L5 Pathology Valvular Heart Disease

Overview

This lecture covers how disease damages the cardiac valves and what that damage does to cardiac structure and function. It starts with normal valve anatomy, then defines the two functional lesions (stenosis and regurgitation) and the chamber changes they force, then works through the causes of valve disease: degenerative (calcific aortic stenosis), hereditary (mitral valve prolapse), immunological (rheumatic fever) and infective (infective endocarditis). The bulk of the lecture follows one connected pathway: group A streptococcal pharyngitis leads by cross-reactivity to acute rheumatic fever, which heals by scarring into chronic rheumatic heart disease, whose deformed valves are then vulnerable to subacute infective endocarditis.

Normal valve anatomy

• Mitral valve: between left atrium and left ventricle; two leaflets; chordae tendineae attached to papillary muscles.
• Tricuspid valve: between right atrium and right ventricle; three leaflets; chordae tendineae attached to papillary muscles.
• Aortic valve: between left ventricle and aorta; semilunar valve with three cusps.
• Pulmonary valve: between right ventricle and pulmonary artery; semilunar valve with three cusps.

Viewed from the base of the heart with the atria removed (heart in diastole), the four valves sit in the fibrous skeleton: the pulmonary valve anteriorly (anterior, right and left semilunar cusps), the aortic valve (right coronary, left coronary and posterior noncoronary semilunar cusps), the tricuspid valve (anterior, septal and posterior cusps) and the mitral valve (anterior, posterior and commissural cusps), surrounded by the conus arteriosus, the fibrous trigones and rings, the atrioventricular part of the membranous septum, and the coronary vessels (right coronary artery, circumflex branch, AV nodal branch, posterior interventricular branch).

Opening the posterolateral wall of the left ventricle shows the mitral apparatus: anterior and posterior cusps, anterior and posterior papillary muscles, and the chordae tendineae connecting them. A normal mitral valve on gross inspection has thin, smooth, translucent leaflets with well defined chordae tendineae running to the papillary muscles.

Warning

One slide shows an unlabelled clip-art heart with coloured dots at the valve positions on both the right (blue) and left (red) sides. [flag: diagram is unlabelled, its meaning/purpose is not stated on the slide]

Types of valve pathology

• Stenosis (narrowing): failure of a valve to open completely, causing obstruction to blood flow, giving pressure overload.
• Regurgitation (incompetence): failure of a valve to close completely, causing reversed or retrograde blood flow, giving volume overload.
• Both stenosis and regurgitation in the same valve: both pressure and volume overload.
• Functional: the valve itself is structurally normal but does not close properly, for example dilation of the right or left ventricle pulling the papillary muscles down and outward.

Valve lesions produce murmurs.

Complications of valve disease

Pressure and/or volume overload on cardiac muscle leads to:

• Chamber hypertrophy with pressure overload, later progressing to failure and dilation. Example: left ventricular hypertrophy due to aortic stenosis.
• Chamber dilation with volume overload. Example: left atrial dilation due to mitral regurgitation.
• Atrial fibrillation secondary to atrial dilation.
• Atrial thrombosis and embolism, predisposed to by the atrial fibrillation.
• Heart failure, the ultimate endpoint.
• Susceptibility to infective endocarditis.

Causes of valve disease

Etiology	Example
Congenital	Aortic stenosis
Degenerative (aging)	Calcific aortic stenosis
Hereditary	Mitral valve prolapse
Immunological	Rheumatic fever
Infective	Infective endocarditis

Calcific aortic stenosis

Occurs in two settings.

• Of an anatomically normal (three cusped) aortic valve: the valve becomes calcified, nodular and heaped up, in contrast to the smooth, thin, pliable normal aortic valve.
• Of a congenitally bicuspid aortic valve: heavy nodular calcific deposits on a valve that has only two cusps, one of which carries a raphe, rather than the normal three cusps.

Mitral valve prolapse

Caused by myxomatous degeneration of the mitral valve, giving a ballooned, redundant, floppy leaflet. The sequence shown is: the normal valve closes fully; in prolapse the valve flap closes abnormally; blood pushes on the prolapsed valve; blood is regurgitated back into the left atrium.

Rheumatic fever: definition and pathogenesis

Rheumatic fever (RF) is an acute, immunologically mediated, multisystem inflammatory disease occurring a few weeks after an episode of group A streptococcal (GAS) pharyngitis, in about 3% of patients.

Pathogenesis is cross-reactivity between group A streptococci and self antigens in the heart, also known as molecular mimicry. The sequence is:

1. Antibodies are raised against M proteins of group A beta haemolytic streptococci, and CD4+ T cells specific for streptococcal peptides are generated.
2. Both cross-react with self proteins/antigens in the heart.
3. The result is a combination of antibody-mediated and CD4+ T cell-mediated inflammation.

The two arms of that inflammation:

• Antibody-mediated (type II hypersensitivity): antibodies deposit in tissues; complement is activated; complement components recruit leukocytes and cause vasodilation and increased vascular permeability; substances released from leukocytes such as lysosomal enzymes cause tissue damage.
• CD4+ T cell-mediated (type IV hypersensitivity): T cells produce cytokines that recruit and activate macrophages.

These reactions cause inflammation and tissue damage in all three layers of the heart and in other tissues.

Key point on why this is not an infection of the heart:

• By the time rheumatic fever develops, streptococci are no longer present in the throat.
• Antibodies against streptococcal antigens can be detected in plasma.
• Streptococci are completely absent from the inflammatory lesions of RF.
• The disease is therefore not due to infection of the heart by GAS bacteria; it is immunologically mediated.

Cardiac morphology is a pancarditis, that is inflammation of all three layers of the heart: endocarditis, myocarditis and pericarditis.

Rheumatic fever: epidemiology and risk factors

• Incidence has declined over the past century because of improved socioeconomic conditions, better diagnosis, and treatment of streptococcal pharyngitis.
• It remains an important public health problem in developing countries and in crowded, economically deprived urban pockets of the western world.
• High incidence in New Zealand among Māori and Pacific people, mostly in the North Island.
• Affects children aged 5 to 15.
• High frequency of recurrence unless prophylactic antibiotics are given.

Risk factors:

• Crowded housing conditions
• Cold damp housing
• Socio-economic deprivation
• Barriers to primary healthcare access
• Higher burden of untreated streptococcal sore throat infections

Public health responses shown include the Healthy Homes Initiative and government funding ($10m) towards a vaccine to prevent rheumatic fever, plus the public message that untreated sore throats lead to rheumatic heart disease whereas checked and treated sore throats leave a healthy heart.

Global prevalence of rheumatic heart disease in children aged 5 to 14 years, in cases per 1000: 0.3 in North America, Europe and Russia; 0.8 in East and South East Asia; 1.0 in parts of Europe and Russia; 1.3 in South America; 1.8 in the Middle East and North Africa; 2.2 in Central and South Asia; 3.5 in Australia and a nearby Pacific island (both highlighted on the map); 5.7 in sub-Saharan Africa.

The Scottish poet Robert Burns (1759 to 1796) reportedly had rheumatic heart disease as a result of rheumatic fever and died at the age of 37.

Rheumatic fever: clinical features

The five features listed are:

1. Pancarditis
2. Migratory polyarthritis of large joints
3. Subcutaneous nodules
4. Erythema marginatum of the skin
5. Sydenham chorea, a neurologic disorder with involuntary rapid, purposeless movements

Mapped onto the patient, the full clinical picture is:

• Head: Sydenham’s chorea (St Vitus dance)
• Neck: a prior sore throat
• Chest (carditis): dyspnoea from congestive cardiac failure, syncope, pericarditis with pain and a rub, a Carey Coombs murmur, aortic or mitral regurgitation, heart block
• Hand and wrist: subcutaneous nodules over bones or tendons
• Knee: flitting polyarthritis and arthralgia
• Legs: oedema from heart failure
• Skin: erythema marginatum, an annular red rash
• Systemic: fever with a spiking temperature chart (37 to 39°C)

Rheumatic pancarditis: morphology

Endocarditis: inflammation of the mural and valvular endocardium on the left side of the heart.

Myocarditis: causes heart failure that may rarely lead to death, in 1% of cases. The myocardium becomes soft and flabby, leading to dilation of the heart chambers, mostly the left ventricle.

Pericarditis: a pericardial friction rub can be heard.

Rheumatic endocarditis

1. Inflammation of the valvular endocardium (valvulitis) of the mitral and aortic valves produces foci of endothelial injury and necrosis within the cusps or along the chordae tendineae.
2. Overlying these foci, small platelet-fibrin thrombi 1 to 2 mm across form. These are called vegetations or, in rheumatic fever specifically, verrucae.
3. Verrucae are sterile and adherent to the lines of closure of the valves, so they do not embolize.

Grossly, the mitral valve shows small red/tan nodular verrucae strung along the lines of closure of the leaflets.

Rheumatic myocarditis

• Foci of inflammation in the heart are called Aschoff bodies.
• An Aschoff body has central necrosis surrounded by lymphocytes (mainly T cells), occasional plasma cells, and plump activated macrophages called Anitschkow cells.
• The chromatin in the nuclei of Anitschkow cells is condensed into long, wavy ribbons, hence the alternative name caterpillar cells.
• Histologically Aschoff bodies are granulomatous structures showing fibrinoid change, lymphocytic infiltration, occasional plasma cells, and abnormal macrophages surrounding necrotic centres. These macrophages may fuse to form multinucleated giant cells.

Rheumatic pericarditis

The inflamed pericardial surface carries a shaggy fibrin-rich (fibrinous) exudate on top, described as “bread-and-butter” pericarditis.

Recap of acute RF

Beta haemolytic streptococcus in the pharynx triggers an immune response (lymph node, B lymphocytes producing anti-streptococcal antibodies, carried in the blood) which reaches the heart, where cross-reactions produce rheumatic fever. Rheumatic fever then manifests in the three layers as valve vegetations, myocardial Aschoff bodies, and fibrinous pericarditis.

Chronic rheumatic heart disease

The active phase of rheumatic fever may progress over time to become chronic Rheumatic Heart Disease (RHD), characterised by permanent valve deformities due to healing by fibrosis after RF.

Outcome and progression:

• After an initial attack there is increased vulnerability to recurrence with subsequent GAS infections.
• Damage to the valves is cumulative over months to years, with fibrosis increasing with every recurrent attack.
• Valvular scarring and deformity is the hallmark of rheumatic heart disease.

Morphology of the chronically damaged valve:

• Valve leaflets are fibrosed, thickened and distorted (opaque and thickened on gross inspection, versus the thin translucent normal valve).
• Commissures are fused, giving a narrow slit-like orifice: the “button-hole” or “fish mouth” appearance.
• Chordae tendineae are thickened and shortened.
• Valve dysfunction: stenosis and/or regurgitation.

Distribution and consequences:

• The mitral valve is almost always involved, and mitral stenosis is the most common deformity.
• The aortic valve can also be involved.
• The mitral valve is affected alone in about two thirds of cases, and together with the aortic valve in a further 25% of cases.
• RHD greatly increases the risk of infection of the deformed valves, that is infective endocarditis.

Infective endocarditis

Yours/Medwiki/Block/CVS/Reference/Disease/Infective endocarditis (IE) is a serious infection characterised by colonisation of the heart valves by an organism, usually bacteria.

• It leads to formation of vegetations composed of thrombotic debris, organisms and inflammatory cells, unlike the sterile verrucae of rheumatic fever.
• Destruction of the valve can occur.
• Vegetations can break off and embolise to distant sites, unlike the adherent verrucae of rheumatic fever.
• Clinically there is a stormy onset with rapidly developing fever and chills.

Subacute type

• Low virulence organisms affect previously damaged valves (for example in RHD), artificial valves, or valves with congenital defects.
• Mechanism: because these valves are distorted, turbulence around them causes endothelial injury and formation of microthrombi, which can later be colonised even by low virulence organisms should bacteraemia occur.
• Low-virulence bacteraemia can follow a minor dental or surgical procedure, hence the need for prophylactic antibiotics when a predisposing valve pathology is known.
• The aortic and mitral valves are the most commonly affected, for example in RHD.
• Grossly the mitral valve shows friable, irregular vegetations along the leaflets and chordae.

Acute type

• IE can develop on previously normal valves, especially with high-virulence organisms.
• The source of high-virulence organisms can be IV access, for example a contaminated needle shared by IV drug users.
• The tricuspid valve is frequently affected in this setting, because the IV injection reaches the right side of the heart first.

Acute versus subacute

	Acute infective endocarditis	Subacute infective endocarditis
Organism	High virulence: Staphylococcus aureus, Streptococcus pyogenes, occasionally fungi	Low virulence: oral flora including Streptococcus viridans, enterococci, Haemophilus
Valve/host	Normal valve, with or without a debilitated patient (for example IV drug use)	Diseased valve: RHD, congenital valve anomaly
Course	Destructive, rampant infection	Low grade infection: fever, heart murmur
Fatality	20 to 40%	(not stated on the slide)

Clinico-pathological features

• Big, bulky, friable vegetations containing bacteria, fibrin and inflammatory cells (septic vegetations). Microscopically a septic vegetation shows dense sheets of neutrophils admixed with fibrin and thrombotic debris, with clusters of bacterial cocci among the neutrophils.
• Ulceration with or without destruction of the valve.
• Deterioration of valve function.
• Possible embolisation by septic emboli to the brain, kidneys and elsewhere, which may cause abscesses or septic infarcts. Gross examples include multiple haemorrhagic wedge-shaped infarcts in a solid abdominal organ and multiple haemorrhagic infarcts/abscesses in both cerebral hemispheres of the brain.
• Less valvular destruction occurs in the subacute form.

The pathway in a nutshell

1. Streptococcal pharyngitis (group A beta haemolytic streptococcal infection)
2. leads by cross reactivity to rheumatic fever (RF)
3. leads by scarring to rheumatic heart disease (RHD)
4. leads by bacteraemia to subacute infective endocarditis

Further reading given

Robbins and Cotran Pathologic Basis of Disease, 10th ed, chapter 12 The Heart: calcific valvular degeneration pp. 557 to 559; rheumatic fever and rheumatic heart disease pp. 560 to 563; infective endocarditis pp. 563 to 564. Or Robbins and Kumar Basic Pathology, 11th ed, chapter 9 Heart: degenerative valve disease pp. 328 to 329; rheumatic valvular disease pp. 329 to 331; infective endocarditis pp. 331 to 332. Also the New Zealand Ministry of Health website.

Self-test

1. Define valvular stenosis and state the type of haemodynamic overload it produces.
2. Define valvular regurgitation and state the type of haemodynamic overload it produces.
3. Explain what is meant by functional valve incompetence, and give the example used in the lecture.
4. List the chamber and rhythm complications that follow pressure and/or volume overload, in the order they develop, ending with the two final consequences.
5. Aortic stenosis and mitral regurgitation each produce a characteristic left-sided chamber change. Distinguish them and explain why they differ.
6. List the five etiological categories of valve disease with one example of each.
7. Describe the two anatomical settings in which calcific aortic stenosis occurs, and how the abnormal congenital valve differs from a normal one.
8. Describe the underlying process in mitral valve prolapse and the four-step sequence by which it produces regurgitation.
9. Define acute rheumatic fever, including the trigger, the timing, and the proportion of patients affected.
10. Describe the steps by which group A streptococcal pharyngitis produces cardiac inflammation in rheumatic fever.
11. Distinguish the antibody-mediated and T cell-mediated arms of rheumatic inflammation, naming the hypersensitivity type and the effector mechanism of each.
12. Give three pieces of evidence that rheumatic fever is not a direct bacterial infection of the heart.
13. List the five clinical features of rheumatic fever.
14. List four risk factors for rheumatic fever, and state the age group and the New Zealand population most affected.
15. Describe the steps by which rheumatic valvulitis produces verrucae, and explain why verrucae do not embolise.
16. Describe the microscopic appearance of an Aschoff body, naming the characteristic cell and the feature that gives it its nickname.
17. Describe the pericardial and myocardial morphology of rheumatic pancarditis, including the mortality figure given for rheumatic myocarditis.
18. Explain how acute rheumatic fever progresses to chronic rheumatic heart disease, and state the hallmark of the chronic disease.
19. List the four morphological changes of the rheumatic mitral valve and the distinctive name given to the resulting orifice.
20. State how often the mitral valve is involved alone in RHD and how often together with the aortic valve.
21. Distinguish the vegetations of infective endocarditis from the verrucae of rheumatic fever, on composition and on behaviour.
22. Distinguish acute from subacute infective endocarditis on organism virulence, valve status, clinical course and fatality.
23. Explain why a previously damaged valve is vulnerable to colonisation by low virulence organisms, and what practical prophylactic measure follows.
24. A person who injects drugs presents with rapidly developing fever and chills. Predict which valve is most likely affected, which organism class is most likely responsible, and why.
25. Predict the possible consequences of a bulky friable vegetation on a mitral valve, both locally and distantly.
26. Trace the whole pathway from streptococcal pharyngitis to subacute infective endocarditis, naming the mechanism linking each stage to the next.

Answers

Reveal answers

1. Failure of a valve to open completely, leading to obstruction to blood flow; it produces pressure overload.
2. Failure of a valve to close completely, leading to reversed or retrograde blood flow; it produces volume overload.
3. The valve is structurally normal but cannot close properly because of a change in its supporting geometry. Example: dilation of the right or left ventricle pulls the papillary muscles down and outward, preventing proper closure.
4. Chamber hypertrophy with pressure overload (later failure and dilation), chamber dilation with volume overload, atrial fibrillation secondary to atrial dilation, atrial thrombosis and embolism predisposed to by the AF, and ultimately heart failure plus susceptibility to infective endocarditis.
5. Aortic stenosis imposes pressure overload on the left ventricle, causing left ventricular hypertrophy. Mitral regurgitation imposes volume overload on the left atrium, causing left atrial dilation. Pressure overload produces hypertrophy and volume overload produces dilation.
6. Congenital (aortic stenosis), degenerative or aging (calcific aortic stenosis), hereditary (mitral valve prolapse), immunological (rheumatic fever), infective (infective endocarditis).
7. On an anatomically normal three-cusped aortic valve, and on a congenitally bicuspid aortic valve. In both the valve becomes calcified, nodular and heaped up rather than smooth, thin and pliable. The bicuspid valve has two cusps instead of three, one of them bearing a raphe.
8. Myxomatous degeneration of the mitral valve, giving a ballooned, redundant, floppy leaflet. Sequence: the normal valve closes fully; in prolapse the flap closes abnormally; blood pushes on the prolapsed valve; blood is regurgitated back into the left atrium.
9. An acute, immunologically mediated, multisystem inflammatory disease occurring a few weeks after an episode of group A streptococcal pharyngitis, in about 3% of patients.
10. Antibodies are raised against the M proteins of group A beta haemolytic streptococci and CD4+ T cells specific for streptococcal peptides are generated; both cross-react with self proteins/antigens in the heart (molecular mimicry); the result is combined antibody-mediated and CD4+ T cell-mediated inflammation damaging all three layers of the heart and other tissues.
11. Antibody-mediated is type II hypersensitivity: antibodies deposit in tissue, complement is activated, complement components recruit leukocytes and cause vasodilation and increased vascular permeability, and leukocyte products such as lysosomal enzymes damage tissue. T cell-mediated is type IV hypersensitivity: CD4+ T cells produce cytokines that recruit and activate macrophages.
12. By the time RF develops, streptococci are no longer present in the throat; streptococci are completely absent from the inflammatory lesions of RF; and antibodies against streptococcal antigens are detectable in plasma, indicating an immune rather than infective mechanism.
13. Pancarditis; migratory polyarthritis of large joints; subcutaneous nodules; erythema marginatum of the skin; Sydenham chorea (involuntary rapid, purposeless movements).
14. Any four of: crowded housing, cold damp housing, socio-economic deprivation, barriers to primary healthcare access, higher burden of untreated streptococcal sore throat. It affects children aged 5 to 15, with high incidence among Māori and Pacific people in New Zealand, mostly in the North Island.
15. Inflammation of the valvular endocardium of the mitral and aortic valves creates foci of endothelial injury and necrosis within the cusps or along the chordae tendineae; small (1 to 2 mm) platelet-fibrin thrombi form over these foci, called vegetations or, in RF, verrucae. They do not embolise because they are sterile and adherent to the lines of closure of the valve.
16. A focus with central necrosis surrounded by lymphocytes (mainly T cells), occasional plasma cells, and plump activated macrophages called Anitschkow cells; it is granulomatous with fibrinoid change, and the macrophages may fuse into multinucleated giant cells. The Anitschkow cell nucleus has chromatin condensed into long wavy ribbons, hence “caterpillar cell”.
17. Myocarditis makes the myocardium soft and flabby with dilation of the heart chambers, mostly the left ventricle, and causes heart failure that may rarely lead to death in 1% of cases. Pericarditis gives a shaggy fibrin-rich exudate on the pericardial surface, “bread-and-butter” pericarditis, with an audible friction rub.
18. The active phase of RF heals by fibrosis, leaving permanent valve deformity; after an initial attack there is increased vulnerability to recurrence with subsequent GAS infections, and damage accumulates over months to years with fibrosis increasing at every attack. Valvular scarring and deformity is the hallmark of RHD.
19. Leaflets fibrosed, thickened and distorted; commissures fused; chordae tendineae thickened and shortened; valve dysfunction with stenosis and/or regurgitation. The narrow slit-like orifice is called a “button-hole” or “fish mouth” valve.
20. The mitral valve is affected alone in about two thirds of cases, and together with the aortic valve in a further 25% of cases. The mitral valve is almost always involved, with mitral stenosis the commonest deformity.
21. IE vegetations are composed of thrombotic debris, organisms and inflammatory cells, are big, bulky and friable, and can break off and embolise to distant sites, destroying the valve. RF verrucae are small (1 to 2 mm) sterile platelet-fibrin thrombi adherent to the lines of closure, and do not embolise.
22. Acute: high virulence organisms (Staphylococcus aureus, Streptococcus pyogenes, occasionally fungi), on a normal valve with or without a debilitated patient such as an IV drug user, giving a destructive rampant infection with 20 to 40% fatality. Subacute: low virulence organisms (oral flora including Streptococcus viridans, enterococci, Haemophilus), on a diseased valve such as in RHD or a congenital anomaly, giving a low grade infection with fever and a heart murmur; no fatality figure was given.
23. Distortion of the valve causes turbulent flow, which injures the endothelium and lets microthrombi form; these can later be colonised even by low virulence organisms if bacteraemia occurs. Since low-virulence bacteraemia can follow a minor dental or surgical procedure, prophylactic antibiotics are given when a predisposing valve pathology is known.
24. The tricuspid valve, because an intravenous injection reaches the right side of the heart first; a high-virulence organism such as Staphylococcus aureus from a contaminated shared needle. This is acute infective endocarditis on a previously normal valve.
25. Locally: ulceration and destruction of the valve with deterioration of valve function. Distantly: the friable vegetation can break off as septic emboli to sites such as the brain and kidneys, causing abscesses or septic infarcts.
26. Group A beta haemolytic streptococcal pharyngitis leads by cross reactivity to rheumatic fever; rheumatic fever leads by scarring to rheumatic heart disease; rheumatic heart disease leads, when bacteraemia occurs, to subacute infective endocarditis.