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disease states result in a significantly increased afterload. However cardiac reserve is severely limited in AS
when compared to hypertension due to the reduced and fixed aortic valve area causing the symptoms of AS
to be predominantly exertional.
Etiologies
The most common cause of AS in a person over the age of 70 results from calcification of a normal trileaflet
aortic valve. This process is sometimes referred to as “senile degeneration”. Known risk factors for
developing degenerative calcific AS include hypercholersterolemia and diabetes. The exact cause of the
degeneration is unknown, however it is speculated that high pressures and turbulence over long periods of
time creates an inflammatory state resulting in infiltration of macrophages and T lymphocytes with resultant
calcification.
The most common cause of AS in a person under the age of 70 results from 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 AS by the age of 50.
Rheumatic valvular disease is responsible for AS on occasion. There is almost always concurrent disease of
the mitral valve present and frequently at least some AI accompanies AS in this situation. While the
incidence of rheumatic AS is quite low in the US, the worldwide incidence is much higher.
Congenital AS results from fusion of the aortic valve leaflets at birth. Infants with congenital AS exhibit
significantly more left ventricular hypertrophy that do adults, yet they rarely develop symptoms of heart
failure. Sudden death without prior symptoms occurs in about 15% of cases.
Other rare causes of AS include inflammatory diseases (i.e. SLE or RA), severe familial
hypercholesterolemia, ochronosis, Paget’s disease of the bone, and Fabry’s disease.
Signs and Symptoms
The classic triad of symptoms of AS occur on exertion and include dyspnea, syncope, and angina. The
development of AS takes many years and is initially asymptomatic. Dyspnea is the first symptom of AS in
about 50% of the cases while syncope and angina account for 35% and 15% of initial symptoms
respectively. The clinical significance of a patient with AS exhibiting symptoms cannot be underemphasized
since the onset of symptoms is accompanied by a dramatic increase in mortality. If aortic valve replacement
is not performed, patients presenting with dyspnea have a mean life expectancy of 2 years, those with
syncope about 3 years, and those with angina an average of 5 years.
Angina in AS occurs frequently in the absence of coronary artery disease. Instead, myocardial ischemia
develops when the oxygen demand of the severely hypertrophied left ventricle exceeds oxygen supply. The
Law of Laplace explains this phenomenon:
LV wall stress = LV pressure X LV radius
2 X LV wall thickness
Note: LV wall stress is directly proportional to myocardial O2 demand, more specifically, O2 demand = wall
stress X HR
Using the above equation, we can understand the pathologic process that develops over many years in
patients with AS. As LV pressure slowly increases over time due to worsening AS, a parallel increase in LV
wall thickness occurs (concentric hypertrophy) in order to maintain the LV wall stress at a constant level
(since LV wall stress is an important determinant of myocardial O2 demand). Eventually, the LV is unable to
hypertrophy any further, but the LV pressure continues to rise as the AS worsens. This leads to a rise in LV
wall stress and thus a rise in LV myocardial oxygen demand. When the heart rate increases in response to
exertion (heart rate is also a determinant of myocardial O2 demand), a significant supply vs demand
mismatch occurs resulting in myocardial ischemia and the clinical symptoms of angina.
Effort syncope occurs in AS due to a sudden decrease in cerebral perfusion upon exertion. During exercise,
the total peripheral resistance decreases significantly since blood is being shunted to working muscles. In
the presence of significant AS, the cardiac output cannot increase enough to accommodate this decreased
TPR and cerebral perfusion is compromised resulting in syncope. This idea can be further reinforced by
recalling the following equation: MAP = CO X TPR (MAP = mean arterial pressure, CO = cardiac output, TPR
= total peripheral resistance). So if the cardiac output cannot increase due to severe AS and the TPR
decreases, the MAP will subsequently decrease leading to decreased cerebral perfusion and syncope. It is
important to note that another important cause of syncope in patients with AS is arrhythmias, especially
atrial fibrillation and AV nodal blocks, as will be described later.
Dyspnea on exertion is due to heart failure. Both systolic and diastolic dysfunction typically contributes to
heart failure in patients with AS. Other classic symptoms of heart failure are also common and include
orthopnea, PND, and signs of right sided heart failure (i.e. peripheral edema and right upper quadrant pain).
Other rare initial symptoms in patient with AS include embolic phenomenon from calcified AV plaques and
massive gastrointestinal bleeding due to angiodysplasia (Heyde’s syndrome). Heyde’s syndrome is thought
to be due to disruption of the pentamer structure of the von Willibrand factor as it traverses the severely
stenotic aortic valve leading to an increase tendency to bleed from angiodysplasias.
Physical Examination
Auscultation of the heart in patients with AS can be very helpful in both diagnosis and determining the
severity of disease. The typical murmur of AS is a high-pitched crescendo-decrescendo systolic ejection
murmur heard best at the right upper sternal border radiating to the carotid arteries (see figure below). In
mild AS the murmur peaks in early systole, however as disease progresses the peak moves later in systole.
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 may sound holosystolic and mimic the murmur
of mitral regurgitation. However this is commonly the result of radiation of the murmur of AS to the apex
rather than coexistent mitral regurgitation. This finding is referred as Gallivardin’s dissociation. To determine
if the apical murmur is indeed due to MR or radiation of the murmur of AS, dynamic auscultation can be
undertaken (see section on dynamic auscultation). The murmur of hypertrophic cardiomyopathy can also at
times sound similar to that of AS. The valsalva maneuver decreases the murmur of AS while it increase the
murmur of hypertrophic cardiomyopathy.
The S2 heart sound is often paradoxically split in patients with AS due to the significantly delayed closure of
the aortic valve resulting from the increased time needed to complete LV systole. As disease progresses and
the aortic valve leaflets lose their mobility, the intensity of S2 decreases. When the S2 sound is no longer
audible, in can be concluded that the AS is relatively severe. A S4 heart sound is also often present due to
the severe concentric left ventricular hypertrophy that develops in AS. If a S3 heart sound is present, then
significant systolic dysfunction has developed which is common in end stage AS.
Perhaps the best bedside method to estimate the severity of AS is derived from evaluation of the carotid
arteries. The phenomenon known as “pulses parvus et tardus” refers to a weak (parvus) and delayed
(tardus) carotid upstroke. To assess for “parvus”, it is often helpful to palpate your own carotid artery
(assuming you do not have significant AS) 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 indicating severe AS.
Other physical exam findings in patients with AS include those of both right and left heart failure.
Diagnosis
The EKG in patients with AS frequently shows LVH with strain and left atrial enlargement, however no
findings are specific for AS. The chest radiograph may reveal a normal cardiac size since the hypertrophy in
AS is concentric. Calcification of the aorta, pulmonary congestion, and post-stenotic dilation of the aorta are
other non-specific findings.
The echocardiogram can both confirm the diagnosis of AS and quantify the severity. Two-dimensional
echocardiography can demonstrate a thickened aortic valve, reduced leaflet mobility and concentric LVH.
Dopplar is used to quantify the severity of AS by measuring the pressure gradient across the aortic valve
and by calculating the aortic valve area (AVA). The velocity of blood flow across the aortic valve, as
determined by m-mode dopplar, is used to calculate the transaortic pressure gradient using the modified
Bernoulli equation: pressure gradient = 4v2 where v = velocity. The AVA is calculated using the continuity
equation:
A1 X V1 = A2 X V2
A2 = (A1 X 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 using either m-mode or dopplar echocardiography. The AVA is
the calculated as shown above.
Cardiac catheterization is indicated when the angina of AS may be due to coexistent coronary disease or
when aortic valve replacement is indicated. Rarely catheterization may be needed if echocardiography is
unable to determine if severe AS is present. During cardiac catheterization, the cardiac output and pressure
gradient are measured and used to calculate the AVA using the Gorlin equation below:
AVA = CO/SEP X HR/(44.3(G)½)
The pressure gradient is found simply by using the catheter to measure the pressure in the aorta, then
advancing the catheter into the LV and taking another pressure reading. The difference between these two
pressures is the pressure gradient. The mean transaortic valve pressure gradient is used in the Gorlin
equation to calculate the AVA. The cardiac output is calculated using either the Fick principle or the indicator-
dilution principle. It is important to note that the Gorlin formula was originally derived using patients with
mitral stenosis, not aortic stenosis. The Gorlin equation is also flow dependant, so if the patient has a
significantly decreased ejection fraction, the AVA may be underestimated. Another useful indicator of
severity of AS, the valvular resistance (VR), can be calculated during cardiac catheterization. The equation
to do so is below:
VR = (pressure gradient X HR X SEP X 1.33)/CO
INSERT TABLE WITH DISEASE SEVERITY BASED ON AVA AND G HERE
Treatment
The only effective treatment for aortic stenosis is removal of the mechanical obstruction. To this end, only
aortic valve replacement has been shown to achieve this while reducing mortality. Aortic valve debridement
via surgery or ultrasound debridement is a poor alternative to AVR. High rates of aortic regurgitation occur
with these procedures and the AS may recur in a large percentage of patients. Pharmacological therapy is in
general not effective in AS. In fact, in severe AS, many of the standard cardiovascular medications such as
ACE inhibitors and B-blockers are considered contraindicated.
Aortic balloon valvuloplasty is very beneficial in congenital AS where no calcification of the AV has occurred,
however, every other type of AS is accompanied by significant calcification and this modality is generally not
effective. In adults with AS, valvuloplasty does not result in regression of LVH. In fact, at 6 months after
valvuloplasty about 50% of patients have completely restenosed their AV to the same extent as before the
procedure. The procedural mortality rate is 2-5%, similar to that of aortic valve replacement (AVR). In
addition, long term studies have shown that the overall mortality of patients undergoing AV valvuloplasty
for AS are the same as if they did not have the procedure at all. Therefore, the role of valvuloplasty is
limited to palliative treatment of severe as or as a bridge to AVR in patients with severe AS.
Surgical AVR is the definitive treatment for all types of AS excluding congenital AS. Any patient who is
symptomatic from AS should undergo AVR as soon as possible. AVR is generally not indicated for
asymptomatic patients unless echocardiographic surveillance reveals rapidly progressing AS with LV
dysfunction or severe calcification of the AV. Even in patients with critical AS, AVR is still beneficial. The
ejection fraction may double or return to normal and the LVH usually regresses. It is rarely ever considered
too late to replace the aortic valve in patients with critical AS unless coexisting conditions increase the risk
of surgery.
A good approach to AS is to order regular echocardiograms and if the pressure gradient is > 30 mmHg,
repeat the history and physical every 6 months and instruct the patient to notify their physician if any signs
of AS develop.
In general, patients with a low transaortic valve gradient of less than 30 mmHg and advanced heart failure
do not improve after AVR. It is thought that in this subgroup irreversible myocardial remodeling has
occurred. However, a minority of these patients to improve significantly after AVR, so the risks of no
improvement must be discussed with these patients before AVR is undertaken.
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