Systemic disease of connective tissues

June 16, 2024
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GENERAL MORPHOLOGY OF RHEUMATOID DISEASE. RHEUMATIC  FEVER. SYSTEMIC LUPUS ERYTHEMATOSUS. POLYARTERITIS NODOSA.

ANKYLOSING SPONDYLITIS. SLERODERMA.

 

CONNECTIVE TISSUE DISEASES

There is no agreed definition of a ‘connective tissue disease’. It is a convenient general term which covers a wide variety of disorders:

  • rheumatoid arthritis

  • systemic lupus erythematosus (SLE)

  • polyarteritis nodosa

  • ankylosing spondylitis, Reiter’s disease and related disorders

  • polymyositis and dermatomyositis

  • polymyalgia rheumatica

  • temporal/cranial (giant cell) arteritis

  • systemic sclerosis (scleroderma)

  • mixed connective tissue disease (MCTD).

These disorders have the following common features:

  • multisystem disorders, often affecting joints, skin and subcutaneous tissues

  • females preferentially affected (except in polyarteritis nodosa and ankylosing spondylitis), weak genetic tendency

  • chronic clinical course, may respond to anti-inflammatory drugs

  • first presentation may be during adolescence or early adult life

  • immunological abnormalities often present, either circulating auto-antibodies or evidence of immune complex deposition.

Ankylosing spondylitis

  • Relatively uncommon inflammatory disorder of spinal joints

  • 90% of cases have the HLA-B27 haplotype

  • Systemic features include peripheral arthritis, uveitis, aortic valve incompetence and chronic inflammatory bowel disease

The term ‘spondylitis’ implies an inflammatory disorder of the spine, whereas ‘spondylosis’ is used to describe the commoner degenerative osteoarthritic change.

Epidemiology

Fully developed ankylosing spondylitis is rare and occurs in only 1 in 1000 middle-aged male adults, and rather fewer females. About 90% of patients with unequivocal ankylosing spondylitis have the HLA antigen B27-one of the strongest disease associations with a particular HLA haplotype. Once this association was established, surveys were undertaken to determine what proportion of the 5-10% of the Caucasian population who are B27-positive had signs of spondylitis. Depending on the stringency of the criteria used for diagnosis, up to 15% of these patients have some evidence of mild spondylitis but only 1-2% of severe spondylitis. The first symptoms usually occur before the age of 30 years.  

Clinicopathological features

Information on the underlying pathological changes can be obtained only by sequential radiological studies or postmortem examination of the occasional patients who die in the early stages of the disease. The inflammatory process begins at the entheses where ligaments are attached to vertebral bone. As these lesions heal, there is reactive new bone formation in the adjacent ligaments and sclerosis of the underlying bone. The earliest changes are often present in the sacro-iliac joints and may be detected by careful radiological examination or computerised tomography. Pain may be produced if the lower portion of the sacrum is depressed forward with the patient lying face down. Fusion of the vertebral bodies inhibits both flexion and rotation, and this is particularly disabling when the cervical segment is affected. Some patients develop fixed spinal deformities.

The symptoms and lesions strongly associated with ankylosing spondylitis are:

  • pelvic and back pain; chronic inflammatory changes in entheses, progressing to bony ankylosis

  • peripheral arthritis (30%), often sparing the hands

  • anterior uveitis

  • aortic incompetence

  • inflammatory bowel disease.

At least 30% of patients with typical ankylosing spondylitis have a peripheral arthropathy. There are no specific histological features that distinguish this from other low-grade forms of arthropathy, but the clinical distribution is distinctive. Lower limb joints and the shoulders are often involved, but the lower arm, and particularly the hands, are usually spared. The arthritis may begin before, together with, or some time after the first back symptoms.

Ankylosing spondylitis is one of the diseases that is associated with uveitis. In most cases, the anterior part of the eye, the iris and ciliary body, are affected, and choroidal changes are less common. The cause of the majority of cases of uveitis is unknown but between 10 and 20% will have some evidence of spondylitis. Uveitis is also associated with inflammatory bowel disease, and there is no doubt that both Crohn’s disease and ulcerative colitis are more common in those with ankylosing spondylitis than in the general population. The best-recognised cardiovascular complication of spondylitis is aortic incompetence, but this is present in only 1-2% of longstanding cases. Pathologically, there is a chronic inflammatory aortitis, usually restricted to the valve ring and ascending aorta.

RHEUMATIC FEVER

  • Characterised by joint pain, skin rashes and fever

  • Due to a disordered immune reaction to a Lancefield group A β-haemolytic streptococcal pharyngeal infection

  • Associated with pancarditis

  • Commonest in children 5-15 years, boys more than girls

Rheumatic fever is a disease of disordered immunity characterised by inflammatory changes in the heart  and joints and in some cases associated with neurological symptoms (chorea). The disease is common in India, the Middle East and Central Africa. Although it is now rare in Europe and North America, occasional clusters of cases do occur and several recent outbreaks in the United States have emphasised that the disease must be considered in any child or adolescent with joint pain, skin rashes or unexplained fever. Polyarthritis is the presenting feature in over 75% of cases and usually involves the large joints of the wrists, elbows, knees and ankles. The arthritis characteristically ‘flits’ from joint to joint, involving each for 2-4 days, and may cause severe pain. In the acute phase the inflammation involves the endocardium, the myocardium and the pericardium (‘pancarditis’). Heart murmurs are common and children can die from cardiac failure.

Most patients have had a recent sore throat, typically a group A β-haemolytic streptococcal infection. Disappointingly there have beeo recent advances in the understanding of the underlying immunopathology. For many years it has been known that there is a strong antibody reaction to the streptococcus and it is thought that this may cross-react with as yet unknown antigens in connective tissues, especially in the heart and joints.

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 Myxomatous degeneration of the mitral valve. A, Long axis of lew ventricle demonstrating hooding with prolapse of the posterior mitral leaflet intothi left atrium (arrow). The left ventricle is on right in this apical four-chamber view, j (Courtesy of William D. Edwards, M.D., Mayo Clinic, Rochester, MN.) 6, Opened I valve, showing pronounced hooding of the posterior mitral leaflet with thrombolitI plaques at sites of leaflet-left atrium contact (arrows). C, Opened valve with pro-1 nounced hooding from patient who died suddenly (double arrows). Note alsomilnj annular calcification (arrowhead).

 

    The pathogenetic sequence and key morphologic features of acute rheumatic heart disease.

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 Infective (bacterial) endocarditis. A, Endocarditis of mitral valve (subacute, caused by Strep, viridans). The large, (r J vegetations are denoted by arrows. B, Acute endocarditis of congenitally bicuspid aortic valve (caused by Staph, aureus!wfnteM sive cuspal destruction and ring abscess (arrow). C, Histologic appearance of vegetation of endocarditis with extensive aculeinU matory cells and fibrin. Bacterial organisms were demonstrated by tissue Gram stain. (C, reproduced from Schoen FJ: Su9 pathology of removed natural and prosthetic heart valves. Human Pathol 18:558, 1987.) D, Healed endocarditis, demonstratingd valvular destruction but no active vegetations.

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  Diagrammatic comparison of the lesions in the four major forms of vegetative endocarditis. The rheumatic fever phase MD (rheumatic heart disease) is marked by a row of small, warty vegetations along the lines of closure of the valve leaflets. IE

fcliveendocarditis) is characterized by large, irregular masses on the valve cusps that can extend onto the chordae.

«TE (nonbacterial thrombotic endocarditis) typically exhibits small, bland vegetations, usually attached at the line of closure. One or

Mymav be present . LSE (Libman-Sacks endocarditis) has small or medium-sized vegetations on either or both sides

fttevelve leaflets.

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 Nonbacterial thrombotic endocarditis (NBTE). A, Nearly complete row of thrombotic vegetations along the line of lure of the mitral valve leaflets (arrows). B, Photomicrograph of NBTE, showing bland thrombus, with virtually no inflammation in iwwcusp (c)or the thrombotic deposit (t). The thrombus is only loosely attached to the cusp (arrow)

g

Carcinoid heart disease. A, Characteristic endocardial fibrotic lesion involving the right ventricle and tricuspid valve. t,Microscopic appearance of carcinoid heart disease with intimal thickening. Movat stain shows underlying myocardial elastic tissue Hack and acid mucopolysaccharides blue-green.

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 Complications of artificial heart valves. A, Thrombosis of a mechanical prosthetic valve. 8, Calcification with secondi tearing of a porcine bioprosthetic heart valve, viewed from the inflow aspect.

 

 Dilated cardiomyopathy. A, Gross photograph. Four-chamber dilatation and hypertrophy are evident. There is granu-ralthrombus at the apex of the left ventricle (on the right in this apical four-chamber view). The coronary arteries were unob-pd. 8, Histology demonstrating variable myocyte hypertrophy and interstitial fibrosis (collagen is highlighted as blue in this won trichrome stain).

 

 Arrythmogenic right ventricular cardiomyopathy. A, Gross photograph, showing dilation of the right ventricle c-ri J transmural replacement of the right ventricular free-wall myocardium by fat and fibrosis. The left ventricle has a virtually ncrmd:] figuration. 6, Histologic section of the right ventricular free wall, demonstrating replacement of myocardium (red) by fibtosiiJ arrow) and fat (collagen is blue in this Masson trichrome stain).

 

 Hypertrophic cardiomyopathy with asymmetric septal hypertrophy. A, The septal muscle bulges into the left ventricular tract, and the left atrium is enlarged, the anterior mitral leaflet has been moved away from the septum to reveal a fibrous endo-* plaque larrow) (see text). B, Histologic appearance demonstrating disarray, extreme hypertrophy, and characteristic branching of Wesaswell as the interstitial fibrosis characteristic of hypertrophic cardiomyopathy (collagen is blue in this Masson trichrome stain). tSchematic structure of the sarcomere of cardiac muscle, highlighting proteins in which mutations cause defective contraction, hyper-tBpliy.and myocyte disarray in hypertrophic cardiomyopathy. The frequency of a particular gene mutation is indicated as a percentage lallcasesof HCM; most common are mutations in p-myosin heavy chain. Normal contraction of the sarcomere involves myosin-actin fraction initiated by calcium binding to troponin C, I, and T and a-tropomyosin. Actin stimulates ATPase activity in the myosin head nlproduces force along the actin filaments. Myocyte-binding protein C modulates contraction. (A, reproduced by permission from IwnFJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, W.B. Saunders, fctfrom Spirito P, et al: The management of hypertrophic cardiomyopathy.

 

 Myocarditis. A, Lymphocytic myocarditis, with mononuclear inflammatory cell infiltrate and associated myocyte injury.

persensitivity myocarditis, characterized by interstitial inflammatory infiltrate composed largely of eosinophils and mononuclear Hjrnatory cells, predominantly localized to perivascular and large interstitial spaces. This form of myocarditis is associated with (hypersensitivity. C, Giant cell myocarditis, with mononuclear inflammatory infiltrate containing lymphocytes and macrophages, Wve loss of muscle, and multinucleated giant cells. D, The myocarditis of Chagas disease. A myofiber is distended with try-toes [arrow). There is a surrounding inflammatory reaction and individual myofiber necrosis.

 

Acute suppurative pericarditis as an extension from a pneumonia. Extensive purulent exudate is evident in this in situ photograph.

 

myxoma. A, Gross photograph showing large pedunculated lesion arising from the region of the fossa ovalis and extending into the mitral valve orifice. S, Micro­scopic appearance, with abundant amorphous extracellular matrix in which are scattered collections of myxoma cells in various group­ings, including abnormal vascular formations (arrow).

 

 Complications of heart transplantation. A, Cardiac allograft rejection typified by lymphocytic infiltrate, with associated peto cardiac myocytes. B, Graft coronary arteriosclerosis, demonstrating severe diffuse concentric intimal thickening producing ■stenosis. The internal elastic lamina (arrow) and media are intact (Movat pentachrome stain, elastin black). (B, reproduced by ■Won from Salomon RN, et ah Human coronary transplantation-associated arteriosclerosis. Evidence for chronic immune reac-Itoictivated graft endothelial cells.

Systemic Pathology

production of myofilaments, myofibrils, other cell organelles and nuclear enlargement. Since the adult myocardial fibres do not divide, the fibres are hyper-trophied. However, the sarcomeres may divide to increase the cell width.

PATHOLOGIC CHANGES. Grossly, the most signifi­cant finding is marked hypertrophy of the heart, chiefly of the left ventricle. The weight of the heart increases to 500 gm or more (normal weight about 300 gm). The thickness of the left ventri­cular wall increases from its normal 13 to 15 mm upto 20 mm or more. The papillary muscles and trabeculae carneae are rounded and prominent. Initially, there is concentric hypertrophy of the left ventricle (without dilatation). But when decompen­sation and cardiac failure supervene, there is eccentric hypertrophy (with dilatation) with thinning of the ventricular wall and there may be dilatation and hypertrophy of right heart as well. Microscopically, the features are not as prominent as macroscopic appearance. The changes include enlargement and degeneration of myocardial fibres with focal areas of myocardial fibrosis. In advanced cases, there may be myocardial oedema and foci of necrosis in the myocardium.

COR PULMONALE

Cor pulmonale (cor = heart; pulmonale = lung) or pulmo­nary heart disease is the disease of right side of the heart resulting from disorders of the lungs. It is charac­terised by right ventricular dilatation or hypertrophy, or both. Thus, cor pulmonale is the right-sided counter­part of the hypertensive heart disease described above. Depending upon the rapidity of development, cor pulmonale may be acute or chronic:

   Acute cor pulmonale occurs following massive pulmonary embolism resulting in sudden dilatation of the pulmonary trunk, conus and right ventricle.

   Chronic cor pulmonale is more common and is often preceded by chronic pulmonary hypertension . The various chronic lung diseases causing chronic pulmonary hypertension and subsequent cor pulmonale are:

i) chronic emphysema; ii) chronic bronchitis; iii) pulmonary tuberculosis; iv) pneumoconiosis; v) cystic fibrosis; vi) hyperventilation in marked obesity

syndrome); and vii) multiple organised pulmonary emboli.

PATHOGENESIS. Chronic lung diseases as diseases of the pulmonary vessels cause incr pulmonary vascular resistance and increased pu nary blood pressure (pulmonary hypertension). P nary hypertension causes pressure overload on the ventricle and hence right ventricular enlarge Initially, there is right ventricular hypertrophy, I cardiac decompensation sets in and right heart f ensues, dilatation of right ventricle occurs.

PATHOLOGIC CHANGES. In acute cor pulmonale,] there is characteristic ovoid dilatation of the right ventricle, and sometimes of the right atrium. In chronic cor pulmonale, there is increase in thickness of the right ventricular wall from its normal 3 to 5 mm upto 10 mm or more. Often, there is dilatation of the right ventricle too.

RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE

DEFINITION

Rheumatic fever (RF) is a systemic, post-streptococcal, I non-suppurative inflammatory disease, principally’ affecting the heart, joints, central nervous system, skiii, and subcutaneous tissues. The chronic stage of RF involves all the layers of the heart (pancarditis) causing! major cardiac sequelae referred to as rheumatic heart disease (RHD). In spite of its name suggesting an acute arthritis migrating from joint to joint, it is now well known that it is the heart rather than the joints which

CHRONIC LUNG DISEASES. PULMONARY VASCULAR DISEASE

 

AORTIC VALVE (VENTRICULAR SURFACE)

 

Rheumatic valvulitis. A, Location of vegetations on the valves of the left heart. The location of vegetations on mitral valve (above) is shown as viewed from the left atrium, while the vegetations on aortic valve (below) are shown as seen from the left ventricular surface. B, Microscopic structure of the rheumatic valvulitis and a vegetation on the cusp of mitral valve in sagittal section.

   Aortic alone=2%.

   Mitral+aortic+tricuspid+pulmonary=less than 1% cases.

Thus, mitral valve is almost always invoved in RHD. Gross appearance of chronic healed mitral valve in RHD is characteristically ‘fish mouth’ or ‘button hole’ stenosis. Mitral stenosis and insufficiency are commonly combined in chronic RHD; calcific aortic stenosis may also be found. These healed chronic valvular lesions in RHD occur due to diffuse fibrocollagenous thickening and calcification of the valve cusps or leaflets which cause adhesions between the lateral portions, especially in the region of the commissures. Thickening, shortening and fusion of the chordae tendineae further contribute to the chronic valvular lesions.

Microscopically, the inflammatory changes begin in the region of the valve rings (where the leaflets are attached to the fibrous annulus) and then extend throughout the entire leaflet, whereas vegetations are usually located on the free margin of the leaflets and cusps.

INCIDENCE

The disease appears most commonly in children between the age of 5 to 15 years when the streptococcal infection is most frequent and intense. Both the sexes are affected equally, though some investigators have noted a slight female preponderance.

The geographic distribution, incidence and severity of RFand RHD are generally related to the frequency and severity of streptococcal pharyngeal infection. The disease is seen more commonly in poor socioeconomic strata of the society living in damp and overcrowded places which promote interpersonal spread of the streptococcal infection. Its incidence has declined in the developed countries as a result of improved living conditions and use of antibiotics in streptococcal infection. But it is still common in the developing countries of the world like in India, Pakistan, some Arab countries, parts of Africa and South America. In India, RHD and RF continue to a major public health problem. In a multicentric survey in school-going children by the Indian Council of Medical Research, an incidence of 1 to 5.5 per 1000 children has been reported.

ЕTIOPATHOGENESIS

After a long controversy, the etiologic role of preceding throat infection with p-haemolytic streptococci of group ^ in RF is now generally accepted. However, the mechanism of lesions in the heart, joints and other tissues is not by direct infection but by induction of hypersensitivity or autoimmunity. Thus, there are 2 types of evidences in the etiology and pathogenesis of RF and RHD: the epidemiologic evidence and the immunologic evidence.

A. EPIDEMIOLOGIC EVIDENCE. There is a body of clinical and epidemiological evidence to support the concept that RF occurs following infection of the throat and upper respiratory tract with P-haemolytic streptococci of Lancefield group A. These evidences are as under:

 There is often a history of infection of the pharynx and upper respiratory tract with this microorganism about 2 to 3 weeks prior to the attack of RF. This period is usually the latent period required for sensitisation to the bacteria.

I Subsequent attacks of streptococcal infection are generally associated with exacerbations of RF.

3.   A higher incidence of RF has been observed after outbreaks and epidemics of streptococcal infection erf throat in children from schools or in youngmen from

training camps.

4.   Administration of antibiotics leads to lowering of the incidence as well as severity of RF and its recurrences.

5.   Cardiac lesions similar to those seen in RHD have been produced in experimental animals by induction of repeated infection with p-haemolytic streptococci of group A.

6.   Patients with RF have elevated titres of antibodies to the antigens of p-haemolytic streptococci of group A such as antistreptolysin O (ASO) and S, antjstrepto-kinase, antistreptohyaluronidase and anti- DNAase B_

7.   Socioeconomic factors like poverty, poor nutrition, density of population, overcrowding in quarters fox sleeping etc are associated with spread of infe.’Ctioin„ lack of proper medical attention, and hence higher incidence of RF.

8.   The geographic distribution of the disease, as already pointed out, shows higher frequency and severity of the disease in the developing countries of the world; where the living conditions are substandard and medical facilities are insufficient. Populations in fjiese regions develop recurrent throat infections which remain untreated and have higher incidence of RF.

9.   The role of climate in the development of RF has been reported by some workers. The incidence of the disease is higher in subtropical and tropical; regions with cold, damp climate near the rivers and’ water-ways. which favour the spread of infection

10.  The individual susceptibility to RF and familial incidence have been reported. The factors contributing to proneness to develop RF include adverse social conditions, presence of streptococcali carrier at home and, as yet unclear role of hereditary detect.

Despite all these evidences, only a small proportion of patients with streptococcal pharyngeal infection develop RF—the attack rate is less than 3%. There iis a suggestion that a concomitant tnrus enhances the effect of streptococci in individuals who develop RF.

 

Acute and chronic rheumatic heart disease. A, Acute rheumatic mitral valvulitis superimposed on chronic rheumatic heart disease. Small vegetations (verrucae) are visible along the line of closure of the mitral valve leaflet (arrows). Previous episodes of rheumatic valvulitis have caused fibrous thickening and fusion of the chordae tendineae. B, Microscopic appearance of Aschoff body in a patient with acute rheumatic carditis. The myocardial interstitium has a circumscribed collection of mononuclear inflammatory cells, including some large histiocytes with prominent nucleoli and a prominent binuclear histiocyte, and central necrosis. C and D, Mitral stenosis with diffuse fibrous thickening and distortion of the valve leaflets, commissural fusion (arrows!, and thick­ening and shortening of the chordae tendineae. Marked dila­tion of the left atrium is noted in the left atrial view (CI. D, Opened valve. Note neovascularization of anterior mitral leaflet (arrow). E, Surgically removed specimen of rheumatic aortic stenosis, demonstrating thickening and distortion of the cusps with commissural fusion (E, reproduced from Schoen FJ, St. John-Sutton M: Contemporary issues in the pathology of valvular heart disease.

 

B. IMMUNOLOGIC EVIDENCE It has ben observed that though throat of patients during acute RF contain streptococci, the clinical symptoms of RF appear after a delay of 2-3 weeks and the organisms caot be grown from the lesions in the target tissues. This has led to the concept that lesions are produced as a result of immune response by formation of autoantibodies against bacter

identify or cross-react with target human tissues in RHD i.e. cardiac muscle, valves, joints, skin, neurons etc. One such important component is M-protein identified as a surface protein of streptococcus which has various antigenic types, and hence corresponding antibodies in humans which target different tissues. The evidences in support are as under:

1.   Cell wall polysaccharide of group A streptococcus forms antibodies which are reactive against cardiac valves. This is supported by observation of persistently elevated corresponding autoantibodies in patients who have cardiac valvular involvement than those without cardiac valve involvement.

2.   Hyaturonate capsule of group A streptococcus is identical to human hyaluronate present in joint tissues and thus these tissues are the target of attack.

3. Membrane antigens of group A streptococcus react with sarcolemma of smooth and cardiac muscle, dermal

I fibroblasts and neurons of caudate nucleus. PATHOLOGIC CHANGES RF is generally regarded as an autoimmune focal inflammatory disorder of the connective tissues throughout the body. The cardiac lesions of RF in the form of pancarditis, particularly the valvular lesions, are its major manifestations. However, supportive connective tissues at other sites like the synovial membrane, periarticular tissue, skin and subcuta­neous tissue, arterial wall, lungs, pleura and the CNS are all affected (extracardiac lesions).

 Cardiac Lesions

The cardiac manifestations of RF are in the form of focal inflammatory involvement of the interstitial tissue of all the three layers of the heart, the so-called pancarditis. The pathognomonic feature of pancarditis in RF is the presence of distinctive Aschoff nodules or Aschoff bodies.

THE ASCHOFF NODULES OR BODIES. The

Aschoff nodules or the Aschoff bodies are spheroidal or fusiform distinct tiny structures, 1-2 mm in size, occurring in the interstitium of the heart in RF and may be visible to naked eye. They are especially found in the vicinity of small blood vessels in the myocardium and endocardium and occasionally in the pericardium and the adventitia of the proximal part of the aorta. Lesions similar to the Aschoff nodules may be found in the extracardiac tissues.

Evolution of fully-developed   Aschoff bodies involves 3 stages all of which may be found in the I same heart at different stages of development. These are as follows:

1.   Early (exudative or degenerative) stage. The earliest sign of injury in the heart in RF is apparent I by about 4th week of illness. Initially, there is oedema of the connective tissue and increase in acid mucopolysaccharide in the ground substance. This results in separation of the collagen fibres by I accumulating ground substance. Eventually, uVI collagen fibres are fragmented and disintegrated and the affected focus takes the appearance and staining I characteristics of fibrin. This change is referred to as fibrinoid degeneration.

2.  Intermediate (proliferative or granulomatous) stage. It is this stage of the Aschoff body which is i pathognomonic of rheumatic conditions (Fig, 12.19). This stage is apparent in 4th to 13th week of illness.1 The early stage of fibrinoid change is followed by proliferation of cells that includes infiltration by lymphocytes (mostly T cells), plasma cells, a fewl neutrophils and the characteristic cardiac histiocyte (Anitschkow cells) at the margin of the lesion. Cardiac histiocytes or Anitschkow cells are present in small numbers iormal heart but their number is increased in the Aschoff bodies; therefore they are not characteristic of RHD. These are large mono­nuclear cells having central round nuclei and contain moderate amount of amphophilic cytoplasm. The nuclei are vesicular and contain prominent central chromatin mass which in longitudinal section appears serrated or caterpillar-like, while in cross-section the chromatin mass appears as a small rounded body in the centre of the vesicular nucleus, just like an owl’s eye (Fig. 12.19, inbox). Some of these modified cardiac histiocytes become multinucleate cells containing 1 to 4 nuclei and are called Aschoff cells and are pathognomonic of RHD.

3.  Late (healing or fibrous) stage. The stage of healing by fibrosis of the Aschoff nodule occurs in about 12 to 16 weeks after the illness. The nodule becomes oval or fusiform in shape, about 200 im wide and 600 urn long. The Anitschkow cells in the nodule become spindle-shaped with diminished cytoplasm and the nuclei stain solidly rather than showing vesicular character. These cells tend to be arranged in a palisaded manner. With passage of months and years, the Aschoff body becomes less cellular and the collagenous tissue is increased.

 

RHEUMATIC PANCARDITIS. Although all the three layers of the heart are affected in RF, the intensity of their involvement is variable.

1. RHEUMATIC ENDOCARDITIS. Endocardia] lesions of RF may involve the valvular and mural endocardium, causing rheumatic valvulitis and mural endocarditis, respectively. Rheumatic valvulitis is chiefly responsible for the major cardiac manifestations in chronic RHD.

RHEUMATIC VALVULITIS. Grossly, the valves in acute RF show thickening and loss of translucency of the valve leaflets or cusps. This is followed by the formation of characteristic, small (1 to 3 mm in dia­meter), multiple, warty vegetations or verrucae, chiefly along the line of closure of the leaflets and cusps. These tiny vegetations are almost continuous so that the free margin of the cusps or leaflets appears as a rough and irregular ridge. The vegetations in RF appear grey-brown, translucent and are firmly attached so that they are not likely to get detached to form emboli, unlike the friable vegetations of infective endocarditis.

Though all the four heart valves are affected, their frequency and severity of involvement varies: mitral

valve alone being the most common site, followed in decreasing order of frequency, by combined mitral and aortic valve . The tricuspid and pulmonary valves usually show infrequent and slight involvement. The higher incidence of vegetations on left side of the heart is possibly because of the greater mechanical stresses on the valves of the left heart, especially along the line of closure of the valve cusps . The occurrence of vegetations on the atrial surfaces of the atrioventricular valves (mitral and tricuspid) and on the ventricular surface of the semilunar valves (aortic and pulmonary) further lends support to the role of mechanical pressure on the valves in the pathogenesis of vegetations.

The chronic stage of RHD is characterised by permanent deformity of one or more valves, espe­cially the mitral (in 98% cases alone or along with other valves) and aortic. The approximate frequency of deformity of various valves is  as under:

   Mitral alone=37% cases.

   Mitral+aortic=27% cases.

   Mitral+aortic+tricuspid=22% cases.

   Mitral+tricuspid=ll% cases.

 

RHEUMATIC MURAL ENDOCARDITIS. Mural endocardium may also show features of rheumatic

I carditis though the changes are less conspicuous as

I  compared to valvular changes.

Grossly, the lesions are seen most commonly as I MncCallum’s patch which is the region of endocardial

surface in the posterior wall of the left atrium just I above the posterior leaflet of the mitral valve.

MacCallum’s patch appears as a map-like area of I thickened, roughened and  wrinkled part of the endocardium .

Microscopically, the appearance of MacCallum’s I patch is similar to that seen in rheumatic valvulitis. The affected area shows oedema, fibrinoid change in [ the collagen, and cellular infiltrate of lymphocytes, I plasma cells and macrophages with many ^Bnitschkow cells. Typical Aschoff bodies may some-limes be found.

2.  RHEUMATIC MYOCARDITIS. Grossly, in the early (acute) stage, the myocardium, especially of the I left ventricle, is soft and flabby. In the intermediate stage, Ihe interstitial tissue of the myocardium shows I small foci of necrosis. Later, tiny pale foci of the I  Aschoff bodies may be visible throughout the myocardium.

Microscopically, the most characteristic feature of rheumatic myocarditis is the presence of distinctive

I Aschoff bodies. These diagnostic nodules are scattered throughout the interstitial tissue of the myocardium and are most frequent in the interventri   cular septum, left ventricle and left atrium. Derange ments of the conduction system may, thus, be present. The Aschoff bodies are best identified in the inter mediate stage when they appear as granulomas with central fibrinoid necrosis and are surrounded by palisade of Anitschkow cells and multinucleate Aschoff cells. There is infiltration by lymphocytes, plasma cells and some neutrophils. In the late stage,

I me Aschoff bodies are gradually replaced by small fibrous scars in the vicinity of blood vessels and the inflammatory infiltrate subsides. Presence of active Aschoff bodies along with old healed lesions is

I   indicative of rheumatic activity.

 

3.  RHEUMATIC PERICARDITIS. Inflammatory I involvement  of   the   pericardium   commonly accompanies RHD.

Grossly, the usual finding is fibrinous pericarditis in which there is loss of normal shiny pericardial surface due to deposition of fibrin on its surface and accumu lation of slight amount of fibrinous exudate in the pericardial sac. If the parietal pericardium is pulled off from the visceral pericardium, the two separated surfaces are shaggy due to thick fibrin covering them. This appearance is often likened to ‘bread and butter appearance’ i.e. resembling the buttered surfaces of two slices in a sandwich when they are gently pulled apart. If fibrinous pericarditis fails to resolve and, instead, undergoes organisation, the two layers of the pericardium form fibrous adhesions resulting in chronic adhesive pericarditis.

Microscopically, fibrin is identified on the surfaces. The subserosal connective tissue is infiltrated by lymphocytes, plasma cells, histiocytes and a few neutrophils. Characteristic Aschoff bodies may be seen which later undergo organisation and fibrosis. Organisation of the exudate causes fibrous adhesions between the visceral and parietal surfaces of the pericardial sac and obliterates the pericardiaLcavity.

Histologically, the subcutaneous nodules of RF are representative of giant Aschoff bodies of the heart. They consist of 3 distinct zones: a central area with

 Extracardiac Lesions

Patients of the syndrome of acute rheumatism develop lesions in connective tissue elsewhere in the body, chiefly the joints, subcutaneous tissue, arteries, brain and lungs.

1.   POLYARTHRITIS. Acute and painful inflammation of the synovial membranes of some of the joints, espe­cially the larger joints of the limbs, is seen in about 90% cases of RF in adults and less often in children. As pain and swelling subside in one joint, others tend to get involved, producing the characteristic ‘migratory polyarthritis’ involving two or more joints at a time.

Histologically, the changes are transitory. The synovial membrane and the periarticular connective tissue show hyperaemia, oedema, fibrinoid change and neutrophilic infiltration. Sometimes, focal lesions resembling Aschoff bodies are observed. A serous effusion into the joint cavity is commonly present.

2.   SUBCUTANEOUS NODULES. The subcutaneous nodules of RF occur more often in children than in adult. These nodules are small (0.5 to 2 cm in diameter), spherical or ovoid and painless. They are attached to deeper structures like tendons, ligaments, fascia or periosteum and therefore often remain unnoticed by the patient. Characteristic locations are extensor surfaces of the wrists, elbows, ankles and knees. fibrinoid changes, surrounded by a zone of histio­cytes and fibroblasts forming a palisade arrangement, and the outermost zone of connective tissue which is infiltrated by non-specific chronic inflammatory cells and proliferating blood vessels.

It may be mentioned here that histologically similar but clinically different subcutaneous lesions appear in rheumatoid arthritis; they are larger, painful and tender and persist for months to years.

3.   ERYTHEMA MARGINATUM. This non-pruritic erythematous rash is characteristic of RF. The lesions occur mainly on the trunk and proximal parts of the extremities. The erythematous area develops central clearing and has slightly elevated red margins. The erythema is transient and migratory.

4.   RHEUMATIC ARTERITIS. Arteritis in RF involves not only the coronary arteries and aorta but also occurs in arteries of various other organs such as renal, mesenteric and cerebral arteries. The lesions in the coronaries are seen mainly in the small intramyocardial branches.

Histologically, the lesions may be like those of hypersensitivity angiitis (Chapter 11), or sometimes may resemble polyarteritis nodosa. Occasionally, foci of fibrinoid necrosis or ill-formed Aschoff bodies may be present close to the vessel wall.

5.   CHOREA MINOR. Chorea minor or Sydenham’s chorea or Saint Vitus’ dance is a delayed manifestation of RF as a result of involvement of the central nervous system. The condition is characterised by disordered and involuntary jerky movements of the trunk and the extremities accompanied by some degree of emotional instability. The condition occurs more often in younger age, particularly in girls.

Histologically, the lesions are located in the cerebral hemispheres, brainstem and the basal ganglia. They consist of small haemorrhages, oedema and peri­vascular infiltration of lymphocytes. There may be endarteritis obliterans and thrombosis of cortical and meningeal vessels.

6.   RHEUMATIC PNEUMONITIS AND PLEURITIS.

Involvement of the lungs and pleura occurs rarely in RF. Pleuritis is often accompanied with serofibrinous pleural effusion but definite Aschoff bodies are not present. In rheumatic pneumonitis, the lungs are large, firm and rubbery. Histologically, the changes are oedema, capillar}’ haemorrhages and focal areas of fibrinous exudate in the alveoli. Aschoff bodies are generally not found.

CLINICAL FEATURES

The first attack of acute RF generally appears 2 to 3 weeks after streptococcal pharyngitis, most often in children between the age of 5 to 15 years. With subse­quent streptococcal pharyngitis, there is reactivation of the disease and similar clinical manifestations appear with each recurrent attack. The disease generally pre­sents with migratory polyarthritis and fever. However, RF has widespread systemic involvement and no single specific laboratory diagnostic test is available. Therefore, for diagnosis, the following set of guidelines called revised Jones’ criteria are followed:

A.  Major criteria are:

1.   Carditis

2.   Polyarthritis

3.   Chorea (Sydenham’s chorea)

4.   Erythema marginatum

5.   Subcutaneous nodules

B.   Minor criteria are:

1.   Fever

2.   Arthralgia

3.   Previous history of RF

4.   Laboratory findings of elevated ESR, raised C-reactive protein, and leucocytosis

5.   ECG finding of prolonged PR interval.

C.   Supportive evidence of preceding group A streptococcal infection: positive throat culture for group A streptococci, raised titres of streptococcal antibodies (antistreptolysin O and S, antistreptokinase, anti-streptohyaluronidase and anti DNAase B).

Clinical diagnosis of RF is made in a case with antecedent laboratory evidence of streptococcal throat infection in the presence of: any two of the major crite­ria, or occurrence of one major and two minor criteria.

If the heart is spared in a case of acute RF, the patient may have complete recovery without any sequelae. However, once the heart is involved, it is often asso­ciated with reactivation and recurrences of the disease. Myocarditis, in particular, is the most life-threatening due to involvement of the conduction system of the heart and results in serious arrhythmias. The long term sequelae or stigmata are the chronic valvular defor­mities, especially the mitral stenosis, as already explained on page 331. Initially, a state of compensation occurs, while later decompensation of the heart leads  to full-blown cardiac failure. Currently, surgical replace­ment of the damaged valves can alter the clinical course of the disease.

The major  causes of death in RHD are cardiac failure, bacterial endocarditis and embolism:

B. Cardiac failure is the most common cause of death Bom RHD. In young patients, cardiac failure occurs due to the chronic valvular deformities, while in older patients coronary artery disease may be superimposed kin old RHD.

1 Bacterial endocarditis of both acute and subacute type may supervene due to inadequate use of antibiotics.

3.  Embolism in RHD originates most commonly from mural thrombi in the left atrium and its appendages, in association with mitral stenosis. The organs most frequently affected are the brain, kidneys, spleen and

lungs.

4.  Sudden death may occur in RHD as a result of ball thrombus in the left atrium or due to acute coronary insufficiency in association with aortic stenosis.

NON-RHEUMATIC ENDOCARDITIS

Inflammatory involvement of the endocardial layer of the heart is called endocarditis. Though in common usage, if not specified endocarditis would mean inflam­mation of the valvular endocardium, several workers designate endocarditis on the basis of anatomic area of the involved endocardium such as: valvular for valvular endocardium, mural for inner lining of the lumina of cardiac chambers, chordal for the endocardium of the chordae tendineae, trabecular for the endocardium of trabeculae carneae, and papillary for the endocardium covering the papillary muscles. Endocarditis can be broadly grouped into non-infective and infective types . Most types of endocarditis are characterised by the presence of ‘vegetations’ or ‘verrucae’ which have distinct features. A summary of the distinguishing features of the principal types of vegetations is presen ted in Table 12.7.

ATYPICALVERRUCOUS (UBMAN-SACKS) ENDOCARDITIS

Libman and Sacks, two American physicians, described a form of endocarditis in 1924 that is characterised by sterile endocardial vegetations which are distinguishable from the vegetations of RHD and bacterial endocarditis.

ETIOPATHOGENESIS. Atypical verrucous endo­carditis is one of the manifestations of ‘collagen

A.    NON-INFECTIVE

1.     Rheumatic endocarditis

2.     Atypical verrucous (Libman-Sacks) endocarditis

3.     Non-bacterial thrombotic (cachectic, marantic) endocarditis

B.    INFECTIVE

1.     Bacterial endocarditis

2.     Other infective types (tuberculous, syphilitic, fungal, viral, rickettsial)

diseases’. Characteristic lesions of Libman-Sacks endo­carditis are seen in 50% cases of acute systemic lupus erythematosus (SLE); other diseases associated with this form of endocarditis are systemic sclerosis, thrombotic thrombocytopenic purpura (TTP) and other collagen diseases.

PATHOLOGIC CHANGES. Grossly, characteristic vegetations occur most frequently on the mitral and tricuspid valves. The vegetations of atypical verru­cous endocarditis are small (1 to 4 mm in diameter), granular, multiple and tend to occur on both surfaces of affected valves, in the valve pockets and on the adjoining ventricular and atrial endocardium. The vegetations are sterile unless superimposed by bacterial endocarditis. Unlike vegetations of RHD, the healed vegetations of Libman-Sacks endocarditis do not produce any significant valvular deformity. Frequently, fibrinous or serofibrinous pericarditis with pericardial effusion is associated. Microscopically, the verrucae of Libman-Sacks endocarditis are composed of fibrinoid material with superimposed fibrin and platelet thrombi. The endocardium underlying the verrucae shows characteristic histological changes which include fibri­noid necrosis, proliferation of capillaries and infil­tration by histiocytes, plasma cells, lymphocytes, neutrophils and the pathognomonic haematoxylih bodies of Gross which are counterparts of LE cells of the blood. Similar inflammatory changes may be found in the interstitial connective tissue of the myo­cardium. The Aschoff bodies are never found in the endocardium or myocardium.

NON-BACTERIALTHROMBOTIC (CACHECTIC, MARANTIC) ENDOCARDITIS

Non-bacterial thrombotic, cachectic, marantic or terminal endocarditis or endocarditis simplex is an involvement of the heart valves by sterile thrombotic vegetations.

FEATURE

I Valves commonly affected

Location on valve cusps or leaflets

3. Macroscopy

  Microscopy

RHEUMATIC

Mitral alone; mitral and aortic combined

Occur along the line of closure, atrial surface of atrio-ventricular valves and ventricular surface of semilunar valves

Small, multiple, warty, grey brown, translucent, firmly attached, generally produce permanent valvular deformity

Composed of fibrin with superimposed platelet thrombi and no bacteria, Adjacent and underlying endocardium shows oedema, proliferation of capillaries, mononuclear inflammatory infiltrate and occasional Aschoff bodies.

L1BMAN-SACKS Mitral, tricuspid

Occur on both surfaces of valve leaflets or cusps, in the valve pockets

Medium-sized, multiple, generally do not produce significant valvular deformity

Composed of fibrinoid material with superimposed fibrin and platelet thrombi and no bacteria. The underlying endocardium shows fibrinoid necrosis, proliferation of capillaries and acute and chronic in­flammatory infiltrate including the haematoxylin bodies of Gross.

NON-BACTERIAL THROMBOTIC

Mainly mitral; less often aortic and tricuspid

Occur along the line of closure

Small but larger than those of rheumatic, single or multiple, brownish, firm, but more friable than those of rheumatic

Composed of degenerated valvular tissue, fibrin-platelets thrombi and no bacteria. The underlying valve shows swelling of collagen, fibrinoid change, proliferation of capillaries but no significant inflam­matory cell infiltrate.

BACTERIAL

Mitral; aortic; combined mitral and aortic

SABE more often on diseased valves: ABE on previously normal valves; location same as in RHD

Often large, grey-tawny to greenish, irregular, single or multiple, typically friable

Composed of outer eosinophilic zone of fibrin and platelets, covering colonies of bacteria and deeper zone of non-specific acute and chronic inflammatory cells. The underlying endocardium may show abscesses in ABE and inflam­matory granulation tissue in the SABE.

j Streptococcus viridans, which forms part of normal flora

I of the mouth and pharynx. Other less common etiologic

agents include other strains of streptococci and staphylo-

cocri (e.g.   Streptococcus bovis which is the normal

inhabitant of gastrointestinal tract,   Streptococcus

pneumoniae, and Staphylococcus epidermidis which is a

commensal of the skin), gram-negative enteric bacilli

(eg. E. colt, Klebsiella, Pseudomonas and Salmonella),

pneumococci, gonococci and Haemophilus influenzae.

B. Predisposing factors. There are 3 main factors which predispose to the development of both forms of BE:

1.  conditions initiating transient bacteraemia, septicae­mia and pyaemia;

2.  underlying heart disease; and

3.  impaired host defenses.

1. Bacteraemia, septicaemia and pyaemia: Bacteria gain entrance to the bloodstream causing transient and clinically silent bacteraemia in a variety of day-to-day proce­dures as well as from other sources of infection. Some of the common examples are:

i) Periodontal infections such as trauma from vigorous brushing of teeth, hard chewing, tooth extraction and other dental procedures.

ii) Infections of the genitourinary tract such as in catheterisation, cystoscopy, obstetrical procedures including normal delivery and abortions, iii) Infections of gastrointestinal and biliary tract, iv) Surgery of the bowel, biliary tract and genitourinary tracts.

v) Skin infections such as boils, carbuncles and abscesses.

vi) Upper and lower respiratory tract infections including bacterial pneumonias.

vii) Intravenous drug abuse.

viii) Cardiac catheterisation and cardiac surgery for

implantation of prosthetic valves.

2. Underlying heart disease: SABE occurs much more frequently in previously diseased heart valves, whereas the  ABE is common in previously normal heart. Amongst the commonly associated underlying heart

diseases are the following:

i)   Chronic rheumatic valvular disease in about 50%

cases.

ii) Congenital heart diseases in about 20% cases. These

include VSD, subaortic stenosis, pulmonary stenosis,

bicuspid aortic valve, coarctation of the aorta, and PDA.

iii) Other causes are syphilitic aortic valve disease,

atherosclerotic valvular disease, floppy mitral valve, and

prosthetic heart valves.

3. Impaired host defenses: All conditions in which there is depression of specific immunity, deficiency of complement and defective phagocytic function, predispose to BE. Following are some of the examples of such conditions:

i)   Impaired specific immunity in lymphomas, ii) Leukaemias.

iii) Cytotoxic therapy for various forms of cancers and transplant patients, iv) Deficient functions of neutrophils and macrophages.

PATHOLOGIC CHANGES. The characteristic pathologic feature in both ABE and SABE is the presence of typical vegetations or verrucae on the valve cusps or leaflets, and less often, on mural endocardium.

Macroscopically, the lesions are found commonly on the valves of the left heart, mosl frequently on the mitral, followed in descending frequency, by the aortic, simultaneous involvement of both mitral and aortic valves, and quite rarely on the valves of the right heart. The vegetations in SABE are more often seen on previously diseased valves, whereas the vegetations of ABE are often found on previously normal valves. Like in RHD, the vegetations are often

located on the atrial surface of atrioventricular valves and ventricular surface of the semilunar valves. They begin from the contact areas of the valve and may I extend along the surface of the valves and on to the I adjacent endocardium.

The vegetations of BE vary in size from a few millimeters to several centimeters, grey-tawny to I greenish, irregular, single or multiple, and typically friable. They may appear flat, filiform, fungating or I polypoid. The vegetations in ABE tend to be bulkier and globular than those of SABE and are located more often on previously normal valves, may cause  I ulceration or perforation of the underlying valve  I leaflet, or may produce myocardial abscesses

Microscopically, the vegetations of BE consist of 3 zones

i)   The outer layer or cap consists of eosinophilic material composed of fibrin and platelets, ii) Underneath this layer is the basophilic zone contain­ing colonies of bacteria. However, bacterial compo- I nent of the vegetations may be lacking in treated cases.

iii) The deeper zone consists of non-specific inflam­matory reaction in the cusp itself, and in the case of I SABE there may be evidence of repair

In the acute fulminant form of the disease, the I inflammatory cell infiltrate chiefly consists of neutro- I phils and is accompanied with tissue necrosis and I abscesses in the valve rings and in the myocardium. In I the subacute form, there is healing by granulation tissue, I mononuclear inflammatory cell infiltration and fibro- I blastic proliferation. Histological evidence of pre-ifl existing valvular disease such as RHD may be present I in SABE.

COMPLICATIONS AND SEQUELAE. Most cases  BE present with fever. The acute form of BE is I characterised by high grade fever, chills, weakness and I malaise while the subacute form of the disease has non- I specific manifestations like slight fever, fatigue, loss of I weight and flu-like symptoms. In the early stage, the I lesions are confined to the heart, while subsequent I progression of the disease leads to involvement of I extracardiac organs. In general, severe complications I develop early in ABE than in SABF.. Complications and I sequelae of BE are divided into cardiac and extracardiac I :

A. Cardiac complications. These include the following: I

i)   Valvular stenosis or insufficiency

ii) Perforation, rupture, and aneurysm of valve leaflets I

PATHOGENESIS. Bacteria on entering the bloodstream from any of the above-mentioned routes are implanted on the cardiac valves or mural endocardium. There are different hypotheses to explain the occurrence of bacterial implants on the valves:

1.   The circulating bacteria are lodged much more frequently on previously damaged valves from diseases, chiefly RHD and congenital heart diseases, than on healthy valves.

2.   Conditions producing haemodynamic stress on the valves are liable to cause damage to the endothelium, favouring the formation of platelet thrombi which get infected from circulating bacteria.

3.   Another alternative hypothesis is the occurrence of non-bacterial thrombotic endocarditis from prolonged stress which is followed by bacterial contamination.

  MITRAL VALVE (ATRIAL SURFACE)

Outer layer (cap)

Bacterial colonies

Vegetations in BE

 

Left atrium

Mitral valve

Necrotic debris

AORTIC VALVE (VENTRICULAR SURFACE)

Polymorphonuclear           .

neutrophils

Left ventricle

Bacterial endocarditis. A, Location of vegetations on the valves of the left heart. The vegetations are shown on the mitral valve (above) as wed from the left atrium, while those on the aortic valve (below) are shown as seen from the left ventricle. B, Microscopic structure of ivegetation of BE on the surface of mitral valve in sagittal section.

1} Abscesses in the valve ring

iv) Myocardial abscesses

i) Suppurative pericarditis

vi) Cardiac failure from one or more of the foregoing

complications.

B. Extracardiac complications. Since the vegetations in BE are typically friable, they tend to get dislodged due to rapid stream of blood and give rise to embolism which is responsible for very’ common and serious extra-cardiac complications. These are as under:

i) Emboli originating from the left side of the heart and entering the systemic circulation affect organs like the spleen, kidneys, and brain causing infarcts, abscesses ffld mycotic aneurysms.

i) Emboli arising from right side of the heart enter the pulmonary circulation and produce pulmonary

abscesses.

ii) Petechiae may be seen in the skin and conjunctiva lue to either emboli or toxic damage to the capillaries.

iv) In SABE, there are painful, tender nodules on the linger tips of hands and feet called Osier’s nodes, while ABE there is appearance of painless, non-tender subcutaneous maculopapular lesions on the pulp of the

fingers called janeway’s spots. In either case, their origin is due to toxic or allergic inflammation of the vessel wall.

v) Focal necrotising glomerulonephritis is seen more commonly in SABE than in ABE. Occasionally diffuse glomerulonephritis may occur. Both these have their pathogenesis in circulating immune complexes (hyper­sensitivity phenomenon).

Treatment of BE with antibiotics in adequate dosage kills the bacteria but complications and sequelae of healed endocardial lesions may occur even after success­ful therapy. The causes of death are cardiac failure, persis­tent infection, embolism to vital organs, renal failure and rupture of mycotic aneurysm of cerebral arteries.

OTHER INFECTIVE ENDOCARDITIS

Besides BE, various other microorganisms may occasionally produce infective endocarditis. These include the following:

1. Tuberculous endocarditis. Though tubercle bacilli are bacteria, tuberculous endocarditis is described separate from the bacterial endocarditis due to specific granulomatous inflammation found in tuberculosis. It is characterised by presence of typical tubercles on the  valvular as well as mural endocardium and may form tuberculous thromboemboli.

2.   Syphilitic endocarditis. The endocardial lesions in syphilis have already been described in relation to syphilitic aortitis . The severest manifestation of cardiovascular syphilis is aortic valvular incompetence.

3.   Fungal endocarditis. Rarely, endocardium may be infected with fungi such as from Candida albicans, Histoplasma capsulatum, Aspergillus, Mucor, coccidioido­mycosis, cryptococcosis, blastomycosis and actino­mycosis. Opportunistic fungal infections like candidiasis and aspergillosis are seen more commonly in patients receiving long-term antibiotic therapy, intravenous drug abusers and after prosthetic valve replacement.

4.   Viral endocarditis. There is only experimental evidence of existence of this entity.

5.   Rickettsial endocarditis. Another rare cause of endocarditis is from infection with rickettsiae in Q fever.

VALVULAR DISEASES AND DEFORMITIES

Valvular diseases are various forms of congenital and acquired diseases which cause valvular deformities.

Many of them result in cardiac failure. Rheumatic heart disease is the most common form of acquired valvular disease. Valves of the left side of the heart are involved much more frequently than those of the right side of the heart. The mitral valve is affected most often, followed in descending frequency, by aortic valve, and combined mitral and aortic valves. The valvular deformities may be of 2 types: stenosis and insufficiency Stenosis is the term used for failure of a valve to open completely during diastole resulting in obstruction to the forward flow of the blood. Insufficiency or incompe­tence or regurgitation is the failure of a valve to close completely during systole resulting in back flow or regurgitation of the blood.

The congenital valvular diseases have already been described (page 312). Various acquired valvular diseases that may deform the heart valves are listed below:

1.   RHD, the commonest cause

2.   Infective endocarditis

3.   Non-bacterial thrombotic endocarditis

4.   Libman-Sacks endocarditis

5.   Syphilitic valvulitis

6.   Calcific aortic valve stenosis

\l Calcification of mitral annulus

E Myxomatous degeneration (floppy valve syndrome)

■ Carcinoid heart disease.

The major forms of vegetative endocarditis involving Be valves have already been described. Others Blongvvith the consequences of these valvular diseases Bthe form of stenosis and insufficiency of the heart reives are described below.

MITRAL STENOSIS

Mitral stenosis occurs in approximately 40% of all

larients with RHD.   About  70% of the  patients are

women. The latent period between  the rheumatic

carditis and development of symptomatic mitral stenosis Is about two decades.

ETIOLOGY. Mitral stenosis is generally rheumatic in origin. Less common causes include bacterial endocarditis, Libman-Sacks endocarditis, endocardial fibroelastosis and congenital parachute mitral valve.

PATHOLOGIC CHANGES. The appearance of the iBiitral valve in stenosis varies according to the extent pf involvement. Generally, the valve leaflets are diffusely thickened by fibrous tissue and /or calcific deports, especially towards the closing margin. There are [fibrous adhesions of mitral commissures and fusion

and shortening of chordae tendineae. In less extensive

involvement, the bases of the leaflets of mitral valve

 mobile while the free margins have puckered j.snd thickened tissue with narrowed orifice; this is I  called as ‘purse-string puckering’. The more advanced

cases have rigid, fixed and immobile diaphragm-like Rvalve leaflets with narrow, slit-like or oval mitral opening, commonly referred to as ‘button-hole’ or ‘fish-mouth’ mitral orifice.

EFFECTS. Iormal adults, the mitral orifice is about 5 cm2. Symptomatic mitral stenosis develops if the valve opening is reduced to 1 cm2 resulting in significant elevation of left atrial pressure from the normal of 12 mmHg to about 25 mmHg leading to dilatation of the left atrium. The elevated left atrial pressure, in turn, raises pressure in the pulmonary veins and capillaries, reducing the pulmonary function and causing exertional dyspnoea which is the chief symptom of mitral stenosis. The effects of mitral stenosis can thus be summarised as under:

1.   Dilatation and hypertrophy of the left atrium.

2.   Normal-sized or atrophic left ventricle due to reduced inflow of blood.

3.   Pulmonary hypertension resulting from passive backward transmission of elevated left artial pressure which causes:

i) chronic passive congestion of the lungs; ii) hypertrophy and dilatation of the right ventricle;

and iii) dilatation of the right atrium when right heart failure supervenes.

MITRAL INSUFFICIENCY

Mitral insufficiency is caused by RHD in about 50% of patients but in contrast to mitral stenosis, pure mitral insufficiency occurs more often in men (75%). Subsequently, mitral insufficiency is associated with some degree of mitral stenosis.

   ETIOLOGY. All the causes of mitral stenosis may produce mitral insufficiency, RHD being the most common cause. In addition, mitral insufficiency may result from non-inflammatory calcification of mitral valve annulus (in the elderly), myxomatous transfor­mation of mitral valve (floppy valve syndrome), rupture of a leaflet or of the chordae tendineae or of a papillary muscle. A few other conditions cause mitral insufficiency by dilatation of the mitral ring such as in myocardial infarction, myocarditis and left ventricular failure in hypertension.

PATHOLOGIC CHANGES. The appearance of the mitral valve in insufficiency varies according to the underlying cause. The rheumatic process produces rigidity, deformity and retraction of the valve leaflets and fusion of commissures as well as shortening and fusion of chordae tendineae .

   In myxomatous degeneration of the mitral valve leaflets (floppy valve syndrome) which is described on , there is prolapse of one or both leaflets into the left atrium during systole.

   In non-inflammatory calcification of mitral annulus seen in the aged, there is irregular, stony-hard, bead­like thickening in the region of mitral annulus without any associated inflammatory changes. It is thought to reflect degenerative changes of aging.

EFFECTS. The regurgitant mitral orifice produces progressive increase in left ventricular end-diastolic volume as well as pressure since the left ventricle cannot empty completely This results in rise in left atrial pressure and dilatation. As a consequence of left atrial hypertension, pulmonary hypertension occurs resulting in pulmonary oedema and right heart failure. In symptomatic cases of mitral insufficiency, the major symptoms are related to decreased cardiac output (e.g. fatigue and weakness) and due to pulmonary congestion (e.g. exertional dyspnoea and orthopnoea) but the features are less well marked than in mitral stenosis. The effects of mitral insufficiency may be summarised as under:

1.   Dilatation and hypertrophy of the left ventricle.

2.   Marked dilatation of the left atrium.

3.   Features of pulmonary hypertension such as: i) chronic passive congestion of the lungs;

ii) hypertrophy and dilatation of the right ventricle;

and iii) dilatation of the right atrium when right heart

failure supervenes.

AORTIC STENOSIS

Aortic stenosis comprises about one-fourth of all paigfl with chronic valvular heart disease. About 80%pjM of symptomatic aortic stenosis are males. It is of 2 ml types: non-calcific and calcific type, the latter being J common.

1.   Non-calcific aortic stenosis. The most conuJ cause of non-calcific aortic stenosis is chronic RHDm Other causes are congenital valvular and subaotjl stenosis and congenitally bicuspid aortic valve.

2.   Calcific aortic stenosis. Calcific aortic stenosis ■ the more common type. Various causes have ben ascribed to it. These include healing by scarring followe« by calcification of aortic valve such as in RHD, bacterim endocarditis, Brucella endocarditis, Monckeberg’scalc$B aortic stenosis, healed congenital malformM tion and familial hypercholesterolaemic xanthomatosffl

PATHOLOGIC CHANGES. The aortic cusps show I characteristic fibrous thickening and calcific nodularity of the closing edges. Calcified nodules! are often found in the sinuses of Valsalva. In rheu-1 ma tic aortic stenosis, the commissures are fused and! calcified, while ion-rheumatic aortic stenosis there I is no commissural fusion.

EFFECTS. Aortic stenosis becomes symptomatic whj the valve orifice is reduced to 1 cm2 from its normal! cm2. The symptoms appear many years later whentrl heart cannot compensate and the stenosis is quite seval The major effect of aortic stenosis is obstruction to til outflow resulting in concentric hypertrophy of thekl ventricle. Later, when cardiac failure supervenes, then is dilatation as well as hypertrophy of the left ventriea (eccentric hypertrophy).                                          

The three cardinal symptoms of aortic stenosis aid exertional dyspnoea, angina pectoris and syncope. Exq tional dyspnoea results from elevation of pulmonaj capillary pressure. Angina pectoris usually results fro] elevation of pulmonary capillary pressure and usual develops due to increased demand of hypertrophic myocardial mass. Syncope results from accompanying coronary insufficiency. Sudden death may also occuri an occasional case of aortic stenosis.

AORTIC INSUFFICIENCY

About three-fourth of all patients with aorta insufficiency are males with some having family histon of Marian’s syndrome.

Thickening and nodularity

Shortening and deformity

Аоrtic valve diseases. Normal aortic valve (A) contrasted with aortic stenosis (B) and aortic insufficiency (C).

 

  Calcific valvular degeneration. A, Calcific aortic stenosis of a previously normal valve having three cusps Iviewsdfa aortic aspect). Nodular masses of calcium are heaped-up within the sinuses of Valsalva (arrow). Note that the commissures am fused, as in postrheumatic aortic valve stenosis . S, Calcific aortic stenosis occurring on a congenially bicuspid win] One cusp has a partial fusion at its center, called a raphe (arrow). C and D, Mitral annular calcification, with calcific nodules at? (attachment margin) of the anterior mitral leaflet (arrows). C, Left atrial view. D, Cut section of myocardium.

ЕTIOLOGY. In about 75% of patients, the cause is hronic RHD. However, isolated aortic insufficiency is ess often due to rheumatic etiology. Other causes nclude syphilitic valvulitis, infective endocarditis, ongenital subaortic stenosis (congenitally bicuspid ortic valve), myxomatous degeneration of aortic valve floppy valve syndrome), traumatic rupture of the valve usps, dissecting aneurysm, Marfan’s syndrome and nkylosing spondylitis.

PATHOLOGIC CHANGES. The aortic valve cusps are thickened, deformed and shortened and fail to dose. There is generally distension and distortion of the ring.

iFFECTS. As a result of regurgitant aortic orifice, there s increase of the left ventricular end-diastolic volume, lis leads to hypertrophy and dilatation of the left entricle producing massive cardiac enlargement so that he heart may weigh as much as 1000 gm. Failure of the eft ventricle increases the pressure in the left atrium and iventually pulmonary hypertension and right heart ailure occurs.

The characteristic physical findings in a patient of lortic insufficiency are awareness of the beatings of the teart, poundings in the head with each heartbeat, low liastolic and high pulse pressure, rapidly rising and :ollapsing water hammer pulse (Corrigan’s pulse), looming ‘pistol shot’ sound over the femoral artery, md systolic and diastolic murmur heard over the femo-

ral artery when it is lightly compressed (Durozier’s sign). Sometimes, angina pectoris occurs due to increased myocardial demand or due to coronary insufficiency.

CARCINOID HEART DISEASE

ETIOLOGY. Carcinoid syndrome developing in patients with extensive hepatic metastases from a carcinoid tumour is characterised by cardiac manifestations in about half the cases . The lesions are characteristically located in the valves and endocardium of the right side of the heart. The pathogenesis of the cardiac lesions is not certain. But in carcinoid tumour with hepatic metastasis, there is increased blood level of serotonin secreted by the tumour. The increased concentration of serotonin reaches the right side of the heart and causes the lesions but serotonin is inactivated on passage of the blood through the lungs and hence the left heart is relatively spared. In addition, high levels of bradykinin may play contributory role in carcinoid heart disease. However, chronic infusion of serotonin or bradykinin in experimental animals has not succeeded in producing cardiac lesions; hence the exact pathogenesis of carcinoid heart disease remains obscure

PATHOLOGIC CHANGES. In majority of cases, the lesions are limited to the right side of the heart. Both pulmonary and tricuspid valves as well as the endocardium of the right chambers show charac­teristic cartilage-like fibrous plaques. Similar plaques may occur on the intima of the great veins, the coronary sinus and the great arteries. Occasionally, the lesions may be found on the left side of the heart.

EFFECTS. The thickening and contraction of the cusps and leaflets of the valves of the outflow tracts of the right heart result mainly in pulmonary stenosis and tricuspid regurgitation, and to a lesser extent, pulmonary regurgitation and tricuspid stenosis.

MYXOMATOUS DEGENERATION OF MITRALVALVE (MITRALVALVE PROLAPSE)

Myxomatous or mucoid degeneration of the valves of the heart is a peculiar condition occurring in young patients between the age of 20 and 40 years and is more common in women. The condition is common and seen in 5% of general adult population. The condition is also known by other synonyms like ‘floppy valve syndrome’ or ‘mitral valve prolapse’.

ETIOLOGY. The cause of the condition is not known. Association with Marfan’s syndrome has been observed in 90% of patients. Others have noted myxomatous degeneration in cases of Ehlers-Danlos syndrome and in myotonic dystrophy. A rheumatic or congenital etiology has been suggested by a few others. However, the myxomatous valvular changes seen in the aged patients are not related to this entity.

PATHOLOGIC CHANGES. Any cardiac valve may be involved but mitral valve is affected most frequently. The disease is usually most severe and most common in the posterior leaflet of the mitral valve. The affected leaflet is enlarged, thickened, opaque white, soft and floppy. Cut section of the valve reveals mucoid or myxoid appearance. A significant feature is the ballooning or aneurysmal protrusion of the affected leaflet and hence the name ‘mitral valve prolapse’ and ‘floppy valve syndrome’. Microscopically, the enlarged cusp shows loose connective tissue with abundant mucoid or myxoid material between stellate cells.

EFFECTS. Usually the condition does not produce any symptoms or significant valvular dysfunction. The condition is recognised during life by the characteristic mid-systolic click followed by a systolic murmur due to mildly incompetent mitral valve caused by the mitral valve prolapse. Occasionally, complications may develop such as superimposed infective endocarditis, mitral insufficiency and arrhythmias. Rarely, sudden death from serious ventricular arrhythmias may occur.

MYOCARDIAL DISEASE

Involvement of the myocardium occurs in three major I forms of diseases already discussed—ischaemic heart disease, hypertensive heart disease and rheumatic heart I disease. There are two other broad groups of myocardial I diseases considered here:

I.    Myocarditis i.e. inflammatory involvement of the myocardium; and

II.   Cardiomyopathy i.e. a non-inflammatory myocardial involvement with unknown (primary) or known] (secondary) etiology.

MYOCARDITIS

Inflammation of the heart muscle is called myocarditis. It is a rather common form of heart disease that can 1 occur at any age. Its exact incidence is difficult to ascer- I tain as the histological examination has been confined to autopsy material only. Reports from different studies I have estimated the incidence of myocarditis in 1 to4% of all autopsies.

A number of classifications of myocarditis have been proposed in the past as follows:

   Interstitial and parenchymatous type, depending upon whether the inflammation is confined to interstitial \ tissue or the parenchyma;

    Specific and non-specific type, depending upon whether the inflammation is granulomatous or non-specific type; and

    Acute, subacute and chronic type, depending upon the duration of inflammatory response.

However, currently most commonly used is efiologic classification based upon the causative factors as shown I in Table 12.8. According to this classification, myocar-j ditis is divided into 4 main etiologic types described below.

I.    INFECTIVE MYOCARDITIS

A number of infectious agents such as bacteria, viruses, protozoa, parasites, fungi, rickettsiae and spirochaetes’ may cause myocarditis by direct invasion or by their toxins. Some of the common forms are described below. [

1. VIRAL MYOCARDITIS. A number of viral infec-) tions are associated with myocarditis. Some of the common examples are influenza, poliomyelitis, infec­tious mononucleosis, hepatitis, smallpox, chickenpox, measles, mumps, rubella, viral pneumonias, coxsackie­virus and HIV infections. Cardiac involvement occurs in about 5% of viral infections. Viral myocarditis usually appears after a few days to a few weeks of

L INFECTIVE MYOCARDITIS

I 1.   Viral myocarditis

I  2.   Suppurative myocarditis

L 3.   Toxic myocarditis

I  4.   Infective granulomatous myocarditis

5.   Syphilitic myocarditis

I 6.   Rickettsial myocarditis

7.   Protozoal myocarditis

  8.   Helminthic myocarditis

9.   Fungal myocarditis

D. IDIOPATHIC (FIEDLER’S) MYOCARDITIS

1.    Diffuse type

2.   Giant cell (idiopathic granulomatous) type

I.MYOCARDITIS IN CONNECTIVE TISSUE DISEASES

1.    Rheumatoid arthritis

2.    Lupus erythematosus T  3.   Polyarteritis nodosa ■ 4.   Dermatomyositis

I 5.   Scleroderma

IV,MISCELLANEOUS TYPES OF MYOCARDITIS

[   1.   Physical agents

2.    Chemical agents

3.    Drugs

4.    Immunologic agents

  5.   Metabolic derangements

viral infections elsewhere in the body. The damage to the myocardium is caused either by direct viral cytotoxi­city or by cell-mediated immune reaction. Regardless of the type of virus, the pathologic changes are similar.

Grossly, the myocardium is pale and flabby with dilatation of the chambers. There may be focal or patchy areas of necrosis.

Histologically, there are changes of acute myo­carditis. Initially, there is oedema and infiltration of the interstitial tissue by neutrophils and lymphocytes. Later, there is necrosis of individual myocardial fibres and the infiltrate consists of lymphocytes and macrophages.

 SUPPURATIVE   MYOCARDITIS.   Pyogenic

bacteria, chiefly Staphylococcus aureus or Streptococcus pyogenes, which cause septicaemia and pyaemia may produce suppurative myocarditis. As already pointed out, acute bacterial endocarditis may sometimes cause bacterial myocarditis .

Grossly, There are either abscesses in the myocar­dium or there is diffuse myocardial involvement. Microscopically, the exudate chiefly consists of neutrophils, admixed with lymphocytes, plasma cells

and macrophages. There may be foci of myocardial degeneration and necrosis with areas of healing by fibrosis.

3.   TOXIC MYOCARDITIS. A number of acute bacte­rial infections produce myocarditis by toxins e.g. in diphtheria, typhoid fever and pneumococcal pneumonia.

Grossly, the appearance is similar to that seen in viral myocarditis.

Histologically, there are small foci of coagulative necrosis in the muscle which are surrounded by non­specific acute and chronic inflammatory infiltrate.

Toxic myocarditis manifests clinically by cardiac arrhythmias or acute cardiac failure due to involvement of the conduction system. It may cause sudden death.

4.   INFECTIVE GRANULOMATOUS MYOCAR­DITIS. Tuberculosis, brucellosis and tularaemia are some examples characterised by granulomatous inflammation in the myocardium. Sarcoidosis, though not a proved bacterial infection, has histological resemb­lance to other granulomatous myocarditis. Tuberculous myocarditis is rare and occurs either by haematogenous spread or by extension from tuberculous pericarditis. The condition must be distinguished from idiopathic granulomatous (giant cell) myocarditis (described later).

5.   SYPHILITIC MYOCARDITIS. Syphilitic involve­ment of the myocardium may occur in 2 forms—a gummatous lesion consisting of granulomatous inflam­mation which is more common, and a primary non­specific myocarditis which is rare. The syphilitic gummas in the myocardium may be single or multiple and may be grossly discernible. The gummas may affect the conduction system of the heart.

6.   RICKETTSIAL MYOCARDITIS. Myocarditis occurs quite frequently in scrub typhus (K- tsutsuga-mushi) and Rocky Mountain typhus fever caused by spotted rickettsii

Microscopically, there is interstitial oedema and focal or patchy infiltration by inflammatory cells which include lymphocytes, plasma cells, macrophages, mast cells and eosinophils but necrosis and degene­ration are generally not present.

7.   PROTOZOAL MYOCARDITIS. Chagas’ disease and toxoplasmosis are the two protozoal diseases caus­ing myocarditis. Chagas’ disease caused by Trypanosoma cruzi frequently attacks myocardium besides involving 

the skeletal muscle and the central nervous system. Toxoplasmosis caused by intracellular protozoan, Toxo­plasma gondii, sometimes causes myocarditis in children and adults.

Microscopically, both these conditions show focal degeneration and necrosis of the myocardium, oedema and cellular infiltrate consisting of histio­cytes, plasma cells, lymphocytes and a few poly-morphs.The organisms are found in the muscle fibres.

8. HELMINTHIC MYOCARDITIS. Echinococcus granulosus and Trichinella spiralis are the two intestinal helminths which may cause myocarditis. Echinococcus rarely produces hydatid cyst in the myocardium while the larvae of Trichinella in trichinosis cause heavy inflam­mation in the myocardium as well as in the interstitial tissue.

II.   IDIOPATHIC (FIEDLER’S) MYOCARDITIS

Idiopathic or Fiedler’s myocarditis is an isolated myocarditis unaccompanied by inflammatory changes in the endocardium or pericardium and occurs without the usual apparent causes. The condition is rapidly progressive and causes sudden severe cardiac failure or sudden death.

Grossly, the heart is soft and flabby. The cardiac chambers are generally dilated and sometimes show hypertrophy. There are yellow-grey focal lesions throughout the myocardium. Mural thrombi are commonly present.

Histologically, two forms of idiopathic myocarditis are described: diffuse type and giant cell (idiopathic granulomatous) type.

i) Diffuse type is more common of the two. It is characterised by diffuse non-specific inflammatory infiltrate consisting of lymphocytes, plasma cells, macrophages, eosinophils and a few polymorphs in the interstitial tissue without formation of granulomas. Late stage shows healing by fibrosis, ii) Giant cell type or idiopathic granulomatous type is characterised by formation of non-caseating granu­lomas consisting of macrophages, lymphocytes,

plasma cells and multinucleate giant cells. The giant cells are of foreign body or Langhans’ type or of myogenic origin. The granulomas do not show presence of acid-fast bacilli or spirochaetes. Some have suggested relationship of this condition with sarcoidosis but sarcoid granulomas are known to occur in the myocardium secondary to generalised sarcoidosis.

III.  MYOCARDITIS IN CONNECTIVE TISSUE DISEASES

Inflammatory involvement of the myocardium occus in a number of connective tissue diseases sudi a rheumatoid arthritis, lupus erythematosus, polyarterij nodosa, dermatomyositis and scleroderma. The pathoj logic changes in the heart muscle are similar to the changes seen in other organs in these conditions as described elsewhere in relevant chapters.

IV.  MISCELLANEOUS TYPES OF MYOCARDITIS

Apart from the three forms of myocarditis describe  above, the last group consists of myocarditis caused Ii ,1 variety of agents—physical and chemical agents,druaj and metabolic derangements.

1.   Physical agents. Physical agents like contusion J the myocardium, heatstroke, cardiac surgery and irradiation can initiate non-specific myocarditis. In features consist of an infiltrate of neutrophils, eosino phils and mononuclear cells and shows contraction-bara necrosis of the myocardial fibres.

2.    Chemical agents. Toxic chemicals such as arseniS phosphorus and carbon monoxide cause focal areas a degeneration and necrosis of myocardial fibres andnoa specific inflammatory reaction, chiefly consisting of lymphocytes and macrophages.

3.   Drugs. Changes similar to those induced by chemic poisons are produced by certain drugs suchl phenothiazine compounds, sulfonamides, catechol mines, and cytotoxic compounds.

4.    Immunologic agents. Myasthenia gravil Friedreich’s ataxia, and progressive muscular dystffl phies initiate a state of autoimmunisation against tha myocardium resulting in focal myocardial degeneratm and necrosis with secondary inflammatory reaction. Later, there may be myocardial fibrosis.

5.   Metabolic derangements. Uraemia, hypokalaemia and shock are associated with degeneration and necrosis of the myocardial fibres, oedema of the interstitial tissue and non-specific inflammatory reaction.

9. FUNGAL MYOCARDITIS. Patients with immunodeficiency, cancer and other chronic debilitating diseases are more prone to develop fungal myocarditis. These include: candidiasis, aspergillosis, blastomycosis, actino-myosis, cryptococcosis, coccidioidomycosis and histoplasmosis.

CARDIOMYOPATHY

Cardiomyopathy literally means disease of the heart piscle but the term was originally coined to restrict its ! to myocardial disease of unkown cause. The WHO ifmition of cardiomyopathy also excludes heart muscle pases of known etiologies. However, the term cardio­pathy has been loosely used by various workers ^myocardial diseases of known etiology as well e.g. koholic cardiomyopathy, amyloid cardiomyopathy, Sschaemic cardiomyopathy etc. This controversy is solved by classifying all cardiomyopathies into two broad groups:

primary cardiomyopathy; and R secondary cardiomyopathy i.e. myocardial disease with nown underlying cause.

PRIMARY CARDIOMYOPATHY

lis is a group of myocardial diseases of unknown puse. it is subdivided into the following 3 pathophysio-

categories (Fig. 12.26): I Idiopathic dilated (congestive) cardiomyopathy. I Idiopathic hypertrophic cardiomyopathy. I Idiopathic restrictive or obliterative or infiltrative jcardiomyopathy.

 

I. PRIMARY CARDIOMYOPATHY

·        Idiopathic dilated (or congestive) cardiomyopathy

·          Idiopathic hypertrophic cardiomyopathy   

·        Obstructive type

·          Non-obstructive type

·        Idiopathic restrictive (or obliterative or infiltrative) cardio­myopathy

·          Cardiac amyloidosis

·          Endocardial fibroelastosis

·         Endomyocardial fibrosis

·         Loeffler’s endocarditis (fibroplastic parietal endocarditis with peripheral blood eosinophilia)

H. SECONDARY CARDIOMYOPATHY

1 Nutritional disorders (e.g. alcoholic cardiomyopathy, beriberi heart disease)

1 Toxic chemicals (e.g. cobalt, arsenic, lithium, hydrocarbons)

Drugs (e.g. emetrine, cyclophosphamide, adriamycin, catechola­mines)

i Metabolic diseases (e.g. cardiac amyloidosis, haemochromatosis, glycogen storage diseases)

3 Neuromuscular diseases (e.g. Friedreich’s ataxia, muscular dystrophies)

6  Infiltrations (e.g. leukaemia, carcinomas)

7  Connective tissue diseases (e.g. rheumatoid arthritis, lupus erythematosus, systemic sclerosis, dermatomyositis)

1.  Idiopathic Dilated (Congestive) Cardiomyopathy

This type of cardiomyopathy is characterised by gradu­ally progressive cardiac failure alongwith dilatation of all the four chambers of the heart. The condition occurs more often in adults and the average survival from onset to death is less than 5 years. Though the etiology is unknown, a few hypotheses based on associations with the following conditions have been proposed: i) Possible association of viral myocarditis (especially coxsackievirus B) with dilated cardiomyopathy, due to presence of viral nucleic acids in the myocardium, has beeoted.

ii) Association with toxic damage from cobalt and chemotherapy with doxorubicin and other anthracyc-lines is implicated in some cases, iii) Role of inherited mutations has ben emphasised lately. Mutations in certain sarcomere proteins such as cardiac troponin-T and P-myosin have been observed. Another mutation in cytoskeletal protein dystrophin gene on X-chromosome has been held responsible for muscular dystrophy as well as dilated cardiomyopathy.

iv) Chronic alcoholism has been found associated with dilated cardiomyopathy. It may be due to thiamine deficiency induced by alcohol and resulting in beri-beri heart disease . This is referred to as ‘alcoholic cardiomyopathy’ and included by some workers as one of the subtypes of secondary cardiomyopathy. Another form of alcoholic cardiomyopathy is associated with consumption of large quantities of beer (beer drinkers’ myocardiosis). Cobalt added to the beer so as to improve the appearance of foam is thought to cause direct toxic injury to the heart in this condition. v) Peripartum association has been observed in some cases. Poorly-nourished women may develop this form of cardiomyopathy within a month before or after delivery.

PATHOLOGIC CHANGES. Grossly, the heart is enlarged and increased in weight (upto 1000 gm). The most characteristic feature is prominent dilatation of all the four chambers giving the heart typical globular appearance. Thickening of the ventricular walls even if present is masked by the ventricular dilatation . The endocardium is thickened and mural thrombi are often found in the ventricles and atria. The cardiac valves are usually normal. Microscopically, The endomyocardial biopsies or autopsy examination of the heart reveal non-specific and variable changes. There may be hypertrophy of some myocardial fibres and atrophy of others. Some- times degenerative changes and small areas of inter­stitial fibrosis are found with focal mononuclear inflammatory cell infiltrate.

2.  Idiopathic Hypertrophic Cardiomyopathy

This form of cardiomyopathy is known by various synonyms like asymmetrical hypertrophy, hypertrophic subaortic stenosis and Teare’s disease. The disease occurs more frequently between the age of 25 and 50 years. It is often asymptomatic but becomes sympto­matic due to heavy physical activity causing dyspnoea, angina, congestive heart failure and even sudden death. Though idiopathic, the following factors have been implicated:

·        ) Autosomal dominant inheritance of the disease is available in about half the cases suggesting genetic factors in its causation.

·        ) Inherited mutations in genes encoding for sarcomere proteins have been reported in much larger number of cases of hypertrophic cardiomyopathy than those of dilated cardiomyopathy. Particularly implicated are the mutations in heavy and light chains of p-myosin, troponin-I and troponin-T. The condition may result from myocardial ischaemia resulting in fibrosis of the intramyocardial arteries and compensatory hypertrophy iii) Other contributory factors are: increased circulating level of catecholamines, myocardial ischaemia as a result of thickened vasculature of the myocardium and abnormally increased fibrous tissue in the myocardium due to hypertrophy.

PATHOLOGIC CHANGES. Grossly, the characteristic features are cardiac enlargement, increase in weight, normal or small ventricular cavities and myocardial hypertrophy. The hypertrophy of the myocardium is typically asymmetrical and affects the interventricular septum more than the free walls of the ventricles. This asymmetric septal hypertrophy may be confined to the apical region of the septum  (non-obstructive type) or may extend upto the level of the mitral valve causing obstruction to left ventricular outflow in the form of subaortic stenosis). The designation of rhabdomyoma of the septum was applied to this form of cardiomyopathy in the old literature.

Microscopically, the classical feature is the myocar­dial cell disorganisation in the ventricular septum, The bundles of myocardial fibres are irregularly and haphazardly arranged rather than the usual parallel pattern and are separated by bands of interstitial I fibrous tissue. The individual muscle cells show I hypertrophy and large prominent nuclei.

     1 Idiopathic Restrictive (Obliterative or Infiltrative) Cardiomyopathy

pis form of cardiomyopathy is characterised by restric-pin ventricular filling due to reduction in the volume jffhe ventricles. It includes the following entities:

J Cardiac amyloidosis

i) Endocardial fibroelastosis

lEndomyocardial fibrosis

fe) Loeffler ‘s endocarditis (Fibroplastic parietal endo-

BHditis with peripheral blood eosinophilia).

I CARDIAC AMYLOIDOSIS. Amyloidosis of the feart may occur in any form of systemic amyloidosis  may occur as isolated organ amyloidosis in amyloid paging and result in subendocardial deposits

(Chapter 4).

I ENDOCARDIAL FIBROELASTOSIS. This is an  usual and uncommon form of heart disease occurring pedominantly in infants and children under 2 years of Bf and less often in adults. The infantile form is clinically practerised by sudden breathlessness, cyanosis, cardiac failure and death whereas the symptoms in the mltform last for longer duration. The etiology of the [condition remains obscure. However, a number of [‘theories have been proposed. These are as under: 1) The infantile form is believed to be congenital in [origin occurring due to the effect of intrauterine endo-I anoxia. The adult form may also be induced by [anoxia-causing lesions such as anomalous coronary  arteries, metabolic derangements influencing myocar­dial function etc.

 It may occur due to haemodynamic pressure overload such as in congenital septal defects and coarctation of the aorta.

c) It may be an expression of genetic disorder as noticed in twins, triplets and siblings. Association of endocardial fibroelastosis with various congenital malformations in the heart or elsewhere further supports the genetic theory.

e)  Certain factors causing myocardial injury may initiate the endocardial disease such as in thiamine deficiency (beri-beri heart disease) or from preceding idiopathic myocarditis.

1 lymphatic obstruction of the heart has been suggested [by some as the causative mechanism.

PATHOLOGIC CHANGES. Grossly, the characteristic feature is the diffuse or patchy, rigid, pearly-white

thickening of the mural endocardium . Left ventricle is predominantly involved, followed in decreasing frequency by left atrium, right ventricle and right atrium. Quite often, the valves, especially of the left heart, are affected. Some cases contain mural thrombi. Enlargement of the heart is present and is mainly due to left ventricular hypertrophy but the volume of the chamber is decreased. Microscopically, the typical finding is the prolife­ration of the collagen and elastic tissue (fibroelastosis) comprising the thickened endocardium. The fibro­elastosis generally does not extend into the subjacent myocardium. The lesion is devoid of inflammatory cells.

 ENDOMYOCARDIAL FIBROSIS. This form of restrictive cardiomyopathy is a tropical condition prevalent in Africa, especially in Uganda and Nigeria, but some cases occur in South India, Sri Lanka, Malaysia and tropical South America. It is seen in children and young adults. The clinical manifestations consist of congestive heart failure of unknown cause just as in adult variety of endocardial fibroelastosis. The etiology of the condition remains obscure but the geographic distribution suggests the role of certain factors like malnutrition, viral infections and heavy consumption of banana (rich in serotonin).

PATHOLOGIC CHANGES. Grossly, endomyocardial fibrosis is characterised by fibrous scarring of the ventricular endocardium that extends to involve the inner third of the myocardium. The atrioventricular valve leaflets are often affected but the semilunar valves are uninvolved. Mural thrombi may be present. The heart may be normal-sized or hyper-trophied but the volume of the affected chambers is diminished due to fibrous scarring. Microscopically, the endocardium and parts of inner third of the myocardium show destruction of normal tissue and replacement by fibrous tissue. The condition differs from endocardial fibroelastosis in having mononuclear inflammatory cell infiltrate and lacking in elastic tissue. The superficial layer may show dense hyalinised connective tissue and even calcification.

B. SECONDARY CARDIOMYOPATHY

This is a group of myocardial diseases of known etiologies or having clinical associations. This, however, excludes well-defined entities such as ischaemic, hyper­tensive, valvular, pericardial, congenital and inflammatory involvements of the heart. The main entities included in this group are described elsewhere in the text and are listed below:

1.   Nutritional disorders e.g. chronic alcoholism, thiamine deficiency causing beri-beri heart disease .

2.   Toxic chemicals e.g. cobalt, arsenic, lithium and hydrocarbons.

3.   Drugs e.g. cyclophosphamide, adriamycin, catecholamines.

4.   Metabolic diseases e.g. amyloidosis, haemochromatosis, glycogen storage diseases, hypo-and hyperthyroidism, hypo-and hyperkalaemia.

5.   Neuromuscular diseases e.g. Friedreich’s ataxia, muscular dystrophies.

6.   Infiltrations e.g. from leukaemia and carcinoma.

7.   Connective tissue diseases e.g. rheumatoid arthritis, systemic sclerosis, dermatomyositis, lupus erythematosus.

PERICARDIAL DISEASE

Diseases of the pericardium are usually secondary to, or associated with, other cardiac and systemic diseases. They are broadly of 2 types:

I.    Pericardial fluid accumulations

II.  Pericarditis

PERICARDIAL FLUID ACCUMULATIONS

Accumulation of fluid in the pericardial sac may be watery or pure blood. Accordingly, it is of 2 types: hydro-pericardium (pericardial effusion) and haemo-pericardium.

A. HYDROPERICARDIUM (PERICARDIAL EFFU­SION). Accumulation of fluid in the pericardial cavity due to non-inflammatory causes is called hydroperi-cardium or pericardial effusion. Normally, the pericardial cavity contains 30 to 50 ml of clear watery fluid. Considerable quantities of fluid (upto 1000 ml) can be accommodated in the pericardial cavity without

seriously affecting the cardiac function if the accumtl lation is slow. But sudden accumulation of a smalm volume (upto 250 ml) may produce deficient diastolfl filling of the cardiac chambers (cardiac tamponade)! Pericardial effusion is detected by cardiac enlargemew in the X-rays and by faint apex beat.

The various types of effusions and their causes are as follows:

1.   Serous effusions. This is the most common type] occurring in conditions in which there is generalise oedema e.g. in cardiac (in CHF), renal, nutritional an hepatic causes. The serous effusion is clear, watery, strata coloured with specific gravity less than 1.015 (transq date). The serosal surface is smooth and glistening,

2.    Seiosanguineous effusion. This type is foua following blunt trauma to chest and cardiopulmonai resuscitation.

3.   Chylous effusion. Milky or chylous fluid accum lates in conditions causing lymphatic obstruction.  

4.   Cholesterol effusion. This is a rare type of fluid accumulation characterised by the presence of choles­terol crystals such as in myxoedema.

B. HAEMOPERICARDIUM. Accumulation of pun blood in the pericardial sac is termed haemoperi-cardium. The condition must be distinguished from haemorrhagic pericarditis in which there is escape of small quantities of blood into the pericardial cavil Massive and sudden bleeding into the sac causes compression of the heart leading to cardiac tamponade, The causes of haemopericardium are: i) Rupture of the heart through a myocardial infarct ii) Rupture of dissecting aneurysm. iii) Bleeding diathesis such as in scurvy, acute leukaemias, thrombocytopenia.

iv) Trauma following cardiopulmonary resuscitation ot by laceration of a coronary artery.

PERICARDITIS

Pericarditis is the inflammation of the pericardial lay! and is generally secondary to diseases in the heart m caused by systemic diseases. Primary or idiopathic peri­carditis is quite rare. Based on the morphologic appearance, pericarditis is classified into acute an chronic types, each of which may have several etw logies. Acute and chronic pericarditis have further sub types based on the character of the exudate .

 Acute Pericarditis

Acute bacterial and non-bacterial pericarditis are the most frequently encountered forms of pericarditis. The  may have the following subtypes:

           Classification of Pericarditis.

A. ACUTE PERICARDITIS

 1.  Serous pericarditis

 2.   Fibrinous or serofibrinous pericarditis

 3.   Purulent or hbrinopurulent pericarditis

 4.   Haemorrhagic pericarditis

 CHRONIC PERICARDITIS

  1.   Tuberculous pericarditis

  2.   Chronic adhesive pericarditis

 3.  Chronic constrictive pericarditis

 4.   Pericardial plaques (milk spots, soldiers’ spots)

1.  SEROUS PERICARDITIS. Acute pericarditis may be accompanied by accumulation of serous effusion which differs from transudate of hydropericardium in .having increased protein content and higher specific gravity. Its various causes are as under:

 Viral infection e.g. coxsackie A or B viruses, influenza virus, mumps virus, adenovirus and  infectious mononucleosis. ii) Rheumatic fever. 🙂 Rheumatoid arthritis. p) Systemic lupus erythematosus. v) Involvement of the pericardium by malignant tumour in the vicinity e.g. carcinoma lung, meso­thelioma and mediastinal tumours. vi) Tuberculous pericarditis in the early stage.

The fluid accumulation is generally not much and ranges from 50 to 200 ml but may rarely be large enough to cause cardiac tamponade.

Microscopically, the epicardial and pericardial surfaces show infiltration by some neutrophils, lymphocytes and histiocytes. The fluid usually resorbs with the resolution of underlying disease.

2.  FIBRINOUS AND SEROFIBRINOUS PERICAR­DITIS. The response of the pericardium by fibrinous exudate is the most common type of pericarditis. Quite often, there is admixture of fibrinous exudate with serous fluid. The various causes of this type of peri-tardiris are:

 Uraemia

p) Myocardial infarction

h) Rheumatic fever

i) Trauma such as in cardiac surgery

a) Acute bacterial infections.

The amount of fluid accumulation is variable. The cardiac surface is characteristically covered by dry or moist, shaggy, fibrinous exudate which gives ‘bread and butter’ appearance

3.   PURULENT OR FIBRINOPURULENT PERICARDITIS. Purulent or fibrinopurulent pericarditis is mainly caused by pyogenic bacteria (e.g. staphylococci, streptococci and pneumococci) and less frequently by fungi and parasites. The infection may spread to the pericardium by the following routes:

i)   By direct extension from neighbouring inflammation

e.g. in empyema of the pleural cavity, lobar pneumonia,

infective endocarditis and mediastinal infections.

ii) By haematogenous spread.

iii) By lymphatic permeation.

iv) Direct implantation during cardiac surgery.

Generally, fibrinous or serofibrinous pericarditis precedes the development of purulent pericarditis. The amount of exudate is variable and is generally thick, creamy pus, coating the pericardial surfaces.

Microscopically, besides the purulent exudate on the pericardial surfaces, the serosal layers show dense infiltration by neutrophils. Purulent exudate gene­rally does not resolve completely but instead heals by organisation resulting in adhesive or chronic constrictive pericarditis.

4.   HAEMORRHAGIC PERICARDITIS. Haemor­rhagic pericarditis is the one in which the exudate consists of admixture of an inflammatory effusion of one of the foregoing types alongwith blood. The causes are:

i)   Neoplastic involvement of the pericardium ii) Haemorrhagic diathesis with effusion iii) Tuberculosis iv) Severe acute infections

The outcome of haemorrhagic pericarditis is generally similar to that of purulent pericarditis.

B. Chronic Pericarditis

Chronic pericarditis is the term used for tuberculous pericarditis and the healed stage of one of the various forms of acute pericarditis already described. Included under this are: tuberculous pericarditis, chronic adhe­sive pericarditis, chronic constrictive pericarditis, and the pericardial plaques.

1. TUBERCULOUS PERICARDITIS. Tuberculous pericarditis is the most frequent form of granulomatous inflammation of the pericardium. The lesions may occur by one of the following mechanisms: i) Direct extension from an adjacent focus of tuber­culosis.

ii) By lymphatic spread e.g. from tracheobronchial lymph nodes, chronic pulmonary tuberculosis or infec­ted pleura.

The exudate is slightly turbid, caseous or blood­stained with sufficient fibrin. Tubercles are generally visible on the pericardial surfaces and sometimes caseous areas are also visible to the naked eye.

Microscopically, typical tuberculous granulomas with caseatioecrosis are seen in the pericardial wall. The lesions generally do not resolve but heal by fibrosis and calcification resulting in chronic constric­tive pericarditis.

3.   CHRONIC CONSTRICTIVE PERICARDITIS. This

is a rare condition characterised by dense fibrous or

fibrocalcific thickening of the pericardium resulting in

mechanical interference with the function of the heart

and reduced cardiac output. The condition usually

results from a long-standing preceding causes such as:

i)   Tuberculous pericarditis

ii) Purulent pericarditis

iii) Haemopericardium

iv) Concato’s disease (polyserositis)

v) Rarely, acute non-specific and viral pericarditis.

The heart is encased in 0.5 to 1 cm thick and dense collagenous scar which may be calcified. As a result, the heart fails to dilate during diastole. The dense

fibrocollagenous tissue may cause narrowing ot the I openings of the vena cavae, resulting in obstruction to I the venous return to the right heart and consequom right hear! failure. In contrast to chronic adhesiva pericarditis, hypertrophy and dilatation donotoccm due to dense fibrous scarring. Instead, the heartsizeH normal or smaller .

4. PERICARDIAL PLAQUES (MILK SPOM SOLDIERS’ SPOTS). These are opaque, white, shinJ and well-circumscribed areas of organisation with fiw rosis in the pericardium measuring 1 to 3 cm in diameter, They are seen most frequently on the anterior surtaS of the right ventricle. The exact cause is not knownbm they are generally believed to arise from healingn preceding pericarditis. The plaque-like lesions pericardial thickenings are also termed milk spots n si ildiers’ spots as they were often found at autopsy inthl soldiers in World War I who carried their shoulder bag causing pressure against the chest wall by the straps] which produced chronic irritation of the pericardiuM

TUMOURS OFTHE HEART

Tumours of the heart are classified into primary arm secondary, the latter being more common than the former.

PRIMARY TUMOURS

Primary tumours of the heart are quite rare, found 0.04°/. of autopsies. In decreasing order of frequenqa the benign tumours encountered in the heart are! myxoma, lipoma, fibroelastoma, rhabdomyoma haemangioma and lymphangioma. The maligna» tumours are still rarer, the important ones are: rhabdomyosarcoma, angiosarcoma and maligna* mesothelioma. Out of all these, only myxoma of ftel heart requires elaboration.

MYXOMA. This is the most common primary tumour of the heart comprising about 50% of all primary caidjfl tumours. Majority of them occur in the age rangeoffl to 60 years. Myxomas may be located in any cardjfl chamber or the valves, but 90% of them are situated in J the left atrium.

Grossly, they are often single but may be multiple. They range in size from less than 1 to 10 cm, polypoid, pedunculated, spherical, soft and haemorrhagic I masses resembling an organising mural thrombus, Some investigators actually consider them to be organising mural thrombi rather than true neoplasms,

2. CHRONIC ADHESIVE PERICARDITIS. Chronic adhesive pericarditis is the stage of organisation and healing by formation of fibrous adhesions in the peri­cardium following preceding fibrinous, suppurative or haemorrhagic pericarditis. The process begins by formation of granulation tissue and neovascularisation. Subsequently, fibrous adhesions develop between the parietal and the visceral layers of the pericardium and obliterate the pericardial space . Some­times, fibrous adhesions develop between the parietal pericardium and the adjacent mediastinum and is termed as adhesive mediastinopericarditis. Chronic adhesive pericarditis differs from chronic constrictive pericarditis iot embarrassing the function of the heart. However, cardiac hypertrophy and dilatation may occur in severe cases due to increased workload.

   Appearance of the heart and the pericardium in chronic adhesive (A) and chronic constrictive pericarditis (B).

Microscopically, the tumour shows the following

features:

i) There is abundant myxoid or mucoid intercellular

stroma positive for mucin.

ii) The cellularity is sparse. The tumour cells are

generally stellate-shaped, spindled and polyhedral,

scattered in the stroma. Occasional multinucleate

tumour giant cells are present.

iii) Numerous capillary-sized blood vessels are found

and the tumour cells may be aggregated around

them.

iv) A few lymphocytes, plasma cells and macrophages

are seen.

v) Fod of haemorrhage and deposits of haemosiderin

granules are often present.

SECONDARY TUMOURS

Metastatic tumours of the heart are more common than thepdmary tumours. About 10% cases with dissemi­nated cancer have metastases in the heart. Most of these result from haematogenous or lymphatic spread. In descending order of frequency, primary sites of origin are:carrinoma of the lung, breast, malignant lymphoma, leukaemia and malignant melanoma. Occasionally, there may be direct extension of a primary intrathoracic tumour such as carcinoma of the lung into the peri­cardium and into the cardiac chambers.

PATHOLOGY OF CARDIAC INTERVENTIONS

Balloon angioplasty is a non-surgical procedure that employs percutaneous insertion and manipulation of a balloon catheter into the occluded coronary artery. The balloon is inflated to dilate the stenotic artery which causes endothelial damage, plaque fracture, medial

Nowadays, with the development of surgical and non- I surgical therapeutic interventions in coronary artery Ej disease, it has been possible to study the pathology of I native as well as grafted vessel and also the myocardium I by endomyocardial biopsy.

ENDOMYOCARDIAL BIOPSY

Currently, it is possible to perform endomyocardial biopsy (EMB) for making a final histopathologic diagnosis in certain cardiac diseases. The main indications for EMB are: myocarditis, cardiac transplant cases, restrictive heart disease, infiltrative heart diseases such as in amyloidosis, storage disorders etc.

EMB is done by biopsy forceps introduced via cardiac catheter in to either of the ventricles but preferably right ventricle is biopsied for its relative ease and safety. The route for the catheter may be through internal jugular vein or femoral vein for accessing the right ventricle. dissection and haemorrhage in the affected arterial wall. At this stage, unstable angioplasty is liable to be associated with acute coronary syndromes.After 3-6 months of angioplasty, 30-40% cases of satisfactorily dilated vessel lumen are followed by reste­nosis. The restenosis is multifactorial in etiology that includes smooth muscle cell proliferation, extracellular matrix and local thrombosis. Currently, radioactive stents which emit low dose particles to inhibit smooth cell proliferation are also available.

CORONARY BYPASS GRAFTING

which develop in grafted vein include thrombosis early stage, intimal thickening and atherosclerosis with or without complicated lesions.

2.Internal mammary artery graft, however, has i patency of more than 90% after 10 years.

3.Atherosclerosis with superimposed complications may develop iative coronary artery distal to the grafted vessel as well as in the grafted vessel.

CARDIACTRANSPLANTATION

Cardiac transplantation is done in end-stage cardia diseases, most often in idiopathic cardiomyopathies Worldwide, about 40,000 cardiac transplants have been carried out. The survival following heart transplantsi reported as: 1 year in 85%, 5 years in 65 % and 10 yeais in 45% cases. Major complications are transplant rejec­tion reaction and infections, particularly with Toxoplasm gondii and cytomegaloviruses. One of the main problems in cardiac transplant centres is the availability of donors The stem cell research in this area holds grea promise for the future because then it would be possible to transplant transformed embryonic stem cells.

Autologous grafts are used to replace or bypass diseased cornary arteries. Most frequently used is autologous graft of saphenous vein which is reversed (due to valves in the vein) and transplanted, or left internal mammary artery may be used being in the operative area of the heart. Long-term follow-up of bypass surgery has yielded following observations on pathology of grafted vessel.

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