifiable high-risk subset of asymptomatic patients with severe AS could benefit from AVR. Studies show that asymptomatic patients with an aortic jet velocity greater than 4 m/sec,36 patients with high rates of aortic jet velocity progression and valve calcification,61 and those with small AVAs and LVH38 progress to symptom development quickly and will soon require AVR. Exercise stress testing, as described earlier, is also useful to stratify high-risk patients.

A number of recent studies have explored the potential benefit of AVR in asymptomatic patients. In studies of propensity matched cohorts of asymptomatic patients with severe AS, those who had AVR had significantly improved survival.62,63 It has also been shown that, among patients undergoing AVR for severe AS, LVH is only partly reversed and is associated with decreased long-term survival even after initially successful surgery. This suggests that intervening before development of LVH may improve outcomes.28 In summary, there is increasing evidence that AVR can be beneficial in a subset of asymptomatic patients with severe AS.

Aortic regurgitation (AR) is the diastolic reflux of blood from the aorta into the left ventricle due to failure of coaptation of the valve leaflets at the onset of diastole.

Prevalence and Etiology

AR has numerous causes, which can be grouped according to the structural components of the valve apparatus affected. AR may be caused by primary disease of the aortic leaflets and/or disease of the aortic root.

Aortic leaflet calcific degeneration, myxomatous degeneration, infective endocarditis, rheumatic disease, a bicuspid AV, and anorectic medications, such as fenfluramine and phentermine, all lead to distortion of the valve leaflets and prevent proper coaptation.64–67 Aortic root dilatation caused by aortic dissection; trauma; chronic systemic hypertension; aortitis from syphilis, viral syndromes, or other systemic arteritides (eg, giant cell and Takayasu); and connective tissue disorders, such as Marfan's syndrome, Reiter's disease, Ehlers-Danlos syndrome, osteogenesis imperfecta, and rheumatoid arthritis, leads to improper leaflet coaptation and consequent AR.68–73 AR is seen most commonly in combination with AS due to calcific or rheumatic disease in which some degree (usually mild) of AR is present in the vast majority of patients. However, AR secondary to aortic dilation is now more common than primary valve disease in patients undergoing AVR for pure AR.74

Pathophysiology

The pathophysiology of AR varies according to the onset and duration of the disease process.

Acute Aortic Regurgitation

AR that presents in the acute setting is typically caused by aortic dissection, endocarditis, or trauma. By definition, acute AR is a significant aortic incompetence of sudden onset across a previously competent AV. The blood returned to the left ventricle in diastole causes a sudden increase in LV end-diastolic volume (LVEDV) and reduces the effective or forward stroke volume. LVEDV only increases mildly (20 to 30%) because the ability of the left ventricle to dilate acutely is limited. This leads to a rapid increase in LVEDP. This increase is greatest in the less compliant, concentrically thickened, hypertrophic myocardium seen in those with AS or chronic systemic hypertension. Increased LVEDP results in increased mean LA and pulmonary venous pressures and produces varying degrees of pulmonary edema.75 The rapid rise in LVEDP also blunts or abolishes the normally widened pulse pressure seen in chronic AR.76 In the acute setting, two compensatory mechanisms attempt to maintain an effective CO: an increase in contractility attributable to the Frank-Starling mechanism and an increase in HR. The maintenance of an appropriate effective CO depends on the adequacy of these mechanisms, especially systolic pump function.

Chronic Aortic Regurgitation

In contrast, chronic AR is a slow, insidious process, which sets in motion numerous compensatory mechanisms. The diastolic regurgitant flow in AR increases LVEDV, LVEDP, and wall stress. Adaptive signals lead to an increase in myocyte length and addition of sarcomeres in series in a pattern of remodeling known as eccentric hypertrophy. Typically there is a modest increase in LV wall thickness such that the ratio of wall thickness to radius is close to normal. Chamber enlargement in the setting of normal systolic function increases total stroke volume and maintains forward stroke volume (total stroke volume minus regurgitant volume).77 The increased total stroke volume coupled with a normal to slightly elevated LVEDP is responsible for the wide pulse pressure seen in chronic AR. Forward stroke volume in AR is increased by any physiologic change that decreases afterload or increases HR. Increasing HR increases forward stroke volume by itself, but it also decreases diastolic filling time and hence regurgitant flow time and volume. The peripheral vasodilatation and increased HR that accompany exercise increase forward stroke volume in this manner.78 This also illustrates the physiologic basis for vasodilator therapy in the treatment of AR, and explains why bradycardia and use of negative chronotropic agents should be avoided.

As AR progresses, the hypertrophic response becomes inadequate, 79 and/or the preload reserve is eventually exhausted.80 Thereafter, any further increase in afterload creates afterload mismatch and results in a reduction in EF. Although the hypertrophied myocardium may provide adequate compensation for many years, eventually maladaptive signals, which lead to decreased myocyte survival and fibrosis, predominate. The myocardium becomes incapable of sustaining the increased work load imposed upon it and heart failure ensues.

Myocardial ischemia in AR, which can result from both decreased coronary artery perfusion and increased myocardial oxygen demand, may lead to further impairment of LVF. The decrease in diastolic coronary perfusion that occurs with a severe reduction in aortic diastolic pressure is only partially compensated by increased coronary arterial flow during systole. In severe AR, there may even be reversal of coronary arterial flow. Superimposed CAD only exacerbates the effect of decreased diastolic coronary perfusion pressure. On the other hand, increased LV muscle mass, wall tension, and systolic ventricular pressure all contribute to increased myocardial oxygen demand. The subsequent ischemia caused by decreased perfusion and increased oxygen demand can lead to cell death and fibrosis, and chronically, can contribute to systolic dysfunction.

Clinical Presentation

Symptoms

The presentation varies depending on the acuity of onset, severity of regurgitation, compliance of the ventricle and aorta, and hemodynamic conditions present at the time. Acute AR can be debilitating and life threatening if not treated emergently, whereas chronic AR is usually well tolerated for years. Severe acute AR commonly presents catastrophically with sudden cardiovascular collapse. Patients also often present with ischemic chest pain caused by decreased coronary blood flow coupled with rapidly increased myocardial oxygen consumption.

Patients with chronic, compensated AR remain asymptomatic for prolonged periods of time while the left ventricle gradually enlarges. Symptoms of heart failure, such as exertional dyspnea, orthopnea, and paroxysmal nocturnal dyspnea, usually develop gradually only after considerable ventricular hypertrophy and decompensation. Patients with severe AR may experience palpitations during emotional stress or exertion; an uncomfortable awareness of each heartbeat, especially at the ventricular apex; angina pectoris; nocturnal angina; or atypical chest pain syndromes, such as thoracic pain owing to pounding of the heart against the chest wall.81

Signs

Physical examination findings of AR vary with the chronicity of the disease process. Many of the classic findings of chronic AR are a result of the widened pulse pressure. They include a "water-hammer pulse" (Corrigan pulse), head bobbing with each heartbeat (De Musset sign), capillary pulsations in the lips and fingers (Quincke pulses), pulsus bisferiens, "pistol shot sounds" on auscultation of the femoral artery (Traube sign), pulsations of the uvula (Müller sign). Although interesting, these signs are not necessarily clinically useful. The classic auscultatory finding of AR is an immediate to early diastolic, blowing, decrescendo murmur. It is best heard with the diaphragm at the left sternal border while the patient is sitting, leaning forward, and holding respiration in deep exhalation. The murmur is often better heard along the right sternal border when AR is caused primarily by root disease.82 When it is soft, isometric exercise, such as handgrip, can increase its intensity by increasing aortic diastolic pressure. In severe AR, the murmur may be holodiastolic. S1 is usually soft because the mitral leaflets are close to each other at the onset of systole. S2 is usually single because the AV does not close properly, or because LV ejection time is prolonged and P2 is obscured by the early diastolic murmur. Other findings, if present, are associated with CHF, for example, rales, S3, etc.81 As discussed, the pulse pressure in acute AR is not widened, hence many of the classic signs of chronic AR are not seen in the acute setting. Instead, signs of CHF predominate.

Electrocardiogram

The increased LV mass in chronic AR leads to left axis deviation and increased QRS complex amplitude. A strain pattern and reduction in the total QRS complex amplitude in patients with chronic severe AR is highly predictive of severe depression of EF resulting from inadequate hypertrophy.83 Q waves in leads I, V1, and V3 through V6 are indicative of diastolic volume overload.84 LV conduction defects occur late in the course and are usually associated with LV dysfunction. Overall, ECG is an inaccurate predictor of AR severity.

Roentgenogram

The chest radiograph typically shows a "normal"-sized heart with pulmonary edema, although there may be some enlargement of all cardiac chambers and the main pulmonary artery. The aorta may be dilated if aortic root disease is the cause of AR. There may be signs of pulmonary emboli in AR caused by endocarditis when there is concomitant tricuspid valve endocarditis.

Echocardiography

Echocardiography is the most useful diagnostic modality in both the initial diagnosis and continued monitoring of patients with AR. Transthoracic echocardiography (TTE) is the most commonly used imaging tool. TTE provides noninvasive assessment of the AV and aortic anatomy; the presence, severity, and etiology of regurgitation; and the size and function of the left ventricle. TEE is used when the patient's body habitus does not allow for adequate assessment with TTE and to evaluate the AV and ascending aorta in patients with suspected aortic dissection (Fig. 31-8).

Two-dimensional (2D) echocardiography with Doppler color-flow mapping has been used routinely to assess the severity of AR.85–87 The color-flow jets are typically composed of three components: (1) a proximal flow convergence zone (area of acceleration into the orifice); (2) the vena contracta (the narrowest and highest-velocity region of the jet); and (3) the distal jet itself in the LV cavity. Assessment of the severity of AR is determined qualitatively by jet width and vena contracta width, and quantitatively by regurgitant volume, regurgitant fraction, and regurgitant orifice area (Table 31-2). The regurgitant orifice area is calculated by dividing the regurgitant volume by the velocity time integral of the AR jet calculated by continuous wave Doppler.88 Measurement of LV dimensions, such as end-systolic and end-diastolic volumes and wall thickness, are useful for determining LV changes and function. Additional echocardiographic findings in AR include premature closure of the mitral valve, diastolic fluttering of the anterior mitral leaflet from regurgitant flow, and less commonly, diastolic fluttering of the posterior mitral leaflet.89

Exercise Stress Testing

Exercise stress testing can provide valuable information in patients with AR, especially in those whose symptoms are equivocal or difficult to assess. In the management of AR, the presence of symptoms with exercise testing is equivalent to symptoms at rest because both circumstances warrant AVR.

Cardiac Catheterization

Cardiac catheterization is less frequently used to assess the severity of AR. It is most commonly used during preoperative assessment of coronary anatomy in patients requiring AV repair or replacement. The amount of regurgitant flow can be determined by calculating the angiographic stroke volume minus a measured fixed stroke volume. The difference between these two measured volumes divided by the angiographic stroke volume determines the regurgitant fraction. LVEDP is measured directly and EF is estimated roughly.

Computed Tomography

CT can be used to assess the severity of AR by measurement of the regurgitant orifice area, but currently the results are inferior to echocardiography.90 Several studies have demonstrated the utility of CT to detect moderate and severe AR, but inaccuracies are seen with lesser degrees of AR.91–93

Magnetic Resonance Imaging

With the recent advancements in MRI technology, MRI cineangiography is able to provide some of the same information provided by TTE and TEE. MRI in some aspects provides superior resolution of the valves and better quantification of regurgitant flow and LVF. The regurgitant volume can be calculated by quantitative assessment, wherein aortic flow is subtracted from the ventricular stroke volume measured by the volumetric technique. It also can be assessed using flow mapping downstream from the AV by measuring the retrograde volume flow after valve closure. This method is more reproducible and is used more frequently for follow-up studies. However, MRI is costly, and expertise is not available in most centers. Future improvements in technology may reduce costs and increase its availability, thereby making it a standard imaging modality along with or in substitution for echocardiography.94–96

Management

Acute AR is treated by early AV repair or replacement, depending on the etiology. With inadequate time for the left ventricle to compensate by eccentric hypertrophy, progressive CHF, tachycardia, and diminished CO occur rapidly. Vasodilators and inotropic agents, which augment forward flow and reduce LVEDP, may be helpful to manage the patient temporarily before surgery.

Compensated chronic AR is well tolerated by most patients.97–99 Current recommendations for the management of chronic AR depend on the presence of symptoms, LVF, and LV dimensions. Patients with symptoms or EFs less than or equal to 50% should undergo AV repair or replacement.100 Surgery is currently not recommended for patients who are asymptomatic, even with severe chronic AR. However, these patients must have normal LVF and LV dimensions. In asymptomatic patients with normal LVF, it is reasonable to perform surgery with an LV end-diastolic dimension (LVEDD) approaching 75 mm or an LV end-systolic dimension (LVESD) approaching 55 mm.100

After surgery, LVEDV and LVEDP decrease significantly and with the decrease in preload, EF also decreases.101 LV size and function eventually return to normal if the operation is timed correctly.102–113 The best postoperative predictor of recovery in systolic function is reduction in LVEDD because the magnitude of reduction correlates well with the magnitude of increase in EF.102 Importantly, 80% of the total reduction in LVEDD after AVR occurs within 10 to 14 days after surgery.102,107,114 Additional changes postoperatively include regression of myocardial hypertrophy, normalization of mass-to-volume ratio, increase in diastolic coronary perfusion, and decrease in peak systolic wall stress.102,114,115

Despite surgery, LV dilation and/or impaired LVF may continue in some patients. The best predictors of persistent LV dilation are greater preoperative LVESD and end-diastolic radius to wall thickness ratio.116,117 In addition to these measures, greater preoperative LVEDD and duration of LV dysfunction, and reduced EF and fractional shortening predict persistent LV dysfunction.102,106,118–121

Medical management with chronic vasodilator therapy is indicated in patients with severe AR who have symptoms or LV dysfunction, and are poor candidates for surgery. Vasodilator therapy may be beneficial in asymptomatic patients with severe AR, normal LVF, and LV dilation. Other than these instances, chronic therapy with vasodilators is not indicated in patients with AR.

In asymptomatic patients with normal LVF, the overall rate of progression to symptoms or LV dysfunction averages 4.5% per year and the mortality rate is 0.2% per year.100 Predictors for the development of future symptoms, LV dysfunction, or death include age, LVESV, LVEDV, and EF during exercise.97,122–125 Currently, there is insufficient evidence to determine if EF during exercise is a reliable predictor because exercise EF is dependent on too many factors, such as myocardial contractility,126 severity of volume overload,97,126–128 and exercise-induced changes in preload and PVR.128