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                        Pathology 655 January 23, 2008
                                Peter B. Baker, M.D.

1. List the pathologic processes that cause valvular stenosis and insufficiency.
2. Know the pathogenesis and complications of infectious endocarditis.
3. Describe the pathology, etiology, and clinical features for each form of vasculitis.
4. Describe the pathology of aortic dissection and know the complications and
   predisposing factors.

REFERENCE: Cotran, Kumar, Robbins, Pathologic Basis of Disease, 8th ed.,
Chapter 10, pages 359-369 and Chapter 11, pages 401-408.


   A. Mitral Stenosis
      Acquired stenosis is usually due to chronic rheumatic valvular disease. Acute
      rheumatic fever is a systemic disease which follows a group A beta-hemolytic
      streptococcal pharyngitis. Acute rheumatic fever (RF) produces myocarditis,
      pericarditis, arthralgia or arthritis, and other manifestation. The myocarditis is
      characterized by Aschoff bodies which are collections of mononuclear
      inflammatory cells and fibroblasts. Recurrent bouts of RF eventually lead to
      severe fibrosis and calcification of the mitral valve and possibly other heart
      valves. The disease is thought to be due to the production of antibodies against
      the streptococcal bacteria which cross react with various antigens in the heart,
      joints and other sites.

  B. Mitral Valve Regurgitation
     This may be caused by a variety of conditions including IHD and endocarditis.
     Mitral valve prolapse is a condition in which the leaflets balloon into the left
     atrium during left ventricular contraction (systole). Mild prolapse is very common
     and occurs in 5-10% of the general population. Severe prolapse may be
     associated with valvular regurgitation. Some patients also experience chest pain
     and palpitations. Endocarditis, mitral regurgitation, thromboemboli and sudden
     death (rare) are potential complications. In severe prolapse (also called floppy
     mitral valve) the valve cusps are large and microscopically show fragmentation,
     separation and loss of collagen (myxomatous degeneration). Floppy mitral valve
     may be an isolated abnormality or part of a systemic connective tissue disorder
     such as Marfan’s syndrome.

  C. Aortic Valve Stenosis
     Fibrosis and calcification reduce the valve cusp mobility. This can be due to
     chronic rheumatic valvular disease (in these cases the mitral valve is almost
     always stenotic), or may occur with advanced age (over 65 years). Bicuspid

      aortic valve is a common congenital malformation and these valves are
      predisposed to calcification and fibrosis beginning at about 40 years of age.

  D. Aortic Valve Regurgitation
     The mechanisms include valve cusp destruction (endocarditis), myxomatous
     degeneration and dilation of the aortic root.

  E. Infectious Endocarditis
     This is usually caused by a bacterial infection in a heart valve, although it may
     also be caused by fungus or other unusual infections. Predisposing factors
     include abnormal heart valves, prosthetic valves, intravenous drug use,
     intracardiac shunts and immunosuppression. The three factors that have been
     identified as having importance in the pathogenesis include: 1) endocardial
     damage due to abnormalities in blood flow; 2) fibrin thrombi; and 3) organisms in
     the blood.

      1. Clinical manifestations include: fever, heart murmur, fatigue, anemia,
         arthralgia, myalgia, and Roth spots (retinal hemorrhages)
      2. Complications:
         a. rupture of chordae tendineae
         b. spread of infection into myocardium or aorta
         c. thromboembolism with infarctions
         d. septic thrombi with metastatic abscesses
         e. valvular dysfunction and CHF

             Acute Endocarditis                    Subacute Endocarditis

             short duration                        longer duration
             virulent organism                     organism of low virulence
             (Staphylococcus aureus)               (Streptococcus viridans)
             large friable vegetations             small vegetations
             previously normal valve               previously abnormal valve
             prominent tissue destruction          less tissue destruction


      Vasculitis may be caused by infection (usually due to direct spread of an
      adjacent infection; some microorganisms infect endothelial cells and cause a
      vasculitis). Other causes include mechanical trauma, toxins, caustic substances,
      radiation and immune complexes.

   A. Classification
      1. Large vessel
             Giant cell (temporal) arteritis
             Takayasu arteritis
      2. Medium vessel

         Polyarteritis nodosa (classic)
         Kawasaki syndrome
   3. Small vessel
         Microscopic polyarteritis
         Wegener’s granulomatosis

B. Pathogenesis of immune-mediated vasculitis
   1. immune complex formation
   2. antineutrophilic cytoplasmic antibodies (ANCA)
          Perinuclear localization (pANCA) – microscopic polyarteritis
          Diffuse cytoplasmic (cANCA) – Wegener’s granulomatosis

 C. Giant Cell (Temporal) Arteritis

   Etiology:    Unknown (?T-cell mediated)

   Clinical:    Fever, weight loss, headache, visual problems, claudication of jaw,
                pain and tenderness over temporal artery, polymyalgia rheumatica.
                Rare under the age of 50 years.

   Pathology:   Granulomatous inflammation with giant cells, fibrosis.

D. Takayasu’s Arteritis

   Etiology:    Unknown

   Clinical:    Thickening of the wall reduces blood flow in the major branches off
                the arch (“pulseless disease” due to weak pulses in the arms).
                Usually affects young women.

   Pathology:   Granulomatous inflammation with fibrosis involving the aortic arch
                and the arch branches.

E. Polyarteritis nodosa

   Etiology:    Unknown in most cases. Thirty percent (30%) have hepatitis B
                surface antigen in the serum.

   Clinical:    Fever, weight loss, hematuria, renal failure, hypertension,
                abdominal pain, melena. Clinical presentation may be very
                confusing due to involvement of multiple organ systems.

   Pathology:   Haphazard and segmental involvement of medium and small
                muscular arteries. Acute lesions show fibrinoid necrosis,
                thrombosis, neutrophils, aneurysms. With healing there is
                predominance of macrophages and plasma cells; progressive
                fibrous scarring. Usual sites of involvement are: kidneys (85%),
                heart (75%), liver (65%), and GI tract (50%).

F. Kawasaki’s Disease

   Etiology:    It is suspected that a viral infection triggers a hypersensitivity

   Clinical:    Affects infants and young children. Skin rash, mucous membrane
                lesions, lymphadenopathy. Usually self-limited but 1-2% die with
                coronary artery vasculitis.

G. Microscopic Polyarteritis

   Etiology:    Often due to antigen-antibody complexes.

   Clinical:    Fever, rash, joint swelling, pleural effusion, pulmonary infiltrates,
                myocarditis, GI bleeding, renal failure, presence of circulating anti-
                neutrophilic cytoplasmic antibodies (pANCA). May be manifestation
                of malignancy, autoimmune disease or other disorder.

   Pathology:   Involves arterioles, capillaries, venules. Fibrinoid necrosis,
                neutrophils (leukocytoclastic vasculitis).

G. Wegener’s granulomatosis

   Etiology:    Probably a form of T-cell mediated hypersensitivity.

   Clinical:    Involves sinuses, lungs and kidneys glomerulonephritis).Associated
                with the presence of anti-neutrophilic cytoplasmic antibodies

   Pathology:   Necrotizing granulomas with vasculitis.

D. Buerger’s Disease (Thromboangiitis obliterans)

   Etiology:    Endothelial injury from a substance in cigarette smoke

     Clinical:     Usually begins before age 35. Pain and ischemia in extremities.

     Pathology:    Segmental acute and chronic vasculitis mainly in extremities with


  A. Longitudinal tear of the aortic media which begins in the ascending aorta and
     extends variable distance proximal (toward the heart) and distal to the
     descending aorta.

  B. Complications: severe hemorrhage from rupture, organ ischemia due to luminal
     compression by the expanding hematoma.

  C. Predisposing factors: hypertension, inherited connective tissue disorders (i.e.,
     Marfan’s syndrome) with medial degeneration.

Key Points

  1. Repeated episodes of acute rheumatic fever; mitral valve fibrosis and
     calcification; valvular stenosis

  2. Histopathologic feature (myxomatous degeneration) and complications of severe
     mitral valve prolapse

  3. Mechanisms of aortic valve stenosis and regurgitation

  4. Features (acute and subacute) and complications of endocarditis

  5. Giant cell arteritis: large arteries, temporal artery, granulomatous inflammation

  6. Polyarteritis nodosa: medium to small arteries, haphazard involvement, fibrinoid
     necrosis and aneurysm formation

  7. Microscopic polyarteritis: microvasculature, fibrinoid necrosis and

  8. ANCA positive forms of vasculitis: Wegener’s granulomatosis, microscopic

  9. Dissecting hematoma: split (hematoma) in the media, complications -
     hemorrhage and branch obstruction


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