1. Pathology of Valvular Diseases
Peter B. Baker, M.D.
Clinical Professor, Pathology
Different etiologies of valvular disease have specific pathologic features. Understanding these features provides a basis for recognizing clinical manifestations and the rationale for treatment options.

2. Cardiopulmonary Block Objectives
Describe the etiologies and pathologic changes causing stenosis and/or regurgitation of the cardiac valves
Describe the changes in the cardiovascular system that occur with aging

3. Objective for Part 1
List the etiologies and describe the pathologic features for aortic valve stenosis, aortic valve regurgitation, mitral valve stenosis and mitral valve regurgitation.

4. Aortic Valve Stenosis Handout VIII
Left ventricular pressure overload lead to concentric hypertrophy as the compensatory mechanism Etiologies 1. Congenital stenosis (often unicuspid valve) 2. Post-inflammatory valve disease (usually due to chronic rheumatic valvular disease) 3. Degenerative calcification on a previously normal valve 4. Congenital valve malformation with acquired stenosis (usually congenital bicuspid valve)
Aortic stenosis results in a pure pressure overload on the left ventricle and the left ventricular morphologic compensatory change to help maintain cardiac output is concentric hypertrophy. There are 4 etiologies for aortic valve stenosis.

5. Unicuspid Aortic Valve
Congenital aortic stenosis is often due to a congenital unicuspid aortic valve. The surgically excised valve in this image has a single, donut-shaped flap of valve cusp tissue surrounding a central orifice. The cusp is often thickened and stiff at birth due to increased fibrous tissue. The thickening reduces valve leaflet mobility resulting in congenital stenosis. Over time, the cusp becomes increasingly fibrotic and calcified as in this example.

6. Congenital Bicuspid Aortic Valve Handout VIII.B.4
Incidence 1%
M:F ratio 3:1
Hemodynamics
1. normal function for many years
2. stenosis – usually acquired starting at about age 40 years
3. insufficiency (less frequent) – myxomatous degeneration
Congenital bicuspid aortic valves are found in about 1% of the population. If the leaflets are not thickened at birth, the valve functions normally for many years. Aortic valve stenosis begins to appear in this population at about 40 years of age, probably due to increased stress on the leaflets compared with a normal 3 – leaflet valve. Occasionally, bicuspid valves develop myxomatous degeneration, described later, and this leads to valvular regurgitation.

7. Congenital Bicuspid Aortic Valve
This is a congenital bicuspid aortic valve seen from the outflow or aortic side. One cusp usually has a thickened ridge extending from the base or annulus to the free edge. The ridge, also called a raphe, is designated by the arrow in this image.

8. Degenerative (senile) Calcification Handout VIII.B.3
Calcification on a previously normal 3-leaflet valve
Stenosis usually does not occur until after age 65 years
Degenerative calcification, sometimes called senile calcification, occurs in previously normal 3 – leaflet aortic valves. Stenosis due to degenerative calcification, begins to appear at about age 65 years of age and becomes more prevalent with increasing age.

9. Degenerative Calcification in an Aortic Valve
Aortic Valve with Degenerative Calcification
This is an aortic valve with degenerative calcification seen from the outflow or aortic side. The three leaflets have large nodular calcifications, bulging into the sinus of Valsalva. These calcifications significantly reduce valve leaflet mobility. The commissures between the leaflets (arrows) are not fused. The combination of unfused commissures and the cusps fixed in a closed position resembles a “Mercedes-Benz” symbol.

10. Postinflammatory (chronic rheumatic) valvular disease Handout VIII.B.2
Fibrosis, commissural fusion and calcification
Always associated with anatomic pathology in the mitral valve
Repeated bouts of rheumatic fever causes fibrosis, calcification and commissural fusion. The fibrosis leads to leaflet retraction due to the process of scar contraction, similar to the process of scar contraction in the skin. The result is shortening of the distance from the valve annulus to the leaflet free edge and the leaflets may no longer be large enough to cover the valve orifice during diastole. Thus, chronic rheumatic valvular disease is often associated with a combination of valvular stenosis and regurgitation. In patients who develop valvular disease from rheumatic fever, the mitral valve is always involved. Aortic valve involvement is variable.

11. Aortic Valve with Chronic Rheumatic Valvular Disease
Chronic rheumatic valvular disease in an aortic valve seen from the outflow side – The leaflets are thick and fibrotic with areas of calcification. All three commissures are fused (arrows).

12. Aortic Valve Regurgitation Handout IX
Left Ventricular volume overload leads to eccentric hypertrophy as the compensatory mechanism
Mechanisms of Aortic Valve Regurgitation
1. Valve cusps do not cover the orifice
Infectious endocarditis
Collagen disorders (ie Marfan’s syndrome)
Chronic rheumatic valvular disease
2. Aortic root dilation enlarges the orifice
Rheumatoid arthritis
Syphilis
There are two basic mechanisms that lead to aortic valve regurgitation. The valve cusps do not completely cover the orifice during diastole when there has been destruction of valve leaflet tissue by infectious endocarditis, when there has been scarring and retraction of the leaflets due to chronic rheumatic valvular disease and when the tensile strength of the leaflets is reduced due to myxomatous degeneration. Infectious endocarditis is the subject of a separate elearning module. Medial degeneration of the aortic root can be seen in tertiary syphilis, rheumatoid arthritis and other conditions. The weakened media leads to aortic root dilation and enlargement of the valve orifice. The leaflets, even though they may be normal, do not completely close over the enlarged orifice.

13. Aortic Valve with Myxomatous Degeneration
This aortic valve was surgically excised from a patient with aortic regurgitation. The cloudy, translucent areas represent myxomatous degeneration and are best appreciated at the arrows.

14. Aortic Valve Leaflet with Myxomatous Degeneration
This histologic section from an aortic valve shows severe myxomatous degeneration. The labeled central pale zone represents marked expansion of the spongiosa layer which has largely replaced the markedly attenuated fibrosa layer. Remember that the fibrosa layer produces the tensile strength of the leaflet. Myxomatous degeneration results in loss of tensile strength. The leaflets can not withstand the pressure difference between the aorta and left ventricle during diastole and they prolapse toward the left ventricular outflow tract leading to regurgitation.

15. Mitral Valve Regurgitation Handout X
Left Ventricular volume overload leads to eccentric hypertrophy as the compensatory mechanism Causes of Mitral Valve Regurgitation 1. Cusp destruction 2. Leaflet prolapse 3. Rupture of chordae 4. Ischemic necrosis/fibrosis of papillary muscles 5. Severe ventricular dilation
Mitral valve regurgitation can be caused by pathologic processes involving any component of the valve apparatus including the annulus, valve leaflets, chordae tendineae, papillary muscle or even the ventricular wall. This slide lists common causes of mitral valve regurgitation.

16. Normal Mitral Valve Normal Mitral Valve PL AL PM
A brief review of the normal mitral valve anatomy will help you to understand how different pathologic conditions lead to mitral valve regurgitation. The valve cusps attach to the heart wall along the annulus. The anterior and posterior leaflets, designated “AL” and “PL”, are composed of tough but flexible fibrous tissue. The thin chordae tendineae are attached to the papillary muscles. The posterior papillary muscle is designated “PM” and the anterior papillary muscle is just out of the image on the lower left. There is a small portion of valve cusp tissue that bridges across the posteromedial commissure at the arrow. There is subtle scalloping along the free edge of the posterior leaflet. The anterolateral commissure is just out of the image on the right. PM

17. Floppy Mitral Valve (Severe Mitral Valve Prolapse) Handout X.B.2
Gross Pathology Large cusps Ballooning or hooding Elongated chordae tendineae Fibrous thickening of endocardial surface
Severe mitral valve prolapse, also called floppy mitral valve, is associated with valvular regurgitation. This is an important feature of Marfan’s syndrome as well as other systemic connective tissue diseases, and also occurs as an isolated mitral valve disorder in the absence of a systemic connective tissue disease. The gross pathologic features include stretching and enlargement of the cusps resulting in cuspal ballooning or hooding into the left atrium during systole. The chordae tendineae are also stretched and elongated. Fibrous thickening on the endocardial surfaces results from abnormal contact between the leaflets and between leaflets and chordae or mural endocardium.

18. Floppy Mitral Valve with Ballooning of Leaflets
This image of a floppy mitral valve shows ballooning of the leaflets toward the left atrium. The arrow points to an area of prominent ballooning in the posterior leaflet. You can imagine that during systole the pressure in the ventricle would increase the extent of ballooning, even more than is evident in this image. With severe ballooning, the leaflets do not properly coapt resulting in regurgitation.

19. Normal Mitral Valve Histology
Remember that the normal spongiosa layer, labeled “S” is normally thin and discontinuous. The fibrosa, designate “F” comprises most of the leaflet thickness and provides the tensile strength of the leaflet.

20. Floppy Mitral Valve Histology
This image shows a histologic section of a floppy mitral valve with the atrial surface at the top. The collagen is stained black. The histologic features include fibrous thickening of the endocardial surfaces designated “E” and expansion of the spongiosa layer designated “S” which has largely replaced the fibrosa layer. The remaining attenuated fibrosa is labeled “F”. As a result of these changes there is a marked reduction in tensile strength.

21. Comparison of Normal and Floppy Mitral Valves
Comparison of Normal (Bottom) and Floppy (Top) Mitral Valves
Comparison of Normal and Floppy Mitral Valves
This is a comparison between normal and Floppy mitral valves. The markedly stretched and expanded floppy mitral valve leaflets are larger than the normal mitral valve leaflets. The annulus is also much longer in the floppy valve.

22. Floppy Mitral Valve – Complications Handout X.B.2.b
Rupture of chordae tendineae
Infectious endocarditis
Thromboembolism
Arrhythmia
Sudden death
Complications of floppy mitral valves are listed in this slide. Sudden death is a rare potential complication with mitral valve prolapse. Clinical aspects of mitral valve prolapse will be covered in other modules.

23. Mitral Valve Stenosis Postinflammatory Valvular Disease Handout XI
Gross Pathology Diffuse fibrosis Commissural and scallop fusion Fusion of chordae tendineae Shortening of chordae tendineae Calcification “Funnel”-shaped valve apparatus
Mitral valve stenosis is caused by postinflammatory valvular disease which is most often due to chronic rheumatic valvular disease. The gross pathologic features include diffuse fibrosis of the valve leaflets with fusion of the posterior leaflet scallops and fusion of the commissures between the anterior and posterior leaflets. Shortening of the chordae pull the free edges of the leaflets down into the left ventricular cavity. These changes result in a “funnel”-shaped valve with the large opening of the funnel at the plane of the valve annulus and the narrow opening below the annulus.

24. Mitral Valve with Chronic Rheumatic Valvular DiseasePL
This image of a mitral valve with chronic rheumatic valvular disease shows diffuse fibrosis of the anterior and posterior leaflets, designated “AL” and “PL”. There is severe commissural fusion between the arrows.

25. Chronic Rheumatic Mitral Valve Disease with Severe Left Atrial Dilation
This image shows a very stenotic mitral valve at the arrow with severe dilation of the left atrium, designated LA. Luminal atrial thrombus formation frequently complicates the severe chamber dilation and blood stasis that occurs with mitral valve stenosis.

26. Objectives for Part 2
Describe the pathologic features and list a few complications of mitral valve annular calcification
List the pathologic conditions that cause stenosis and/or regurgitation of the tricuspid and pulmonary valves
Name the major 2 types of prosthetic valves and list the complications of prosthetic valves.

27. Calcification of Mitral Valve Annulus – Handout XII.A
The prevalence of mitral annular calcification is approximately 8% over the age of 50 years and is seen in more than 40% of women over the age of 90 years. The calcification extends as a shelf, designated by the yellow arrow, below the posterior leaflet. The calcification can extend into the myocardium, designated by the black arrow. Complications include extension into the atrioventricular node with heart block. Thrombus formation with embolization is also a potential complication. There is an increased risk for developing infectious endocarditis.

28. Tricuspid Valve Tricuspid Valve Regurgitation
1. Annular dilation due to right ventricular dilation
2. Infectious endocarditis
3. Chronic rheumatic valvular disease
4. Carcinoid tumors
Tricuspid Valve Stenosis
1. Chronic rheumatic valvular disease
The most common cause of tricuspid valve regurgitation is dilation of the valve annulus due to right ventricular dilation. The normal valve leaflets can not cover the enlarged valve orifice. Involvement of the tricuspid valve with chronic rheumatic valvular disease is much less common than involvement of the aortic and especially the mitral valve. Regurgitation results when scarring causes retraction of the leaflets. Stenosis may also occur as the leaflets become thickened and fibrotic. Carcinoid tumors release bioactive substances such as serotonin into the circulation. These substances induce fibrous thickening of the valvular endocardium. The hemodynamic effect is usually valvular regurgitation although stenosis can occasionally develop. The bioactive substances are inactivated in the lungs, thus the mitral and aortic valves are not usually effected.

29. Pulmonary Valve Pulmonary valve regurgitation
1. Infectious endocarditis
2. Carcinoid tumors
Pulmonary valve stenosis
1. Congenital stenosis
Infectious endocarditis and carcinoid tumors can result in pulmonary valve regurgitation. Pulmonary valve stenosis is usually due to congenital malformation or narrowing of the valve resulting in congenital stenosis.

30. Types of Prosthetic Valves
Prosthetic valves are divided into 2 major types. Mechanical valves have no biologic material as part of the valve. Bioprosthetic valves have leaflets bade from biologic material. The prosthetic valves in this image are shown from the inflow surfaces. The two valves on the top have discs that tilt open and close during the cardiac cycle. A Bjork-Shiley valve is at he upper left and a St. Jude’s valve is at the upper right. The Starr-Edwards valve on the lower left has a ball instead of a disc that opens and closes over the orifice. These 3 valves are mechanical valves. The porcine xenograft valve on the lower right is a bioprosthetic valve. The leaflets in this valve are porcine valve leaflets sewn onto a supporting valve ring.

31. Complications of Prosthetic Valves
Mechanical Bioprosthetic Thromboembolism ++ + Paravalvular leak + + Infection + + Deterioration + ++ Fibrosis + + Hemolysis + rare
The complications of prosthetic valves are shown on this slide. The risk of thromboembolism is higher in mechanical valves. Paravalvular leaks occur if there is a break down in the suture line holding the valve in position. Deterioration is more likely to occur in the leaflets of bioprosthetic valves. Fibrosis occurs if fibrous tissue overgrowth from the patient’s endocardium covers part of the prosthetic valve.

32. Pathology of Valvular Diseases Quiz
A 52 year old woman developed shortness of breath with exercise. Which of the following is most likely to be associated with aortic valve regurgitation due to aortic root dilation, as was found in this patient?
Infectious endocarditis
Incorrect – An infection from aortic valve endocarditis could extend into the aortic root, weaken the wall and cause aortic root dilation. This would most likely be associated with valve cusp destruction, also contributing to valvular regurgitation. This is not the best choice of the answers given.
Post-inflammatory (chronic rheumatic) valvular disease
Incorrect – The mechanism for valvular regurgitation in chronic rheumatic valvular disease is retraction of the cusps from scarring.
Rheumatoid arthritis
Correct – Rheumatoid arthritis can be associated with aortitis. The inflammation weakens the wall leading to aortic root dilation with normal valve cusps.
Hypertrophic cardiomyopathy
Incorrect – Hypertrophic cardiomyopathy is associated with thickening of the mitral valve. There is no associated pathologic change in the aortic valve.
A 48 year old man presented with palpitations and shortness of breath on exertion. He was found to have aortic valve stenosis and a normal mitral valve. The most likely cause for the aortic valve stenosis in this patient was:
Degenerative (senile) calcification
Incorrect – Degenerative calcification does not begin to appear in the population until about age 65 years. This patient is too young to consider degenerative calcification as the most likely etiology.
Congenital bicuspid aortic valve
Correct – Aortic stenosis begins to appear in patients with congenital bicuspid valve after about age 40 years.
Congenital unicuspid aortic valve
Incorrect – Congenital unicuspid aortic valves usually are associated with congenital aortic valve stenosis.
Elongation of the valve annular circumference
Incorrect – The mitral valve is always involved in chronic rheumatic valvular disease. The fact that the patient has a normal mitral valve essentially excludes the diagnosis of chronic rheumatic valvular disease.
A 55 year old woman with floppy mitral valve died suddenly prior to a scheduled surgical procedure. At autopsy, which of the following pathologic features would you expect to find in her mitral valve?
Incorrect – Commissural fusion is a feature of chronic rheumatic valvular disease contributing to valvular stenosis.
Fusion of the commissures
Short chordae tendineae
Incorrect – Shortening of chordae is a feature of chronic rheumatic valvular disease. Chordae are elongated in floppy mitral valves.
Retraction of the valve leaflets
Incorrect – Retraction of leaflets is a feature of chronic rheumatic valvular disease. The leaflets are larger than normal in floppy mitral valves.
Correct – The annular circumference is longer in floppy mitral valves and contributes to valvular regurgitation. Part of the surgical repair of floppy mitral valves includes reduction of the annular circumference by placing an annuloplasty ring.
A 63 year old man had a history of aortic valve regurgitation and the valve was surgically replaced with a porcine xenograft valve. Which of the following complications is more likely to occur in his valve compared with a mechanical valve?
Incorrect – There is a higher risk for thrombosis and thromboembolism in mechanical valves.
Thromboembolism
Incorrect – There is not a significant difference in the risk for infectious endocarditis between mechanical and bioprosthetic valves.
Deterioration of the valve
Correct – After 8 to 10 years, there is a significant risk for deterioration of bioprosthetic valve cusps resulting in tears and calcification. It is very rare to have a break in the disc or strut (which holds the disc in place) in a mechanical valve.
Incorrect – Hemolysis is rarely a complication with bioprosthetic valves. The risk of clinically significant hemolysis in newer mechanical valves is also very low.
Clinically significant hemolysis

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