1. The Pathology of Endocardial & Valvular Disease
Doç. Dr. A. Işın Doğan Ekici
Department of Pathology

2. Valvular & Endocardial Disorders
calcific aortic valve stenosis (degenerative),
bicuspid aortic valve (congenital)
calcification of the mitral annulus,
mitral annular calcification,
mitral valve prolapse,
rheumatic heart disease,
three forms of vegetative endocarditis (including infective endocarditis, nonbacterial thrombotic endocarditis, and endocarditis of systemic lupus erythematosus), and
carcinoid heart disease.

3. Valvular abnormalities congenital disorders, acquired diseases.
Valvular insufficiency
intrinsic disease of the valve cusps
damage
distortion of the supporting structures (e.g., the aorta, mitral annulus, chorda tendinea, papillary muscles, ventricular free wall) without primary changes in the cusps.

4. Terminology Stenosis vs. insufficiency / regurgitation
If the cusps stick together, stenosis results.
If scar contraction shortens and bends the valve leaflets, insufficiency / regurgitation results.
Isolated disease refers to disease affecting one valve.
More than one valve may be dysfunctional (combined disease).

5. Stenosis is the failure of a valve to open completely, thereby impeding forward flow.
Insufficiency or regurgitation, in contrast, results from failure of a valve to close completely, thereby allowing reversed flow.
These abnormalities can be either pure, when only stenosis or regurgitation is present, or mixed, when both stenosis and regurgitation are present in a single valve.

6. Valve Deformities

7. Valvular dysfunction can vary in degree from slight and physiologically unimportant to severe and rapidly fatal (sudden death).
At one end of the spectrum, sudden destruction of an aortic valve cusp by infection (as in infective endocarditis) may cause rapidly fatal cardiac failure owing to massive regurgitation.

8. The Vegetations (thrombotic debris/with or without organisms-on the valves)
Acute rheumatic fever
Small, warty, sterile, on the lines of closure
Seldom embolize
Bacterial endocarditis
Often large, loaded with bacteria
On any deformed endocardial surface
Very prone to embolize
Non-bacterial thrombotic ("marantic") endocarditis
Small, sterile, on the lines of closure
May embolize
Libman-Sacks endocarditis (of lupus and antiphosopholipid-antibody syndrome)
Any size, sterile, on either surface of the leaflet

9. Vegetations

11. Mitral Valve
Acquired mitral valve stenosis (MS) is virtually synonymous with rheumatic heart disease.
Rheumatic fever occurs, in genetically susceptible individuals, as a complication of group A streptococcal infection.
Other rare causes of acquired MS include carcinoid causes, systemic lupus erythematosus, rheumatoid arthritis, and some mucopolysaccharidoses.
The underlying pathological process is a diffuse inflammation of connective tissue.

12. Old rheumatic fever (post-inflammatory scarring).
Mitral regurgitation
Abnormalities of leaflets & commisures (birth defects)
Old rheumatic fever
Bacterial endocarditis
Disorders of papillary muscle (rupture-MI, fibrosis)
Ruptured chorda (bacterial endocarditis, Barlow's syndrome)
Dilated annulus (left CHF)
Calcified mitral annulus
Degenerative changes of old age
Mitral valve prolapsus (Barlow's syndrome)
Myocarditis & left ventricle hypertrophy.
Mitral stenosis
Old rheumatic fever (post-inflammatory scarring).

13. Myxomatous degeneration of the mitral valve
Myxomatous degeneration of the mitral valve. Long axis of left ventricle demonstrating hooding with prolapse of the posterior mitral leaflet into the left atrium (arrow). The left ventricle is on the right in this apical four-chamber view.

15. Aortic valve
Aortic stenosis is the obstruction of blood flow across the aortic valve.
Pathophysiology:
When the aortic valve becomes stenotic, resistance to systolic ejection occurs and a systolic pressure gradient develops between the left ventricle and the aorta.
Stenotic aortic valves have a decreased aperture that leads to a progressive increase in left ventricular systolic pressure.
This leads to pressure overload in the left ventricle, which, over time, causes an increase in ventricular wall thickness (ie, concentric hypertrophy).
At this stage, the chamber is not dilated and ventricular function is preserved, although diastolic compliance may be affected.

16. Causes of aortic stenosis
Congenital:
congenital unicuspid aortic valve
congenital bicuspid aortic valves
Congenital bicuspid valves cause calcific aortic stenosis 4 times more frequently than acquired forms do.
Acquired:
rheumatic disease
acquired bicuspid aortic valves
normal valve that calcified
senile calcific aortic stenosis

17. Causes of aortic regurgitation
Aortic root abnormalities
Dilatation
Marfan syndrome
Familial conditions
Ehlers-Danlos syndrome
Pseudoxanthoma elasticum
Idiopathic
Distortion (aortitis)
Syphilis
Rheumatoid arthritis
Ankylosing spondylitis
Nonspecific aortitis
Dissecting hematoma
Aortic cusp abnormalities
Perforation (eg, infective endocarditis)
Cusp shrinkage
Rheumatic disease
Rheumatoid disease
Ankylosing spondylitis
Bicuspid aortic valve
Loss of commissural support
Ventricular septal defect
Dissection (tears) of the aorta

18. Tricuspid Valve
Tricuspid valve dysfunction can result from morphological alterations in the valve or from functional aberrations of the myocardium.
Tricuspid stenosis is almost always rheumatic in origin and is generally accompanied by mitral stenosis.
Stenotic tricuspid valves are always anatomically abnormal, and the cause is limited to a few conditions.
With the exceptions of congenital causes or active infective endocarditis, tricuspid stenosis takes years to develop.

19. Tricuspid regurgitation
Old rheumatic fever (postinflammatory scarring)
Carcinoid syndrome
Bacterial endocarditis
Löffler's syndrome
Dilated annulus (right CHF).
Tricuspid stenosis
Old rheumatic fever (postinflammatory scarring)
Carcinoid syndrome
Congenital abnormalities,
Metabolic or enzymatic abnormalities,
Active infective endocarditis.

20. Pulmonic Valve Pulmonic stenosis Pulmonic insufficiency
Tetralogy of Fallot
Congenital
Carcinoid heart disease
Pulmonic insufficiency
Dilated annulus (right CHF)
Carcinoid heart disease

21. Disorders Degenerative calcific aortic valve stenosis,
Calcification of the mitral annulus,
Bicuspid aortic valve (congenital),
Mitral annular calcification,
Mitral valve prolapse,
Rheumatic heart disease,
Vegetative endocarditis (including infective endocarditis, nonbacterial thrombotic endocarditis, and endocarditis of systemic lupus erythematosus)
Carcinoid heart disease.

22. Degenerative calcific aortic valve stenosis
Bicuspid valves and tricuspid valve accumulates calcium-rich excrescences in its cusps.
Dystrophic calcification
Aortic stenosis
Congenital or acquired (senile degeneration-women are at lower risk).
The calcification is an active process
No commissural fusion
Can block the coronary ostia.

24. Calcific valvular degeneration.
A, Calcific aortic stenosis of a previously normal valve having three cusps (viewed from aortic aspect). Nodular masses of calcium are heaped up within the sinuses of Valsalva (arrow).
B, Calcific aortic stenosis occurring on a congenitally bicuspid valve. One cusp has a partial fusion at its center, called a raphe (arrow).
C-D, Mitral annular calcification, with calcific nodules at the base (attachment margin) of the anterior mitral leaflet (arrows). C, Left atrial view. D, Cut section of myocardium.

25. Bicuspid aortic valve (congenital)
In approximately 1 to 2% of the population, the aortic valve is congenitally bicuspid.
The two cusps are usually of unequal size, less frequently the cusps are of the same size.
Valves that become bicuspid owing to an acquired deformity (e.g., post inflammatory commissural fusion in rheumatic valve disease).

27. Bicuspid aortic valves are generally predisposed to progressive calcification.
The raphe that composes the incomplete commissure is frequently a major site of calcific deposits.
With or without calcification, bicuspid aortic valves may also become incompetent or be complicated by infective endocarditis.

28. Left ventricular outflow obstruction leads to the development of concentric left ventricular (pressure overload) hypertrophy.
Eventually as the stenosis worsens, angina or syncope may appear.
Patients with aortic stenosis are often drastically improved by surgical aortic valve repair or replacement.

29. Mitral Annular Calcification
Degenerative calcific deposits can develop in the ring (annulus) of the mitral valve.
In elderly individuals, especially women.
Irregular, stony hard nodules (2 to 5 mm in thickness) that lie behind the leaflets.
Inflammatory change is absent. The process generally does not affect valvular function .
Calcific nodules may provide a site for thrombi that can embolize (patients with mitral annular calcification have an increased risk of stroke).
Heavy calcific deposits are sometimes visualized on echocardiography or seen as a distinctive, ring-like opacity on chest radiographs.

30. Mitral valve prolapse
("Barlow's disease, "floppy mitral valve", "ballooning mitral valve“)
The mitral valve has an elongated posterior leaflet with some extra ground substance (“myxomatous degeneration”; affects around 2-3% of humankind),
One or both mitral leaflets are enlarged, redundant, or “floppy” and prolapse, or balloon back, into the left atrium during systole.
The histopathology exhibits derangements of all connective-tissue components.

31. MVP Prone to: Mitral valve prolapse is common in Marfan syndrome.
Most patients with mitral valve prolapse are non-familial and asymptomatic
MVP Prone to:
Infective endocarditis,
Mitral insufficiency,
Embolism (stroke),
Arrhythmia,
Chorda may rupture (producing serious mitral regurgitation).

32. Rheumatic fever / rheumatic heart disease
The cardiac pathology is a pancarditis
The endocarditis manifests as verrucae, tiny sterile masses of fibrin and platelets along the lines of closure of the valve leaflets.
Unfortunately, the verrucae are prone to organize, causing deformity of the heart.
If the cusps stick together, stenosis results.
If scar contraction shortens and bends the valve leaflets, insufficiency / regurgitation results.
The aortic and mitral valves are usually affected; the tricuspid sometimes, the pulmonic rarely.

33. Infective Endocarditis
Infective endocarditis is defined as an infection of the endocardial surface of the heart, which may include one or more heart valves, the mural endocardium, or a septal defect.
Endocarditis can be broken down into the following categories:
Native valve (acute and subacute) endocarditis
Prosthetic valve (early and late) endocarditis
Endocarditis related to intravenous drug use.

34. Infective Endocarditis is characterized by;
Colonization or invasion of the heart valves or the mural endocardium by a microbiologic agent, leading to the formation of bulky, friable vegetations laden with organisms.
Not only the valves, but also
the aorta (infective endoaortitis),
aneurysmal sacs,
other blood vessels can also become infected.

35. Native valve endocarditis (acute and subacute)
Native valve acute endocarditis usually has an aggressive course.
Staphylococcus aureus and group B streptococci, are causative agents when underlying structural valve disease is not present.
Subacute endocarditis usually has a more indolent course than the acute form.
In the setting of underlying structural valve disease, Alpha-hemolytic streptococci or enterococci, usually typically are the causative agents of this type of endocarditis.

36. Prosthetic valve endocarditis (early and late)
Early prosthetic valve endocarditis occurs within 60 days of valve implantation:
Staphylococci, gram-negative bacilli, and Candida species are the common infecting organisms.
Late prosthetic valve endocarditis occurs 60 days or more after valve implantation:
Staphylococcus epidermidis, alpha-hemolytic streptococci, and enterococci are the common causative organisms.

37. Complications of Artificial Valves
(1) thromboembolism (local occlusion of the prosthesis by thrombus or distant thromboemboli),
(2) infective endocarditis,
(3) partial dehiscence (separation) of the suture line anchoring the valve leading to a paravalvular leak,
(4) durability problems caused by structural deterioration,
(5) intrinsic (design-related) obstruction to forward flow.

38. Endocarditis related to intravenous drug use
Endocarditis in intravenous drug abusers commonly involves the tricuspid valve. S. aureus is the most common causative organism.

39. Infectious agents
Every form of microbiologic agent, including fungi, rickettsiae (Q fever), and chlamydia, has at one time or another been responsible for these infections, but most cases are bacterial, hence the usual term, bacterial endocarditis.
More than half of cases are attributable to various streptococci–most prominently the viridans group,
Streptococci are the dominant cause of subacute disease.

40. The highly virulent Staphylococcus aureus accounts overall for about 20 to 30% of cases; it can infect normal valves and is the leading cause of acute endocarditis.
Other significant etiologic agents include Streptococcus pneumoniae, gram negative enteric bacilli, and fungi.
Fungal endocarditis
Fungal endocarditis is found in intravenous drug users and intensive care unit patients who receive broad-spectrum antibiotics.
Blood cultures are often negative, and diagnosis frequently is made after microscopic examination of large emboli.

41. Predisposing influences of IE
neutropenia,
immunodeficiency (including patients infected with HIV ),
therapeutic immunosuppression (as in organ transplant recipients),
indwelling vascular catheters,
diabetes mellitus,
alcohol,
intravenous drug abuse.

42. Clinical signs
One or more classic signs of infective endocarditis are found in as many as 50% of patients. They include the following:
Petechiae- Common but nonspecific finding
Splinter hemorrhages - Dark red linear lesions in the nailbeds
Osler nodes - Tender subcutaneous nodules usually found on the distal pads of the digits
Janeway lesions - Nontender maculae on the palms and soles
Roth spots - Retinal hemorrhages with small, clear centers; rare and observed in only 5% of patients.

43. Signs of neurologic disease (40%; Embolic stroke with focal neurologic deficits, intracerebral hemorrhage, multiple microabscesses)
Multiple embolic pulmonary infections or infarctions are due to right heart disease
Congestive heart failure frequently due to acute left-sided valvular insufficiency
Splenomegaly.
Splinter hemorrhages
Seen here in the finger are small splinter hemorrhages in a patient with infective endocarditis.
These hemorrhages are subungual, linear, dark red streaks.
Similar hemorrhages can also appear with trauma.

44. PATHOGENESIS Blood flow in the normal heart is laminar.
If the flow becomes turbulent (i.e., usually due to congenital or rheumatic deformities), endothelium is likely to be damaged.
If endothelium is damaged, tiny platelet-fibrin clots (vegetation) can form on the valves.
A bacterium can get enwrapped in the clot.
The vegetations are composed of fibrin, inflammatory cells, and organisms.

45. Acute infective endocarditis
Destructive infection,
usually of a previously normal heart valve
with a highly virulent organism,
leads to death within days to weeks of more than 50% of patients,
Drug abuse with repeated contamination of the blood,
Indwelling vascular catheters,
Prosthetic valves (that constitute foreign bodies inviting the localization of blood-borne agents).
Direct attachment of bacteria to valvular endothelial cells may also be important in the pathogenesis of acute endocarditis.

46. Subacute infective endocarditis
Previously abnormal heart, organisms of low virulence can cause infection,
particularly on deformed valves;
the disease may appear insidiously and, even untreated, pursue a protracted course of weeks to months (subacute endocarditis).
in contrast to the high mortality of acute form, most patients with subacute infective endocarditis recover after appropriate therapy.

47. In subacute endocarditis, the portal of entry of the agent into the bloodstream may be overt, as with an
established infection elsewhere,
drug addiction,
a previous dental or surgical procedure or nosocomial.
transient bacteremias (frequently from the gut, oral cavity, and trivial injuries, seeding the blood with organisms that are usually of low virulence, e.g., Streptococcus viridans, Streptococcus faecalis, Escherichia coli).

48. Nosocomial bacteremias
Endoscopy
Rate of 0-20%
CONS, streptococci, diphtheroids
Colonoscopy
Escherichia coli, Bacteroides species
Barium enema
Enterococci, aerobic and anaerobic gram-negative rods
Dental extractions
Rate of %
S viridans
Transurethral resection of the prostate
Rate of 20-40%
Coliforms, enterococci, S aureus
Transesophageal echocardiography
Rate of 0-20%
S viridans, anaerobic organisms, streptococci.

49. Morphology
The vegetations are composed of fibrin, inflammatory cells, and organisms.
the highly virulent organisms of acute endocarditis tend to produce necrotizing, ulcerative, invasive valvular infections,
the lower virulence organisms of subacute disease are less destructive, and the vegetations often show evidence of healing.

50. The diagnostic findings in both the subacute and acute forms of the disease are
friable,
bulky,
usually bacteria-laden fibrinous vegetations
most commonly on the heart valves.
They may occur singly or multiply on one or more valves on either side of the heart, are up to several centimeters in greatest dimension, and are readily fragmented.

52. Morphology: Acute endocarditis
The vegetations are situated more often on previously normal valves,
cause perforation or erosion of the underlying valve leaflet,
sometimes erode into the underlying myocardium to produce an abscess cavity (ring abscess),

53. Acute endocarditis

54. Acute endocarditis

55. Acute endocarditis

56. Myocardial abscess

57. Morphology: Subacute endocarditis
Vegetations are smaller and less often erode or perforate the cusps.
With non-valvular congenital defects, the vegetations tend to be located on the “downstream” margin of the jet stream (e.g., on the right ventricular margins of a ventricular septal defect).

58. Subcute endocarditis

59. Subcute endocarditis

60. After treatment
The vegetations sometimes undergo progressive sterilization, organization, and fibrosis
eventually become calcified, leaving only irregular heaped-up fibrocalcific nodular excrescences on the valve leaflets (“healed endocarditis”).
A residual perforation that occurred during the active phase may be noted.
Valves with healed endocarditis frequently show neovascularization.

61. Pathologic effects due to infection:
Prognosis:
Acute endocarditis due to S. aureus is associated with a high mortality rate (40%), except when it is associated with IV drug use.
Endocarditis due to streptococci has a mortality rate of approximately 10%.
Prognosis largely depends on whether or not complications develop.
Pathologic effects due to infection:
Local tissue destruction
Septic embolism
Secondary autoimmune effects,
immune complex glomerulonephritis
vasculitis.

62. Complications: Cardiovascular complications: Renal complications:
Myocardial infarction, pericarditis, cardiac arrhythmia
Cardiac valvular insufficiency
Congestive heart failure
Sinus of Valsalva aneurysm
Aortic root or myocardial abscesses
Arterial emboli, infarcts, mycotic aneurysms
Renal complications:
Renal failure
Glomerulonephritis (focal or diffuse),
Infarction,
Others:
Stroke syndromes
Mesenteric or splenic abscess or infarct
Arthritis, myositis.

63. Nonbacterial Thrombotic Endocarditis
A form of vegetative endocarditis most often encountered in debilitated patients, such as those with cancer or sepsis– hence the previously used term marantic endocarditis.
Frequently occurs concomitantly with venous thromboses or pulmonary embolism
in a hypercoagulable state with systemic activation of blood coagulation.
Underlying diseases:
Cancer (particularly, mucinous adenocarcinomas of the pancreas, gastrointestinal tract, or ovary)
Promyelocytic leukemia
Endocardial trauma (as from an indwelling catheter ).

64. MORPHOLOGY of nonbacterial thrombotic endocarditis
The deposition of small, sterile masses of fibrin and other blood elements on the valve leaflets of either side of the heart, usually on previously normal valves.
The vegetations do not contain organisms, are nondestructive, tend to be small (1 to 5 mm), and occur singly or multiply along the line of closure of the leaflets or cusps
Histologically, they are composed of bland thrombus without accompanying inflammatory reaction, organization, or induced valve damage.

65. Complications The local effect on the valves is unimportant,
Embolism and resultant infarcts in the
brain,
heart.

66. Libman-Sacks Disease
In Systemic lupus erythematosus (SLE) and in Antiphospholipid syndrome,
mitral and tricuspid valvulitis,
small, sterile vegetations (1-4 mm in diameter)
granular pink vegetations ( single or multiple)
vegetations are located on the undersurfaces of the atrioventricular valves, (may be scattered on the valvular endocardium, on the chordae tendineae, and on the mural endocardium of atria or ventricles).

67. An intense valvulitis is present,
Histology:
The verrucae consist of a finely granular, fibrinous eosinophilic material that may contain hematoxylin bodies
the tissue equivalent of the lupus erythematosus cell of the blood and bone marrow
An intense valvulitis is present,
characterized by fibrinoid necrosis of the valve substance that is often contiguous with the vegetation.

68. Libman-Sacks Disease

69. Carcinoid Heart Disease
In patients with carcinoid tumors,
Cardiac involvement, principally of the endocardium and valves of the right heart.
The Carcinoid syndrome
distinctive episodic flushing of the skin and cramps,
nausea, vomiting, and diarrhea
bronchoconstrictive episodes resembling asthma.
cardiac lesions in about one-half (tricuspid and pulmonic valves may malfunction, with tricuspid regurgitation).

70. The cardiac changes are largely right-sided
Carcinoid tumors primary in organs outside of the portal system of venous drainage (e.g., ovary or lung), whose venous drainage bypasses the liver, may induce the carcinoid syndrome (because there is rapid metabolism of serotonin during passage of blood through the liver)
HISTOLOGY: distinctive, comprising fibrous intimal thickenings on
the inside surfaces of the cardiac chambers and valvular leaflets,
mainly in the right ventricle and tricuspid and pulmonic valves,
and occasionally the major blood vessels.