Aortic Stenosis Topic Review
Aortic stenosis occurs when the orifice of the aortic valve is significantly reduced due to the failure of the aortic valve leaflets to open fully during systole.
This causes an effective increase in afterload, left ventricular hypertrophy and, eventually, symptoms of congestive heart failure. The classic triad of symptoms of aortic stenosis are angina, syncope and dyspnea. Mortality from aortic stenosis dramatically increases once symptoms develop. No medical therapy has convincingly slowed or reversed the disease process, and aortic valve replacement (AVR) is the definitive treatment.
Etiology – Aortic Stenosis
The most common cause of aortic stenosis in a person over age 70 years is calcification of a normal trileaflet aortic valve; this process is sometimes referred to as “senile degeneration.” No medical therapy has been shown to delay the valve degeneration. The exact cause of the degeneration is unknown; however, high pressures and turbulence over long periods of time create an inflammatory milieu that results in infiltration of macrophages and T lymphocytes and leads to calcification.
The most common cause of aortic stenosis in a person under age 70 years is a congenital bicuspid aortic valve. Approximately 2% of the population is born with a bicuspid aortic valve, and about half of these individuals develop at least mild aortic stenosis by the age of 50 years.
Rheumatic valvular disease is responsible for aortic stenosis on occasion. In this setting, rheumatic mitral valve disease is almost always present. Some degree of aortic regurgitation generally accompanies rheumatic aortic valve disease.
Congenital aortic stenosis results from fusion of the aortic valve leaflets that is present at birth. Sudden death without prior symptoms occurs in about 15% of cases. Balloon valvotomy is the treatment of choice for congenital aortic stenosis, unlike other causes.
Other rare causes of aortic stenosis include inflammatory diseases (ie, systemic lupus erythematosus or rheumatoid arthritis), severe familial hypercholesterolemia, ochronosis, Paget’s disease of the bone and Fabry disease.
Left ventricular outflow obstruction most commonly occurs at the aortic valve itself; however, it can occur above the aortic valve (supravalvular) as in William’s syndrome, or below the aortic valve as in hypertrophic obstructive cardiomyopathy (HOCM) or subvalvular aortic stenosis (SAS; often caused by a thin, crescent-shaped subvalvular membrane). (Devabhaktuni SR, et al. Clin Cardiol. 2018; 1a-1b.)
Symptoms – Aortic Stenosis
The classic symptoms of aortic stenosis occur with exertion: dyspnea, syncope and angina. Valvular aortic stenosis takes many years to develop and is initially asymptomatic (latent period). Dyspnea is the initial symptom in about 50% of the cases; syncope and angina account for 35% and 15% of initial symptoms, respectively.
The clinical significance of symptoms with aortic stenosis must not be underemphasized; a dramatic increase in mortality accompanies the onset of symptoms. In one large series, in the absence of aortic valve replacement, patients who presented with dyspnea had a mean life expectancy of 2 years, those with syncope about 3 years and those with angina lived an average of 5 years.
Angina in aortic stenosis frequently occurs in the absence of coronary artery disease. Instead, myocardial ischemia and angina develop when the oxygen demand of the severely hypertrophied left ventricle exceeds oxygen supply. LaPlace’s Law explains the phenomenon:
Note: Left ventricular (LV) wall stress is directly proportional to myocardial O2 demand or, more specifically, O2 demand = wall stress × heart rate.
The equation above explains the pathologic process that develops over many years in patients with aortic stenosis. As obstruction to forward flow slowly increases over time with worsening aortic stenosis, a parallel increase in LV wall thickness (concentric hypertrophy) initially occurs to maintain LV wall stress at a constant level. As discussed, LV wall stress is one of the critical determinants of myocardial O2 demand. However, worsening aortic stenosis eventually leads to a rise in LV wall stress, and thus a rise in LV myocardial oxygen demand. As the heart rate increases in response to exertion, a significant myocardial oxygen supply vs. demand mismatch occurs, resulting in myocardial ischemia and the clinical symptoms of angina. Heart rate is also a key determinant of O2 demand.
Syncope on exertion, or effort syncope, occurs in aortic stenosis due to a sudden decrease in cerebral perfusion with physical activity. During exercise, total peripheral resistance (TPR) decreases with vasodilation in the working muscles. In the presence of significant aortic stenosis, the LV cannot increase cardiac output sufficiently to compensate for this decreased total peripheral resistance (TPR). Systemic hypotension occurs, compromising cerebral perfusion and resulting in syncope. This idea can be further reinforced by the following equation:
MAP = CO x TPR
MAP = mean arterial pressure CO = cardiac output
If aortic stenosis limits the increase in the cardiac output required to maintain MAP when TPR decreases during exertion, MAP will be reduced, leading to decreased cerebral perfusion and syncope.
Arrhythmias (especially atrial fibrillation) and atrioventricular (AV) nodal blocks may also cause syncope in patients with aortic stenosis, as described later in this section.
Dyspnea on exertion indicates early heart failure. Both systolic and diastolic dysfunction typically contribute to heart failure with aortic stenosis. Other classic symptoms of heart failure — orthopnea, paroxysmal nocturnal dyspnea (PND) and signs of right-sided heart failure (eg, peripheral edema) — may also occur.
Rarely, initial symptoms of aortic stenosis may include systemic emboli from calcified aortic valve plaque or gastrointestinal (GI) bleeding due to angiodysplasia (Heyde’s syndrome). Heyde’s syndrome is attributed to disruption of the pentamer structure of the von Willebrand factor as it traverses the severely stenotic aortic valve, leading to increased tendency to bleed from angiodysplasias.
Physical Examination – Aortic Stenosis
Auscultation of the heart in patients with aortic stenosis can be very helpful in both the diagnosis and in determining the severity of disease. The typical murmur of aortic stenosis is a high-pitched, “diamond shaped” crescendo-decrescendo, midsystolic ejection murmur heard best at the right upper sternal border radiating to the neck and carotid arteries (see image below). In mild aortic stenosis, the murmur peaks in early systole. As the disease progresses, the peak moves to later in systole; with longer time required to complete LV systole, aortic valve closure is delayed. The intensity of the murmur typically increases as disease progresses. However, when heart failure develops and cardiac output declines, the murmur becomes softer. Thus, the intensity of the murmur is not a good indicator of disease severity.
Auscultation at the cardiac apex may reveal a murmur that sounds midsystolic or holosystolic and could mimic the murmur of mitral regurgitation. However, this is commonly the result of radiation of the aortic stenosis murmur to the apex rather than coexistent mitral regurgitation. This finding is referred to as “Gallavardin dissociation.” Dynamic auscultation is useful to determine if the apical murmur is indeed due to mitral regurgitation or radiation of the murmur of aortic stenosis (see section on dynamic auscultation).
At rest, the murmur of hypertrophic cardiomyopathy can mimic the murmur of aortic stenosis. However, the strain phase of the Valsalva maneuver decreases the aortic stenosis murmur while it increases the hypertrophic cardiomyopathy murmur.
The S2 heart sound is often paradoxically split in patients with aortic stenosis, though the splitting disappears on inspiration. The split is due to the significantly delayed closure of the aortic valve resulting from the increased time needed to complete LV systole; for more on splitting of S2, see Heart Sounds Topic Review.
As the disease progresses and the aortic valve leaflets lose their mobility, the intensity of S2 decreases. When the S2 sound is no longer audible, the aortic stenosis is relatively severe. An S4 heart sound is also often present due to the severe concentric left ventricular hypertrophy that develops in aortic stenosis. If an S3 heart sound is present, significant systolic dysfunction has developed; this is common in end-stage aortic stenosis.
Evaluation of the carotid pulse adds to bedside evaluation of aortic stenosis. The phenomenon known as pulsus parvus et tardus, referring to a weak (parvus) and delayed (tardus) carotid upstroke, serves as a peripheral indication of aortic stenosis.
To assess for parvus, it is often helpful to palpate one’s own carotid artery while concurrently palpating the patient’s carotid artery. It is important to note that in some elderly individuals, the carotids may be stiff due to calcification, which may falsely normalize the carotid upstroke.
To assess for tardus, auscultate the patient’s S2 heart sound while palpating their carotid upstroke. The S2 and carotid upstroke should occur almost simultaneously. If the carotid upstroke comes significantly after the S2 heart sound, tardus is present.
Other important physical examination findings in patients with aortic stenosis include the signs of left and right heart failure.
Diagnosis – Aortic Stenosis
The diagnosis of aortic stenosis is often made initially on physical examination and confirmed by echocardiography. The ECG findings of left ventricular hypertrophy with strain and left atrial enlargement are non-specific.
Two-dimensional echocardiography can demonstrate a thickened aortic valve, reduced leaflet mobility and concentric left ventricular hypertrophy. The echocardiogram can also quantify aortic stenosis severity. Transthoracic echocardiography (TTE) can assess the size of the left ventricle, the presence of concurrent aortic or mitral regurgitation, and estimate pulmonary systolic pressure. (Otto CM, et al. J Am Coll Cardiol. 2020;19b[e90].)
The 2020 ACC/AHA Guidelines for the Management of Patients With Valvular Heart Disease categorize aortic stenosis into four stages, including: risk of AS (Stage A), progressive hemodynamic obstruction (Stage B), asymptomatic severe AS (Stage C, with substages C1 and C2), and symptomatic severe AS (Stage D, with substages D1, D2, and D3). The formal criteria for each stage consider valve anatomy, hemodynamics, changes in the left ventricle and vasculature, and the presence or absence of symptoms. The most important hemodynamic parameters for staging are the maximum transaortic velocity (Vmax), the mean pressure gradient (ΔP) across the aortic valve, and the aortic valve area (AVA). (Otto CM, et al. J Am Coll Cardiol. 2020;19c[e90].)
The velocity of blood flow across the aortic valve, as determined by continuous wave Doppler, is used to calculate the transaortic pressure gradient using the modified Bernoulli equation: [Harris P, et al. BJA Education. 2016;2a-b.]
Pressure = 4V2
V = velocity
Pressure gradient (ΔP) = 4 (V22 - V12)
V1 = pre-valve velocity; V2 = post-valve velocity
In most cases, V12 is significantly lower than V22 and can therefore be ignored: [Harris P, et al. BJA Education. 2016;2a-b.]
Pressure gradient (ΔP) = 4 V22
However, the full formula should be used if V1 is abnormally high (> 1 m/s), such as with obstructive cardiomyopathy. [Harris P, et al. BJA Education. 2016;2c.]
The AVA is calculated using the continuity equation:
A1 × V1 = A2 × V2
A2 = (A1 × V1) / V2
Where A1 is the area of the left ventricular outflow tract, V1 is the velocity of flow at the left ventricular outflow tract, A2 is the area of the aortic valve and V2 is the velocity of flow at the aortic valve. All of the above except A2 can be directly measured by 2D echocardiography (LV outflow tract area) or measured using continuous wave (CW) Doppler. The AVA is then calculated as shown above.
Another metric used for assessing AS severity that can be determined using echocardiography is the dimensionless index (DI). This unitless measure is the ratio of left ventricular outflow tract (LVOT) velocity and vena contracta velocity. (Saikrishnan N, et al. Circulation. 2014;3a.) The vena contracta is the narrowest portion of a jet that occurs at or just downstream from the orifice. (Zoghbi WA, et al. J Am Soc Echocardiogr. 2017;7a.)
Chest radiography may reveal a normal cardiac size since the hypertrophy in aortic stenosis is concentric; however, once LV systolic failure occurs, cardiomegaly will often be seen. Calcification of the aortic valve, pulmonary congestion, and post-stenotic dilation of the aorta are other non-specific findings.
Cardiac catheterization is indicated to determine whether angina may be due to coexistent coronary disease or when aortic valve replacement is indicated. Rarely, left heart catheterization with hemodynamic measurements may be needed if echocardiographic findings are equivocal.
At cardiac catheterization for aortic stenosis, the transvalvular pressure gradient is determined by directly recording ascending aortic and left ventricular pressures (preferably simultaneously). Cardiac output should be determined at the same time. The difference between these two pressures is the pressure gradient. The cardiac output and pressure gradient are used to calculate the AVA using the Gorlin equation below.
The mean transaortic valve pressure gradient, not the peak-to-peak gradient, is used in the Gorlin equation to calculate the AVA. Cardiac output may be determined using either the Fick principle or the indicator-dilution principle. The Gorlin equation is also flow-dependent; if the patient has significantly decreased ventricular function and reduced cardiac output, the AVA may be underestimated.
Once obtained, the anatomic and hemodynamic parameters are used to define each of the four stages of AS, as described below.
Stage A (at risk of AS) is characterized by aortic valve sclerosis or a congenital aortic valve anomaly, a Vmax of less than 2 m/s, an absence of hemodynamic consequences on the left ventricle, and an absence of symptoms. (Otto CM, et al. J Am Coll Cardiol. 2020;20a[e91].)
Stage B aortic stenosis (progressive AS) entails mild to moderate aortic valve calcification/fibrosis causing some impairment of leaflet motion or rheumatic changes with fusion at the commissures (areas where the leaflets come together). Hemodynamically, Stage B disease may be divided into mild AS (aortic Vmax 2.0–2.9 m/s or mean ΔP < 20 mm Hg) and moderate AS (aortic Vmax 3.0–3.9 m/s or mean ΔP 20–39 mm Hg). The left ventricular ejection fraction (LVEF) is normal, but there may be some early left ventricular diastolic dysfunction. Like in Stage A and Stage C disease, no symptoms are present. (Otto CM, et al. J Am Coll Cardiol. 2020;20a[e91].)
Stage C aortic stenosis is subdivided into Stage C1 (asymptomatic severe AS) and Stage C2 (asymptomatic severe AS with LV systolic dysfunction). Both substages are characterized by severe leaflet calcification/fibrosis or congenital stenosis of the aortic valve, with strongly reduced leaflet motion. Hemodynamically, severe AS is defined by an aortic Vmax ≥ 4 m/s or mean ΔP ≥ 40 mm Hg. Very severe Stage C1 aortic stenosis is specified by an aortic Vmax of 5 m/s and higher or a mean pressure differential of 60 mm Hg and greater. AVA is typically ≤ 1.0 cm2 but this criterion is not necessary to diagnose severe AS. In Stage C1 disease, LV diastolic dysfunction is present, as well as mild LV hypertrophy, but LVEF is normal. By contrast, Stage C2 disease is characterized by a LVEF of less than 50%. Like in Stages A and B, no symptoms are present in Stage C aortic stenosis. Exercise testing is reasonable to confirm the absence of symptoms in Stage C1 disease. (Otto CM, et al. J Am Coll Cardiol. 2020;20a[e91].)
Stage D aortic stenosis (symptomatic severe AS) is distinguished from Stages A, B and C by the presence of symptoms. Like Stage C disease, Stage D aortic stenosis is characterized by severe leaflet calcification/fibrosis or congenital stenosis, which greatly restricts leaflet motion/opening. On the basis of hemodynamic properties and their consequences, Stage D is further divided into three sub-stages. (Otto CM, et al. J Am Coll Cardiol. 2020;20a[e91].)
Stage D1 (symptomatic severe high-gradient AS) is characterized by high transaortic flow (aortic Vmax ≥ 4 m/s or mean ΔP ≥ 40 mm Hg) and the AVA is typically 1.0 cm2 or less. Left ventricular hypertrophy and diastolic dysfunction is present, and there may also be pulmonary hypertension. Symptoms characteristic of Stage D1 aortic stenosis include exertional dyspnea, decreased exercise tolerance, or heart failure; exertional angina; and exertional syncope or presyncope. (Otto CM, et al. J Am Coll Cardiol. 2020;20a[e91].)
Stage D2 (symptomatic severe low-flow, low-gradient AS with reduced LVEF) is characterized by low transaortic flow (resting aortic Vmax < 4 m/s or mean ΔP < 40 mm Hg) and an AVA of 1.0 cm2 or less. Left ventricular hypertrophy and diastolic dysfunction are present, and LVEF is below 50%. Patients with these hemodynamic values may have either severe AS or a primary myocardial dysfunction (with only moderate AS). (Otto CM, et al. J Am Coll Cardiol. 2020;20a[e91].) To differentiate between these possibilities, dobutamine stress echocardiography may be performed with concurrent clinical monitoring. If severe AS is present, the AVA will be fixed under dobutamine stress, while Vmax will increase to 4 m/s or higher (or ΔP to 40 mm Hg or greater). Conversely, if primary LV dysfunction is present, the AVA will increase while Vmax and ΔP may increase only slightly or not at all. (Otto CM, et al. J Am Coll Cardiol. 2020;20b, 21a[e91, e92].) Symptoms associated with Stage D2 aortic stenosis include heart failure, angina, and syncope or presyncope. (Otto CM, et al. J Am Coll Cardiol. 2020;20a[e91].)
Stage D3 (symptomatic severe low-gradient AS with normal LVEF; or paradoxical low-flow severe AS) is also characterized by low transaortic flow (aortic Vmax < 4 m/s or mean ΔP < 40 mm Hg) and an AVA of 1.0 cm2 or less. However, the LVEF is normal (50% or greater), and the stroke volume index is below 35 mL/m2. (Otto CM, et al. J Am Coll Cardiol. 2020;20a[e91].) Because hypertension causes a pressure load on the LV (as does aortic valve obstruction), it may result in a lower forward stroke volume and a lower ΔP. Thus, hemodynamic measurements should be done (or repeated) when the patient is normotensive (< 140 mm Hg) to avoid a misdiagnosis of AS severity. (Otto CM, et al. J Am Coll Cardiol. 2020;19e, 20a, 20c[e90, e91].) Stage D3 aortic stenosis is accompanied with the same symptoms as Stage D2 disease (heart failure, angina, and syncope or presyncope). (Otto CM, et al. J Am Coll Cardiol. 2020;20a[e91].)
Treatment – Aortic Stenosis
The only effective treatment for aortic stenosis is relief of the mechanical obstruction. To date, only aortic valve replacement (AVR) has been shown to achieve this while reducing mortality.
In adults with aortic stenosis undergoing balloon valvuloplasty, severe aortic stenosis returns at 6 months in about 50% of cases. Furthermore, valvuloplasty does not result in regression of left ventricular hypertrophy. In fact, in about 50% of patients, the aortic valve re-stenoses to pre-valvuloplasty levels 6 months after the procedure. In addition, long term studies have shown that the overall mortality of patients who underwent a valvuloplasty for aortic stenosis is not different from that of patients who did not. The procedural mortality rate is 2-5%, similar to that of surgical AVR. Aortic balloon valvuloplasty is appropriate in congenital aortic stenosis where no calcification of the aortic valve has occurred. However, this modality is not effective for aortic stenosis accompanied by significant calcification.
Aortic valve debridement via surgery or ultrasound debridement is a poor alternative to AVR. High rates or aortic regurgitation occur with these procedures and aortic stenosis recurs in a large percentage of patients.
Transcatheter aortic valve replacement (TAVR) has gained FDA approval for those patients who are poor surgical candidates due to age and comorbid medical conditions. Programs in many major medical centers now provide TAVR with excellent outcomes. Rapid improvements in the technology and procedural techniques of TAVR have contributed to frequent changes in the accepted indications for the procedure. This remains a dynamic subject of clinical studies. (Elbadawi A, et al. JACC Cardiovasc Interv. 2019;1a-d; Virtanen MPO, et al. JAMA Netw Open. 2019;2a-b.)
Pharmacological therapy is not effective in preventing the hemodynamic progression of aortic stenosis. The ACC/AHA Guidelines specify that hypertension should be treated according to the standard guideline-directed medical therapy in patients with Stage A, B or C disease. Hyperlipidemia should be treated with statin therapy on the basis of standard atherosclerotic risk in all patients with calcific AS. As a class 2b (weak) recommendation, treatment with renin–angiotensin system blockers (ACE inhibitors or ARBs) may be considered in patients who have undergone TAVR to reduce the long-term risk of all-cause mortality. (Otto CM, et al. J Am Coll Cardiol. 2020;22d-e[e93].)
According to the ACC/AHA Guidelines, AVR is indicated for all patients with Stage D disease and patients with Stage C disease that either have a reduced LVEF (< 50%) or are undergoing surgery for another cardiac condition. (Otto CM, et al. J Am Coll Cardiol. 2020;24a[figure 2, e95].) Although surgical AVR (SAVR) is the default option, TAVR is appropriate for patients with prohibitive surgical risk. TAVR may also be considered as an alternative to SAVR in patients receiving bioprosthetic (but not mechanical) valves. However, because of limited data on TAVR durability, SAVR is preferred in patients with longer life expectancy, and the choice of procedure should be individualized according to patient-specific factors, including comorbidities, anatomical amenability and preferences. (Otto CM, et al. J Am Coll Cardiol. 2020;24a[figure 2, e95].)
In patients with Stage C disease and a normal LVEF, the ACC/AHA Guidelines state that SAVR is reasonable (but necessarily indicated) if the patient’s exercise capacity and blood pressure decrease during an exercise treadmill test, or if the patient has low surgical risk and fulfils one of the following criteria: 1) transaortic Vmax of 5 m/s or greater; 2) B-type natriuretic peptide elevation of > 3X normal; or 3) rapid disease progression. (Otto CM, et al. J Am Coll Cardiol. 2020;24a[figure 2, e95].) SAVR may be considered (class 2b recommendation) in patients with Stage C aortic stenosis with a progressive decrease in LVEF (to < 60%) on at least 3 serial imaging studies, or in patients with Stage B (moderate) disease who are undergoing cardiac surgery for another indication. (Otto CM, et al. J Am Coll Cardiol. 2020;24a[figure 2, e95].)
A good approach to aortic stenosis is to follow regular echocardiograms and if the mean pressure gradient is > 25 mm Hg, repeat the history and physical every 6 months and instruct the patient to notify their physician if any signs or symptoms of aortic stenosis develop.
Patients with a low transaortic valve gradient (less than 25 mm Hg) and advanced heart failure may not improve after AVR if irreversible myocardial remodeling has already occurred. The risks of no improvement must be discussed with these patients before undertaking AVR.
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