Aortic stenosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Mohammed A. Sbeih, M.D. [2], Lakshmi Gopalakrishnan, M.B.B.S. [3]; Usama Talib, BSc, MD [4] , Claudia P. Hochberg, M.D. [5], Abdul-Rahman Arabi, M.D. [6], Keri Shafer, M.D. [7], Priyamvada Singh, MBBS [8], Aysha Anwar, M.B.B.S[9] Cafer Zorkun, M.D., Aysha Anwar, M.B.B.S[10] Mandana Chitsazan, M.D. [11] Assistant Editor-In-Chief: Kristin Feeney, B.S. [12]; Rim Halaby

Overview

Aortic stenosis is the progressive narrowing of the aortic valve. Calcific aortic stenosis, in particular, is an active atherosclerotic pathology where inflammation, fibrosis, and calcification are involved in the progressive narrowing of the effective aortic valve area in the absence of any commissural fusion. In contrast, rheumatic aortic stenosis is due to the fusion of the commissures with valvular scarring and calcification. Aortic stenosis causes an impedance to the antegrade blood flow not only at the level of the aortic valve itself but also at the subvalvular (below the aortic valve) or supravalvular (above the aortic valve) levels. As a result, chronic pressure overload develops in the left ventricle. The left ventricle undergoes hypertrophy as an initial adaptive mechanism to overcome the increased afterload. This compensatory mechanism ends up being maladaptive by causing apoptosis of the hypertrophied myocytes and subsequent heart failure. Hence, aortic stenosis is a progressive valvular disease which progression depends mainly on the degree of the narrowing of the aortic valve as well as on the maladaptive ventricular wall response. Gross anatomy dissection may be used as a diagnostic tool in the evaluation of aortic stenosis. Common findings associated with aortic stenosis include left ventricular hypertrophy and heart block.

Pathophysiology

• Aortic stenosis in the progressive narrowing of the aortic valve.
• The decrease in aortic valve area does not cause a change in the antegrade velocity unless the area is decreased by at least half. Aortic stenosis causes an impedance to the antegrade blood flow not only at the level of the aortic valve itself but also at the subvalvular (below the aortic valve) or supravalvular (above the aortic valve) levels. As a result, chronic pressure overload develops in the left ventricle. As a result, chronic pressure overload develops in the left ventricle.
• Slow compensatory mechanisms occur in the heart to adapt to the pressure changes caused by aortic stenosis. The most prominent adaptive mechanism is ventricular hypertrophy which leads early on to diastolic dysfunction and later on to systolic dysfunction.

Shown below is an image summarizing the pathophysiology of aortic stenosis:

Pathophysiology of aortic stenosis

Associated Conditions

Heyde's Syndrome

• In Heyde's syndrome, aortic stenosis is associated with angiodysplasia of the colon. Presenting symptoms include:
  • Hematemesis
  • Melena

Von Willebrand Disease

• Aortic stenosis may result in a form of von Willebrand disease due to an increased turbulence around the stenosed aortic valve which subsequently triggers the break down of coagulation factor VIII-associated antigen, (also called von Willebrand factor) and thus results in a variant of von Willebrand disease.

Narrowing of the Aortic Valve

Calcific Aortic Stenosis

Calcific aortic stenosis has long been thought to be the result of prolonged wear and tear mechanism and age-related degeneration of the valvular cusps as opposed to cusp fusion of the aortic valve in rheumatic heart disease. However, recent studies have revealed that the underlying pathophysiology of calcific aortic stenosis is active inflammation, fibrosis, and calcification. Genetic predisposition plays a role in the rate of progression of aortic stenosis. The stages of the formation of the calcific aortic stenosis are the following:

• Endothelial Damage:

• Endothelial damage is the initial event starting the cascade of events in calcific aortic stenosis.
• It results from increased mechanical stress and decreased shear stress.
• Endothelial damage happens at a faster rate in bicuspid aortic valves than in tricuspid aortic valves as a result of the difference in distribution of stress forces on the valvular cusps.

• Inflammation:

• Endothelial damage triggers accumulation of lipids (LDL and lipoprotens) that subsequently undergo oxidative changes.
• As a result, inflammation is accentuated by:
  • Expression of inflammtory signals
  • Recruitement of monocytes and their activation into macrophages
  • Expression of cytokines
  • Expression of intracellular and vascular cell adhesion molecule 1
  • Expression of tumor necrosis factor, interleukin 1 beta, tumor growth factor beta
• Elevated CRP in patients with aortic stenosis is an evidence of inflammation

• Fibrosis:

• Inflammation eventually leads to activation of fibroblasts and remodeling of the extracellular matrix

• Calcification:

• Calcification is induced by long standing inflammation and fibrosis.
• The following disorders of mineral metabolism accelerates calcification:
  • Hemodialysis
  • Osteoporosis
  • Paget's disease
  • Vitamin D receptor polymorphism
• Calcification starts at the base of the cusps and then reaches the leaflets. Calcification results in a decrease in the leflet motion and hence decrease in the effective valve area in the absence of any fusion of the commissures.
• Calcification is coordinated by osteoblasts in the context of a highly regulated mechanism similar to bone formation.

Rheumatic Aortic Stenosis

• Rheumatic aortic stenosis is due to the fusion of the valve commissures and subsequent scarring and calcification. Rheumatic aortic stenosis is always accompanied by mitral regurgitation.
• Rheumatic fever which depends on a prior autoimmunological stimulation, is a systemic disease affecting the peri-arteriolar connective tissue and can occur after an untreated Group A streptococcal pharyngeal infection. It is believed to be caused by antibody cross-reactivity which is a type II hypersensitivity reaction and is termed 'molecular mimicry'.
• Chronic rheumatic heart disease is characterized by repeated inflammation with fibrinous resolution. The cardinal anatomic changes of the valve include leaflet thickening, commissural fusion and shortening and thickening of the tendinous cords.Rheumatic heart disease may lead to up to 99% stenosis of the aortic valve often resulting in a “fish mouth” gross appearance.

Congenital Aortic Stenosis

Congenital malformation of the aortic valve is one of the less common causes of aortic stenosis.Congenital aortic stenosis is detected in young adults.

Left Ventricular Hypertrophy

• Long-standing aortic stenosis exposes the left ventricle to prolonged pressure overload which leads to concentric hypertrophy as a compensatory mechanism to preserve left ventricular function. The left ventricular wall increases in thickness (i.e. concentric hypertrophy occurs) as a result of the parallel replication of the sarcomeres
• However, left ventricle hypertrophy ends up being a maladpative mechanism and a marker of a bad prognosis. Hypertrophied myocardial cells undergo apoptosis at a rate larger to that of regeneration. In fact, angiotensin II promotes the apoptosis of the hypertrophied vessels, thus angiotensin receptor blockers (ARB) paly a role in the treatment of heart failure secondary to aortic stenosis even without having a great role in decreasing the blood pressure.
• Left ventricular hypertrophy weakly relates to the degree of stenosis itself but rather to advanced age, male sex and obesity. Other factors that participate in the hypertrophy of the left ventricle are hypertension and increased arterial stiffness.
• Fibrosis is an integral component of the myocardial hypertrophy.

Early Diastolic Dysfunction

During the initial period of concentric hypertrophy, the left ventricle is not dilated and there is preservation of the left ventricular systolic function. Diastolic function, however, may be reduced due to a reduction in diastolic compliance.

This diastolic dysfunction may in turn lead to a rise in pulmonary capillary wedge pressure and consequently lead to dyspnea. Cardiac output may also be reduced as a result of diastolic dysfunction and impaired filling of the left ventricle. Early in the course of aortic stenosis, there may be a failure to augment cardiac output during exercise resulting in dyspnea on exertion.

Late Systolic Dysfunction

Later in the course of aortic stenosis, left ventricular dysfunction may develop due to a variety of pathophysiological processes. Systolic dysfunction is associated with a poor prognosis and it often does not partially or fully reverse following operative repair.

Excess Hypertrophy Causes Systolic Dysfunction

The massive concentric hypertrophy, characterized by a reduced diastolic radius-to-wall thickness ratio, has shown to initially counter balance the increased systolic left ventricular pressure; nevertheless, if this process continues, an inverse relationship has been observed such that the ejection fraction eventually goes down as the left ventricular mass increases beyond a certain point.

Myocardial Ischemia

The hypertrophied left ventricle and the prolonged ejection time (the time for the heart to eject blood) result in an increase in the myocardial oxygen requirements. In addition, the elevated diastolic filling pressure reduces the gradient between the aorta and the right atrium ("the height of the waterfall") which normally drives coronary blood flow. There may be a relative reduction in the density of the capillary network. The hypertrophied ventricle may also compress the capillaries. All of the above lead to a reduction in coronary blood flow even in the absence of obstructive epicardial stenosis. This may lead to subendocardial ischemia during stress or exercise.

Myocardial Fibrosis

Myocardial scarring or fibrosis may develop with prolonged aortic stenosis, probably due to chronic subendocardial ischemia or increased wall stress.

Dyssynchronous Contraction

Another factor that may contribute to the reduced left ventricular systolic function is the dyssynchronous contraction subsequent to regional wall motion abnormalities, fibrosis or ischemia.

Atrial Fibrillation

The stiff non-compliant left ventricle can become increasingly dependent on the left atrium for filling, which predisposes to atrial fibrillation. The presence of atrial fibrillation and the associated loss of atrial contractility can result in reduced left ventricular filling and reduced cardiac output.

Hemodynamics of Aortic Stenosis

Pressure Gradient and Valve Area

When the aortic valve becomes stenosed, it can result in the formation of a pressure gradient between the left ventricle (LV) and the aorta. The more constricted the valve is, the bigger the gradient between the LV and the aorta is.

For instance, the pressure gradient in patients with mild AS might be 20 mmHg. This means that, at peak systole, while the LV may generate a pressure of 140 mmHg, the pressure that is transmitted into the aorta will only be 120 mmHg. Therefore, while a blood pressure cuff may measure a normal systolic blood pressure the actual pressure generated by and inside the LV would be considerably higher. As the left ventricle fails, it may no longer be able to mount the contractility necessary to generate a large gradient across the aortic valve.

Therefore, the absence of a large gradient across the aortic valve does not exclude the presence of critical aortic stenosis. The presence of a low gradient and a low ejection results in a low flow aortic stenosis. It is for this reason that the best measure of the severity of aortic stenosis is the aortic valve area and not the aortic valve gradient.

Read in detail by clicking on the topics:

• Aortic valve area
• Aortic valve area calculation

Subvalvular Gradients in AS in the Absence of Anatomic Obstruction

Subvalvular pressure gradients are often present in patients with severe aortic stenosis in the absence of an anatomic subvalvular obstruction. In fact, the subvalvular pressure gradients constitute around 50% of the total measured transvalvular gradient. The extent of increase in cardiac output during exercise is inversely related to the magnitude of subvalvular gradient.

Flow Velocity

If the left ventricular function and contractility are preserved, a flow velocity across the stenosed valve of at least 2.6 m/sec is deemed consistent with aortic stenosis. This is based on the echocardiographic estimation of the aortic jet velocity, the aortic valve area and the mean transvalvular gradient. The aortic valve becomes calcified in aortic valve sclerosis (not stenosis); however, the aortic jet velocity is ≤ 2.5 m/sec (without a significant gradient). Aortic valve sclerosis is commonly characterized by a focal thickening of the aortic cusps with calcific nodules generally at the base of leaflets and a transvalvular velocity within the normal range (Vmax <2 m/s). Until a few years ago, aortic valve sclerosis was considered to be a physiologic process related to aging without any clinical relevance. However, aortic valve sclerosis is not observed in about 50% of people over 80 years old. Furthermore, several experimental and clinical studies have demonstrated that aortic valve sclerosis could represent an active phenomenon significantly related to the risk factors of atherosclerosis.

Relationship of Hemodynamic Severity to Symptoms of Aortic Stenosis

• Patients with aortic stenosis become symptomatic when:

• The valve area is less than 1.0 cm².
• The jet velocity is over 4.0 m/sec.
• Mean transvalvular pressure gradient exceeds 40 mm Hg.

• However, many patients develop symptoms only when more severe valve obstruction is present, other patients become symptomatic at a less severe degree of stenosis, particularly if there is coexisting aortic regurgitation.

ACC/AHA Guidelines - Severity Classification

Indicator	Mild	Moderate	Severe
Jet velocity (m per s)	Less than 3.0	3.0–4.0	Greater than 4.0
Mean gradient (mm Hg)†	Less than 25	25–40	Greater than 40
Valve area (cm2)	Greater than 1.5	1.0–1.5	Less than 1.0
Valve area index (cm2 per m2)			Less than 0.6

^† Valve gradients are flow-dependent. They should be assessed with knowledge of cardiac output or antegrade flow across the valve when used to estimate of the severity of valve stenosis.

Low Flow, Low Gradient Aortic Stenosis

• In aortic stenosis, as the aortic orifice area decreases the transvalvular gradient increases. In fact, when the aortic valve effective orifice area decreases below 1.0 cm² the mean transvalvular gradient is expected to be larger than 40 mm Hg. The transvalvular gradient is highly dependent on the flow of blood through the valve.
• However, when severe systolic or/and diastolic myocardial dysfunction coexist with the aortic stenosis, there is a decrease in the flow through the valve leading to a prominent decrease in the transvalvular gradient. This is called low flow, low gradient aortic stenosis (LFLG AS).
• LFLG AS is a challenging diagnosis that must be done in order to tailor the management plan. It is important to recognize these entities because they might cause either underestimation or overestimation of the degree of severity of the aortic stenosis.
• Two various scenarios occur in the setting of LFLG AS depending on the status of the left ventricular ejection fraction:
  • LFLG AS with low LVEF
  • LFLG AS with normal LVEF

Shown below is a table depicting the differences between LFLG AS with low LVEF and LFLG AS with normal LVEF:

LFLG AS	Percentage of the Cases of Severe AS Caused by LFLG AS	Pathophysiology	Diagnostic Challenges
LFLG AS with low LVEF	5-10% of severe aortic stenosis	Decreased systolic function: Dilated left ventricle Decreased contractility	Differentiation between severe aortic stenosis and pseudo-severe aortic stenosis
LFLG AS with normal LVEF	10-25% of severe aortic stenosis	Decreased diastolic function: Small left ventricle Decreased compliance	Underestimation of the severity of aortic stenosis Differentiation from confounding measurement errors and small ventricle body size

Low Flow, Low Gradient Aortic Stenosis with Low Ejection Fraction

• When ventricular systolic dysfunction is present, the myocardium can not contract strongly enough to pump blood with a lot of pressure. In that case, low flow and subsequent low transvalvular gradient are present and this entity is called LFLG AS with low LVEF.
• LFLG AS with low LVEF is defined as:

1. An aortic valve areas < 1.0 cm²
2. A left ventricular ejection fraction < 40%
3. A mean pressure difference or gradient across the aortic valve of < 30 mm Hg

• When low flow, low gradient aortic stenosis is present, the challenge is to differentiate whether the LFLG AS with low LVEF is a true severe aortic stenosis or a pseudo-severe aortic stenosis. It is very important to differentiate between these two entities as they have different outcomes following aortic valve replacement.

True Severe Aortic Stenosis

• The aortic stenosis is so severe that it caused secondary left ventricular dysfunction. This systolic dysfunction causes decreased contractility and hence causes decreased ejection force and low transvalvular flow and gradient.

Pseudo-Severe Aortic Stenosis

The aortic stenosis in Pseudo-Severe Aortic Stenosis is mild or moderate but it co-exists with another myocardial disease that is independent from the aortic stenosis. Overestimation of the severity of the aortic stenosis happens in this context.

• The presence of fibrosis in the left ventricle may cause an incomplete recovery after aortic valve replacement.
• This scenario can also occur among patients in whom there is a history of myocardial infarction due to the absence of sufficient contractility to mount an aortic gradient.
• It may also occur when myocardial fibrosis develops due to longstanding aortic stenosis.

Low Flow, Low Gradient Aortic Stenosis with Normal Ejection Fraction

LFLG AS with normal ejection fraction has been recently described and it is usually an advanced stage of valvular and myocardial diseases.

• LFLG AS with normal ejection fraction has a lot of similarities with normal ejection fraction diastolic heart failure. In fact, it is usually present in older females in the context of systemic hypertension. The underlying pathophysiology is a restrictive myocardium.
• The characteristics of LFLG AS with normal ejection fraction is the presence of extensive remodeling due to predominant diastolic dysfunction as well as systolic dysfunction. However, the decrease in the systolic performance of the left ventricle does not show a decrease in the ejection fraction.

Gross Pathology

Pathological findings of congenital or acquired aortic stenosis in adults result in thickening and calcification of aortic valve. The following patterns may be seen:

• Calcified bicuspid valve involving anterior or posterior cusps
• Calcified aortic valve cusps with the fusion of commissures seen in post rheumatic cases
• Degenerative calcific aortic stenosis which shows sinuses of Valsalva filled with calcium deposits seen in age >70

Images shown below are courtesy of Professor Peter Anderson DVM Ph.D. and published with permission. © PEIR, the University of Alabama at Birmingham, Department of Pathology

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  Aortic Stenosis, Bicuspid valve: Gross; excellent image of bicuspid and calcific valve showing a false raphe.

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  Aortic Stenosis, Bicuspid valve: Gross; good example of bicuspid valve

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  Aortic Stenosis, Bicuspid valve: Gross; image of bicuspid aortic valve, an excellent example

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  Aortic Stenosis, Bicuspid valve: Gross; close-up image of bicuspid aortic valve.

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  Aortic Stenosis, Bicuspid valve: Gross; close-up image of bicuspid aortic valve.

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  Bicuspid aortic valve

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  Gross natural color opened first portion aortic arch with bicuspid aortic valve shows stenosis and aortic root is dilated

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  Aortic Stenosis Bicuspid: Gross; natural color opened left ventricular outflow tract with calcific masses on valve as well as anterior leaflet mitral valve probably did not cause significant stenosis

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  Bicuspid Aortic Valve with Repaired Aorta Coarctation: Gross natural color opened left ventricular outflow tract with uncomplicated bicuspid aortic valve repaired coarctation barely visible ruptured postoperative young female with ovaries Turner mosaic not ruled out

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  Bicuspid Aortic Stenosis: Gross; fixed tissue

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  Aortic Stenosis, Bicuspid: Gross; fixed tissue view of stenotic valve through ventricular outlet track

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  Aortic Stenosis Bicuspid: Gross; fixed tissue. Bicuspid valve and false raphe classical

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  Bicuspid aortic valve

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  Bicuspid aortic valve

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  Bicuspid aortic valve

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  Left ventricular hypertrophy due to bicuspid aortic valve

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  Congenital aortic stenosis: Gangrene toe In Infant: Gross, natural color, 1-month-old child with congenital aortic stenosis

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  Unicuspid aortic stenosis

Microscopic Pathology

On microscopic histopathological analysis, the calcific aortic stenosis shows pink amorphous material around the calcific foci indicating deposition of calcium. Congenital and calcific aortic stenosis show the areas of fibrosis, thickening, fat cell infiltration and elastosis.