Heart disease is a significant cause of morbidity and mortality throughout the world. The major ailments include ischaemic heart disease, hypertensive heart disease, rheumatic heart disease and congenital heart disease. In India and other developing countries while rheumatic heart disease continues to cause major concern, hypertension and ischaemic (coronary) heart disease have also attained significant proportions.
NORMAL HEART
For better understanding of cardiac diseases it would be in order to recapitulate some of the important aspects of the normal heart. The weight of the normal heart is dependent on the weight and height of an individual. Generally it is lower in females as compared with males varying from 200 to 250 gm and 240 to 300 gm in the average 31female and male respectively. The corresponding figures in the Western population are 250 to 300 gm in females and 300 to 350 gm in males. The thickness of the left and right ventricular walls range from 1 to 1.3 cm and 0.1 to 0.3 cm respectively. The atrial walls on the other hand are 0.2 to 0.3 cm thick. Thickness of the ventricular walls greater than these indicates hypertrophy. However, if the chamber is dilated over a long period of time, the hypertrophy may be masked by stretching of the cardiac muscle resulting in either normal or even decreased thickness of the walls. The normal myocardium has a large reserve capacity to respond to demands for increased workload resulting in hypertrophy which occurs in various diseases of the heart.
Histologically, the myocardium consists of a syncytium of branching myocytes arranged in a parallel fashion and connected with each other by irregular joints called the intercalated discs. The myocardial cell is 60 to 100 µ long with a diameter ranging from 10 to 20 µ. The intermyocardial cell space contains mesenchymal cells, a rich capillary network and loose connective tissue. The centrally located nucleus is round to ovoid and measures 4 to 6 µ in diameter. Ultrastructurally, the myocyte is limited by the sarcolemma and has abundant sarcoplasmic reticulum. A T-system of tubules serve as a channel for ion transport especially Ca++ which is actively involved in cardiac contraction. Mitochondria with their concentration of ATP is the key substance for cardiac contraction. Myofilaments are made up of regularly repetitive functional units—the sarcomeres. Each sarcomere in turn is comprised by Z-lines, A-bands, I-bands, H-zones and M-lines. These bands represent varied concentrations of myosin and actin filaments in different areas within the sarcomere. In the resting phase, the I-band has only thin actin filaments while the A-band consists of partially overlapping actin and myosin filaments. In the centre of the A-band, myosin filaments are cross-linked by fine filamentous bridges which constitute the M-band. The force for myocardial contraction is provided by the myosin and actin filaments and is proportional to the length of the sarcomere which ranges from 1.6 to 2.2 µ. The optimal length of the sarcomere for a forceful contraction ranges between 2 to 2.2 µ. Up to a certain limit, longer lengths enhance contractility which is the basis of the Starling's law of the heart. However, when the sarcomere is stretched beyond 2.2 µ, there is a marked drop in the force of contraction.
CONGESTIVE HEART FAILURE
Congestive heart failure (CHF) is the end result of several cardiac diseases. Herein the output of the heart is unable to maintain the normal metabolic requirements of the body. This is caused either by impaired contractility or increased workload on the myocardium.
Several compensatory mechanisms come into force to maintain a normal cardiac output. These include: (i) cardiac hypertrophy, (ii) cardiac dilatation, and (iii) increased heart rate (tachycardia). As per the Starling's law of the heart, the force of myocardial contraction and size of the stroke volume are increased in the failing dilated heart. Up to a certain limit, longer lengths of the sarcomere in dilated hearts enhance contractility thereby leading to increased stroke volume and expansion of the blood volume. Dilatation beyond a certain point, however, decreases the force of contraction leading to residual blood (volume overload) in the chamber. Beyond the critical limit various compensatory mechanisms also fail and result in heart failure.
Causes of Heart Failure
Intrinsic Pump Failure
The most common cause of heart failure is impairment of ventricular contractility which results either from loss of myocardial mass as occurs in myocardial infarction or extensive myocarditis 32or from systolic dysfunction as in dilated cardiomyopathy.
Pressure Overload
Increased work load on the heart occurs in obstruction to the outflow of blood, e.g. in aortic stenosis and pulmonary stenosis or in increased resistance to outflow as in pulmonary and systemic arterial hypertension.
Increased Volume Overload
In dilated cardiomyopathy, severe anaemias, thyrotoxicosis and incompetence of the cardiac valves, the cardiac chambers have to handle increased volumes of blood.
In heart failure there is disparity between the venous return to the heart and the cardiac output. Heart failure due to insufficient systolic function of the ventricles is commonly termed “forward failure” while that due to impaired return of blood to the heart due to its stagnation in the veins is known as “backward failure”. Failure of the heart may initially involve the right or left side, but eventually failure of all chambers results (Fig. 2.1).
Left heart failure results from damage to the myocardial fibres as in myocardial infarction and myocarditis and excessive workload on the heart, e.g. systemic hypertension and aortic and mitral valve disease. It leads to low cardiac output (forward failure) as a result of which there is impaired perfusion which causes anoxia of various organs or tissues. Renal hypoperfusion, for example leads to ischaemic tubular necrosis and activation of the renin-angiotension-aldosterone system which promotes salt and water retention and therefore increase in the blood volume and interstitial fluid (oedema). Hypoperfusion of the brain may cause encephalopathy. Left sided heart failure leads to stagnation of blood and increased pressure in these chambers which in turn causes increased pulmonary venous and capillary pressures that result in venous congestion and pulmonary oedema. Eventually pulmonary arterial hypertension causes elevated right ventricular pressure and systemic venous congestion leading to right heart failure.
Right heart failure may occur either in isolation or more commonly consequent to left heart failure. All cardiac diseases affecting the left side of the heart leading to left heart failure will ultimately result in failure of right side of the heart. Causes of isolated right heart failure include: (i) cor pulmonale which is heart disease consequent to chronic, diffuse pulmonary parenchymal and vascular diseases, (ii) right sided valvular diseases of varying aetiology, and (iii) myocardial diseases namely cardiomyopathy, myocarditis, and myocardial infarction predominantly involving the right side of the heart.
Increased right ventricular pressure (backward failure) results in systemic and portal venous congestion and raised systemic venous pressure. This manifests as distended leg veins and high hydrostatic pressure and is recognised clinically by raised jugular venous pressure, enlarged and often tender liver and oedema in the gravity-dependent areas such as the feet, ankles and the lower back. Increased hydrostatic pressure along with anoxia favours excess capillary permeability causing leakage of fluid into the interstitial tissues (oedema). Oedema formation is also contributed by the renin-angiotensin-aldosterone system stimulated by renal hypoperfusion consequent to a low cardiac output.
Pathology
Lungs
In left ventricular failure, the lungs are large, heavy, and deeply congested which on squeezing yield frothy often blood-stained oedema fluid. Microscopically, the interalveolar spaces are widened due to dilated and congested capillaries and accumulation of interstitial fluid. The intra-alveolar spaces contain a light pink and homogeneous proteinaceous fluid (oedema fluid) admixed with red blood cells (RBCs).33
Chronic or passive venous congestion of the lungs consequent to right heart failure results in large sized lungs which are non-crepitant, firm and brown in colour. Microscopically, the alveolar septa are widened due to dilated and congested blood vessels and proliferation of fibroconnective tissue. In addition, abundant haemosiderin both free and within macrophages is present within the intraalveolar spaces (Heart failure cells). The term “brown indurated” lungs is due to the haemosiderin pigment and septal fibrosis respectively. Besides the parenchymal changes, varying grades of pulmonary arterial changes may be encountered in some cases of CHF. Pulmonary infarction is unusual in normal lung but is common in CHF due to venous congestion, stasis and/or thromboemboli within the pulmonary vasculature.
Liver
The liver in right heart failure is enlarged and tender. On gross examination, the liver is overweight and congested. In long-standing cases of heart failure, however, the liver may be either normal or reduced in size and feels firm due to fibrosis.34
Fig. 2.2: Gross photograph of liver from a case of chronic venous congestion. It shows alternate light and dark areas (“Nutmeg” liver)
The cut surface of the liver shows alternate light and dark areas, an appearance commonly termed as “nutmeg” liver (Fig. 2.2). Microscopically, centrilobular congestion and dilatation of the sinusoids is present. This is usually associated with variable degree of atrophy of hepatocytes in this region due either to anoxia and/or pressure exerted on them (Fig. 2.3). Fatty metamorphosis of the hepatocytes may also be present. Centrilobular haemorrhagic necrosis of the liver parenchyma occurs when the right ventricular pressures are markedly elevated. In long-standing cases, fibrosis starting in the central area may progress to form prominent wide fibrotic bands giving rise to cardiac fibrosis”.
Elevated pressures in the liver and portal venous system are eventually transmitted to the spleen resulting in chronic venous congestion. The spleen is enlarged and firm. Microscopically, the sinusoids are markedly dilated, congested and focal areas of haemorrhage may be present. In the later stages, fibrosis in the sinusoidal walls is seen. Fibrosiderotic nodules (Gamna-Gandy bodies) which consist of haemosiderin and calcium encrusted within fibrous tissue are encountered in some cases.
Fig. 2.3: Chronic venous congestion liver. The light areas represent sinusoidal dilatation and atrophy of hepatocytes in centrizonal area (cz). Hepatocytes in periportal area (pt) are unremarkable
Other Effects
In heart failure the kidneys suffer hypoperfusion resulting in hypoxic acute tubular necrosis and activation of the renin-angiotensin-aldosterone system. Ischaemia of the intestines may occur in heart failure. The affected segment shows congestion, haemorrhage and depending upon the severity of ischaemia, ulceration of the mucosa and gangrene may result. Brain shows morphological changes of hypoxia. Pleural and pericardial effusion, ascites and accumulation of fluid in the interstitial tissues of the body mostly in the dependent parts is also present in cases of CHF (Fig. 2.1).
RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE
Rheumatic heart disease (RHD) continues to be a major cardiac disease in the developing world. In India it is a major public health challenge associated with high morbidity and mortality. Prevalence figures of RHD range from 1/1000 to 5.5/1000 in school-going children (Multicentre School Survey (5–16 years) by the Indian Council of Medical Research). Rheumatic fever (RF) is characterised by an acute, recurrent, inflammatory, 35febrile systemic disease following pharyngitis caused by group A haemolytic Streptococcus. It develops most frequently in childhood (5–16 years). Rheumatic heart disease is a sequel of acute rheumatic fever (ARF) and occurs in about 3 per cent of the cases. Valvular deformities consequent to chronic RHD are an important cause of cardiac morbidity and mortality.
Clinical diagnosis of RF is based on the major and minor Jones criteria (revised) along with laboratory evidence of a preceding streptococcal infection (Table 2.1).
Major Jones criteria include: (i) pancarditis, involvement of all layers of the heart, (ii) polyarthritis, (iii) subcutaneous nodules, (iv) chorea, and (v) erythema marginatum.
Minor Jones criteria comprise fever, arthralgia, previous history of rheumatic fever, electrocardiographic changes and acute phase reactants such as raised C-reactive proteins (CRP), elevated erythrocyte sedimentation rate (ESR) and leucocytosis.
Laboratory evidence is provided by positive throat culture or rapid streptococcal antigen test and elevated or rising titres of antibodies to the various streptococcal enzymes such as hyaluronidase, streptokinase, streptolysin O and S and anti-DNAse B. These are commonly used in the laboratory diagnosis of streptococcal infection to determine rheumatic activity. Significant antibody response is obtained 4 to 5 weeks after the antecedent streptococcal pharygitis and 2 to 3 weeks after the onset of RF. The most commonly employed antibody for the diagnosis of rheumatic activity is anti-streptolysin-O (ASLO). The diagnostic accuracy is, however, improved by estimating two or more antibodies.
Presence of two major or one major and two minor criteria with supportive laboratory evidence of antecedent streptococcal infection is essential for the clinical diagnosis of RF.
Pathology
Acute rheumatic carditis At autopsy, the heart shows an involvement of all the three layers—pancarditis.
Serofibrinous pericarditis is most often observed in acute rheumatic carditis. Both layers of the pericardium are thickened and covered with varying amounts of fibrin that project between the two layers. Healing produces fibrosis and adhesions between the two layers without any serious cardiac effects. Microscopically, fibrin covers the surface of the epicardium and an infiltrate comprising lymphocytes, histiocytes and plasma cells is seen. Occasionally, fibrinoid necrosis with Aschoff bodies may be present. Myocarditis is a feature of acute carditis which is evident by an enlarged, soft and flabby heart with dilatation of all chambers especially the ventricles. Microscopically, rheumatic myocarditis is characterised by: (i) presence of Aschoff bodies, (ii) non-specific interstitial myocarditis, and (iii) damage and destruction of the myofibres all of which result in a soft and dilated heart.
The most pathognomonic feature of rheumatic carditis is the Aschoff body/nodule. It may be present in various sites but is most commonly located in the interstices of the myocardium often adjacent to intramyocardial blood vessels and in the subendocardial tissue. It may occasionally be encountered in the pericardium, and adventitia of the aorta. Aschoff bodies are oval, elliptical or nodular structures which evolve through several stages.36
Fig. 2.4: Early stage of Aschoff nodule. Fibrinoid necrosis is present in the interstitial tissue of myocardium (M) besides a blood vessel (BV)
Fig. 2.5: Aschoff nodule situated in paravascular location. Notice the uninuclear and multinuclear Aschoff cells
The earliest stage, is characterised by swelling, fragmentation and fibrinoid degeneration of the collagen (Fig. 2.4) which is surrounded by lymphocytes, macrophages and plasms cells. The appearance of the Aschoff body in the granulomatous stage (Fig. 2.5) is characteristic and comprises nodular aggregate of large, plump, mononuclear or multinuclear cells known as the Aschoff cells. Anitschkow cells and lymphocytes are the other components of the Aschoff nodule. The Anitschkow cells are small elogated cells with single nucleus, scanty eosinophilic cytoplasm and indistinct cell borders. The Aschoff cells are large, ovoid in shape, have abundant to light basophilic cytoplasm and ill-defined, ragged cell borders. They may be uninucleate or multinucleated (Aschoff giant cells). The nuclei either have uniformly distributed chromatin or more often the chromatin is arranged as a bar with serrated edges, an appearance known as “caterpillar nuclei”. In cross-sections the chromatin strand is surrounded by a halo and is commonly termed as “owl-eyed” nuclei. Within three to four months the Aschoff bodies eventually heal by scarring. Myocarditis in RF is characterised by an interstitial infiltrate of lymphocytes, plasma cells and histiocytes. Occasionally polymorphs and eosinophils in variable numbers are also seen within the infiltrate. Focal and/or diffuse degeneration and necrosis of the myofibres is frequently encountered.
Endocarditis involves either the valvular or the parietial (mural) endocardium but more commonly both sites are affected simultaneously. Rheumatic valvulitis has characteristic gross and microscopic features and is of extreme clinical importance as recurrent attacks of inflammation and healing produce valvular deformities which cause serious cardiac morbidity and mortality. All four cardiac valves may be involved in the following descending order of frequency—mitral, aortic, tricuspid and pulmonary. Mitral and aortic valves are more frequently affected than the tricuspid and the pulmonary valves. In the acute stage, the valve leaflets are oedematous, opaque and lose their normal transparency. Tiny, firmly attached, nodules 1 to 3 mm in diameter are present along the line of closure of the cusps. This lesion is commonly referred to as rheumatic vegetations. The vegetations are present on the atrial surface of the mitral and tricuspid valves and on the ventricular surface of the semilunar cusps of the aortic and the pulmonary valves. Microcopically, the valve cusps show oedema, increased vascularity and inflammatory cell 37infiltration of the valve substance by lymphocytes, histiocytes, few polymorphs and eosinophils. Rheumatic vegetations reveal fibrinoid necrosis of the valvular collagen on the surface of the valve which at its base is bordered by histiocytes in a palisading arrangement (Fig. 2.6). Few aggregates of Aschoff cells may also be seen within the valve substance. Typical Aschoff nodules are not encountered in the valve.
Fig. 2.6: Vegetation on mitral valve from a case of acute rheumatic fever. Fibrinoid necrosis of surface collagen with histiocytes at the base are seen
Mechanism of formation of these vegetations is possibly related to injury to the endocardium and exposure of the subendocardial connective tisssue caused by the haemodynamic stress and strain on the valves. The inflamed and exposed endocardial surface coupled with fibrinoid degeneration of the collagen favours the deposition of fibrin and platelets. Associated involvement of the mural (parietal) endocardium is often encountered in RF. The most common location is the endocardium lining the posterior wall of the left atrium above the posterior leaflet of the mitral valve. This lesion is commonly known as the MacCallum's patch which shows irregularly thickened endocardium. Microscopically, oedema and inflammation of the endocardium and subendocardial tissues is present. The infiltrate is composed of lymphocytes, histiocytes, few polymorphs and eosinophils. Anitschkow and Aschoff cells may be seen. Classical Aschoff nodules are unusual.
Aetiopathogenesis
Group-A Haemolytic Streptococcus Clinical, epidemiological, laboratory and prophylactic evidences suggest that RF is preceded by pharyngitis/tonsillitis caused by group-A haemolytic Streptococcus.
Clinical Evidence
About two-third of patients of ARF provide a history of sore throat. Recurrent streptococcal infections are associated with reactivation of rheumatic carditis and progressive valvular fibrosis leading to valvular deformities.
Immunological Evidence
Acute rheumatic fever generally follows after a latent period of about 2 to 4 weeks after infection with group-A Streptococcus. During this interval hypersensitivity and/or autoimmunity to group-A Streptococcus develops which forms the basis for the pathogenesis of the disease.
Prophylactic Evidence
Effective control of streptococcal infection by penicillin therapy prevents the initial or recurrent attacks of ARF.
Epidemiologic Evidence
Epidemiological data has clearly shown a relationship between epidemics of streptococcal pharyngitis and RF. Prevalence of RF continues to be high in India and other developing countries. Poor nutrition, overcrowding, unfavourable socioeconomic conditions, damp weather, age and some geographic factors favour its occurrence. An appreciable decline has occurred in the developed countries largely due to the better living conditions. Recent outbreaks of RF in the United States of America are of interest and possibly represent variations in rheumatogenicity and emerence of group A virulent streptococcal strains.
It has been convincingly demonstrated that a number of proteins or enzymes in the cell wall 38and cell membrane of the Streptococcus have an identity/cross-reactivity with several mammalian tissues which are targeted by the rheumatic process. M-protein is one of the very important surface proteins of the Streptococcus which has antiphagocytic properties, provides protective immunity and is the major determinant for virulence. A large number of antigenic types of the M-protein have been recognised. The hyaluronate capsule of the group-A Streptococcus is identical with the human hyaluronate. Antibodies to the group A cell wall polysaccharide cross-react with glycoprotein of heart valves and reveal persistent elevated serum levels in patients with rheumatic valvular disease in contrast with low values in patients with RF without cardiac involvement. Antibodies to the membrane antigen of the group-A Streptococcus exhibit reaction with the sarcolemma of smooth and cardiac muscle, dermal fibroblast and the caudate nucleus. Antibodies reactive with cytoplasm of neurons in the subthalamic and caudate nuclei are encountered more often in rheumatic patients with chorea than in those without chorea. Analysis of the molecular structure of the M-protein has also revealed epitopes that reveal cross-reactivity with cardiac myosin (Table 2.2).
Despite the frequent occurrence of group-A Streptococcus-related pharyngitis, development of RF varies from 1 to 3 per cent only. The reason for the disparity between group A streptococcal pharyngitis and development of RF is not entirely clear. It is likely that certain genetically predisposed individuals have increased susceptibility to develop RF following sensitisation with streptococcal antigens. It has also been observed that once RF has developed, rheumatic subjects are much more prone to develop recurrent streptococcal infection as compared with the general population. In India and other developing countries not only does the prevalence of RF continue to be high but recurrent streptococcal infections lead to fulminant disease with a high incidence in the paediatric and juvenile age groups culminating in juvenile mitral stenosis in a high proportion of cases. This subtype is associated with high morbidity and mortality.
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Complications and Sequelae
Chronic rheumatic heart disease Recurrent rheumatic valvulitis results in valvular deformities which produce severe cardiac disability. Single or multiple valves in various combinations are affected by the rheumatic process. The mitral valve is most frequently affected either in isolation or in combination with other valves. In the developing countries the reported pattern of valvular involvement in descending order of frequency is as follows: mitral valve alone; mitral, tricuspid and aortic—mitral and aortic; mitral and tricuspid; and all four cardiac valves. Healing of the mural endocardium produces thickened endocardium in the posterior wall of the left atrium which is termed as MacCallum's patch. Healing of rheumatic myocarditis and pericarditis produces myocardial fibrosis and fibrous thickening of the pericardium respectively which is generally of little clinical consequence.
Congestive heart failure in acute rheumatic carditis is due to the extensive myocardial involvement including myocarditis with necrosis. Valvular deformities consequent to the chronic rheumatic process is one of the most common 39causes of cardiac failure. Latter, in particular, mitral valve stenosis produces pulmonary arterial and venous hypertension which leads to congestive heart failure. Infective endocarditis is another frequent complication of RHD. Valvular deformities and damage of the valves favour colonisation by infective organisms. Mural thrombi in the cardiac chambers are a source of embolisation commonly to brain, kidneys, spleen, lungs and other viscera. These form most commonly in the left atrium in cases of mitral stenosis and/or atrial fibrillation. Sudden death may occur due to obstruction of the mitral valve orifice by a large thrombus.
Extracardiac Lesions in Rheumatic Fever
Polyarthritis in rheumatic fever affects multiple large joints, is migratory in nature and is short lived. Microscopically, oedema, dilatation and congestion of blood vessels and infiltration by lymphocytes, macrophages and polymorphonuclear leucocytes is seen. No typical Aschoff nodules are encountered. The inflammation within joints heals without any residual effects. Subcutaneous nodules are located most commonly over the extensor tendons of the wrists, elbows, ankles and knees of some patients. When present these are a good indicator of rheumatic activity. Microscopically, the nodule consists of a central large area of fibrinoid necrosis bordered by a palisading arrangement of histiocytes along with other inflammatory cells. The lesions have a resemblance to the Aschoff nodule and skin nodules of rheumatoid arthritis.
Central nervous system In patients of chorea, mild meningoencephalitis, small focal haemorrhages, oedema and perivascular cuffing by lymphocytes are seen in the cerebral cortex and basal ganglia. It has been observed that in RF, antibodies reactive with cytoplasm of neurons in the subthalamic and caudate nuclei are more frequently demonstrated in patients with chorea than in those without it.
VALVULAR HEART DISEASE
Valvular heart disease is a common cause of cardiac disability (Table 2.3). This may be either due to acquired structural disease of the valve apparatus as in RHD, infective endocarditis, systemic lupus erythematosus (SLE), rheumatoid disease, ankylosing spondylitis or congential in nature. Of all these conditions, rheumatic valvulitis is the single most important cause of cardiac morbidity and mortality in India and other developing countries. Valvular dysfunction also occurs secondary to various cardiac diseases namely papillary muscle involvement in myocardial infarction, infective endocarditis, chordal rupture due to trauma, infective endocarditis or myxomatous valve. Dilatation of ventricle and valve rings can occur in dilated cardiomyopathy and ischaemic heart disease and other end stage cardiac diseases. In the latter situation, there is no structural defect of the valve apparatus and therefore this is also termed as functional incompetence of the valve.
Normal Valves
Atrioventricular valves are comprised by the mitral and the tricuspid valve. The mitral valve apparatus includes the annulus; two valve leaflets—a tongue-shaped anterior leaflet and a narrower spread out posterior leaflet; junction of the leaflets—commissures; chordae tendineae and the papillary muscles. Components of tricuspid valve apparatus are identical except that it has three valve leaflets: the anterior, septal and posterior.
Semilunar valves The semilunar valves consist of the pulmonary and the aortic valve. Both semilunar valves consist of 3 semicircular cusps each. They are the anterior, right and left in the pulmonary valve and right and left coronary cusps and non-coronary cusps in the aortic valve. The vessel wall behind each cusp forms a pouch-like dilatation known as the sinus of valsalva. Junction of the adjacent cusps are termed commissures. The ostia of the left and right coronary arteries are located in the centre of their respective sinuses and thus normally covered by the valve cusps.
For the normal functioning of a valve, the entire valve apparatus, i.e. valve ring, valve cusps, commissures, chordae tendinae, papillary and ventricular muscle play an important role.40
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Fig. 2.7: Rheumatic heart disease. Anterior mitral valve (AMV) leaflet and chordae tendineae are thickened and shortened (arrows). Notice jet lesion in the posterior wall of the dilated left atrium (Thick arrows)
Involvement of one or more of these components result in malfunction of the valve.
Mitral Valve Disease
Mitral stenosis with or without incompetence is the most common acquired valvular disease. This valve is affected either in isolation or more commonly in combination with the other cardiac valves.
Mitral Stenosis (MS)
The most common cause of mitral valve stenosis in developing countries remains RHD. Rarely, infective endocarditis and congenital defects cause MS. Physical obstruction of the valve orifice by tumours or thrombi may simulate MS. Recurrent attacks of rheumatic valvulitis cause healing with fibrosis resulting in valvular deformities (Figs 2.7 to 2.10).
Fig. 2.8: Markedly thickened and distorted mitral valve which appears as a rigid cord. Chordae tendineae are thickened, shortened and adherent. Left atrium (LA) is markedly dilated. Left ventricle (LV) appears smaller
The mitral valve leaflets, including the valve ring, the commissures and the chordae tendineae undergo scarring of one or more of the various valve components.42
Fig. 2.10: Rheumatic heart disease. Mitral stenosis (arrow), dilated left atrium (LA) and a mural thrombus (thin arrow) are seen
Fig. 2.11: Photomicrograph from a case of rheumatic mitral valvulitis. Valvular collagen is increased. Numerous blood vessels and chronic inflammation are observed
The fibrotic leaflets become fused and retracted such that the papillary muscles are pulled up closer to the leaflets. At times the fibrotic process may be severe enough to transform the valve into a funnel-shaped structure. Fusion of the leaflets at the free margins may result in a diphragm with a tiny hole or a slit giving the appearance of “buttonhole” or “fish mouth” types of MS respectively. This type of deformity of the mitral valve is commonly encountered in childhood and has been termed as juvenile mitral stenosis. The latter subset of patients appear to be unique to the Indian subcontinent and are characterised by an aggressive clinical course, cardiomegaly, markedly elevated pulmonary arterial and venous pressure, heart failure and a high mortality.
Microscopically, the normal architecture of the valve substance is distorted. Neovascularisation of the valve with blood vessels having prominent smooth muscle in their wall is commonly seen. Varying degrees of chronic inflammatory cell infiltration consisting of lymphocytes, histiocytes and plasma cells is usually present (Fig. 2.11). Calcification particularly in the mitral valve may also be seen. In the myocardium, healed myocarditis is evident as fibrosis.
The normal mitral valve area is 4 to 6 sq cm. Mitral valve area less than 1 sq cm qualifies for severe MS. Clinical effects of MS are a result of obstruction to the flow of blood from the left atrium and the pressure that builds up in this chamber. Dilatation and hypertrophy of the left atrium occurs due to the accumulation and stasis of blood. Occasionally the atrium may assume a large size. Fibrous thickening of the atrial endocardium particularly of the posterior wall of the left atrium is present. The elevated pressure in the left atrium reflects into the pulmonary veins producing chronic pulmonary venous congestion. Latter, eventually leads to pulmonary capillary, atreriolar and arterial hypertension which in turn causes right ventricular hypertrophy and finally right heart failure develops. In predominant MS, the left ventricle is either normal or atrophic. Pulmonary venous congestion and pulmonary oedema produce dyspnoea and persistent cough. Attacks of acute pulmonary oedema may be brought on during the night (paroxysmal nocturnal dyspnoea—PND).
Atrial dilatation in MS is often accompanied by atrial fibrillation which in turn favours blood stasis and thrombus formation both within the atrium and the left atrial appendage. Therefore systemic embolisation is a common complication of left atrial thrombosis producing clinical effects related to the organ which suffers ischaemia.43
Mitral Regurgitation (MR) Incompetence
Incompetence or insufficiency of the mitral valve may result from structural abnormalities of the valvular leaflets, dilatation of the valve ring and conditions causing dysfunction of the papillary muscles (Table 2.3). In developing countries, the most common cause of MR is RHD. It is invariably associated with aortic valve disease. Fibrous thickening and scarring of the valve leaflets cause them to become rigid and there is retraction of the free edges of the leaflets. Associated fusion of the commissures and thickening and fusion of the chordae tendinae is usually present. Insufficiency of the mitral valve is invariably accompanied with some degree of stenosis. Pure MR is unusual although it may occur in isolation.
Besides RHD, floppy mitral valve or mitral valve prolapse syndrome is an important cause of mitral incompetence. In this condition the valve leaflets are large and bulky and appear mucoid and gelatinous. The chordae tendinae also show identical changes. Microscopically, loss of valvular collagen along with an increase in the ground substance in the cusps and the chordae tendinae is characteristically observed. The myxomatous material is rich in mucopolysaccharides. These abnormal cusps bulge into the atrium during ventricular systole resulting in incompetence of the valve. Mitral valve prolapse may either be completely asymptomatic, or may present as MR which may be severe enough to warrant medical and/or surgical treatment. Rupture of chordae tendinae, increased risk of developing infective endocarditis and embolic complications are the other associated events with the floppy mitral valve. The aetiology is unknown and possibly represents a hereditary connective tissue abnormality as is observed in some cases of Marfan's syndrome and other connective tissue disorders.
Sudden mitral valve incompetence may result from rupture of the chorda tendinae, the common underlying causes being mitral valve prolapse, infective endocarditis and ischaemic necrosis. This may lead to fatal left ventricular failure.
Aortic Valve Disease
Aortic valve disease may present either as stenosis or incompetence of the valve. Involvement of both aortic and mitral valves together is a feature of RHD. On the other hand, isolated aortic valve involvement causing aortic stenosis and/or regurgitation is most commonly due to a congenital deformity of the valve (Table 2.4).
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Aortic Valve Stenosis
Aortic valve stenosis (AS) may be either acquired or congenital in nature. Acquired AS when present along with mitral valve disease is most commonly due to rheumatic heart disease (RHD). RHD only very infrequently causes isolated AS. Congenital bicuspid aortic valve is believed to be the underlying abnormality in over half the cases of isolated AS. Calcific AS occurs commonly in congenitally bicuspid or unicuspid valves. In individuals over 70 years of age tricuspid aortic valve may undergo calcification. This is known as senile calcific aortic stenosis. Calcific deposits are usually present in the sinuses of Valsalva and the free margins of the cusps. Understandably, AS causes an increased workload and results in left ventricular hypertrophy. The coronary perfusion may be impaired due to low pressures in the aorta during ventricular diastole. Left ventricular hypertrophy combined with low coronary perfusion may predispose to angina pectoris, syncope and sudden death.44
Fig. 2.12: Rheumatic heart disease. Fibrous thickening of the aortic valve cusps and commissural fusion is observed. Left ventricle is markedly dilated and shows focal endocardial thickening (E)
Fig. 2.13: Rheumatic heart disease. Severe distortion of aortic valve cusps is observed. Aortic sinuses are laid bare due to retracted cusps. Right and left coronary artery ostia are also seen. Jet lesions are present in the subaortic region (arrow)
Left ventricle failure develops eventually.
Aortic Valve Incompetence/Regurgitation (AR)
Aortic valve incompetence/regurgitation (AR) occurs as a result of thickening and distortion of the cusps, commissural fusion, calcification of valves, destruction and/or perforation of the cusps and in conditions associated with aortic root dilatation (Figs 2.12 and 2.13).
Reumatic heart disease remains an important cause of thickening and distortion of the aortic valve appartus which may manifest as stenois and/or incompetence of the valve and is commonly associated with involvement of the mitral valve. Isolated aortic valve disease of rheumatic aetiology is extremely uncommon. Infective endocarditis of the aortic valve may either lead to distortion of the cusps or in some cases may produce erosion, perforation and destruction of the cusps causing sudden and significant incompetence of the aortic valve.45
Dilatation of the aortic valve ring occurs consequent to certain diseases affecting the aorta. In Marfan's syndrome a genetic disorder of connective tissues, AR is common. The wall of the aorta shows loss of elastic tissue of the media in addition to accumulations of increased amounts of mucoid or myxoid material which produces weakening of the tissues of the aorta. Syphilitic aortitis also causes stretching and dilatation of the aortic root along with widening of the commissures. Similar structural changes have been noted in AR associated with ankylosing spondylitis and rheumatoid arthritis. AR may also result from dissecting aortic aneurysm which may extend towards the aortic valve, myxomatous degeneration of aortic valve cusps, atherosclerosis and Takayasu's aortitis.
Incompetence of the aortic valve results in marked cardiac enlargement due to both hypertrophy and dilatation. Due to the low diastolic blood pressure consequent to regurgitation of blood, the coronary blood flow is impaired. Latter combined with the increased oxygen demands of the hypertrophied heart, manifest as angina pectoris. The continuous volume overload of the left ventricle results in left ventricular failure.
Tricuspid Valve Insufficiency
Tricuspid valve insufficiency may be either functional resulting from failure and dilatation of the right ventricle and the valve ring or due to an organic involvement of the valve (Fig. 2.14). Latter is most often caused by rheumatic valvulitis. Involvement by the rheumatic process is much milder in severity and intensity as compared with the mitral valve.
Tricuspid valve stenosis
RHD is the most common cause of acquired tricuspid valve stenosis which is associated with involvement of other heart valves (Fig. 2.15). Rarely it may occur consequent to infective endocarditis, carcinoid syndrome or exist as a congenital anomaly.
Both tricuspid valve stenosis and incompetence cause dilatation of the right atrium with elevated right atrial pressures, systemic venous congestion and right heart failure.
Fig. 2.14: Rheumatic heart disease. Tricuspid valve is involved. Chordae tendineae are shortened and thickened (arrow). The mitral and aortic valves were also affected by the disease process
Fig. 2.15: Rheumatic heart disease. Stenosis (arrow) of tricuspid valve is seen. The aortic and mitral valves were also stenosed in this case: RA—right atrium
Pulmonary valve stenosis
It is almost always congenital in nature. Involvement of this valve has also been reported in carcinoid syndrome, RHD and infective endocarditis. Clinically, effects of right ventricular hypertrophy result.
Pulmonary Valve Insufficiency
Incompetence of the pulmonary valve may result from dilatation of the pulmonary artery and the 46valve ring secondary to pulmonary hypertension and right ventricular failure. Rarely, rheumatic valvulitis, infective endocarditis, carcinoid syndrome and congenital malformations may cause insufficiency of the pulmonary valve.
Carcinoid Valve Disease
The pulmonary and tricuspid valves may get involved in metastatic carcinoid tumour. Involvement of the right sided valves is consequent to effect of vasoactive amines released by the tumour. The affected valve cusps are firm and fibrotic and depending upon the extent and severity of disease, features of valve stenosis or incompetence result. Microscopically, proliferation of fibroconnective tissue is seen on the surface of the cusps.
Replacement of diseased valves can be done successfully. Various types of options are available.
Prosthetic valves
These are of two types: mechanical and bioprostheses. Several types of mechanical prostheses are available commercially. These essentially comprise a metal frame, silicone ball or tilting disc and teflon sewing ring. The major drawback of prosthetic valves is an increased risk of thromboembolism and hence life long anticoagulation. Infective endocarditis, thrombosis, tissue overgrowth, paravalvular leak are some of the causes of failure of valve function.
Bioprostheses also known as tissue valves are made of various types of biological material namely fascia lata, dura mater, bovine or porcine pericardium, porcine aortic valve or human aortic valve (homograft). These tissues are treated with glutaraldehyde before being constructed and mounted on to prosthetic frames. Tissue valves eventually also suffer a risk of degeneration, torn leaflets, calcification, infective endocarditis, thrombosis and thromboembolism.
Biologic valves
To overcome the problem of thromboembolism of prosthetic valves and rapid degenerative changes and failure of bioprostheses, use of biologic valves is an attractive proposition. Homografts and autografts have been used. Mitral, aortic and tricuspid valves, removed from cadavers and stored in appropriate conditions are used as homografts. Autografts are patient's own normal valve used to replace the diseased valve. The normal valve that is removed can be replaced by a homograft. Biologic valves have better survival and less complications as compared with prosthetic valves.
INFECTIVE ENDOCARDITIS
Infective endocarditis is defined as an invasion of the valvular and/or mural endocardium by infective organisms namely bacteria, fungi, rickettsia, chlamydia, viruses, etc.
Based on the clinical course endocarditis has been commonly termed as acute and subacute (Table 2.5). Acute endocarditis is characterised by infection of mostly normal valves with virulent organisms namely Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae and others. The infection is generally fulminant and often associated with invasion and destruction of tissues and a rapidly progressive clinical course. Unless treated aggressively, acute IE is invariably fatal. Subacute endocarditis in contrast is mostly due to infection of previously damaged or distorted heart valves, e.g. rheumatic valvulitis, by organisms of low virulence such as Streptococcus viridans or Staphylococcus epidermidis. The onset is insidious and it runs a prolonged clinical course which may extend over several weeks to months. Unlike acute infective endocarditis, necrosis and destruction of infected valves is unusual. In immunocompromised hosts, however, infection by organisms of even low virulence may result in fulminant disease.
Predisposing Conditions
Infective endocarditis most commonly affects diseased and distorted cardiac valves. In developing countries, RHD still remains the underlying pathologic process in a vast majority of cases.47
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Congenital heart disease such as tight stenoses, small ventricular septal defects, tetralogy of Fallot (TOF), patent ductus arteriosus (PDA) etc. are predisposed to development of infective endocarditis. Mitral valve prolapse is an important condition where infective endocarditis may occur. Endocarditis involving prosthetic and other replaced valves, indwelling catheters and various intracardiac devices, intravenous drug users and immunosuppressed individuals, has emerged as an important group.
Bacteraemia is an essential prerequisite for the development of infective endocarditis. It has been documented in dental extractions, catheterisation of genitourinary tract, cystoscopy, and even in normal delivery. Endocarditis may also develop consequent to fulminant infections of skin, respiratory and genitourinary tract.
Infective Organisms
A variety of infective organisms namely bacteria, fungi, chlamydia, rickettsia, viruses, etc. may invade the endocardium. The most common infection, however, is by the bacterial species. Several large series indicate that Streptococci (50-70%). Staphylococci (25%) and Enterococci (10%) account for the vast majority of cases of endocarditis. Streptococci which account for majority of cases of bacterial endocarditis include Streptococcus viridans, Streptococcus bovis and faecalis. These organisms are of low virulence and generally cause a protracted illness. Staphylococci (mostly Staphylococcus aureus) cause endocarditis of native valves in about 25 per cent of the cases. These can infect either normal or damaged valves and are a common cause of acute fulminant clinical disease. Other organisms which may also cause endocarditis include fungi (Candida, Aspergillus, etc.), Neisseria gonorrheae, Escherichia coli, Haemophilus sp. Pseudomonas, Listeria and a host of other organisms. Brucella, Rickettsiae (Coxiella burnetii) and Chlamydia are documented as rare causes of endocarditis.
There is an appreciable change of causative organisms in the post-antibiotic era. Streptococcus viridans was the most frequent organism isolated in the pre-antibiotic era. Incidence of Staphylococcal endocarditis is on the rise. Staphylococcus aureus is a frequent pathogen in intravenous drug abusers while Staphylococcus epidermidis is commonly isolated in cases of infective endocarditis following cardiac surgery. Infective endocarditis due to gram-negative organisms is common in cases of diabetes mellitus and in intravenous drug abusers.
Blood Cultures
Positive blood cultures and isolation of the organism not only confirm the diagnosis of IE but indicate the specific therapy to be given.48
Fig. 2.16: A case of infective endocarditis showing large, bulbous protrusions (vegetations) from the aortic valve cusps which are entirely covered by these. Left ventricle shows hypertrophy and dilatation
In untreated cases, blood cultures are positive in over 95 per cent of patients and is the most common investigative modality. In cases of infections caused by organisms of low virulence repeated, multiple blood samples need to be examined to obtain positive cultures. If blood cultures are negative despite a strong clinical suspicion of endocarditis, certain possibilities must be kept in mind. Previous partial or complete antimicrobial therapy, endocarditis caused by fastidious and unusual organisms, improper blood culture techniques and inappropriate examination of the samples are some of the reasons for negative blood culture.
Pathology
On gross examination, the vegetations in infective endocarditis are large (range from 5 mm to 2 cm), globular and may occupy the entire surface of the valve (Figs 2.16 to 2.18). They are located on the atrial surface of the atrioventricular valves (Fig. 2.19) and ventricular surface of the semilunar valves (Figs 2.16 to 2.18). The vegetations are pale yellow to dark brown in colour and are often friable. Associated destruction, necrosis, suppuration and perforation of the valve cusps (Figs 2.17, 2.18) is usual in infections with virulent and pyogenic organisms.
Fig. 2.17: Infective endocarditis of the aortic valve. The cusps are destroyed by the vegetations. Marked left ventricular hypertrophy and dilatation is noted. Sections of the spleen and kidney from the same case show multiple infarcts
Fig. 2.18: Infective endocarditis of the aortic valve. Destructive nature of the vegetations is demonstrated by perforation of the valve cusp (pointer)
Microscopically, vegetations of acute infective endocarditis are comprised by fibrin in which platelets and other blood elements are present. Causative organisms, bacteria or fungi are generally easily identified. Morphological characters are brought out clearly by appropriate special stains. The valvular cusps may show evidence of previous damage, the most common being rheumatic valvulitis.49
Fig. 2.19: Specimen of right side of heart showing large, bulbous infective vegetations on the tricuspid valve: RA—right atrium, RV—right ventricle
During the healing phase, the vegetations organise and show chronic inflammation, hyalinisation with or without calcification. The valve substance shows infiltration by lymphocytes, fibroblasts and predominantly histiocytes. When healing is complete, hyalinisation with distortion of the valvular structure results. Numerous thick walled blood vessels are often present in the valve substance.
Pathogenesis
Endothelial injury has been demonstrated even in normal valves at sites where they come in contact with each other. The extent and severity of endothelial damage, however, is well marked in previously damaged valves, e.g. RHD or areas of endocardium exposed to high-velocity jet streams of blood as in small ventricular septal defects, patent ductus arteriosus (PDA) or stenotic valves. Platelet and fibrin aggregates form rapidly at the site of damaged endocardium and provide a trap for infective agents during the course of a bacteraemia.
Fig. 2.20: Flow chart depicting pathogenesis of vegetations in infective and non-infective endocarditis
The organisms thus colonise and proliferate within the platelet fibrin thrombi to form large masses (vegetations) (Fig. 2.20) which may cause invasion, inflammation 50and destruction of the underlying valve substance. Normal valvular endothelium is resistant to invasion by most infective organisms. However, overwhelming infection by virulent organisms namely Staphylococcus aureus in normal or more commonly in immunocompromised hosts may affect healthy valves as in intravenous drug users, prosthetic valves and other implanted cardiac devices.
Complications and Sequelae
Complications of IE may be categorised as: (i) cardiac, (ii) extracardiac due either to septic embolisation and/or bacteraemia/pyaemia resulting in infective foci in various organs, and (iii) immune complex-associated disease.
Cardiac Complications
Infection by virulent and pyogenic organisms may produce erosion and/or destruction of the valve cusps and abscess of the valve or valve rings. Perforation of the cusps (Fig. 2.18), aneurysms and/or rupture of the sinus of valsalva, (Fig. 2.21) rupture of chordae tendineae or the papillary muscles may also occur. These lesions cause significant incompetence of the valves. Healing of the infection by organisms of low virulence cause valvular deformities (Fig. 2.22) with subsequent valvular stenosis or incompetence.
Fig. 2.21: Rupture of sinus of Valsalva into the outflow tract of the right ventricle (probe) in a case of infective endocarditis
Fig. 2.22: Specimen of heart showing aorta (A) and healed infective endocarditis of aortic valve which is almost completely destroyed
Extension of the valvular infection to the myocardium may occur either by direct continuity or by infected emboli within intramyocardial arteries. Foci of myocardial necrosis and/or myocardial abscesses result and may be extensive enough to cause rupture of the interventricular septum or the ventricular free wall. Extension of the myocardial abscesses or the infective foci into the pericardium may cause purulent pericarditis. Coronary artery emboli may also result in myocardial infarction. Heart failure in infective endocarditis may result from one or more causes, namely; volume overload as a result of valvular regurgitation, myocardial dysfunction due to myocarditis.
Embolic Complications
Most of the extracardiac complications are a result of embolic phenomena. Fragments of vegetations from the left side of the heart commonly lodge in the arteries to the brain, spleen, kidney 51and other systemic sites and may produce infarcts, (Fig. 2.17) abscesses and mycotic aneurysms. Pulmonary emboli in right sided endocarditis lead to infarction or abscesses in the lungs.
Immune Complex Associated Disease
As a result of bacteraemia circulating immune complexes have been demonstrated in IE. Bacterial antigens have been demonstrated in circulating immune complexes and in immune complexes deposited in tissues. Petechiae in the skin, conjunctiva and small red and tender nodules seen characteristically on the finger tips known as Osler's nodes in cases of endocarditis possibly represent immune complex mediated vasculitis. Besides renal infarction and abscesses which occur consequent to septic emboli in renal artery, immune-mediated glomerulonephritis either focal or diffuse may develop. Latter may be responsible for renal failure. On naked eye examination the kidney shows tiny diffusely distributed petechial haemorrhages, an appearance commonly known as “flea-bitten” kidney.
Causes of death due to infective endocarditis include overwhelming infections, pyaemia, neurological complications, CHF and renal failure.
Prosthetic Valve Endocarditis (PVE)
Intervention procedures and heart valve replacement predispose to development of endocarditis. Surgical therapy of valvular heart disease has been well streamlined with replacement of diseased valves with either mechanical or bioprosthetic valves. Mechanical valves have an inherent problem of thrombosis (Fig. 2.23) and thromboembolism and therefore these patients have to be maintained on anticoagulation. Prosthetic valves can present with several complications namely hemolysis as a result of mechanical trauma to RBCs, deterioration and degenerative changes within the prosthetic valve, etc. Infection of the prostheses occurs generally at the site of the sewing ring causing abscess formation which often results in dehiscence of the valve with consequent valvular regurgitation. Better designing of valves and management of these cases have resulted in a good clinical outcome.
Fig. 2.23: Prosthetic valve in the mitral position is completely covered by a thrombus: LA—left atrium
The overall incidence of PVE varies from 1 to 4 per cent. PVE may occur either early (less than 60 days) after insertion or at later time periods (after 60 days). Endocarditis in the early period is a result of contaimination introduced at the time of surgery either directly into the wound or acquired from a vaiety of devices used in cardiac surgery namely, catheters, pacing wires, endotracheal tubes or the bypass machine. A wide range of organisms are known to cause PVE. The most common is the Staphylococcus species (aureus and epidermidis) which is implicated in 45 to 50 per cent of cases. The other organisms isolated from PVE include gram-negative bacteria (20%), fungi—Candida and Aspergillus (10-12%), Streptocococci and enterococci (5-10%) and unusual organisms in some cases.
Endocarditis in Intravenous (IV) Drug Abusers
Endocarditis of right sided valves is common in intravenous drug users and is characterised by an acute endocarditis afecting normal valves caused mostly by virulent organisms namely Staphylococcus sp. particularly Staphylococcus aureus in about 60 per cent of the cases. Other organisms implicated are various species of streptocci and enterococci (about 20%), fungi 52usually Candida and Aspergillus (5 to 10% cases) and other organisms. The most common source of infection is skin, contamination of the drugs and/or needles and syringes used for drug administration. The other major cause of tricuspid valve endocarditis is septic thrombophlebitis involving the subclavian or femoral venous system. Patient with endocarditis of the right heart may develop pneumonia or multiple abscesses due to septic emboli and/or pulmonary infarction.
Awareness and recognition of infective endocarditis with prompt and appropriate antimicrobial therapy for optimal periods has significantly reduced the morbidity and mortality of endocarditis. Poorer prognosis is associated with elderly individuals, immunocompromised hosts, and infections caused by fungi, gram-negative organisms and Pseudomonas species and prosthetic valve endocarditis. Prevention of endocarditis is of vital importance and can be achieved by diagnosis and management of the predisposing conditions that are well recognised. Prophylactic antibiotic therapy in cases of RHD or congenital heart disease (CHD) who have to undergo surgery, surgical manipulations or dental extractions is mandatory.
NONBACTERIAL THROMBOTIC ENDOCARDITIS
Non-bacterial thrombotic endocarditis (NBTE) is characterised by sterile vegetations composed of platelet and fibrin thrombi on one or more cardiac valves most commonly the mitral and aortic valves. Rarely other valves may also be affected. The vegetations are generally small varying in size from 1 to 5 mm and are present usually along the line of closure of the valves or sometimes superimposed upon previously diseased or distorted valves as in RHD. Microscopically, the vegetations are composed of fibrin in which are trapped blood elements namely platelets, red and white cells. No infective organisms are present. The underlying valve or cusp does not show any significant inflammatory response.
Pathogenesis of NBTE is unclear. It has been documented in terminally ill cachectic individuals, chronic long-standing infections and in some hypercoaguable states, venous thromboses and in various malignancies such as adenocarcinoma of pancreas, prostate or lung. Thus NBTE has also been termed as terminal endocarditis and marantic endocarditis. The mechanical wear and tear at the contact point of the valve leaflets and cusps lead to trauma of the endothelium which favours the deposition of fibrin, platelets, red and white cells to form vegetations (Fig. 2.20).
Clinical significance of NBTE is two fold: (i) the vegetations are known to fragment and thus cause embolic complications in any of the organs particularly brain, kidney, spleen and heart, and (ii) it provides a potential nidus for infective organisms resulting in IE.
LIBMAN-SACKS ENDOCARDITIS
Libman-Sacks endocarditis is encountered in systemic lupus erythematosis (SLE) in about 50 per cent of the cases. The vegetations occur most often on the mitral and tricuspid valve leaflets as single or multiple flat, granular deposits of variable size (1 to 5 mm) which have a tendency to affect both surfaces of the valve leaflets, valve pockets and rarely may even extend to the atrial and ventricular endocardium. Smaller vegetations have some resemblance to rheumatic vegetations whereas the larger ones may simulate vegetations in infective endocarditis. However, the pattern of gross involvement is unlike that of rheumatic endocarditis and the local infection, suppuration and destructive lesions in the heart so characteristic of infective endocarditis is lacking in endocarditis of SLE. Healing does not produce valvular deformities. Embolic complications are unusual.
Microscopically, the affected valve exhibits oedema, fibrinoid necrosis, neovascularisation and infiltration by lymphocytes, mononuclear cells followed later by fibroblastic proliferation and collagen deposition. The vegetations are comprised by fibrinoid material and fibrin trapped in which are inflammatory cells and blood elements. Haematoxylin bodies may be recognised within the area of fibrinoid necrosis.53
ISCHAEMIC HEART DISEASE
Ischaemic heart disease (IHD) is an imbalance between the supply and demand of the myocardium for oxygen in blood. The most common pathologic basis for this is severe atherosclerotic narrowing or occlusion of the coronary arteries and therefore the terms atherosclerotic coronary artery disease, atherosclerotic heart disease and coronary artery disease are used synonymously for IHD.
Ischaemic heart disease continues to be a major cause of cardiac morbidity and mortality in the developed countries although there has been an appreciable decline (about 40%) in mortality. This is largely due to the recognition, greater awareness, early diagnosis and management of the various risk factors associated with IHD. In the developing countries, however, although RHD still remains a major cardiac disorder, IHD has emerged as an important cardiovascular disease of much public health concern.
Coronary artery disease produces a wide spectrum of clinical manifestations (Fig. 2.24). It is relevant therefore to examine some of important aspects of normal coronary arteries.
The Coronary Circulation
The heart receives its blood supply through the left and the right coronary arteries. Numerous intercoronary anastomoses exist in normal hearts which assume great significance in the event of narrowing or obstruction of the coronary arteries. The left coronary artery has two main branches the left arterior descending (LAD) and the left circumflex (LC) which supply fairly well-defined regions of the heart. The LAD supplies the anterior surface of the left ventricle, the adjacent part of the anterior wall of right ventricle, anterior two-third of the interventricular septum and the apex of the heart. The LC supplies the lateral wall of the left ventricle. The right coronary (RC) artery supplies the major portion of the anterior wall of the right ventricle, posterior wall of right ventricle and the posterior one-third of the interventricular septum. The coronary artery which continues as the posterior descending artery (PDA) is the dominant artery of the heart. Based on the pattern of the normal coronary arterial supply it is possible to predict fairly accurately, the location of an infarct following occlusion of any of its branches (regional infarction).
Majority of cases of ischaemic heart disease are a result of stenosing atherosclerosis of coronary arteries. Thus all factors operative in occurrence of atherosclersis also contribute to IHD. Hypercholesterolemia, hypertension, cigarette smoking and diabetes mellitus are some of the important risk factors related to high incidence of IHD. Several epidemiological studies thus have shown that control of these factors has resulted in an appreciable decline in IHD.
Ischaemic heart disease may manifest in several ways. On the one hand an individual with severe coronary artery atherosclerosis may be completely asymptomatic while on the other hand the first manifestation of coronary artery disease may be sudden death. Between the two extremes, the spectrum includes various types of angina pectoris, acute myocardial infarction and chronic IHD (Fig. 2.24).54
The term acute coronary syndrome has been applied to the triad of unstable angina, myocardial infarction and sudden death. The basis of these clinical syndromes is rupture of an atheromatous plaque followed by thrombus formation. It has been demonstrated that a sequence of dynamic changes take place in the fibrous plaque which lead to progression of the lesion to cause narrowing/occlusion of the coronary artery (Fig. 2.25). The extent and duration of the occlusion to a large extent determines the type of clinical manifestation. Arterial occlusion leads to myocardial ischaemia which manifests clinically as unstable angina. If the occlusion of the artery and consequently ischaemia persists for a long time the myocardial cells die and necrosis occurs.
Angina pectoris is a symptom caused by myocardial ischaemia which is characterised by pain and/or discomfort in the precordium or substernal region. Depending upon the duration, severity and nature of the pain three subtypes have been recognised.
Chronic stable angina pectoris Myocardial ischaemia is manifest by pain or discomfort in the chest occurring on exertion or exposure to cold, emotional stress, etc. The pain does not occur at rest. The most common cause of this symptom is severe and extensive coronary artery atherosclerosis affecting one or more epicardial coronary arteries (Figs 2.26 to 2.28). Multiple segments of stenosis are generally encountered.
Prinzmetal's variant angina differs from the stable angina in that the pain occurs at rest. Coronary artery spasm is well established in this group. Severe coronary artery atherosclerosis is present in most cases. In unstable or crescendo angina, myocardial ischaemia is manifest by progressively increasing frequency of pain which is precipitated by less effort, occurs at rest and is generally of prolonged duration. This type of angina is also termed as preinfarction angina and has a great risk of developing acute myocardial infarction. The ischaemia is transient, of short duration and therefore does not result in necrosis of the myocardium.55
Fig. 2.28: Photomicrograph of the cross-section of coronary artery which shows over 90 per cent occlusion by an atheromatous plaque: L—lumen
Angiographic studies done in cases of unstable angina have revealed eccentric stenotic lesions in the coronary artery with irregular outlines over which an intraluminal filling defect possibly representing a thrombus can be demonstrated in most cases. The irregular outlines represent a ruptured/ulcerated atheromatous plaque over which the thrombus forms. The occlusion is transient and spontaneous lysis restores the blood flow. If, however, the occlusion is complete and persistent, myocardial infarction may result (Fig. 2.25).
Acute Myocardial Infarction
Acute myocardial infarction is an area of ischaemic necrosis (irreversible injury) of the myocytes caused by insufficient or cessation of blood supply.
Pathology
Myocardial infarct cannot be well appreciated by the naked eye until about 4 to 8 hours of onset. Between 18 to 72 hours the infarcted zone may be pale or has a blotchy appearance due to both pallor and congestion. The necrotic area subsequently appears yellowish and acquires a haemorrhagic border which becomes well marked between 3–7 days. During this time the central necrotic area is yellow brown in colour. At 10 to 15 days the necrotic area is soft and is slightly depressed below the surface of the viable myocardium. By 6 to 8 weeks there is progressive collagenisation of the necrotic myocardium which is permanently replaced by scar tissue. The healed ischaemic myocardium appears pale and is firm to feel.
Macroscopic recognition of myocardial infarction in the early stages (4–8 hours of onset of infarction) may be facilitated by staining with tetrazolium dyes—nitroblue tetrazolium—NBT or triphenyl tetrazolium chloride—TTC (Fig. 2.29). Due to its dehydrognenase content, the viable myocardium is capable of reducing these dyes to produce a blue (NBT) or red (TTC) colour. Ischaemic myocardium that has lost its dehydrogenases remains unstained. Staining of myocardium slices identifies distinct zones of ischaemic and viable myocardium.56
Fig. 2.29: Myocardial slices from a rat whose coronary arteries were ligated. The slices were subjected to triphenyl tetrazolium chloride (TTC) reaction. The pale segment represents necrotic myocardium while the viable myocardium stains red
In experimental studies, either of these stains are commonly applied for quantitation of ischaemic areas and assess the effect of various intervention modalities to salvage the myocardium at risk.
Myocardial infarcts are referred to commonly according to their extent, anatomical location and duration. The term regional infarction is applied when the infarct is in an area of myocardium supplied by a major artery (Table 2.6).
Extent of myocardial infarction
Infarcts are classified as regional transmural (full thickness), regional non-transluminal (not full thickness) (massive) and subendocardial. Combinations of these may also occur (Fig. 2.30).
Fig. 2.30: Diagram showing extent of myocardial infarction LV = left ventricle; RV = right ventricle
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Transmural infarction implies ischaemic necrosis of the myocardium involving full thickness of the ventricular wall. Massive myocardial infarction is a large area of ischaemic necrosis which does not involve the full thickness of the myocardium. Subendocardial infarction is characterised by ischaemic necrosis of the inner third of the ventricular wall. It is circumferential and not necessarily in the distribution of any one coronary 57artery. This area of the myocardium is least perfused and has scant collaterals and therefore most vulnerable to ischaemia. Often, subendocardial infarction results from hypotension or shock. Although severe coronary atherosclerosis is almost always present unlike in transmural infarct, coronary thrombosis causing complete occlusion is unusual.
Location of infarcts
These are most often located in the left ventricle possibly because of its greater workload and myocardial mass. Infarcts of the right ventricle and atria occur generally as an extension of left ventricular infarcts. Isolated right ventricular and atrial infarction though rare do occur. Stenosis or occlusion of a coronary artery produces ischaemia or necrosis in areas supplied by that particular artery (Table 2.6). Anteroseptal infarcts are most common and are due to occlusion of the LAD. Other common sites are the anteroseptal, anterolateral, inferior wall and apex of the heart.
Biochemical changes in myocardial ischaemia
Biochemical changes can be demonstrated within minutes of onset of ischaemia. There is depletion of glycogen stores, progressive decline in high-energy phosphate stores and mitochondrial functions, accumulation of lactates and activation of intracellular enzymes such as phospholipases and various lysosomal enzymes.
Microscopic changes
The earliest change described (0–2 hours) is stretching and waviness of the myofibres at the periphery of a myocardial infarct. At 4 to 12 hours coagulative necrosis of the myofibres occurs which is seen as homogeneous and hypereosinophilic cytoplasm of the myofibres with loss of striations, and clumped or pyknotic nuclei. In addition, oedema, congestion and/or haemorrhage within the infarcted area is often observed. These changes progress and become well marked in the following 24 hours. Nuclei undergo further clumping, karyorrhexis and karyolysis. The myofibres show degeneration and lysis and there is congestion of capillaries with margination by polymorphonuclear leucocytes, which are also seen in the interstitium of the myocardium (Figs 2.31 and 2.32).
Fig. 2.31: Acute myocardial infarction showing marked polymorphonuclear infiltration and necrotic myofibres
Fig. 2.32: Photomicrograph from a case of myocardial infarction. Group of myocytes (m) in the centre of the picture are necrotic (loss of nuclei). Viable myocardium (M) is seen on the left side. Rest of the area shows loss of myofibres and evidence of repair (healing myocardial infarct)
The necroic and inflammatory changes intensify progressively between 1 to 3 days at which time there is marked myonecrosis, loss of nuclei and an inflammatory cell infiltraton predominated by polymorphs and abundant nuclear debris. At the end of first week, the ischaemic area shows loss of myofibres and the inflammatory infiltrate is dominated by macrophages.58
Between 1 and 2 weeks of infarction, myofibres are cleared from the necrotic zone which now shows reparative tissue comprising proliferating capillaries, fibroblasts, haemosiderin pigment and macrophages many of which show haemosiderin within them. From 2 week till about 7 to 8 weeks, there is progressive collagenisation with scar formation (Fig. 2.33 and Table 2.7).
Aetiology and Pathogenesis of Ischaemic Heart Disease
Diseases of the coronary artery which cause either incomplete or complete obstruction of its lumen cause myocardial ischaemia (Table 2.8). The most common cause in over 90 per cent of the cases is atherosclerosis. In almost all cases the single most important event leading to myocardial infarction is rupture of an atheromatous plaque with coronary thrombosis. It has been demonstrated clearly by meticulous reconstruction studies of affected coronary artery lesions in cases of myocardial infarction that various events in an atheromatous plaque lead to coronary artery occlusion. Fissuring, ulceration and rupture of the atheromatous plaque have been clearly demonstrated in a vast majority of cases. The culprit coronary artery is totally occluded by a thrombus which is superimposed on a ruptured atheromatous plaque. Minimal injury to the endothelium and/or exposure of the subendothelial collagen leads to platelet adhesion, aggregation and activation. Latter causes release of several vasoactive substances namely histamine, serotonin, and thromboxane which cause vasospasm. Vasospasm is one of the important contributors to ulceration of an atheromatous plaque. Eccentric atheromatous plaque will have a portion of the normal vessel wall which can undergo spasm to vasoconstrictive stimuli. Coronary angiographic studies done within the first few hours of onset of acute myocardial infarction reveal total occlusion of the artery in about 90 per cent of cases. This figure declines progressively with increasing duration of symptoms thus indicating spontaneous thrombolysis. These observations have revolutionised the management of acute MI and is the basis of aggressive thrombolytic therapy in early acute MI with an aim to salvage the myocardium at risk for better survival of these patients.
Much importance has been given to the plaque type rather than the plaque size in the clinical presentation of coronary atherosclerosis. Stable plaques encroach upon the lumen and cause stable angina pectoris. The vulnerable plaques, however, are prone to rupture which in turn promotes thrombosis. The size of the thrombus and duration of occlusion can cause acute coronary syndromes. Thus plaque rupture with a labile thombus which causes transient occlusion may result in unstable angina wheras a large occlusive thrombus may lead to myocardial infarction.
Rarely, myocardial ischaemia can be caused by lesions other than atherosclerosis. Inflammatory disease of the conronary artery may produce myocardial ischaemia. Syphilitic aortitis may extend on to the coronary ostia producing narrowing and decreased myocardial perfusion. Necrotising coronary arteritis as seen in polyarteritis nodosa and Kawasaki disease may cause obstruction due to aneurysm and thrombus formation. Rarely, thromboangiitis obliterans, rheumatic and rheumatiod arteritis may cause narrowing or occlusion of the artery. Embolism occasionally may cause coronary artery occlusion.59
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Source of emboli may be from infective or non-infective endocarditis, mural thrombi, material from ruptured atheromatous plaque and tumours. Thrombosis causing occlusion of the coronary artery may occur in some hematological disorders such as polycythaemia vera, hypercoagulability of blood, thrombocytosis, disseminated intravascular coagulation (DIC) and thrombotic thrombocytopenic purpura. Aneurysms of the coronary artery are rare and may be either congenital or more often acquired consequent to infections (mycotic), atherosclerosis, syphilis, dissection of aorta, and polyarteritis nodosa. Thrombosis or rupture of the aneurysm produces occlusion of the artery.
In some cases of myocardial infarction coronary arteries are normal and no coronary artery disease can be demonstrated. This group of patients are usually young, often cigarette smokers and may lack the usual factors of atherosclerosis. Vasospasm may play an important role in the causation of myocardial infarction in these patients.
Salvage of Ischaemic Myocardium
Occlusive coronary artery thrombosis has been demonstrated in the vast majority of cases of acute myocardial infarction. The aim of management of acute myocardial infarction within the first few hours of its onset is to dissolve the occlusive thrombus in the coronary artery. This is achieved by the use of thrombolytic agents such as streptokinase or tissue plasminogen activiator that not only provide reperfusion but also help to salvage the dependent area of myocardium which otherwise would progress to irreversible damage (ischaemic necrosis). The rationale of therapy for reperfusion and myocardium salvage has been provided by the elegant experimental observations following ligation of the coronary artery (Fig. 2.34). Injury to myocardium about 15 to 20 minutes after occlusion is such that if adequate reperfusion is established the changes are completely reversible. The subendocardial region is most susceptible to ischaemia.
Fig. 2.34: Effects of coronary artery ligation—”Wave front” phenomenon. Persistent ligation causes progressive increase in myocardial necrosis. Picture shows effects of experimental coronary artery ligation at 10 and 45 minutes and 3 and 24 hours
A “wave front” of ischaemic necrosis beginning from the subendocardial zone progressively extends to involve the entire width of the myocardium, the subepicardium region being the last to be affected as it is least susceptible to ischaemia. The latter region has a rich network of collaterals which are sparse in the subendocardium. If reperfusion is carried out early enough, the progresion of cell necrosis can be checked. Beyond the critical time period, however, reperfusion, or any other intervention does not allow recovery as irreversible changes set in.
Other therapeutic interventions that can be applied to restore arterial blood flow include: (i) percutaneous transluminal coronary angioplasty, (ii) coronary artery stenting, (iii) coronary artery bypass grafting, and (iv) transmyocardial revascularisation.
Reperfusion Injury
Ironically, while aggressive measures to induce reperfusion have been devised to minimise cell death consequent to coronary artery occlusion, reperfusion can also accelerate necrosis of ischaemic myofibres. Thus myocardial reperfusion has been likened to a “double-edged sword” in that, while on one hand its beneficial effect is undisputed, on the other hand, there is definite evidence of reperfusion-induced myonecrosis. Latter is believed to be due to the effect of rapid influx of Ca++ and oxygen-derived free radicals during reflow of blood.
Morphology of reperfusion injury
Since thrombolytic therapy is the mainstay of management of acute myocardial infarction today, it is worthwhile to be aware of the morphologic changes associated with it. Myocardial infarcts consequent to reperfusion injury are invariably haemorrhagic possibly due to microvascular ischaemic damage which allows extravasation of blood. Microscopically, irreversibly damaged myocytes reveal contraction band necrosis which is seen as transversely oriented, thick eosinophilic bands within myofibres indicating hypercontractile myofibres.
Fig. 2.35: Enzymes in the serum in acute myocardial infarction. The rise and fall of lactate dehydrogenase (LDH), creatinine phosphokinase (CPK) and serum glutamic-oxaloacetic transaminase (SGOT) are indicated in the graph
Diagnosis of Myocardial Infarction
Diagnosis of myocardial infarction rests on a combination of features such as clinical history, electrocardiographic changes and serial estimation of certain enzymes in the serum (Fig. 2.35).
Irreversibly damaged myocardial cells release a number of enzymes into the circulation which can be estimated. Detection of serum enzymes are extensively used in the diagnosis, clinical monitoring and course of MI. The various enzymes that may be estimated are creatinine phosphokinase (CPK), lactic dehydrogenase (LDH) and aspartate aminotransferase (AST). The most frequently estimated enzymes in the laboratory diagnosis of acute MI are CPK and LDH. The other serum cardiac markers used to assess myocardial injury include myoglobin, troponin-T and myosin light chain 1.
Creatinine phosphokinase (CPK)
Following acute myocardial infarction, serum CPK rises within 4 to 8 hours, attains a peak at about 24 hours and declines to the normal range within 3 to 4 days of onset. Three isoenzymes of CPK have been identified by electrophoresis—MM, BB, and MB. Skeletal muscle contains predominantly MM 62isoenzyme while the BB isoenzyme is present in brain and kidney. Cardiac muscle contains mostly the MB isoenzyme although some quantities of MM isoenzyme is also present. Small quantities of MB isoenzyme can also be detected in tongue, diaphragm, small intestine, uterus and prostate. It is important to remember that false positive results may be obtained in muscle diseases, muscle trauma including intramuscular injections, diabetes mellitus, alcohol intoxication, convulsions, etc.
Lactic dehydrogenase (LDH) has five distinct isoenzymes, LDH-1 to LDH-5 of which LDH-1 is predominantly located in the myocardium. LDH-1 is elevated in MI while LDH-2 is not increased. A LDH-1 to LDH-2 ratio of more than 1 is a good indicator of MI. In sharp contrast with CPK, LDH rises later and falls to normal values much later. It rises by 24 hours attaining peak values at 4 to 6 days and returns to normal anywhere between 8 and 14 days after the onset of infarction. A judicious choice of enzymes to be estimated help in the diagnosis of MI. The enzyme of choice to be estimated within the first few hours of infarction is CPK-MB. Serial estimations of CPK-MB in acute MI are useful not only in diagnosis of early AMI but may also detect reinfarction if the levels do not fall to normal or rise again in the course of hospital stay.
Cardiac troponins
These are regulatory proteins which are complexed with the contractile apparatus. The troponin complex consists of 3 subunits: TnT, TnI and troponin C. Increased levels of cardiac troponins in the serum serve as a useful marker for myocardial necrosis.
Other laboratory estimations in acute myocardial infarction include polymorphonuclear leucocytosis within the first 3 to 4 days of infarction, elevated erythrocyte sedimentation rate (ESR), hyperglycaemia and myoglobinaemia. Myoglobin, like the other enzymes, is released from the ischaemic myocardial cells. Myoglobin rises early after the onset of infarction but the elevation is for a very brief period and is readily excreted in the urine.
Complications of Myocardial Infarction (Table 2.9)
Cardiac arrhythmias
It is one of the most serious complication of acute AMI being present in some form or the other in 70 to 95 per cent of hospitalised patients and accounts for mortality in over 50 per cent of cases. These occur as ventricular tachycardia, ventricular premature beats and ventricular fibrillation indicating electrical instability; sinus tachycardia, atrial fibrillation and paroxysmal ventricular tachycardia due to pump failure and conduction disturbances mainfested by sinus bradycardia and partial or complete heart block. Left ventricular failure and cardiogenic shock is generally associated with massive MI resulting in substantial loss of contractile myocardium which causes pump failure or cardiogenic shock. Myocardial rupture occurs early in the course of acute transmural MI. The most vulnerable period is within the first 2 weeks particularly within 24 to 72 hours of onset when the necrotic myocardium is soft and friable. Transmural myocardial infarction associated with hypertension is particularly prone to rupture. This may produce extensive bleeding into the pericardial cavity resulting in cardiac tamponde which is often fatal. In a few patients, rupture of interventricular septum may produce features of a ventricular septal defect. Rupture of the infarcted papillary muscle may produce sudden massive mitral regurgitation resulting in pulmonary congestion, and acute pulmonary oedema. Mural thrombosis and thromboembolism are a serious complication of MI. Mural thrombi are common in both acute and healed myocardial infarction. Leg vein thrombosis is a potential complication of bed rest and congestive heart failure which occurs commonly in MI. It also poses a great threat to pulmonary embolism. When a myocardial infarct heals the affected area becomes thinned and scarred due to loss of muscle mass. During cardiac systole this area does not contract with the rest of the myocardium but in fact bulges out which over the years results in aneurysm formation (Fig. 2.36). Latter provides for stasis of blood, thrombosis and a source of distant embolism.63
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Pericarditis
Fibrinous pericarditis may occur within the first few days of MI. This reaction in the pericardium may correspond with an underlying area of myocardial necrosis. Rupture of transmural MI results in haemorrhage within the pericardial cavity. Occasionally pericarditis may develop any time between 2 weeks and 2 years after infarction. This has been termed as postmyocardial infarction syndrome (Dressler syndrome) which is characterised by fever, elevated ESR, pericarditis, pericardial effusion, pleurisy and pneumonitis. This condition is believed to be autoimmune in nature.
Fig. 2.36: A case of healed myocardial infarction showing aneurysm formation (arrow) at the left ventricular apex
Chronic ischaemic heart disease (ischaemic cardiomyopathy)
In some individuals with long-standing IHD there is a progressive myofibre loss with fibrosis which results in severely impaired ventricular contractility manifesting clinically as dilated cardiomyopathy.64
Fig. 2.37: Specimen of left side of heart to show large areas of scarring. Fresh infarct is also seen at the apex (arrow). Left ventricular wall is thinned out
The dominant clinical presentation is that of congestive heart failure rather than anginal pain. Generally a previous history of one or more episodes of MI is obtained due to which there is diffuse fibrosis and myocardial dysfunction. Morphologically, the heart may be either normal or increased in size and weight. Evidence of old healed infarcts is usually present. Variable areas of the myocardium reveal fibrosis/scarring (Fig. 2.37). Diffuse, severe coronary atherosclerosis with or without total occlusion is present in almost all cases. Microscopically large area of the myocardium shows replacement fibrosis and scarring.
Sudden cardiac death (SCD)
One of the major consequences of atherosclerotic coronary heart disease is sudden cardiac death. It may be the first and at times the last manifestation of IHD. It is defined as either instantaneous death without any preceding symptoms or death occurring within minutes to hours and according to some workers 24 hours after onset of symptoms. The most common anatomical finding in SCD is coronary atherosclerosis. The mechanism of SCD in most cases is believed to be due to cardiac arrhythmias especially ventricular fibrillation.
MYOCARDITIS
Myocarditis is defined as an acute or chronic focal or diffuse inflammatory cell infiltration in the interstitial tissue of the myocardium with variable degrees of myocyte damage/necrosis (Figs 2.38 and 2.39). Myocarditis in majority of the cases is caused by infectious agents the most common of which are viruses.
Fig. 2.39: Myocarditis. Photomicrograph show extensive inflammatory cell infiltration and destruction of myofibres
It can also be caused by toxins, immunological and/or hypersensitivity reactions, in response to physical agents, chemical poisons, drugs and several metabolic disorders (Table 2.10).
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A non-specific inflammatory response may be seen in myocarditis of varying aetiology. Specific types of myocarditis can be recognised in some cases, e.g. Aschoff nodules in RHD, causative agents such as parasite, fungus, etc. in the tissue or a granulomatous response in which case a diagnosis of sarcoidosis, tuberculosis and giant cell myocarditis needs to be considered. The type of inflammatory infiltrates must be noted carefully as these may provide a clue to the aetiology. However, in a large majority of cases the inflammatory response is common to myocarditis of varying aetiology.
Myocarditis Caused by Infectious Agents
Viral Myocarditis
Viral myocarditis is of significance as it appears to be related to development of dilated cardiomyopathy in some cases. Viruses known to cause 66myocarditis are coxsackie A and B, ECHO, polio, influenza A and B, HIV, cytomegalovirus, hepatitis virus and others. Myocarditis is generally preceded by an initial systemic viral infection. Heart may be the only organ involved and the infection may either have a benign self-limiting course with complete recovery or an aggressive course characterised by rapidly progressive cardiomegaly, congestive heart failure, pulmonary oedema and sudden death.
Diagnosis of viral myocarditis is made by the isolation of the virus in stool, blood, throat washings or myocardium or more commonly by the detection of rising antibody titres of virus neutralising antibodies. These techniques are often not too helpful. cDNA clones representing various regions of the coxackie B virus-specific RNA sequences have been detected in myocardial tissue both by in situ hybridisation and polymerase-chain reaction (PCR). Endomyocardial biopsy may be performed in cases of viral myocarditis to assess the nature, severity and extent of inflammation. If myocarditis is detected it is treated with immunosuppressive agents and/or steroids in some centres. In order to rationalise therapy the diagnosis of myocarditis has to be definitive as immunosuppressive therapy may have its own problems. Morphological criteria for the diagnosis of myocarditis have been laid down by a group of workers (Dallas criteria). Strict application of these criteria has minimised variations in the reported incidence of myocarditis (0-63%).
On gross examination the heart is enlarged, flabby and may show foci of necrosis. Microscopically, inflammatory infiltrate is dominated by T-lymphocytes, other cells being macrophages and plasma cells.
The exact mechanism of viral induced myocardial damage is not known. A lag phase between the onset of myocardial damage and an initial viral infection (flu-like illness) has been well documented in clinicoepidemiological studies of viral myocarditis. This period may provide for the initiation of immunological processes underlying myocardial damage. The virus possibly evokes a cell-mediated immune reaction to the virus or a new antigen related to the virus. Other postulated mechanisms of injury include direct viral cytotoxicity caused by viral replication within the myocardium, antibodies against several myocardial cell components and demonstration of viral specific T-cells. Autoimmune responses to various myocyte components mediated by cytotoxic T-cells may also be operative in destruction of myocytes.
Heart involvement in acquired immune deficiency syndrome (AIDS) has been well recognised and is commonly due to myocarditis caused by opportunistic infections by a wide variety of bacteria, fungi and other organisms. Cytomegalovirus infection is of importance in cases of cardiac transplantation and in immune-suppressed states.
Bacterial and Fungal Myocarditis
A variety of bacterial and fungal species may cause either inflammation or abscess in the myocardium. Infection occurs either consequent to inflammation elsewhere in the body (pyaemia) or by direct extension from adjacent inflammatory/suppurative focus. The most common source of infection is infective endocarditis. Microscopically, infiltration is dominated by polymorphs. Myocarditis caused by fungi is mostly a result of opportunistic infections. Microscopically, inflammatory infiltrate abounds in eosinophils. The nature of fungus can be recognised and characterised in the tissue in most cases. Bacterial toxins as in diphtheritic myocarditis also produce myocarditis consequent to necrosis and degeneration of the myofibres.
Protozoal Myocarditis
Common parasitic diseases of the heart are Chaga's disease caused by Trypanosoma cruzi and Toxoplasma gondii.
Chaga's disease is prevalent in Central and South America. It is acquired through the bite of a reduviid bug. The myocardium, central nervous system (CNS) and skeletal muscle are commonly 67involved. Three phases of the disease—acute, latent and chronic are well recognised. Cardiac manifestations may occur one or two decades after the inital infection and is characterised by cardiomegaly, congestive heart failure (CHF), arrhythmias, thromboembolic phenomena, right bundle branch block and sudden death. On naked eye examination, the heart is overweight having features of dilated cardiomyopathy in most cases. Microscopically, inflammatory infiltrate is composed of lymphocytes, histiocytes, plasma cells and eosinophils. Intracellular trypanosomes may be present. In most cases the presenting features are identical with dilated cardiomyopathy. Pathogenesis of Chaga's disease is ill understood. It is likely that the agent evokes both cellular and humoral responses to various components of myocytes and ganglia. Autoimmune damage to myocardium has also been implicated.
Protozoal myocarditis caused by Toxoplasma gondii may be acquired either in utero through exposure to infected pets or through ingestion of contaminated food. It is characteristically observed in immunosuppressed individuals as in disseminated malignancy, AIDS and cardiac or other organ transplantation. Histologically, non-specific myocarditis is seen. Diagnostic feature is presence of myocytes filled with the organism.
Other parasitic infestations of the heart include echinococcosis the larval cysts of which are most frequently located in the left ventricular muscle. Rupture of the hydatid cyst may excite an anaphylactic reaction. Cysticercosis may also affect the heart as part of the systemic infection. Infestation by Trichinella spiralis is characterised by its larval form within the cardiac muscle which may cause a focal or diffuse myocarditis. Falciparum malaria may produce cardiac haemorrhages consequent to plugging of the myocardial capillaries by the parasite.
Non-Infectious Myocarditis
This group includes several types of myocarditis possibly mediated by immunological/hypersensitivity mechanisms, e.g. rheumatic carditis and carditis in lupus erythematosus. Immune-mediated myocarditis is well documented in cardiac transplant recipients. The most important disease in this group is RHD which has been dealt with earlier.
Physical Agents
Toxic myocarditis may be caused by a wide variety of drugs. The mechanism of injury is either because of direct drug toxicity, e.g. cyclophosphamide, doxorubicin, barbiturates or more commonly as a result of hypersensitivity/allergic response of the myocardium to various drugs namely cyclosporine, sulphonamides, penicillin, streptomycin, methyldopa, diphtheria, tetanus toxoid and horse serum. Scorpion stings and snake bites are common causes of myocarditis in tropical countries.
Myocarditis due to drugs may evoke an extensive inflammatory response in the myocardium which is dominated by eosinophils. Vasculitis may also be present in some cases.
Granulomatous Myocarditis
In this group are included sarcoidosis, giant cell or idiopathic or Fiedler's myocarditis and tuberculosis. These lesions have to be evaluated with the background of clinial and investigative data. In sarcoidosis cardiac involvement is rare and this needs to be considered when granulomas are present. Idiopathic Giant cell myocarditis is characterised by extensive inflammatory cell infiltration within the myocardium with a rapidly progressive clinical course, congestive heart failure and sudden death in some cases. On gross examination the heart is overweight, flabby, pale and the chambers are invariably dilated. If the lesion is extensive, large yellowish grey foci representing necrotic myocardium are characteristically observed. Mural thrombi are encountered in some cases. Microscopically, the inflammatory process may be mild to severe in intensity and focal or diffuse in distribution. Inflammatory cell infiltration with associated degeneration and/or 68necrosis of the muscle fibres is observed. Numerous giant cells are recognised amidst lymphocytes, macrophages, plasma cells and eosinophils (Fig. 2.40). Tuberculosis of the heart is rare. It may occur either in isolation or more commonly as a part of systemic disease or extension from an adjacent focus, e.g. tuberculous pericarditis.
Myocarditis in most cases may be subclinical and escape clinical notice while in others it may present as a rapidly progressive acute illness with a fulminant clinical course and death consequent to CHF. Myocarditis may have a self-limiting course. Histologically, healing is evident as replacement fibrosis of the damaged myocardium. As mentioned earlier some of the cases may later develop signs and symptoms of dilated cardiomyopathy.
CARDIOMYOPATHIES
According to the Report of the 1995 World Health Organisation/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies, the cardiomyopathies are classified by the dominant pathophysiology or by aetiological or pathogenetic factors. Cardiomyopathies are diseases of the myocardium associated with cardiac dysfunction. Four main types are well established clinicopathological entities (Table 2.11).
- Dilated (congestive) cardiomyopathy (DCM)
Table 2.11 Classification of cardiomyopathies Dilated cardiomyopathy (DCM)Hypertropic cardiomyopathy (HCM)Restrictive cardiomyopathy (RCM)Arrhythmogenic right ventricular dysplasiaRestrictive cardiomyopathy (RCM)- Endomyocardial
- Endomyocardial fibrosis
- Hypereosinophilic syndrome (Loeffler's disease)
- Endocardial fibroelastosis
- Radiation injury
- Myocardial (infiltrative storage diseases)
- Amyloidosis
- Sarcoidosis
- Gaucher disease
- Haemochromatosis
- Fabry disease
- Glycogen storage disease
- Neuropolysaccharidosis
- Hypertrophic cardiomyopathy (HCM)
- Restrictive cardiomyopathy (RCM)
- Arrhythmogenic right ventricular dysplasia (ARVD)
A large number of heart muscle diseases that are associated with cardiac or systemic disorders may present with features of cardiomyopathy. It has been recommended that these be designated as specific cardiomyopathies. Latter include ischaemic cardiomyopathy, hypertensive cardiomyopathy, inflammatory cardiomyopathy consequent to extensive myocarditis leading to cardiac dysfunction. A number of metabolic disorders namely thyrotoxicosis, hypothyroidism, diabetes mellitus, familial storage diseases and infiltrations can present as cardiomyopathy. Muscular dystrophies such as Duchenne, Becker-type and myotonic dystrophies are also included in the specific cardiomyopathy group. Peripartal cardiomyopathy is a well established entity that occurs in the peripartum period.
Dilated Cardiomyopathy (DCM)
Dilated cardiomyopathy (DCM) is characterised by an enlarged heart due to dilatation of all chambers, progressive congestive heart failure and reduced systolic function of the ventricles (pump failure) without any recognisable cardiac lesion namely coronary, valvular, hypertensive, congential, pericardial, and cor pulmonale.69
Fig. 2.41: External appearance of heart in a case of dilated cardiomyopathy. Heart is oversized and globular in shape
Fig. 2.42: Opened up right side of heart in a case of dilated cardiomyopathy shows marked dilatation of both right atrium and right ventricle
Pathology
The heart is enlarged, overweight, flabby and shows hypertrophy and dilatation of all its chambers particularly the ventricles (Figs 2.41 and 2.42). The ventricular wall appears mildly thickened or normal due to dilatation of the chambers. Mural thrombi in the cardiac chambers especially in the left ventricle are commonly encountered. Endocardial thickening particularly in the left ventricle may be present. Histological findings in DCM are of a non-specific nature. Hypertrophic myofibres admixed with attenuated ones is a common finding. Nuclei of myofibres are enlarged and hyperchromatic. Variable amount of interstitial fibrosis possibly representing earlier episodes of myocarditis are often present. Inflammatory cells predominantly lymphocytes are recognised in some cases (Figs 2.43 to 2.45).
Endomyocardial biopsy is a safe and, simple procedure indicated in several cardiac diseases one of which is DCM. The histologic features of DCM are non-specific in nature. The role of EMB in DCM is to detect myocarditis and other specific diseases that present as dilated cardiomyopathy.
The aetiology of DCM is unknown and is considered to be multifactorial in nature. Of all the suggested mechanisms, viral myocarditis enjoys the maximum support. A “flu”-like illness often precedes an attack of acute myocarditis which may go unnoticed. Several months later, progressive CHF may result. A large number of viruses most commonly coxsackie A and B have been implicated. It is believed that viral myocarditis induces an immunological injury both humoral and cell mediated to the myofibres. Additional evidence of the role of viruses has been provided by the demonstration of coxsackie virus nucleic acid sequences and viral particles in the myocardium of some patients with DCM. Enterovirus persistence seems to be associated with continuing myocardial damage in cases of DCM. Sequential endomyocardial biopsies (EMBs) done in cases of viral myocarditis have shown inflammation in the earlier stages which resolve with or without immunosuppressive therapy.70
Fig. 2.43: Photomicrograph from a case of dilated cardiomyopathy (DCM) to show hypertrophic myofibres admixed with thin attenuated ones
Fig. 2.44: Photomicrograph from a case of dilated cardiomyopathy (DCM). Aggregates of lymphocytes are observed in the interstitial tissue of myocardium
In later stages of DCM non-specific changes in the myocardium are seen with none or very little inflammatory response.
Heredity appears to play an important role. Familial clustering of DCM has been well documented in about 20 to 25 per cent cases of DCM. Mutation in the dystrophin gene in familial cases of “x-linked” DCM have been reported. Autosomal dominant and recessive patterns have also been detected in familial cases of DCM. Autoimmunity is another mechanism reported in the causation of DCM. Antibodies to several components of the cardiac muscle namely beta-adrenergic receptor, myosin, myolemma, intercalated disc, mitochondrial membrane proteins, ADP/ATP carrier of the inner mitochondrial membrane, and others, have been demonstrated.
Fig. 2.45: Photomicrograph from a case of dilated cardio-myopathy (DCM) to demonstrate fibrosis in interstitial tissue of myocardium
Other factors implicated in the occurrence of DCM include chronic alcohol ingestion, pregnancy/puerperium, hypertension and myocarditis induced by certain drugs. Alcoholic cardiomyopathy is a well-recognised entity. The underlying mechanism appears to be toxic effects of alcohol and its metabolites on the cardiac muscle. Other toxic agents which may produce a picture similar to dilated cardiomyopathy are cobalt as in beer drinker's cardiomyopathy and chemotherapeutic drug namely adriamycin. DCM has also been observed in pregnant women either in the last trimester of pregnancy or within the first 6 months of the post-partum period. This is commonly designated as “peripartum cardiomyopathy”. The pathologic features are identical to DCM.
Dilated cardiomyopathy has an insidious clinical onset and clinical course and is characterised 71by slowly progressive CHF. In some patients heart failure may be associated with acute myocarditis whereas in others the myocarditis may heal and manifest as CHF much later. DCM may occur in any age group including infants and children but is most common in middle age, men being affected more often than women. Dilatation of the valvular rings is common which result in mitral and tricuspid valve regurgitation and heart failure. Systemic thromboembolism contributes importantly to morbidity and mortality in DCM.
The chief causes of death are consequent to heart failure, ventricular arrhythmias and systemic thromboembolism. Management of DCM is essentially symptomatic as no specific cause is recognised. Cardiac transplantation is indicated in dilated cardiomyopathy.
Hypertrophic Cardiomyopathy (HCM)
Hypertrophic cardiomyopathy (HCM) also known as idiopathic hypertrophic subaortic stenosis (IHSS), asymmetric septal hypertrophy (ASH) and hypertrophic obstructive cardiomyopathy (HOCM), is a disease of unknown aetiology and is characterised by impaired diastolic relaxation (reduced diastolic compliance) of the ventricle. The systolic function of the ventricle is normal.
Pathology
The heart is enlarged, hypertrophic and reveals small ventricular cavities which often appear distorted. Left ventricle involvement is usually predominant. Hypertrophy is either symmetrical or more commonly presents as disproportionate thickening of the interventricular septum and the anterolateral wall as compared with free wall of the left ventricle. The term ASH is applied when the hypertrophy is confined to the interventricular septum, the basal part of the septum being affected more than the lower half. Septal hypertrophy may be confined to the midventricular region or apical portions in some cases. In normal hearts the ratio of septal to posterior free wall thickness is 1.A ratio exceeding 1.3 is highly suggestive of HCM (ASH). Systolic anterior motion (SAM) of the anterior leaflet of the mitral valve is an abnormality that is present in some cases of HCM. The degree of SAM is predictive of the severity of left ventricular outflow tract obstruction. Due to the constant contact of the mitral valve, endocardial thickening or plaque formation may occur in the subaortic region. Consequently the anterior leaflet of the mitral valve is also thickened. Subaortic endocardial fibrosis along with thickened basal interventricular septum causes left ventricular outflow tract to be markedly narrowed at the end of cardiac diastole thereby producing functional obstruction. This has been designated as HOCM.
Microscopically, the myofibres show marked hypertrophy and branching. Disorganisation and disarray of the fibres which give a whorled appearance is a striking feature. Perinuclear halo can be recognised in a number of cases. Fine creeping interstitial fibrosis may also be present. It must be remembered that abnormal branching of hypertrophic fibres is not specific of HCM and has also been observed in a variety of congenital and acquired heart diseases. The extent and severity of this change, however, is much more frequent and widespread in HCM than in other cardiac diseases. Intramural coronary artery branches show thickening and luminal obstruction. These changes are observed more often in the ventricular septum than the left ventricular free wall.
The aetiology of HCM is unknown. Autosomal dominant inherited transmission has been documented in over 50 per cent of the patients. In familial cases of HCM genetic abnormalities of beta-heavy chain cardiac myosin located on the long arm of the 14th chromosome (14q.1) have been detected. Chromosomal defects in troponin T gene on the long arm of chromosome 1 and tropomyosin gene on the long arm of chromosome 15 have been identified in patients of HCM having normal beta-heavy chain of cardiac myosin. Mutation of the cardiac myosin heavy chain genes occurring in the myocardial 72precursor cells of an individual may result in some sporadic cases of HCM. Some other factors that contribute to hypertrophy and disorganisation of myofibres include: (i) abnormal calcium kinetics with increase in intracellular calcium, (ii) increased sensitivity of the heart to circulating catecholamines, (iii) myocardial ischaemia as a result of thickened intramyocardial vasculature, and (iv) abnormality of the fibrous skeleton of the heart.
Hypertrophic cardiomyopathy occurs most often in adults in the third to fourth decade of life. The majority of patients are asymptomatic and are generally detected during screening of asymptomatic family members of a patient with HCM. The symptoms in HCM are consequent to left ventricular hypertrophy, subaortic obstruction, reduced diastolic compliance, reduced volume capacity of the left ventricle and myocardial ischaemia. Common symptoms of HCM are dyspnoea which is often accompanied by angina pectoris, fatigue and syncope. Other symptoms include palpitations, paroxysmal nocturnal dyspnoea (PND) and congestive heart failure. Sudden and unexpected death due to arrhythmias may be the first manifestation in otherwise healthy subjects.
Restrictive and Infiltrative Cardiomyopathy
This group of cardiomyopathies is characterised by rigid ventricular wall that results in impaired ventricular filling (abnormal diastolic function) with relatively well-preserved systolic function of the heart. Several disease processes that affect the endomyocardium or the myocardium may result in restrictive heart disease (Table 2.11). The common endomyocardial lesions include endomyocardial fibrosis (EMF) and Löffler's endocarditis. Myocardial diseases comprise infiltrative disorders namely amyloidosis, storage disorders, hemochromatosis and sarcoidosis.
An important subset of patients who have haemodynamic abnormalities of restrictive heart disease in the absence of any significant morphologic change has been well documented. This is designated as “idiopathic or primary” restrictive cardiomyopathy.
Endomyocardial disease
Two variants of this disease namely endomyocardial fibrosis (EMF) and Löffler's endocarditis parietalis fibroplastica are described. These are believed to be manifestations of the same disease process as the pathological findings in the advanced stages of Löffler's disease are indistinguishable from those of EMF.
Endomyocardial Fibrosis
Endomyocardial fibrosis (EMF) is the most common restrictive heart disease in the humid tropical countries particularly Uganda, Nigeria, South and Central, Asia, America and in southern India (Kerala state). The disease affects predominantly children and young adults.
Pathology
The characteristic feature on the naked eye examination is endocardial thickening involving the inflow portions of either one or both ventricles and the apex of the heart. The ventricular cavity may get obliterated. The atrioventricular valves may be enveloped by the fibrotic process. The outflow tract and the semilunar valves are relatively spared of the disease and classically, the fibrosis terminates 2 to 4 cm short of the left ventricular outflow tract where it appears as a prominent fibrous ridge (Figs 2.46 and 2.47). Mural thrombosis occurs frequently. Biatrial dilatation is present. Microscopically, the endocardium is markedly thickened exhibiting a “zonal” or a layering pattern. The most superficial zone is composed of dense fibroconnective tisssue with or without a superimposed fresh or an organised thrombus. Beneath this is a layer of loosely arranged fibroconnective tissue admixed with elastic tissue. The deeper part of the thickened endocardium, at the myocardium/endocardium interphase comprises fibrous tissue and granulation tissue which often extends into the inner third of the myocardium. Chronic inflammatory cell infiltration is mild and recognised in only some cases.73
Fig. 2.46: A case of endomyocardial fibrosis showing marked thickening of endocardium which ends abruptly below the left ventricular outflow tract. Fibrosis is seen in the myocardium. Thrombus is present at the apex (arrow)
Eosinophils are not recognised at this stage.
The aetiology of EMF is unknown. Eosinophilia due to varied causes such as hypereosinophilic syndrome, parasitic infections (filariases/ trichinosis or other) and other conditions associated with eosinophilia has been ascribed. It has been hypothesised that the eosinophil causes damage to the tissues by release of its granule contents that are possibly cardiotoxic. In addition, nutritional deficiencies, consumption of bananas which are rich in serotonin and excessive concentrations or deficiencies of some trace elements in tropical soil have been implicated in causation of the fibrotic endocardium in EMF.
The clinical presentation depends on the distribution of the disease. Left sided EMF results in symptoms of pulmonary congestion whereas right sided involvement simulates features of constrictive pericarditis namely, elevated jugular venous presure, enlarged pulsatile liver, ascites and peripheral oedema. In biventricular EMF findings of right sided EMF may dominate the clinical picture. Incompetence of one or both atrioventricular valves is usually present. Thromboembolic phenomena may also occur in some cases.
Löffler's endocarditis parietalis fibroplastica is an endomyocardial disease described in Europe, Scandinavian countries and other regions with temperate climate.
Fig. 2.47: A case of endomyocardial fibrosis showing plaster like thickening of the endocardium in the left ventricle. Process of fibrosis envelops the mitral valve (MV) leaflets and chordeae tendineae. Fibrosis of myocardium is seen (arrow). Thrombus is present at apex of heart (arrow)
It is characteristically associated with marked peripheral and tissue eosinophilia (hypereosinophilic syndrome) of variable aetiology. The cardiac involvement appears to progress through three stages: (i) necrotic stage which is characterised by intense myocarditis, endocarditis and vasculitis heavily infiltrated by eosinophils, (ii) thrombotic stage that occurs within a few months to a year of the initial acute involvement, acute inflammation of the necrotic stage recedes and a thrombus forms over the endocardial surface, and (iii) fibrotic stage which is a result of organisation of the thrombus leading to thickened endocardium and/or extension of the fibrotic process into the underlying myocardium. It is the latter stage that is identical to the features observed in EMF.
The acute event is characterised by an intense infiltration by eosinophils and much work therefore has been done to elaborate its role in the production of lesions in the heart. It is believed that certain protein contents of the eosinophil granules produce toxic cardiac damage leading to necrosis. No eosinophils are found at later intervals particularly in the fibrotic stage.
Endocardial fibroelastosis (EFE) is an uncommon condition of unknown aetiology affecting mostly infants and children more so in the first 2 years of life and only occasionally in adults. It may occur de novo (primary) or occur consequent to congenital malformations of the heart most commonly, patent foramen ovale, coarctation of the aorta, and aortic stenosis (secondary). Both sporadic and familial forms have been documented.
Examination of the heart reveals a striking diffuse endocardial thickening (several millimetres) involving most commonly the left ventricle. The affected left ventricle is commonly dilated but it may be either normal or even contracted or hypoplastic. The aortic and mitral valve leaflets may be thickened, distorted producing stenosis or incompetence of the valves, particularly the mitral valve. The fibrotic process may also envelop the papillary muscles and chordae tendinae producing shortening, contractures and distortion of these structures. Thromboembolism is common particularly in the adult form of the disease. Microscopically marked fibroelastic thickening of the endocardium which shows several, parallel oriented layers of elastic tissue admixed with varying amounts of collagen is present.
The aetiology of EFE is not known and several hypotheses include: (i) intrauterine endocardial anoxia due either to premature closure of foramen ovale or inadequate subendocardial blood flow, (ii) prenatal or postnatal viral infections and/or inflammation, (iii) haemodynamic pressure overload exerted by congenital malformations of the heart that are associated with EFE, (iv) lymphatic obstruction, and (v) an autoimmune connective tissue disease. In the familial form of EFE, a genetic basis has been suggested. Some recent studies suggest that EFE may develop in a subset of patients with mumps virus-induced myocarditis.
EFE is one of the causes of CHF in infants and children. It may either be insidious in onset or more commonly has a rapidly progressive clinical course. In older children and adults, and in those with a focal disease the clinical course may extend over months to years with development of cardiac hypertrophy, left ventricular dysfunction and eventually CHF. In addition to the latter, thromboembolisation may further contribute to the morbidity and mortality.
Cardiac Amyloidosis
Cardiac amyloidosis affects men more often than women usually beyond the fourth decade of life. Common manifestations of cardiac amyloidosis are restrictive cardiomyopathy and CHF. Cardiac involvement is more common in primary amyloidosis and thereby is associated with an immunocyte dyscrasia in over 90 per cent of cases (amyloid AL). It is encountered in only about 10% of cases with chronic systemic illness (secondary) namely tuberculosis, rheumatoid arthritis, bronchiectasis, etc. (AA amyloid). Cardiac amyloidosis also occurs in a genetic familial form in which the deposits comprise transthyretin protein and as senile amyloidosis. Latter may involve either the 75atria alone (isolated atrial amyloidosis) or affect both atria and ventricles.
Pathology
The heart is enlarged, pale with thickened ventricular walls which feel firm and rubbery. Microscopically, in haematoxylin and eosin stains amyloid is seen as homogeneous, eosinophilic, amorphous deposits in the periphery of the myofibres surrounding and compressing them to produce ring forms, atrophy or complete myofibre loss and replacement. Amyloid deposits are frequent in the walls of medium-and small-sized vessels, in the valves and subendocardial region. Rarely, nodular amyloid deposits may also be seen in the epicardium and endocardium. This amorphous material stains metachromatically with crystal violet and produces an apple green birefringence under polarised light with congo red staining.
The most common clinical presentation is CHF. Increased stiffness of the myocardium due to infiltration by amyloid is evidenced by slow or impaired diastolic filling of the ventricles despite increased venous pressure and poor systolic function. These features can be observed on angiography and echocardiography and a reasonably certain diagnosis of cardiac amyloidosis can be made. Since the sinus node is often involved, atrial arrhythmias are frequent.
Idiopathic Restrictive Cardiomyopathy
In some cases clinical and haemodynamic features of restrictive heart disease are present in the absence of any recognisable morphological lesion in the heart. These cases are designated as idiopathic or primary restrictive cardiomyopathy. Aetiology of this condition remains obscure. However, familial occurrence and autosomal dominant inheritance pattern has been documented.
Arrhythmogenic Right Ventricular Cardiomyopathy
Arrhythmogenic right ventricular cardiomyopathy also known as arrhythmogenic right ventricular dysplasia (ARVD) is characterised by progressive fibrofatty replacement of the right ventricular muscle and myocyte atrophy resulting in myocardial thinning. Clinical presentation is marked by arrhythmias, right ventricular failure and sudden death especially in younger patients. The disease is familial with autosomal dominant inheritance. Recessive forms have also been documented.
Myocardial diseases
Involvement of the myocardium in a host of metabolic, nutritional, drug-induced, neuromyopathic, and endocrine diseases may present as cardiomyopathy. A list of these is provided in Table 2.12 (Please refer to special texts on these subjects).
DISEASES OF THE PERICARDIUM
Heart is encased by the pericardium which in normal states is thin, shiny and transparent and has two layers the visceral and parietal which enclose a pericardial sac that contains about 5 to 30 ml of clear straw-coloured fluid (transudate). The pericardium is lined by mesothelial cells and contains fat, fibrocollagen tissue and blood vessels in the wall.
Pericardial Effusion
The pericardial cavity can accumulate various kinds of fluid within it. The effusion may be in response to inflammatory diseases or it may occur without inflammation (Table 2.13).
Non-Inflammatory Effusion
Hydropericardium is the presence of clear straw-coloured fluid of low protein content as occurs in, e.g. congestive cardiac failure, myxoedema, hypoproteinaemia.
Haemopericardium is collection of blood or blood-stained fluid within the pericardial sac. This occurs in ruptured full thickness myocardial infarction, trauma, ruptured aneurysm of aorta and coronary artery, malignancy, tuberculosis, haemorrhagic disorders, etc.76
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Chylopericardium is accumulation of lymph (milky fluid) in the pericardial cavity. This is due to lymphatic obstruction of varying aetiology.
Chotesterol effusion though rare may occur in hypothyroidism.
Inflammatory Effusion
Pericarditis is an inflammation of the pericardium. Often there is an associated myocarditis when the term myopericarditis is applied. Pericarditis is associated with effusion which may be serous, purulent haemorrhagic or caseous in nature.
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Serous effusion
Accumulation of straw-coloured fluid may occur as a reaction in the initial phase of acute bacterial and viral infections. Viral pericarditis may result from either primary involvement of the pericardium or more commonly be affected secondary to pneumonia. The most common viruses implicated are ECHO viruses, coxsackie A and B, adenovirus and influenza virus. The pericardium retains its normal transparency and the fluid may resolve without any sequelae. Serous effusion occurs in a variety of systemic diseases including non-infectious conditions such as rheumatic fever, systemic lupus erythematosus (SLE), metabolic diseases and drug reactions (Table 2.13). This also results from generalised oedema due to cardiac, renal and nutritional causes.
Serofibrinous pericarditis may result from bacterial, viral or other infections, rheumatic fever, 77myocardial infarction, irradiation to the chest, uraemia, and tuberculosis. The reaction involves exudation of fluid and/or fibrin deposition. Fibrin may be variable in amount often covering the outer aspect of the visceral pericardium and the inner surface of the parietal pericardium. The latter surface appears finely granular or covered by irregular thin or thick strands commonly known as “bread-and-butter” appearance (Figs 2.48 and 2.49). The pericardium appears dull and opaque. Microscopically, the surface of the pericardium shows fibrin which appears as a mesh of homogeneous, pink material. The nature of the inflammatory response rests upon the underlying aetiology. Healing occurs by complete resolution when pericardial surfaces return to normal or the fibrinous exudate is infiltrated by inflammatory granulation tissue which becomes organised. This results in thickening and adhesions between the two layers of the pericardium (adhesive pericarditis). Clinically, fibrinous pericarditis is manifested by a friction rub which disappears when fluid accumulates in the sac.
Purulent pericarditis is a result of inflammation of the pericardium caused by pus producing bacteria such as staphylococci, streptococci and pneumococci and non-bacterial organisms such as fungi, and parasites. The infection reaches the pericardium either by direct extension from an adjacent infected focus, via the blood stream from a distant focus of infection, by direct introduction of infection of open wounds or at the time of surgical procedures.
The pericardial surfaces reveal a covering by yellowish, thick exudate. Often pus pockets are recognised. Varying amounts of purulent fluid may be present in the pericardial sac. Microscopically, inflammatory cell infiltration rich in neutrophils is seen admixed with fibrin and necrotic material. The fibrinopurulent material may extend to involve the myocardium, pleura or mediastinum. Healing is by organisation and complete resolution is unusual. This produces adhesions between the layers of the pericardium (adhesive pericarditis). Organisation of the inflammatory process may extend into other neighbouring structures producing adhesions which may lead to mediastinopericarditis.
Fig. 2.48: Fibrinous pericarditis. External surface of heart with reflected pericardium shows fibrin (arrows) deposition
Fig. 2.49: Serofibrinous pericarditis. External surface of heart shows numerous tags and deposits of fibrin
At times when the suppuration is marked and prolonged, organisation may produce marked thickening of the pericardium causing cardiac embarrassment (constrictive pericarditis).
Haemorrhagic pericarditis is characterised by the presence of blood or more often blood admixed with serofibrinous or purulent effusion. The common causes include tuberculosis, neoplasms in the pericardium, uraemia, acute bacterial and viral infections and bleeding diathesis. Masssive haemorrhage may cause sudden death. Common causes include rupture of an acute transmural myocardial infarct, ruptured aneurysm of the aorta and penetrating injuries to the heart and the great vessels. Organisation of haemorrhagic effusion may result in adhesive pericarditis.
Adhesive (obliterative) pericarditis Adhesion between the visceral and parietal layers of the pericardium leads to obliteration of the pericardial space and occurs as a result of organisation of serofibrinous and fibrinopurulent pericarditis consequent to bacterial or viral infections, rheumatic fever, tuberculosis, irradiation to the mediastinum and cardiac surgery. Adhesive pericarditis may be associated with fibrous adhesions between the pericardium and the mediastinum, pleura and diaphragm leading to mediastinopericarditis. Adhesions provide increased workload for the heart thus leading to cardiac hypertrophy and dilatation in some cases but serious cardiac embarrasement does not occur.
Constrictive pericarditis Healed pericarditis at times may cause marked thickening of both the visceral and parietal layers of the pericardium which becomes rigid and closely envelops the heart such that it mechanically interferes (constricts) with filling of the cardiac chambers. The most common underlying cause in the underdeveloped countries is tuberculous pericarditis. Latter occurs most commonly by extension from tuberculous foci in the lungs or the mediastinum or from a distant focus by the vascular route. Gross examination shows thickening of both layers of the pericardium by irregular fibrous strands (Fig. 2.50). Areas of caseation necrosis may be recognised. It may also result from pyogenic, viral infections and in a sizeable number of cases no cause may be recognised. Microscopically, pericardium shows marked thickening by dense collagen. Granulomatous inflammation with or without necrosis when present indicates tuberculous aetiology. Focal or extensive calcification of the thickened pericardium is not unusual. The thickened pericardium interferes with the diastolic relaxation and therefore impairs the filling of the cardiac chambers. The heart is often reduced in size, stroke volume is low and progresive congestive heart failure results. Pericardiectomy relieves the constriction.
Fig. 2.50: External surface of heart from a case of constrictive pericarditis to show thickened pericardium which has been separated (arrow)
Cholesterol pericarditis is a rare types of pericarditis often associated with myxoedema. It is characterised by the presence of cholesterol in the pericardial fluid. Haemopericardium of any aetiology may also show the presence of cholesterol in the fluid. Microscopically the thickened and hyalinised pericardium shows 79infiltration by chronic inflammatory cells, cholesterol crystals, foamy macrophages and foreign body type of giant cells.
Pericardial Tumours
Pericardium may be involved by both primary and metastatic tumours. As in the case of heart, metastatic tumours are more common, the primary site being from lung and breast in most cases. Metastases from melanoma, leukaemia and lymphoma are also frequent. Amongst primary pericardial tumours, mesothelial and pericardial cysts are the most common. Malignant pericardial tumours are rare and include fibrosarcoma, liposarcoma, haemangiosarcoma and others. Mesothelioma of the pericardium is rare.
Haemorrhagic pericarditis is a common manifestation of tumours of the pericardium. In some cases it may be extensive enough to cause cardiac tamponade.
TUMOURS OF THE HEART
Primary tumours of the heart are rare and much less common than metastatic tumours. About 75 per cent of cardiac tumours are benign in nature. Large pathological series indicate that the most common benign primary tumour of the heart is myxoma which accounts for about 30 to 50 per cent of all cardiac tumours. Other common benign tumours include lipoma, papillary fibroelastoma and rhabdomyoma. Any malignant mesenchymal tumour may occur in the heart the more common ones being angiosarcoma, rhabdomyosarcoma and mesothelioma (Table 2.14).
Benign Cardiac Tumours
Myxoma
Myxoma is the most common tumour of the heart occurring usually in the atria with almost 90 per cent of them being in the left atrium, in the region of the fossa ovalis. Myxomas have also been encountered in the right or left ventricle and the mitral valve. These may be solitary (over 90% cases) and rarely multiple, usually sporadic (over 95% cases) and occasionally occur as familial tumours. They may occur at any age being observed most often between the third and the sixth decade of life. Females are affected more often than males. Familial myxomas have an autosomal dominant inheritance pattern and may be associated with a syndrome comprised by a combination of several abnormalities namely lentigines or naevi, Cushing's syndrome, fibroadenoma breast, testicular tumours and pituitary adenoma.
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Pathology
Gross appearance is characterised by a polypoidal often pedunculated mass varying in size from less than 1 to 10 cm or more. The stalk when present is few mm in length and clearly merges with the atrial septum at its base. The external surface is pearly white, gelatinous, glistening, lobulated and at times has a fine papillary appearance. It is soft, mucoid or firm to feel (Fig. 2.51). Cut surface is pale white, gelatinous with yellowish or red brown foci in a large number of cases. Foci of calcification may be present. Microscopically, the surface of the tumour is thrown into folds which are lined by flattened to cuboidal cells.80
Fig. 2.51: Photograph of an excised left atrial cardiac myxoma. External surface is lobulated and myxoid
The most classical feature is the abundant, loose, pale, myxoid ground substance rich in acid mucopolysaccharides in which are embedded uniform round to oval cells, or stellate-shaped cells (Fig. 2.52). These cells are present singly, in clusters or more characteristically oriented around blood vascular spaces. Occasionally, myxoma cells may be arranged in a gland-like pattern. Other cellular infiltrates comprise varying amounts of lymphocytes, plasma cells, mast cells and numerous histiocytes many of which contain haemosiderin pigment. Latter is also present extracellularly. Foci of extramedullary haematopoiesis and calcification are also encountered occasionally. The stalk of the cardiac myxoma comprises of dense fibrocollagen tissue which merges with the endocardium of the chamber to which it is attached.
The nature of myxoma has been controversial. While some investigators believe that these are organising mural thrombi there is enough evidence which is in favour of it being a neoplasm. Thrombogenic origin appears unlikely as thrombi in the heart generally develop in individuals with an underlying heart disease, occur most often in the right atrium and the atrial appendages and eventually organise into fibrous tissue. All these features are lacking in a cardiac myxoma. Additionally, thrombi grown in tissue culture exhibit fibroblastic proliferation while myxomas in tissue culture elaborate multipotential mesenchymal cells. High incidence of abnormal DNA ploidy has been reported with familial, recurrent cardiac myxomas as compared with sporadic ones. Due to the aforementioned reasons and based on observations in immunohistochemical and electron microscopic studies cardiac myxomas are considered as true neoplasms rather than thrombi.
Fig. 2.52: Cardiac myxoma. Abundant myxoid matrix, myxoma cells arranged singly and in groups oriented around blood vessels are observed
Clinical features
Cardiac myxomas produce a variety of systemic manifestations including fever, malaise other constitutional features and arthralgias. The most common clinical presentation is related with signs and symptoms of mitral valve disease and embolic phenomena. Left atrial myxomas may behave as ball valves, thus, causing obstruction of the mitral valve orifice which may produce valve insufficiency, syncopal attacks and sometimes sudden death. Embolisation from cardiac myxoma may produce serious clinical complications.
Rhabdomyoma
This lesion is almost exclusively confined to the paediatric age group and is the most common 81primary tumour of the heart the vast majority occurring within the first year of life. These occur as multiple grey white nodules within the myocardium of either ventricle (commonly) or the atria. They vary in size from 1 mm or less to several cm in diameter. The mass may protrude into the ventricular cavity to produce obstruction of a cardiac chamber or valvular orifice. Microscopically, the lesions are circumscribed unencapsulated and distinct from the adjacent myofibres. They consist of large round to polyhedral vacuolated cells which are rich in glycogen. The classical cells are the “spider cells” which are large swollen cells with a central nucleus from which radiate thin cytoplasmic strands that extend to the cell membrane (Fig. 2.53). The cytoplasm in between these is either vacuolated or at times appears pink and granular and myofibril remnants can be often recognised and demonstrated on special stains. Ultrastructure examination of these cells reveal myofibrils, abundant glycogen and intercellular junctions resembling intercalated discs.
In about half the cases rhabdomyomas are associated with tuberous sclerosis a syndrome characterised by hamartomatous lesions in several organs, namely brain (epilepsy, mental retardation) skin (adenoma sebacum) and kidney (angiomyolipoma). The exact nature of this lesion is not known, but the most accepted view is that these represent a hamartomatous condition. Small multiple rhabdomyomas may be asymptomatic and discovered only incidentally. Large sized lesions, however, may protrude into the cardiac lumen and become symptomatic. They are amenable to surgical excision but complete removal is difficult due to multiplicity and deep location within the myocardium.
Fig. 2.53: Rhabdomyoma showing the classical large, round vacuolated cells with a central nucleus. Tiny cytoplasmic strands radiate from the nucleus
Papillary Fibroelastoma
These are rare tumours discovered incidentially either at autopsy or in surgically excised valves and generally produce no symptoms. They usually occur along the line of closure of valves involving the aortic, tricuspid, pulmonary and mitral valves in that order. On naked eye examination these appear as a cluster having delicate, multiple, papillary projections attached to the valvular endocardium by a short pedicle. Microscopically papillae lined by endocardial cells contain a core of dense connective tissue comprising acid mucopolysaccharide matrix in which are embedded variable amounts of elastic and collagen fibres and smooth muscle cells.
According to some workers, these are true tumours derived from the endocardium. Some believe that they represent a hamartomatous lesion whereas others have considered them to be organised thrombi.
Secondary Cardiac Tumours
Metastases to the heart may originate from a variety of neoplasms the most common among which are melanoma, lung cancer, leukaemias, sarcomas, breast cancer, lymphomas, oesophageal cancer and others in that order. Clinical manifestations of the primary tumour often overshadow cardiac involvement. However, extensive metastasis to the heart may be the primary reason for morbidity and mortality due to arrhythmias, CHF, haemorrhagic pericardial effusion producing cardiac tamponade and obstruction within the cardiac chambers or to the large blood vessels.82
Fig. 2.54: Endomyocardial biopsy from a case of rheumatic fever. A well formed Aschoff nodule is seen in the interstitium of myocardium
Fig. 2.55: Cardiac amyloidosis. Endomyocardial biopsy from a case of restrictive heart disease. Pink homogeneous material which stained positive for amyloid is seen in the subendocardial region and in the interstitium of the myocardium. Some of the myofibres are atrophic
ENDOMYOCARDIAL BIOPSY
Endomyocardial biopsy (EMB) is a well established procedure in the diagnosis of several cardiac disorders. In experienced hands it is an easy and safe technique with minimal morbidity and mortality. Indications of EMB include diagnosis and monitoring of myocarditis, cardiac transplantation, restrictive heart disease, anthracycline cardiotoxicity and other conditions (Figs 2.54 to 2.56). It is also performed in infiltrative disorders of the heart such as amyloidosis, haemochromatosis, storage disorders, etc. and to differentiate between constrictive and restrictive cardiomyopathy. One of the most important indications of EMB is in the diagnosis and monitoring of cardiac allograft rejection wherein multiple, sequential biopsies need to be performed at regular prescribed intervals.
Fig. 2.56: Endomyocardial fibrosis. Right sided endomyocardial biopsy reveals markedly thickened endocardium (E) in which a few myofibres and adipose tissue is entrapped
The biopsy is performed using a long sheath to introduce the biopsy catheter forceps into either of the ventricles. Biopsy procedure is generally carried out along with routine cardiac catheterisation or angiography. Under fluoroscopic guidance the catheter is introduced into the ventricle. Both left and right sides of the heart may be biopsied, but right ventricular biopsy is most commonly performed as it is easier and safer. Additionally, right ventricular biopsy is representative of heart diseases that are diffuse in nature. Left ventricular biopsy is performed only when the disease affects that chamber exclusively/predominantly. The routes for introducing the biopsy forceps include internal jugular vein and femoral vein for the right side and brachial and femoral artery for left side of the heart. Complications of the procedure are few and most can be managed conservatively. Mortality is virtually nil.83
Biopsy tissue can be subject to both simple and sophisticated techniques for diagnosis and understanding of pathogenesis of cardiac disorders. Careful and systemic evaluation of the biopsy material can provide vital information in the management of several cardiac diseases.
PATHOLOGY OF CARDIAC INTERVENTIONS
Cardiac Transplantation
Cardiac transplantation is an accepted therapeutic modality for end-stage cardiac disease. The introduction of cyclosporine a fungal metabolite having immunosuppressive properties and the development of the biopsy forceps to obtain tissue from the heart has completely revolutionised clinical cardiac allograft transplantation. Interpretation of sequential biopsies performed in cardiac allograft recipients have resulted in better management and survival of these patients.
Due to limited donor pool, recipient selection criteria have to be rigid and transplantation should be carried out for patients with end-stage cardiac disease refractory to conventional therapy. Indications of cardiac transplantation include cardiomyopathy, ischaemic heart disease, valvular disease, congenital heart disease and retransplantation.
Over 38,000 cardiac transplants have been performed worldwide with survival figures of 85 per cent, 65 per cent and 43 per cent at 1,5 and 10 years respectively. The major problems following transplantation are rejection and infections. Rejection in most instances is acute cellular mediated. Humoral mediated rejection may also occur. Most common type of infections after transplantation are cytomegalovirus and Toxoplasma gondii. These are constantly monitored in the sera and biopsy tissue of transplanted cases. Awareness, diagnosis, monitoring and management of these complications with appropriate drugs poses a challenge to the transplantation team. Other complications include toxicity of immunosuppressive agents and rarely, malignancy. Long-term survival is also influenced by graft vascular disease which affects infants, children and adults alike. A serious threat to cardiac transplantation is the availability of donors. To bridge this gap cross-species transplantation (xenotransplantation) is being researched actively with an aim to provide relief to the long waiting list of cardiac recipients. Permanent left ventricular assist devices may also provide for refractory heart failure and meet the donor demand.
Coronary Bypass Grafting
Coronary bypass grafting is the most common modality used for myocardial revascularisation. The saphenous vein or the left internal mammary artery are used as grafts. The grafts, however, are prone to develop narrowing of the lumen due to intimal hyperplasia characterised by the proliferation of smooth muscle cells and fibroblasts and atherosclerosis. Latter is the most common cause of graft failure.
Percutaneous Transluminal Coronary Angioplasty
Percutaneous transluminal coronary angioplasty (PTCA) is a common modality to dilate an artery narrowed by an atherosclerotic plaque. A balloon catheter which is inflated at the narrowed site induces breaking of the plaque and/or stretching of the vessel wall resulting in restoration of blood flow. Though the procedure is used widely it is associated with complications namely dissection, thrombus formation, and perforation of the vessel wall. The major drawback is progressive restenosis of the artery. Latter results from migration and proliferation of smooth muscle cells after balloon-induced intimal injury which leads to intimal hyperplasia of varying degrees. Various efforts to reduce restenosis include anticoagulants, antiplatelet agents, calcium channel blockers, growth factors and intravascular stents. Radioactive intravascular stents have also been introduced. Low-dose particle emission inhibit smooth muscle cells proliferation, thus, delaying or preventing restenosis.84
Angiogenesis for Revascularisation of Ischaemic Tissues
Recently much interest has been generated for growth of collaterals to increase perfusion to the ischaemic myocardium. This strategy is termed as therapeutic angiogenesis. Latter can be achieved by drugs, growth factors, somatic gene therapy and transmyocardial laser and non-laser revascularisation. This is a novel method which involves increasing the ventricular blood supply to the myocardium through channels created by laser. The created channels get endothelialised and maintain flow of blood.
A number of growth factors/cytokines can induce angiogenesis. Platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-B) are some of the important factors that stimulate angiogenesis or neovascularisation. Well-controlled clinical studies have demonstrated the beneficial role of growth factors in increasing perfusion to the ischaemic myocardium.
Somatic Cell Transplantation
Damaged cardiac muscle is replaced with non-functional scar tissue resulting in loss of contractility and heart failure. The common conditions in which cardiac muscle undergoes necrosis and or replacement are myocardial infarction and myocarditis. Somatic cell transplantation is a novel therapeutic approach to replace lost cardiomyocytes and thereby the contractile capacity of heart. Encouraging results have been achieved in experimental studies. Potential donor cells for transplantation are (i) fetal cardiocytes, (ii) skeletal muscle, and (iii) transformed embryonic stem cells.
CONGENITAL HEART DISEASE
SS Kothari
The study of congenital heart disease (CHD) is an excellent exercise in synthesis of structure and function. With the availability of various curative and palliative forms of treatment for these disorders, such study has become more relevant than before.
Aetiology
While the aetiology of CHD largely remains unknown, it occurs in about 6 to 8/1000 live births all over the world. In only 1 to 2 per cent of the patients with CHD an environmental factor can be incriminated.
The cardiac embryogenesis is completed by 55 days of gestation. Teratogens exposure to be responsible for cardiac defects should occur before this time. Thalidomide and more recently Vit A derivative-induced teratogenesis are lessons for the medical community. Even though teratogen exposure is a rare cause of CHD, their identification would guarantee no recurrence if the exposure is avoided. The important known teratogens are listed in Table 2.15. In another 3 to 5 per cent of cases, CHD occurs as a result of genetic disorder due to a single gene defect (autosomal dominant or recessive pattern) or due to chromosomal aneuploidy. Trisomy of a chromosome (i.e. three copies of a chromosome rather than two) could arise due to translocation or non-disjunction during meiosis. Trisomy-21 (Down's syndrome) is the most common genetic disorder resulting in cardiac disease and occurs in 1 in 600 pregnancies (Table 2.15).
Most of the CHD, however, occurs as the result of ill understood genetic—environmental interactions. The recurrence risks in these situations is generally about 2 to 4 per cent.
Cardiac Lesions in Congenital Heart Disease
In order of frequency the common lesions in patients with CHD are: (i) ventricular septal defect (VSD), (ii) tetralogy of Fallot (TOF), (iii) atrial septal defect (ASD), (iv) patent (persistent) ductus arteriosus (PDA), (v) coarctation of aorta, (vi) transposition of great vessels (TGV), (vii) others.
There are potentially numerous variations possible in patients with CHD. A systematic stepwise approach delineating the basic building blocks, viz. atrial, ventricular, great arterial alignment to one another simplifies the diagnosis.85
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The important anatomic features of these segments are outlined below.
The most important features of atria are morphology of their appendages. The right atrial appendage is broad or triangular while the left atrial appendage is narrow and tubular. In addition, the right atrial septal surface has septum secundum, it drains the superior vena cava and contains the sinoatrial and atrioventricular nodal tissues. The suprahepatic segment of inferior vena cava almost always drains into the morphologic right atrium. The left atrium has septum primum on its septal surface and receives pulmonary veins. In the normal situs solitus arrangement, the right atrium is to the right side of the left and converse is true for situs inversus. The viscera in normal position are usually accompanied by situs solitus atria. The ventricular mass, however, may be in the right or left thorax.
The morphologic right ventricle is recognised by coarse trabeculations on its septal surface, and three leaflet tricuspid valve which is attached more apically than the mitral valve and by the papillary muscles which have septal attachments. The morphologic left ventricle has smooth septal surface, well-defined papillary muscles that do not attach to the septum and bileaflet mitral valve. The outflow tract of right venticle has a well-defined infundibulum which results in pulmonary valve and tricuspid valve discontinuity in contrast to left ventricle. The infundibulum consists of an infundibular septum that separates the two great vessels, has a free wall, parietal band and a septal band that merges with the moderator band in the cavity. In the usual situs solitus and d-loop arrangement, the right ventricle lies anterior and to right of left ventricle. In the L-loop the reverse is true. The normal heart in situs inversus has a L-loop. Hearts in situs inversus with a d-loop are not normal. When right atrium attaches to right ventricle, it is concordant (Figs 2.57 and 2.58), and to left ventricle the alignment is termed discordant. Thus atrioventricular discordance and ventriculoarterial discordance in a patient would physiologically, not anatomically, restore the circulation to normal (corrected transposition of great vessels) (Figs 2.57 and 2.58).86
Fig. 2.57: When right ventricle is to the right of the left ventricle d-loop exists as in normal hearts. The mirror image of this arrangement is l-loop and occurs in normal right sided hearts in situs inversus. However, if right atrium is connected to left ventricle, a l-loop is present in left sided heart also (l-loop). This is atrioventricular discordance. The great arteries may be either concordant or discordant irrespective of loop arrangement
Fig. 2.58: Transposition of great vessels (uncorrected). There is atrioventricular concordance and ventriculoarterial discordance
Such considerations are useful in approaching hearts with complex defects. Disorders of situs organisation occur in visceral heterotaxy syndromes. Thus, intestinal malrotations, bilateral vena cavae, abnormal pulmonary venous drainage, superoinferior ventricles or other complex defects occur. Interestingly, splenic abnormalities (asplenia or polysplenia) and bilateral right sided or left sided lungs are also present with these.
Fig. 2.59: Fetal circulation. % refers to hemoglobin saturation. Other numbers indicate pressure in mmHg. SVC—superior vena cava; IVC—inferior vena cava; RV—right ventricle; LV—left ventricle; PA—pulmonary artery; PDA—patent ductus arteriosus; Ao—aorta
Fetal Circulation and Circulatory Changes at Birth
It is imperative to understand the fetal circulation in order to appreciate many clinical issues of CHD. The gas exchange at the placenta in fetus mandates a circulatory circuit that is different from adults. The venous blood returning from placenta is highly saturated with oxygen and it selectively streams to left atrium to perfuse developing brain and heart (Fig. 2.59). The lungs are collapsed and pulmonary vascular resistance is high. Most of the blood pumped by right ventricle to pulmonary artery (PA) bypasses the lungs through ductus arteriosus to descending 87aorta. The right ventricle pumps two-third of combined ventricular output and is thicker of the two ventricles at birth. The flow through aortic isthmus (aortic area between left subclavian and descending aorta) is less and any condition which decreases forward flow through aorta (e.g. mitral stenosis) is frequently associated with isthmic hypoplasia and coarctation. Conversely in lesions with decreased pulmonary blood flow which have larger than normal aortic flow, coarctation is rarely seen. Similarly, the premature closure of patent foramen ovale results in low blood flow to left heart and may account for hypoplastic left heart syndrome (marked underdevelopment of left ventricle).
With the first breath of the baby, the lungs expand. Partly because of mechanical factors and partly due to effects of increased oxygen tension within alveoli, the pulmonary vascular resistance falls. The ductus arteriosus also constricts as a result of effects of oxygen, local prostaglandins and other unknown factors. (The ductus can be kept patent with use of prostaglandin-E1). The placenta which imparted low resistance to systemic circuit is eliminated. As a result of these factors, the pulmonary blood flow and the left atrial pressure rises and the flap of foramen ovale closes. Within few hours, adult pattern of circulation is established. The pulmonary vascular resistance and PA pressure falls to adult range within 2 to 7 days in normals.
These sequence of circulatory changes at birth accounts for many clinical observations for example: (i) VSD murmur is not heard at birth (till PA pressure falls), (ii) abnormal coronary artery from pulmonary artery causes angina after 1 to 2 weeks (when PA pressure is low and perfusion therefore is inadequate), and (iii) many disorders that were compatible with normal fetal life are life threatening with closure of PDA (pulmonary atresia when ductus is the only mode of blood flow to lungs).
Congenital heart diseases can be grouped into:
- Shunt lesions
- Valvular disorders.
Shunt Lesions
Left to Right Shunts (L->R)
Blood, like other fluids flows from a high pressure to a low pressure area and follows the path of least resistance. Normally, pulmonary vascular resistance is much lower than systemic vascular resistance after the first week of life and therefore through any ventricular or aortopulmonary communication, blood flows from systemic to pulmonary circulation. These lesions where pulmonary blood flow exceeds systemic blood flow are said to have left to right shunts.
Two factors determine the amount of blood flow: (i) pulmonary vascular resistance, and (ii) size of the communication. If the communication is very small, this by itself leads to obstruction and lessens flow. However, in presence of large defects the pulmonary vascular resistance determines the shunt.
Consequences of L->R Shunt
Congestive heart failure
With a L->R shunt excessive, even torrential pulmonary blood flow results. This is responsible for tachypnoea and frequent chest infections in these patients. The excess of volume load is poorly tolerated by the left ventricle and congestive heart failure results. The right ventricle frequently serves as a conduit to extra blood flow. However, it also faces a higher than usual pulmonary artery pressure and therefore hypertrophies.
Growth retardation
Congestive heart failure, poor feeding and frequent chest infections lead to catabolic state and failure to gain weight.
Pulmonary arterial hypertension
Excess of blood flow in the lungs is accommodated by recruitment of pulmonary vessels not normally used. However, when the volume is large, the pulmonary artery pressure is increased. Initially the pulmonary arterial hypertension is solely due to increased flow and vascular resistance is normal or mildly elevated (hyperkinetic pulmonary arterial hypertension). However, persistently 88increased flow leads to organic changes in the pulmonary vascular bed. The shear stress of the shunt on the endothelium and other poorly understood factors lead to a series of reactions whereby the pulmonary vasculature gradually undergoes medial smooth muscle hypertrophy, fibrosis and thrombotic occlusive changes. The resultant increase in pulmonary vascular resistance may be irreversible. Due to increased pulmonary vascular resistance nearly equal to systemic vascular resistance, the left to right shunt reduces and eventually a right to left shunt with cyanosis results (Eisenmenger syndrome). It is now appreciated that such changes occur quite early in life and a surgical correction of defects should be undertaken before such changes have occurred.
For a patient with VSD or PDA a pulmonary vascular resistance index of 8 Wood units or more is considered high enough to render him inoperable. Such changes may occur as early as one year of age. These changes are accelerated in patients with transposition of great vessels and in patients of Down's syndrome. The increase in pulmonary vascular resistance resulting from venous obstruction or mitral stenosis are reversible after relief of obstruction, whereas the obstructive change of shunt lesions if established may progress despite closure of the defect. It is unfortunate that many patients with Eisenmenger's syndrome are still seen in the developing countries. This has practically become unknown in the developed countries because of early surgical closure of the L->R shunt lesions.
Infective endocarditis
The jet of the blood stream through the defect traumatises the endothelium. Any transient bacteraemia colonises the platelet aggregate formed at the jet lesion and forms vegetations. The risks of endocarditis are higher in smaller ventricular septal defects than larger ones. Endocarditis rarely occurs in patient with atrial septal defect because the pressure difference in the two atria is small and jets do not occur. Similarly, endocarditis is very rare in patients with Eisenmenger's syndrome.
Pathoanatomy of Left to Right Shunts (L->R)
Ventricular septal defect (VSD)
The ventricular septum has an interventricular component and an atrioventricular component resulting from the attachment of tricuspid valve more apically than mitral valve. The lesions in the area of atrioventricular septum are discussed seperately. The interventricular septum is conveniently considered to have: (i) an inflow or sinus component, (ii) a trabecular, and (iii) an outlet area. The area of the septum where these three components merge and abut on the central fibrous body is thin, membranous and is the most common site for a VSD.
Most often the VSDs are not confined to the area of the membranous septum but extend into the inlet, trabecular or outlet zone and hence are designated perimembranous VSD. The defects which are not bordering on the membranous septum but instead have a rim of muscle all around are muscular VSDs. Further these may be located in the muscular inlet, muscular trabeculae or the outlet zone. When the pulmonary annulus and aortic annulus directly forms the border of VSD, these are known as the subarterial type (supracristal VSD). Since the aortic cusps are unsupported, a higher incidence of aortic regurgitation due to cusp prolapse is manifest in these patients. Aortic regurgitation similarly occurs in patients with perimembranous VSD presumably due to venturi effects from the jet of VSD that causes prolapse of aortic cusp.
The VSD classification proposed has relevance to the surgical closure. The penetrating bundle of His lies in close relation to the membranous septum and is at risk of damage during VSD closure in the perimembranous type of VSD. It is remote from muscular or subarterial VSD.
Atrioventricular (AV) defects
The defects in the AV septum are associated with typical anatomical alterations in the valve morphology and in primum interatrial septum. These areas are linked embryologically and are perhaps derived from the endocardial cushions. The AV valve in this defect may be common, divided or cleft valve with varying degrees of regurgitation—common atrioventricular valve (Fig. 2.60).89
Fig. 2.60: Wide atrial septal defect—common atrioventricular (AV) canal. Common A-V valve is straddling ventricular septal defect
The inlet-outlet dimensions of the left ventricle are altered. The combination of lesions result in L->R shunt and valvar regurgitation. A relatively more rapid development of Eisenmenger state might occur in these patients.
Patent ductus arteriosus (PDA)
A persistently patent ductus connects the aorta just distal of the left subclavian artery to the left pulmonary artery. Normally the ductus closes within few hours functionally and by 2 to 3 months anatomically. The histology of a patent ductus differs from the normal ductus.
Incidence of PDA is higher in prematures, in females and in people living at high altitudes. Rarely, PDA may arise from the base of the innominate artery. Even in patients with right aortic arch, PDA is usually on left side.
Atrial septal defect (ASD)
Defect in the atrial septum can be: (i) secundum type, (ii) sinus venosus type, and (iii) primum type.
The secundum ASD is in the environs of the septum primum. The sinus venosus ASD may be at the junction of the superior or inferior vena cava with right atrium. The primum ASD is part of atrioventricular canal defects.
The shunt in ASD depends on the compliance of the ventricles, and since the right ventricle is much more compliant than the left ventricle, ASD usually shunts L-> R. This is not established at birth but only after fall in pulmonary artery pressure and involution in right ventricular thickness. Since the flow in ASD is usually at lower pressure, the obstructive pulmonary arterial changes do not usually occur before the third decade of life or so. Associated mitral valve lesion with ASD are common and result in much larger shunts. Anomalies of pulmonary venous drainage (right upper pulmonary vein to superior vena cava) with sinus venosus type ASD is common.
Clinical Recognition
The L->R shunt is generally not obvious at birth. With fall in pulmonary vascular resistance the shunt is established. In presence of a significant shunt, tachypnoea, tachycardia and by 2 to 3 months congestive heart failure results. Cardiomegaly is universal and its degree varies with the degree of shunt. With a PDA, a wide pulse pressure and palpable aorta in the suprasternal notch is seen. There is a continuous murmur at the second, third left intercostal space. The murmur may be only heard in systole once the pulmonary arterial hypertension is significant enough to abolish the shunt in diastole. In both VSD and PDA, excessive pulmonary flow is responsible for left ventricular S3 and mitral diastolic murmur whereas in ASD excessive flow causes a tricuspid flow murmur. The second sound is wide, fixed split in ASD, closely split in VSD and normally split in PDA with pulmonary hypertension. Thus this diagnosis of the type of 90defect causing L->R shunt is easily made on clinical examination.
Right to Left (R-L) Shunts
Pathophysiology of Right to Left (R-L) Shunts
When a part of systemic venous return finds access to arterial circulation without having traversed the lungs, a R->L shunt is said to exist. Consequently systemic arterial oxygen tension (PaO2) and haemoglobin oxygen saturation falls. Presence of 3 g or more of deoxyhaemoglobin in arterial blood leads to cyanosis. In response to systemic hypoxia, polycythemia occurs. The severity of hypoxia indirectly determines the severity of polycythemia but individuals vary in their response. Severe polycythemia predisposes to thrombotic infarction. Iron deficiency in the polycythemic individuals can exist resulting in many red blood cells (RBC) that are microcytic and hypochromic. Thus mean corpuscular haemoglobin concentration (MCHC) and serum iron are low. Such RBCs have increased viscosity and this further hampers the circulation and predisposes to thrombotic infarcts.
Brain abscess is a well-known complication of cyanotic patients. It usually occurs in patients older than two years and in those with severe cyanosis. Infective endocarditis can occur in jet lesions as in patients with L->R shunts. The pulmonary valve, right ventricle mural endocardium, aortic valve or tricuspid valve may be involved.
In patients with cyanotic heart disease and decreased pulmonary blood flow most patients would have a lesion that physiologically can be understood as a VSD with pulmonic stenosis. Tetralogy of Fallot (TOF) is the most common and prototype of this physiology. In such patients CHF does not occur unless additional load is imposed due to anaemia, systemic hypertension, aortic regurgitation, endocarditis or myocardial dysfunction consequent to severe long-standing hypoxia.
Episodic, marked reduction in pulmonary blood flow in patients with TOF often occurs during infancy and early childhood resulting in dramatic increase in severity of cyanosis. These cyanotic spells may result in cerebrovascular accidents or death, although commonly these are self-limited. The pathogenesis of these spells are incompletely understood but they all occur as a result of reduced pulmonary blood flow.
Pathoanatomy of R->L Shunts
A number of different anatomic lesions produce the same clinical picture of cyanotic heart disease and VSD PS physiology.
Tetralogy of Fallot (TOF)
This is the most common anomaly. Esentially the pathoanatomy results from anterior deviation of infundibular septum producing a large malaligned VSD, infundibular obstruction and as a result of the deviation, aorta arises from both ventricles above the VSD. The right ventricle is hypertrophied but not dilated (Fig. 2.61).
The other lesions producing a similar clinical picture (Fig. 2.62) are.
- Double outlet right ventricle with pulmonic stenosis. In this type the aorta is overriding the VSD more than in TOF such that more than 50 per cent of it arises from the right ventricle.
- Tricuspid atresia with VSD and pulmonic stenosis.
- VSD and pulmonic stenosis in atrioventricular and ventriculoarterial discordance (corrected transposition).
- Single ventricle and pulmonic stenosis.
Transposition of great vessels (TGV)
A different lesion from TOF that results in cyanosis and CHF is TGA. The great arteries are misplaced above the ventricles. Thus the aorta arises from right ventricle and pulmonary arteries from left ventricle. This results in two circulations in parallel (Fig. 2.58). Unless there is intercirculatory mixing at atrial, ventricular or great arterial level, survival is impossible. Rerouting the blood flow from the right atrium to left ventricle and from left atrium to right ventricle (Senning's operation) corrects the physiology. Alternatively, switching the arteries in their proper place (arterial switch operation) with transfer of coronary vessels restores the physiology as well as the anatomy.
Cyanotic heart diseases with increased pulmonary blood flow
More complex disorders that have increased pulmonary blood flow but mixture of systemic and pulmonary venous return result in cyanosis and CHF. These lesions do not have pulmonic stenosis and could result from a number of complex disorders like double outlet right ventricle (DORV) without pulmonic stenosis, single ventricle, tricuspid atresia, truncus arteriosus, total anomalous pulmonary venous return. Like in patients with L->R shunts, pulmonary vascular obstructive disease may result from excessive pulmonary blood flow (Eisenmenger's syndrome).
Valvular Heart Disease
Aortic Valve Disease
Normal aortic valve has three leaflets and three commissures. A valve with two leaflets (bicuspid) is the most common congenital heart disease and occurs in about 2 per cent of the population. Bicuspid valve results from fusion of two leaflets and has asymmetric closure. These valves are prone to wear and tear and may lead to aortic stenosis later on in life. A valve can rarely be stenotic at birth. Such valves may be even unicuspid with no commissures and have a diaphragm with small orifice. Aortic stenosis leads to left ventricular hypertrophy and eventually heart failure.
Pulmonary Valve Disease
Normal pulmonary valve is identical to aortic valve structurally. Pulmonic stenosis also could result from bicuspid inadequately opening pulmonary valve. Sometimes a dysplastic valve—thick sheet like, poorly mobile, results in 92obstruction. Such valves are commonly present in patients with Noonan's syndrome. Congenital pulmonic stenosis if severe may result in right ventricular hypertrophy and dilatation. Sometimes with severe stenosis, right ventricular dilatation may result in tricuspid regurgitation. Cyanosis from shunting of blood from right to left atrium across a patent foramen ovale may result.
Ebstein's Anomaly of Tricuspid Valve
The mitral or tricuspid valves are formed from their respective ventricles by a process of excavation and undermining. In the rare disorder of Ebstein's anomaly of the tricuspid valve (TV) the process of separation from the ventricles is incomplete. The TV is abnormal. The anterior leaflet is large. The septal leaflet is incompletely separated from the right ventricular septum and thus appears to be displaced towards the apex as compared to normals. The leaflets are variably tethered and may be obstructed. Tricuspid regurgitation is usually present. The portion of the right ventricle between the tricuspid annulus (the normal attachment) and the leaflet attachment (the abnormal site) is atrialised and poorly contractile. The right atrium is dilated. Cyanosis may result from shunting across patent foramen ovale or an atrial septal defect. The severity of this anomaly is variable. Ebstein's anomaly may result in death in-utero or may be compatible with a reasonable span of life.
Disorders of Conduction System
Normally the atria and ventricles are electrically insulated and an electrical impulse can travel from atria to ventricles only through the bundle of His. In few people (about 3%) strands of muscle fibres connect atria to ventricles and function as bypass tracts. These areas can serve as alternative pathways for impulse travel in either direction and may provide a substrate for re-entry and arrhythmias sometimes in life. Some accessory pathways exist in free wall of ventricles or in the septum and are more common in patients with heart defects (especially Ebstein's anomaly).
The normal connection from atrioventricular node via bundle of His to the right and left branches of Purkinje fibres is often different in hearts with congenital heart defects. A knowledge of variation in anatomy of conduction axis helps in avoiding damage to these structures during cardiac operations. Some of the lesions like corrected transposition of great vessels, endocardial cushion defects and single ventricle are known to develop complete heart block even without surgery. Also, in fetus of mother with systemic lupus erythematosus, autoantibodies (SS-Ro) cross the placenta and may cause congenital complete heart block.
DISEASES OF THE BLOOD VESSELS
Vascular system is an extensive network throughout the body comprising large elastic arteries, e.g. the aorta and its major branches, medium-sized muscular arteries, e.g. renal, coronary and cerebral arteries which continue as small muscular arteries, arterioles, capillaries and venules. Maintenance of patency and vascular resistance are essential for normal perfusion of the tissues.
Aorta is the major vascular channel and is over 1 cm in diameter. The media is composed of continuous rows of elastic fibres with few interspersed smooth muscle cells. The endothelial lining cells rest on the basement membrane and the subendothelial connective tissue. The adventitia is comprised by collagen and elastic tissue, nerves, lymphatics and blood vessels. Medium-sized arteries have a media rich in smooth muscle which is bound on either side by the internal and external elastic lamina. These laminae are ill developed in the large arteries (Table 2.16). The adventitia and outer part of media of the large and medium-sized arteries are fed by the vasa vasorum. As the arteries divide and extend distally, there is thinning of the media and intima. Important morphologic features of blood vessels are provided in Table 2.16.
Integrity of the vascular system is maintained by the endothelial cells which lines the entire vascular tree. Ultrastructure of the endothelium shows that the endothelial cells are attached to each other by tight and gap junctions.93
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This allows the endothelium to function as a semipermeable membrane for active exchange between blood and subendothelial tissues of vessel wall. The endothelial cell is an extremely versatile and a highly metabolic cell and is involved in a host of important functions. While on one hand the endothelium elaborates substances to provide a non-thrombogenic surface on the other hand, it secretes a variety of prothrombotic agents. The endothelial cell also participates actively in various immunologic reactions, inflammation and is one of the important contributor to the process of atherosclerosis. It reacts to various stimuli such as anoxia, chemicals, infective agents, haemodynamic alterations, blood flow pattern all of which result in changes in its structure and function.
Arteriosclerosis
The term arteriosclerosis implies hardening or rigidity of the arterial wall. It includes entities such as: (i) senile arteriosclerosis (Fig. 2.63), (ii) arteriolosclerosis (Fig. 2.63), (iii) Monckeberg's medial calcific sclerosis, (iv) hypertensive arteriosclerosis (Fig. 2.63), and (v) atherosclerosis.
Senile arteriosclerosis
Ageing produces changes in the media and intima. These are possibly induced by stress and strain that the vessel is subjected to throughout lifetime. Consequently the arteries become stiff in old age. Histologically, thickening of the intima due to increase in the elastic and collagen fibres with fibrosis of both intima and media is observed. These fibrotic rigid vessels are responsible for the age-related increase in the systolic pressure.
Arteriolosclerosis
This term encompasses two morphologic changes of arterioles: (i) hyaline arteriolosclerosis, and (ii) hyperplastic (proliferative) arteriolosclerosis.
Hyaline arteriolosclerosis
Hyaline arteriolosclerosis is seen histologically as hyalinisation of the arteriolar wall by a material that appears homogeneous and pink in hematoxylin and eosin-stained sections. Thickening of the wall may compromise the lumen. These morphologic changes in arterioles are seen in ageing, hypertensive individuals and in microangiopathy of diabetes mellitus.
Hyperplastic (proliferative) arteriolosclerosis
Hyperplastic arteriolosclerosis is characteristically associated with accelerated/ malignant hypertension. Morphologically, it is characterised by thickening of intima by loosely arranged layers of smooth muscle cells and fibroconnective tissue in a concentric and laminated fashion giving an “onion skin” appearance.94
Monckeberg's medial calcification
Medial calcific sclerosis is a degenerative, age-related deposition of calcification in the media of large and medium-sized muscular arteries of no clinical significance. The intima and the adventitia are free. Arteries most commonly affected are femoral, tibial, radial, ulnar and uterine arteries. Other visceral arteries may also be affected.
Hypertensive Arteriosclerosis
Clinically, hypertension is classified into primary (essential) or “benign” hypertension and accelerated or “malignant” hypertension. Blood vessels of all sizes show changes consequent to systemic arterial hypertension. The aorta and the large-sized arteries show thickening of media because of increased numbers and size of elastic and smooth muscle cells. Long-standing rises in pressure eventually cause hyalinisation of the media of the medium sized and arteries and the arterioles. Fibrous intimal thickening is also seen.
Changes in benign and accelerated phases of hypertension are characteristic and best appreciated in small-sized muscular arteries and arterioles of kidneys and other viscera.
Benign hypertension
Morphologic changes consist of changes in the small arteries and arterioles (Fig. 2.63).
- Small arteries show both medial and intimal thickening. Reduplication of the internal elastic lamina and fibrous thickening of the intima results in narrowing of vessel lumina. In later stages hyalinisation of the media may also occur.
- Small arteries and arterioles undergo progressive hyalinisation of the vessel wall which eventually involve the entire circumference. This change is commonly referred to as hyaline arteriosclerosis and arteriolosclerosis.
Malignant (accelerated) hypertension (Fig. 2.63)
Changes of accelerated hypertension are characteristically seen in arterioles and small-sized arteries.
- Fibrinoid necrosis of arterioles, glomerular capillary tuft and small arteries is classic of accelerated/malignant hypertension. The vessel wall shows a smudgy, homogeneous deep pink appearance (fibrinoid necrosis). This material stains positively for fibrin, immunoglobulins, complement and other proteins.
- The other morphologic change in the intima of small-sized arteries is seen as concentrically arranged collagen and smooth muscle cells giving an “onion skin” appearance.
Target Organ Damage
Hypertension exerts its effect on several organs or systems important amongst which are eyes, 95heart, blood vascular system, brain and kidneys.
Eyes
Examination of the fundus for vascular changes is a good index to assess the severity of hypertension (hypertensive retinopathy). Severity of vascular changes are generally graded. Grade 1 retinopathy is evident by narrowing of the arteriolar lumen, this progresses to thickening and narrowing of the retinal vessels which is visible as arteriovenous nicking (grade 2). Progressive changes in the retinal vessels include haemorrhages and exudates (grade 3) and finally papilloedema (grade 4) occurs. Grades 3 and 4 are indicators of malignant or accelerated hypertension.
Heart
Hypertensive heart disease is a common cause of cardiac morbidity and mortality. Left ventricular hypertrophy develops consequent to an increased systemic vascular resistance. The hypertrophic ventricle has reduced ventricular compliance thereby causing diastolic dysfunction which eventually leads to congestive heart failure. The heart is enlarged and overweight, average weight being between 450 to 550 gm. The left ventricle is thickened in a concentric fashion thus reducing the left ventricle cavity. When heart failure sets in dilatation of the chamber occurs. Microscopically, hypertrophic myofibres have an increased diameter and nuclear changes namely hyperchromasia, variation in size and shape and rectangular nuclei.
Blood vascular system
Hypertension accelerates the atherosclerotic disease process and therefore it is a major risk factor for cardiovascular diseases due to atherosclerosis namely ischaemic heart disease, cerebrovascular accidents, peripheral vascular disease and sudden death. Long-standing hypertension leads to thickening of the arteries and arterioles throughout the body. This is termed as arteriosclerosis and arteriolosclerosis.
Kidneys
In cases of long-standing hypertension, benign nephrosclerosis develops (Fig. 2.64). The changes affect the renal arteries, arterioles and result in atrophy of the renal parenchyma. In malignant/accelerated hypertension small arteries, arterioles and capillaries show fibrinoid necrosis of the vessel wall. The small arteries show concentric thickening of the wall due to smooth muscle cell proliferation. These vascular changes are designated as malignant nephrosclerosis.
Central nervous system
Atherosclerotic narrowing/occlusion of the cerebral arteries predispose to ischaemia, cerebrovascular accidents and infarction. Small arteries and arterioles show changes of hypertension. Malignant or accelerated hypertension presents as headache and vomiting which may progress to coma and death. This is referred to as hypertensive encephalopathy.
Aetiology
In about 95 per cent cases of hypertension there is no identifiable cause. This type is variably designated as primary, essential or idiopathic hypertension. In the rest of the cases hypertension is secondary (secondary hypertension) to end-stage renal disease, renal artery stenosis, co-arctation of aorta, cushing's syndrome, phaeochromocytoma, renin-secreting tumours and Conn syndrome (primary elevation of aldosterone levels).
Pathogenesis
Blood pressure in a normal individual is dependent upon cardiac output and systemic vascular 96resistance. Any condition causing alterations in the cardiac output and/or the vascular resistance result in variations of the blood pressure. Renal function and sodium haemeostasis are intimately related with maintenance of blood pressure.
The renin-angiotensin aldosterone axis is importantly linked with blood pressure as it maintains the cardiac output, peripheral resistance and sodium homeostasis all of which contribute to maintain blood pressure. This axis plays a role in both primary and secondary hypertension.
Renal artery stenosis, end stage renal diseases or salt restriction in the diet leads to increased secretion of renin by the kidney. Renin facilitates the conversion of angiotensinogen to angiotensin – I which is converted to angiotensin II by angiotensin-converting enzyme (ACE) which is located on the surface of endothelial cells. Angiotensin II is not only a potent vasoconstrictor but it also increases the sympathetic output and aldosterone release from the adrenal gland.
Primary (essential) hypertension
The cause of primary hypertension is unclear. Imbalance in sodium homeostasis including dietary sodium content, alterations in the membrane transport of sodium and sodium excretion, genetic predisposition and the renin-angiotensin system are some of the factors that have been implicated in the pathogenesis of primary hypertension.
Secondary hypertension
The mechanism of hypertension consequent to various end stage renal diseases is chiefly mediated by the renin-angiotension aldosterone system which results in increased blood and extracellular volume consequent to sodium retention.
Atherosclerosis
Atherosclerosis is a common cause of hardening of the blood vessels. It is a generalised, slowly progressive disorder of the aorta and the large-and medium-sized muscular arteries. It is characterised by an accumulation of lipid, smooth muscle cells and connective tissue material within the intima which is capped on the luminal aspect by fibrous tissue. This disease evolves through several morphologic stages namely fatty streak, fibrous plaque and various complicated lesions. Latter in the medium-sized arteries leads to narrowing or occlusion of the lumen resulting in several important clinical syndromes such as myocardial infarction, cerebrovascular accidents, peripheral vascular disease and ischaemia or necrosis in any of the organs or tissues whose vascular supply is affected by the process.
Fig. 2.65: Abdominal aorta along with kidney. Fatty streak and fibrous plaques cover the intimal surface
Pathology
The pathological lesions of atherosclerosis (AS) are: fatty streak, fibrous or fibrofatty plaque and complicated lesions.
Fatty streak
Fatty streak is a flat or slightly elevated usually liner lesion (Fig. 2.65) that contains accumulation of foam cells in the intima. The foam cells are derived from macrophages which are bloated up due to intracellular cellular lipid.97
Fig. 2.66: Specimen of heart and aorta which shows fibrous plaques and complicated atherosclerotic lesions
However, smooth muscle cells also contain fat. Fat is mostly intracellular.
Grossly, fatty streaks can be seen in children as early as one year of age. In children who die accidentally, significant number of fatty streaks are usually present in many parts of the arterial tree. However, these do not correspond to the distribution of atherosclerotic lesions seen in adults. However, it is possible that if fatty streak represents an initial lesion, other additional factors may contribute to the progression and distribution of more clinically significant lesions seen in later life.
Fibrous/fibro fatty plaque
The hallmark of atherosclerosis is the fibrofatty plaque which grossly appears as elevated pale yellow, smooth-surfaced lesions with irregular but well-defined borders (Figs 2.65 and 2.66). In smaller vessels like coronary and cerebral arteries, a plaque can be eccentric or concentric depending on its extent of distribution.
Microscopically, an initial fibrofatty plaque is an intimal lesion with an intact overlying endothelium. The central core of an atheromatous plaque contains necrotic debris with cholesterol crystals, an occasional foreign body giant cell and foam cells. The area between the lumen and the necrotic area, termed the fibrous cap contains smooth muscle cells, monocytes, lymphocytes, foam cells and connective tissue components. The foam cells are derived from macrophages and smooth muscle cells that have taken up lipids. Smooth muscle cells are also present diffusely throughout the plaque matrix. Various inflammatory and immunocompetent cells, especially T-cells are present in the plaque. The smooth muscles in an intimal plaque migrates from the media. Further proliferation is augmented by various growth factors such as fibroblast growth factor (FGF), transformation growth factor-beta (TGF-B), angiotensin II, etc. A fibrofatty plaque undergoes neovascularisation by sprouting of vessels from the vasa vasorum. These new vessels are fragile and may rupture giving rise to intraplaque haemorrhage and consequently expansion of the plaque. Few haemosiderin-laden macrophages are often present in atheromatous plaque which represent episodes of previous haemorrhage.
Complicated lesions (Fig. 2.66)
The term complicated plaque includes several lesions, namely ulceration or fissuring of the plaque, mural thrombosis, plaque haemorrhage, calcification and aneurysm formation.
Ulceration/fissuring results from focal denudation of the surface endothelium. In smaller arteries such as coronary arteries this has serious consequences. Autopsy observations suggest that majority of the plaques that undergo fissuring have a large lipid core and it is into this core that the tear in the cap allows blood from the lumen to enter. In coronary atherosclerosis, a large lipid core with a thin fibrous cap makes the plaque vulnerable for rupture. Plaques where the extracellular lipid pool exceeds 45 per cent of the vessel circumference are more prone for this complication. Additionally, a macrophage-rich plaque has more tendency to rupture. This is because macrophages can release elastase and collagenase, that together with free radical production may lead to plaque disruption. Rupture of a lipid-rich atheroma can lead to embolisation of atheromatous gruel into the distal circulation.98
Mural thrombosis results from denudation of the surface endothelium and disrupted blood flow around the plaque. Mural thombi may lead to complete occlusion of the lumen and when present in the proximal portion of a coronary artery it may embolise to more distal sites.
Calcification can occur within the central necrotic area and elsewhere in the plaque. The calcium crystals are often deposited on collagen fibrils and consist of calcium, phosphate and carbonate.
Aneurysm formation Atherosclerosis is an important aetiological factor for aneurysm formation. In severe atherosclerosis, the media beneath the intimal plaque very often becomes thin and attenuated. The weakened wall may show segmental dilatation forming an aneurysm. Once it is formed, stasis within the aneurysmal sac may lead to thrombus formation.
Pathogenesis
Atherosclerosis is an intimal disease of large-and medium-sized arteries. It is characterised by accumulation of lipids, smooth muscle cells and connective tissue within the intima. The progressive expansion of the lesions compromises the luminal area of medium-sized arteries and leads to the major complications including ischaemic heart disease, cerebrovascular accidents and gangrene of the extremities. Compression and thinning of the vessel wall predisposes to aneurysm formation. Cardiovascular disease due to atheroscleosis is a global problem and is the principal cause of mortality in the United States, Europe and much of Asia. It is fast emerging as a major problem in India and other developing countries. Atherogenesis is an intricate process and various hypotheses have evolved to settle the tissue.
Insudation hypothesis
According to this, the lipid derived from plasma lipoproteins enters the vessel wall and incites formation of an atherosclerotic plaque. High plasma concentrations of cholesterol, in particular low-density lipoproten (LDL) cholesterol, are one of the principal risk factors for atherosclerosis. Endothelial cells have receptors for both LDL and modified forms of LDL. Apart from the receptor-mediated uptake there can be non-specific uptake via micropinocytic channels.
Encrustation hypothesis
This theory envisages that small mural thrombi initiate the process of atherogensis. Organisation of these thrombi contribute to the formation of plaques and the gradual expansion of this lesion is the consequence of repeated episodes of thrombosis and organisation.
Reaction to injury hypothesis
Various pathophysiologic observations suggest that atherosclerosis results as a response to injury. It was believed that the initial event was denudation of the endothelial cells. Recent observations emphasise endothelial dysfunction rather than denudation as the primary mechanism. Whatever the nature of injury, it destroys the intact endothelial barrier to the circulating macromolecules. Additionally there is activation of leucocyte adhesion molecules which promote macrophage influx in the subendothelium.
Monoclonal hypothesis
Several studies have established the monoclonality of consitituent cells in atherosclerotic plaques. The monoclonality of the fibrous cap suggests the role of some unknown aetiological factors like circulating mutagens or oncogenic viruses as stimulus for growth.
Inflammatory hypothesis
This theory emphasises that the lesions of atherosclerosis represent a series of highly specific and molecular responses that can be described as an inflammatory disease. The cellular response and interactions in atherosclerosis are akin to those found in any chronic inflammatory fibroproliferative disease. Macrophages and various cytokines have a prime role not only in the evolution of the disease but also in the subsequent complications like plaque instability and rupture.
Haemodynnamic hypothesis
Atherosclerotic lesions usually occur at sites where there is maximum turbulence to the flow of blood. The fact that hypertension enchances the severity of 99atherosclerotic lesions supports the haemodyanamic hypothesis. Haemodyanamic forces are known to induce gene expression of several factors including growth factors like fibroblast growth factor-2 that promote atherosclerosis.
A Unifying Concept of Atherosclerosis
Endothelial dysfunction initiates the formation of an intimal lesion in atherosclerosis. Endothelial dysfunction alters normal homeostasis in endothelial cells. Thus any injury increases the adhesive capacity of the endothelium with respect to platelets and leucocytes. The injury also potentiates the procoagulant activity and increased endothelial permeability to lipoproteins and other plasma constituents. There is simultaneous upregulation of leucocyte and endothelial adhesion molecules that lead to migration of leucocytes in the arterial wall. If the inflammatory response fails to remove the offending agents, cellular traffic can continue indefinitely. In this perpetuating process, the inflammatory response stimulates migration and proliferation of smooth muscle cells from the medial into the subendothelial space which becomes a component of the lesion. If these processes continue unabated, there will be thickening of the arterial wall, which is compensated by gradual dilatation. So up to a certain limit, the arterial lumen will not be compromised a phenomenon known as “remodelling”. Continued influx of macrophages and lymphocytes and subsequent activation of these cells within the lesion lead to the release of hydrolytic enzymes, cytokines, chemokines and various growth factors. The enzymes eventually lead to focal necrosis which along with insudated lipid and cellular components yield an advanced atherosclerotic plaque having a central necrotic core and peripheral fibrous cap. At some point, the artery can no longer compensate by dilatation, the lesion now obliterates the lumen and compromises the blood flow. Once half of the lumen is encroached upon by the plaque, compensatory remodelling can no longer maintain the normal size of the lumen and stenosis supervenes.
As the lesion progresses, endothelial injury leads to the loss of normal anticoagulant properties of the wall. This results in mural thrombosis with release of platelet-derived growth factor (PDGF). This further accentuates smooth muscle proliferation and the secretion of matrix material. The thrombus once organised gets incorporated into the plaque and contributes to intimal thickening. The deeper part of the intima being poorly nourished undergoes necrosis which adds to the soft central core of an advanced atherosclerotic plaque.
Plaque progression is a dynamic process involving smooth muscle cells, macrophages, lymphocytes, matrix synthesis and degradation. Subsequently, plaque complications may develop, which include ulceration, fissure formation, haemorrhage, calcification and aneurysm formation. Continued plaque growth may occlude the lumen. Plaque rupture is of serious consequence as thrombosis and occlusion occur in advanced plaques.
Risk Factors
Many risk factors have been identified in the aetiopathogenesis of atherosclerosis.
Hypertension
An increase in blood pressure is consistently associated with an augmented risk of atherosclerosis and its complications. Concentrations of angiotensin II, the principal product of renin-angiotensin system are often elevated in patients with hypertension. Angiotensin II, a potent vasoconstrictor can cause smooth muscle hypertrophy and contraction. It also increases, smooth muscle lipooxygenase activity which can cause oxidation of LDL. In fat fed animals, hypertension enhances lipid accumulation in the vessel wall and leads to increased endothelial permeability to lipoproteins. In the absence of a fatty diet, hypertension has also been shown to augment the rate of intimal thickening.
Hypercholesterolaemia
This is a major risk factor for atherosclerosis and its complications. Cholesterol and triglycerides being insoluble are transported in the blood in combination with 100lipoproteins which comprise a central core of lipid with associated proteins (apolipoprotein). The major classes of lipoproteins are: chylomicrons whose chief constituent is triglycerides; very low density lipoproteins (VLDL), the major lipids being triglycerides and phospholipid; low density lipoprotein (LDL) carries triglyceride and esterified cholesterol; and high density lipoprotein (HDL) which is bound to phospholipid and cholesterol.
Sixty per cent of total cholesterol is in the form of LDL which is highly atherogenic. LDL, which may be modified by oxidation, glycation, agggregation etc. is a major cause of endothelial injury. Once LDL get trapped in an artery, they can undergo progressive oxidation and internalisation by macrophages through the scavenger receptors present on the surfaces of these cells. This leads to the formation of foam cells. Unlike the uptake of native LDL by the LDL receptors on macrophages, the uptake of oxidised LDL by these cells via scavenger receptors is not subject to negative feedback regulation. As the scavenger receptors are not downregulated this leads to massive uptake within the macrophages. Removal and sequesteration of modified LDL is a protective response in order to minimise its deleterious effects on endothelial and smooth muscle cells. Oxidised LDL is toxic to the vascular endothelium and can disrupt endothelial integrity. It is chemotactic for other monocytes and can upregulate the gene expression of macrophage colony stimulating factor derived from endothelial cells. Thus it may stimulate the replication of monocyte-derived macrophages and recruitment of new monocytes into the lesions.
Hereditary dyslipoproteinaemias
Certain genetic defects of lipid metabolism predispose to ischaemic heart disease in young individuals which run in families. These defects include: receptor defects, enzyme defects and apolipoprotein defects.
Familial hypercholesterolaemia
This is an autosomal dominant disease due to mutations in the LDL receptor gene which is located on the short arm of chromosome 17. It is characterised by severely elevated levels of LDL, xanthomas and premature atherosclerosis. In hymozygous form of the disease young individuals suffer from severe and rapidly progressive acute myocardial infarction.
Apolipoprotein defects include ApoA1 deficiency, abetalipoproteinaemia, Apo B-100 absence, Apo CII deficiency, ApoA1 and ApoE variants. Genetic variations in apoproteins are associated with altered lipid levels. Apoliporotein E is the chief constituent of VLDL. ApoE-deficient mouse model of atherosclerosis demonstrate human-like lesions of atherosclerosis and associated elevated levels of chylomicronus and VLDL remnants.
Enzyme defects in dystipoproteinaemias also give rise to hyperlipidaemias with variable degrees of atherosclerosis. The genetic defects are due to mutations in the genes controlling liproprotein lipase hepatic lipase and lecithin cholesterol acyltransferase production resulting in the corresponding enzyme deficiency.
Infection At least two types of infectious microorganisms are known to be associated with atherosclerosis. They are herpes viruses and Chlamydia pneumoniae infection. Both organisms have been detected in coronary atherosclerotic lesions and increased titres of these antibodies have been used as a predictor of further adverse consequences in patients with myocardial infarction. It is possible that infection combined with other intitiating factors may be responsible for atherosclerosis at least in some patients.
Smoking Atherosclerosis of the blood vessels is more severe and extensive in smokers. Cigarette smoking is a risk for atherosclerotic coronary heart disease. It has been shown that this risk declines significantly in ex-smokers. Smoking also enhances the effect of other risk factors such as hypertension and hyperlipidaemia.
Diabetes mellitus Atherosclerotic related vascular disease occurs early and is more extensive in distribution in diabetics as compared with non-diabetics.
Other factors Obesity, physical inactivity, stressful life and oral contraceptive drugs have an increased risk to develop atherosclerotic coronary artery/heart disease.101
Other major factors implicated in increased risk of developing atherosclerosis are the heredofamilial predisposition, increasing age and the male sex. Familial predisposition to an increased risk of atherosclerosis may also be related to other risk factors, e.g. hyperlipidaemia, hypertension and diabetes mellitus.
INFLAMMATORY DISEASES OF BLOOD VESSELS
Vasculitis is a clinopathological entity and comprises of a heterogeneous group of rare diseases characterised by inflammation and necrosis of the vessel wall including arteries, capillaries, venules and veins. Vasculitis may be either localised or more commonly it is generalised with multisystem or organs involvement. The inflammatory process often causes destruction of the vessel wall which may result in thinning, aneurysm formation of the vessel wall and thrombosis. Consequently this results in haemorrhage and/or infarction of the vital organs. There is considerable overlap in the clinical manifestations of the various types of vasculitis. Several pathologic findings are common to different vasculitides. Therefore morphologic findings in the tissues biopsy need to be correlated with the clinical presentation and laboratory findings to arrive at a precise diagnosis.
Aetiopathogenesis
Aetiopathogenesis of most systemic vasculitides is ill understood and appears to be multifactorial. However, only a few factors have been demonstrated to have a possible cause and effect relationship in some forms of vasculitis. The most usual pathogenetic mechanism of vasculitis is the immune complex-mediated vasculitis evidenced by deposition of circulating immune complexes often with complement activation, injury by antibodies and cell-mediated immunity. Though these may be demonstrated in several vasculitides, they are considered to be characteristic of small vessel vasculitis, e.g. leucocytoclastic vasculitis (hypersensitivity or allergic vasculitis), microscopic polyarteritis nodosa, Henoch-Schonlein purpura, allograft rejection, essential mixed cryoglobulinemia, systemic lupus erythematosus, (SLE), etc. Vasculitis may also occur due to direct invasion of vessel wall by antigens including infective agents. Role of cytotoxic antibodies to endothelium, cell-mediated immune reactions to cell wall antigens and anti-neutrophilic cytoplasmic antibodies (ANCA) has been recognised in vasculitides. Elevated plasma levels of von Willebrand factor antigen has also been reported in systemic vasculitis.
Antineutrophilic cytoplasmic antibodies (ANCAs) are commonly ultilised in the diagnosis of some types of vasculitis. These have affinity for proteins in the cytoplasmic granules of neutrophils and lysosomes of monocytes. Two patterns of staining can be detected by immunofluorescence in which normal neutrophils are used as substrate. Diffuse cytoplasmic staining (C-ANCA) indicates activity of the antibody to neutrophilic proteinase 3. This pattern of staining is sen in over 85 per cent cases of Wegener's granulomatosis. Staining can also be observed in the perinuclear location (P-ANCA). This pattern indicates activity against neutrophilic myeloperoxidase and is seen most commonly in cases of microscopic polyarteritis nodosa. ANCA titres are useful not only in the diagnosis of type of vasculitis, they also correlate well with disease activity. The titres fall in remission and rise with relapse and thus can be used in monitoring the clinical course of disease.
Classification
Classification of systemic vasculitides has been confusing due to its variable aetiology, pathology, pathogenesis, involvement of various sized vessels and a considerable overlap of clnical manifestations and pathologic findings. Classification of vasculitis can be based on the aetiology, size of the vessel affected, pathological changes and on pathogenesis of the lesion. Classification based on size of blood vessel involvement is given in Table 2.17.
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Polyarteritis Nodosa
Polyarteritis nodosa is a non-infective, acute necrotising vasculitis involving the small-and medium-sized muscular arteries. It has two major forms: (i) classical polyarteritis nodosa (PAN), and (ii) microscopic polyarteritis nodosa (MPAN).
Classical polyarteritis nodosa (PAN)
This is generally a multisystem disease characterised by necrotising inflammation of small-to medium-sized arteries to various viscera leading to weakness of vessel wall, aneurysm formation and thrombus formation in some cases. Classic PAN affects young adults, men more frequently than women (2:1). The clinical picture is variable and is often associated with constitutional symptoms such as malaise, fever and weight loss. Arthralgias, skin rash and features of peripheral neuropathy may also be encountered. Since multiple organs or systems are affected, the patient may present predominantly with symptoms pertaining to either involvement of the kidney (85%), heart (75%), liver (60%), gastrointestinal tract (50%) musculoskeletal (40%) or the central nervous system (25%).
Pathology
Involvement of the affected vessel is characteristically patchy and different stages of inflammation may be seen in an involved artery. Nodular indurations or aneurysms may be evident in the course of the affected vessel. Microscopically, extensive fibrinoid necrosis and inflammation involving all the layers of the artery-panarteritis is seen in earlier stages of the disease (Fig. 2.67). Necrosis affects either a part or the entire circumference of the vessel. Intense inflammatory cell infiltration of all layers comprised by neutrophils, lymphocytes, plasma cells, eosinophils and macrophages are seen. The internal elastic lamina may or may not be destroyed. The necrotic vessel wall becomes thin and may show a bulge (aneurysm) at the site of thinning. Aneurysms of visceral arteries can be clearly demonstrated on angiography. Thrombosis may occur. The lesions may heal at which time infiltrate is dominated by macrophages and plasma cells followed by fibrosis and scarring.
Fig. 2.67: Photomicrograph from kidney in a case of polyarteritis nodosa showing extensive fibrinoid necrosis with inflammatory cell infiltration and nuclear debris in the wall of branch of renal artery. The lumen shows an organised thrombus
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Arteritis accompanied with arterial occlusion results in ischaemic necrosis, haemorrhages or ischaemic atrophy of the corresponding organ. Clinically, renal involvement is common (85%) and manifests as haematuria, albuminuria, hypertension and renal failure. Gastrointestinal involvement due to mesenteric arteritis is frequent and manifests most commonly as abdominal pain. Underlying pathology includes infarction of the intestine and bleeding.
Aetiology of PAN is ill understood. Immune complex deposition may result from hepatitis B surface antigen, drugs, tumour antigens, etc. Circulating HBsAG-Ab complex has been reported to range between 5 and 40 per cent of patients of PAN. Immunofluorescence studies are negative for immunoglobulins and complement. In most cases, however, the circulating antigen is unidentified. Hypergammaglobulinaemia, leucocytosis and elevated erythrocyte sedimentation rate (ESR) has also been detected in some cases.
Microscopic polyarteritis nodosa (MPAN)
In MPAN focal, segmental necrotising vasculitis of the glomerular capillary tuft is the predominant lesion. The walls of the capillaries show fibrinoid necrosis and infiltration by polymorphs. Thrombosis is common. Extensive crescent formation in glomeruli may be seen in some cases. Consequently renal impairment is the most common clinical presentation. Microscopic 104haematuria and proteinuria is present in over 80 per cent of patients. Rarely frank haematuria may occur. Unlike classic PAN, multisystem involvement is insignificant in MPAN. Glomerular immune deposits of immunoglobulins and complement is unusual. Laboratory diagnosis is considerably helped by the presence of P-ANCA in most cases. C-ANCA has also been demonstrated in some cases.
Wegener's Granulomatosis
Wegener's granulomatosis is a syndrome characterised in its full-blown form by a triad of systemic necrotising vasculitis of small arteries, necrotising granulomatous inflammation of the lungs (100%), nasal cavity, paranasal sinuses and upper airways (90%) with associated focal or diffuse glomerulonephritis (80%). In the early stage the disease may be seen in a limited form when it involves the upper and lower respiratory passages. Some cases may present with isolated lung or renal involvement. Males are more frequently affected than females the peak incidence being in the fifth decade of life. High mortality is associated with untreated cases.
Pathology
Microscopically, vasculitis affecting small arteries, veins and capillaries often associated with necrotising granulomatous inflammation in the tissues is a classical finding. The acute stage is characterised by large areas of necrosis, epithelioid cell granulomas, multinucleated giant cells, dense infiltration by neutrophils, with abundant nuclear and cell debris, lymphocytes, plasma cells and macrophages. The necrotising process is often invasive and destructive and can destroy cartilage and bone resulting in nasal septal perforation which may extend into base of skull and orbit. The acute lesion may heal by scarring. Kidneys show a focal segmental necrotising glomerulonephritis. Crescentic glomerulonephritis may also be observed in fulminant disease.
Aetiology of Wegener's granulomatosis is unknown. It is believed to be an immune complex-mediated disease due to the observation of subepithelial immunoglobulin deposits on the glomerular basement membrane and/or circulating immune complexes in some patients. Cytoplasmic antinuclear cytoplasmic autoantibodies (C-ANCA) have been demonstrated in about 85 per cent of patients in the active phase of the disease. Serial measurements of C-ANCA titres provide a useful guide both for disease activity and to monitor the efficacy of immunosuppressive therapy. Addition of cyclophosphamide to steroids have improved the outcome appreciably and about 80 per cent of patients may survive over 5 years.
Churg-Strauss Syndrome
Churg-Strauss syndrome is characterised by a triad of systemic vasculitis, asthma and hypereosinophilia. Microscopically, necrotising vasculitis of small-sized arteries, capillaries and veins in various viscera is present. Infiltrate of eosinophils is a striking feature. Granulomas with giant cells can be seen. ANCA (both C-ANCA and P-ANCA) is positive in some cases.
Small Vessel Vasculitis
This important clinicopathological entity is characterised by necrotising vasculitis affecting capillaries, arterioles and postcapillary venules. Muscular arteries are not involved. The most common clinical manifestation of this group of vasculitis is cutaneous involvement including palpable purpura, ecchymoses, urticaria, vesicles, nodules, pustules, erosions and ulcerations. However, microvasculature of any viscera particularly joints and kidney can also be affected. Systemic manifestations are frequent and consist of fever, myalgia, arthralgias and abdominal pain.
Leucocytoclastic vasculitis
This type of small vessel vasculitis is encountered in various clinical conditions and is characterised by endothelial cell swelling, fibrinoid necrosis of vessel wall, marked infiltration by polymorphs, presence of nuclear fragments (leucocytoclasia) and extravasation of RBCs. Fibrin thrombi in affected vessel are frequent.
The most accepted mechanism of vasculitis is the deposition of circulating immune complexes 105which can be demonstrated by direct immunofluorescence. The disease process is often triggered by a hypersensitivity response to drugs, vaccinations, insect bite, fulminating viral and bacterial infections. This type of vasculitis is also known as allergic or hypersensitivity vasculitis.
Henoch-schonlein purpura (HSP)
This is a type of leucocytoclastic vasculitis that is characterised by necrotising vasculitis of small vessels of skin, kidney, joints and gastrointostinal tract. Common clinical manifestations include palpable purpura, acute abdominal pain and microscopic haematuria. It is most commonly seen in children from 4 to 8 years. Males are more prone than females. Recurrent episodes can occur along with spontaneous resolution. IgA deposition can be demonstrated in dermal capillaries and glomerular mesangium. IgA-ANCA has been reported in about 80 per cent patients of HSP. Several precipitating factors such as hypersensitivity to drugs, β-hemolytic streptococcal and viral infection of upper respiratory tract have been implicated.
Large Vessel Vasculitis
Main diseases in this group are giant cell arteritis (temporal and cranial arteritis), Takayasu's disease, aortitis associated with rheumatoid arthritis and ankylosing spondylitis (Table 2.17).
Giant cell arteritis
This entity is also referred to as temporal arteritis, cranial arteritis and granulomatous arteritis. It is a granulomatous disease of medium-and large-sized arteries occurring generally over the age of 50 years. Women are more predisposed than men. Cranial arteries particularly the temporal artery is most commonly involved. Rarely giant cell arteritis of aorta (giant cell aortitis) has also been reported. Headache with throbbing pain in the temporal region along with fever, malaise, visual symptoms, anaemia and elevated ESR are commonly associated.
The affected artery feels thick and tortuous. This is best visualised when the temporal artery is affected which is easily accessible and therefore often subject to biopsy for diagnosis of the disease. Microscopically, giant cell arteritis is characterised by panarteritis with granulomatous inflammation of media and intima. Infiltration by polymorphs and some eosinophils along with necrosis of medial smooth muscle is seen in the early stage of the disease. Lymphocytes, macrophages and giant cells is frequently observed in later stages and is fairly characteristic of the disease. Giant cells are frequently encountered and are classically located in relation to the fragmented internal elastic lamina (Fig. 2.68). Thrombus formation is common. The intima shows a marked thickening by fibrous connective tissue and may result in obliteration of the lumen. Fibrosis and scarring result in a rigid cord-like blood vessel that may be both visible and palpable.
Fig. 2.68: Photomicrograph of temporal artery biopsied in a case of temporal arteritis. Giant cells (arrows) are seen in relation to the internal elastic lamina which is destroyed. Intima (I) shows marked thickening leading to narrowing of lumen (L)
Aetiology of giant cell arteritis is unclear. Association with HLA-D4 has been described. Both humoral and cell-mediated mechanisms have been postulated. It is believed that the damaged elastic tissue of the elastic lamina may be antigenic and incites an immunological response. Antibodies to cardiolipin have been demonstrated in some patients, however, their role in causation of the disease is not clear. Excess of T-helper/inducer and low levels of CD8+T-cells in the inflammatory infiltrate has also been reported. Cytokines namely, IL-I, IL-6 and tumour necrosis factor (TNF) seem to play an important role.
Takayasu's Arteritis
This is a chronic inflammatory panarteritis of the large-and medium-sized arteries. This disease described by Takayasu in 1908 is variably known as pulseless disease, aortic arch syndrome, obliterative branchiocephalic arteritis, primary arteritis of the aorta and its branches, idiopathic medial aortopathy and arteriopathy, giant cell arteritis, non-specific aortoarteritis, occlusive thromboaortopathy and panaortitis.
Takayasu's disease though worldwide in distribution is predominantly an Oriental disease and reported largely from Japan, China, India and Srilanka. It affects mostly young females in the second to the fourth decades of life. Although the original cases highlighted involvement of the aortic arch and its main branches (pulseless disease), the disease process may affect any segment of the aorta and medium-sized arteries namely renal, cranial, mesenteric, coronary and the pulmonary artery branches. Involvement of the renal artery bearing segment of the abdominal aorta is common and renal artery stenosis consequent to this disease is the most common cause of hypertension in young individuals in India. Disease of the infrarenal segment of the aorta may extend to involve the iliac arteries producing ischaemia of the lower extremiies.
Pathology
Gross examination of the affected segment reveals thickening of all layers of the vessel wall. This causes narrowing or obliteration of the medium-sized arteries and aorta in some cases (Figs 2.69 and 2.70). The intimal surface is pearly white, irregular and “wrinkled”. Microscopically panaortitis or panarteritis is a common feature (Figs 2.71 and 2.72). Prominent perivascular cuffing by lymphomononuclear cells is seen in the adventitia. In the early stages, granulomatous aortitis/arteritis with transmural inflammation comprised by lymphocytes and macrophages may be seen. Media shows variable degrees of destruction evident as either focal or more commonly diffuse destruction and loss of elastic tissue in the aorta and smooth muscle in the medium-sized arteries. In the later stages, fibrosis and scarring of the media and/or the adventitia leading to obliteration of the lumen occurs. The intima is markedly thickened and displays loose fibroconnective tissue, abundant bluish myxoid ground substance and myofibroblasts. Inflammation is minimal. Superimposed thrombus may be present.
Fig. 2.69: Gross specimen of the arch of aorta in a case of Takayasu's aortitis showing thickening and occlusion of the arch vessels
Clinical features are related to the narrowing or occlusion of the arteries. Involvement of the aortic arch and its branches manifest as weak pulsations or “pulselessness” in the upper limbs, visual disturbances including blindness and neurologic deficits. Myocardial infarction and infarction of intestine may result due to disease of the coronary and mesenteric arteries respectively.107
Fig. 2.70: Specimen of ascending aorta in a case of Takayasu's aortitis showing marked thickening of the wall of aorta and narrowing of the lumen which is filled with a thrombus
Pulmonary artery is involved in about half of the cases.
Aetiology of this condition is not known. Hypersensitivity reaction to tuberculous antigen and an autoimmune inflammatory response to aortic tissue particularly elastic tissue have been implicated. Circulating immune complexes and antibodies to vessel wall components including endothelial cells have been reported. Cellular immune mechanisms may also be involved.
Thromboangiitis Obliterans—TAO (Buerger's Disease)
Thromboangiitis obliterans is a relatively uncommon, occlusive inflammatory disease of the medium-sized and small arteries and veins of the extremities especially the leg and feet.
Fig. 2.71: Photomicrograph of a case of aortoarteritis showing marked thickening of all layers of the aorta: A—adventitia, M—media, I—intima
Fig. 2.72: Photomicrograph from a case of aortoarteritis. Media shows focal destruction (M) and adventitia (A) is markedly thickened
It affects almost exclusively males who smoke heavily in third to fourth decade of life.
Pathology The affected vessel shows segmental involvement with healed and/or fresh thrombus. Microscopically, in the early stages, the vessel wall shows infiltration with predominantly polymorphs and microabscesses may be seen in some cases. The infiltrate also envelops the accompanying veins and nerves. Inflammation is often accompanied by thrombosis and thickening of the intima leading to obliteration of the lumen (Fig. 2.73).
Fig. 2.73: Photomicrograph of anterior tibial artery from a case of thromboangiitis obliterans. An organised thrombus is seen: M—media, IEL—internal elastic lamina, T—thrombus
Arterial obstruction and the often accompanying phlebitis produce symptoms. Ischaemia related pain is common due to the involvement of the nerves. The pain is exaggerated on walking and on exercise which is relieved by rest (intermittent claudication). Progressive and long-standing ischaemia gives rise to more severe ischaemic changes such as gangrene with ulceration of the skin.
Aetiology of TAO is unknown. Cigarette smoking is an important predisposing factor. Clinical remissions of the disease have been documented on cessation of smoking. Possible causative mechanisms of smoking include hypersensitivity reaction to tobacco protein, endothelial injury leading to local reactions of inflammation and thrombosis, and hypercoagulability of blood contributing to thrombosis. Genetic factors are also reported to predispose to TAO. An increased prevalence of HLA-A9 and HLA-B5 antigens and hypersensitivity to collagen types II and III have been demonstrated in some patients with Buerger's disease.
Kawasaki Disease (Mucocutaneous Lymph Node Syndrome)
Kawasaki disease is an acute, necrotising vasculitis of young children and infants occuring most commonly in the first two years of life. Although most widely prevalent in Japan, it is worldwide in distribution. It is characterised by high fever, rash, conjunctival and oral lesions and non-suppurative lymphadenitis. Acute necrotising panarteritis of the medium-sized arteries with aneurysm and thrombus formation is common. Coronary artery involvement occurs in about 70 per cent of the patients and extensive arteritis, thrombosis, and ruptured aneurysm of this artery is a common cause of mortality. Myocardial infarction may also occur. Microscopically, necrosis and extensive inflammation often producing thinning of the vessel wall with aneurysm formation is seen. Thrombosis is frequent. Fibrosis with luminal stenosis is seen in the healed stage. Kawasaki disease is usually self-limiting.
The exact aetiopathogenesis is unclear. Possible factors that may contribute to its occurrence are a genetic predisposition, infections with parvovirus-B19 and toxic agents. Several immunologic abnormalities have been documented in these individuals. Autoantibodies to activated endothelial cells have been reported in acute phase of the disease.
Infective Arteritis
Inflammation of the vessel wall may be caused by infective organisms namely bacteria including tubercle bacilli, fungi, parasites and other organisms. It occurs commonly either by direct invasion of the vessel from an adjacent infected focus, e.g. abscess, necrotic tuberculous focus or an area of necrotising acute inflammation or less frequently by a hematogenous spread of infection from infected thrombi (infective endocarditis) and septicaemia.109
Following invasion, there is inflammation and necrosis causing destruction and thinning of the wall which may result in formation of aneurysms (infective or mycotic) or rupture of the vessel wall. Inflammation favours vascular thrombosis which leads to ischaemia contributing to further necrosis of the tissue.
ANEURYSMS
An aneurysm is a localised dilatation of the blood vessel due to thinning/weakening, and/or destruction of the wall. Aneurysms may occur in any artery of the body but are most common and of great clinical significance in the aorta. The wall of the aneurysm itself may be composed of all or most layers of the vessel wall (true aneurysm) or only of fibrous tissue (false aneurysm). Latter is formed consequent to traumatic leakage of blood from the artery which is contained by perivascular tissues.
Certain terms have been applied to describe aneurysms based upon aetiology, location and shape. Based on the shape/etiology of the aneurysm the following types are recognised.
- Fusiform aneurysm (Fig. 2.74A) is a symmetrical outpouching of the entire circumference of a vessel that is spindle shaped. The circumference and the length of this type of aneurysm is variable and may involve large extents of the abdominal aorta
- Saccular aneurysm (Fig. 2.74B) is a sac-like dilatation that protrudes from one side of the artery
- Berry aneurysm (Fig. 2.74C) is commonly encountered in the small arteries of brain
- Racemose (circoid) aneurysm is a complex of intercommunicating small arteries and veins.
- Dissecting “aneurysm”/haematoma (Fig. 2.75) results when blood enters and displaces the layers of the blood vessel wall to form a parallel column of blood/haematoma.
- Mycotic aneurysm is a result of destruction and weakening of vessel wall by infective organisms.
Aetioloy
Weakening of the wall may be acquired or there may be congenital structural defects in the media of the vessel. Atherosclerosis is the most common and important cause of aneurysm of the aorta.110
Fig. 2.75: Diagram depicting dissection haematoma. The vessel wall is split and occupied by blood DA = Dissecting aneurysm; L = Lumen; M = Media
Other causes include cystic medial necrosis (dissecting haematoma), syphilis and trauma-induced dilatation of the vessel. Infections of the vessel wall by bacteria, fungi and other infective organisms commonly produce aneurysms (mycotic). Non-infective vasculitides such as polyarteritis nodosa and Kawasaki disease are associated with aneurysm formation. Berry aneurysms are most common in the cerebral vascular tree and are a result of congenital defect in the vessel wall.
Atherosclerotic Aneurysm
The commonest cause of aortic aneurysms is atherosclerosis. These are most often located in the abdominal aorta and the common iliac arteries though, the other parts of the aorta and its branches may also be involved. These aneurysms are more common in males after the age of 50 years and the frequency increases with advancing age. Associated hypertension is seen in about half the cases. Shape of this type of aneurysm is mostly fusiform (Fig. 2.74A) and only occasionally saccular (Fig. 2.74B) forms are seen. They are variable in length and width and may assume large proportions when they involve the entire length of the abdominal aorta.
Pathology
Microscopically, wall of the aneurysmal sac consists of all layers of the aorta which are distorted/destroyed, compressed and replaced by fibrous tissue. Remnants of elastic tissue of the media are only recognised. The intima shows atheromatous plaques and fibrosis. Superimposed thrombosis is common.
Diffuse and extensive complicated atheromatous involvement of the aorta (ulceration, calcification, thrombosis) leads to compression and thinning of the media which forms the basis of the lesion. The aneurysmal sac provides for stasis and thrombosis which may fragment and embolise to distal vessels producing ischaemia of the extremities. Large aneurysms may compress adjacent structures and produce pressure effects. The vessel wall may become attenuated and rupture producing extensive haemorrhage which when unattended to is fatal.
Syphilitic Aneurysms
Aneurysms secondary to syphilis are now uncommon due to effective treatment of this disease. These are classically located in the ascending and arch of the aorta where the causative organisms lodge due to the rich vascular and lymphatic network in this area. Involvement of the aortic valve is commonly associated. This leads to dilatation of the valve ring producing aortic valve incompetence which in turn leads to left ventricular hypertrophy and dilatation. Syphilitic aneurysms are caused by inflammation and destruction of the wall of the aorta. The disease process may encroach on to the coronary ostia and cause ostial stenosis.
Pathology
Grossly, intima has an appearance of the bark of a tree. It is pearly white, irregular and wrinkled. Latter appearance is due to thickened portions of intima alternating with normal intima. Microscopically, inflammation of the adventitia affecting predominantly the vasa vasorum is striking. The vasa vasora show a concentric thickening producing endarteritis obliterans. Perivascular cuffing by lymphocytes and plasma cells is often present. Destruction of the elastic and muscle tissue of the media consequent to both ischaemia and inflammation followed by scarring is commonly encountered. This results 111in weakening of the wall which may then become dilated. The dilated segment is usually saccular (Fig. 2.74B) in shape. Syphilitic aneurysms like atherosclerotic aneurysms may also assume large proportions. These are true aneurysms and thus all layers of the aorta are recognised in the aneurysmal sac. Fibrosis of all the layers with scarring which also involves the intima is seen in long-standing cases. Thrombus formation is common within the aneurysmal sac.
Aneurysms of the thoracic aorta become symptomatic due to pressure effects. Compression of the mediastinal structures may also result in superior vena cava syndrome. Erosion of the vertebra, sternum and ribs may result in pain. In the event of involvement of the aortic valve, aortic incompetence may result leadin to marked left ventricular hypertrophy and dilatation. In addition to these effects, the aneurysm may rupture and produce massive and fatal haemorrhage.
Dissecting Aneurysm
In a dissecting aneurysm blood from the lumen enters and dissects the vessel wall. The dissection extends along the length of the artery thereby creating a false blood filled channel within the wall of the blood vessel eventually leading to an intramural haematoma (Fig. 2.75). Thus intramural dissecting haematoma is a more appropriate term than dissecting aneurysm. The condition may occur at any age but is most often encountered in the fifth and sixth decades of life, men being affected more often than women. Associated hypertension is present in vast majority of cases. The onset is sudden and if untreated the mortality is high due to extensive haemorrhage or compression of vital organs and structures.
Dissection is generally (in more than 95% cases) initiated by an intimal tear in the ascending aorta which is 3 to 4 cm in length and is oriented transversely or obliquely (Fig. 2.76). Dissection of the blood occurs commonly between the inner two-third and outer third of the media and proceeds in both directions, i.e. proximally towards the heart and distally along the arch and the abdominal aorta. The process may involve the coronary arteries, branches of the aortic arch, renal and mesenteric arteries and even extend into the iliac arteries. If the patient survives, haematoma is formed and endothelialisation of the cavity (false lumen) occurs. Microscopically, varying degrees of degenerative changes are seen in the media of the aorta. There is fragmentation of the elastic tissue and the muscle and elastic fibres of the media are interrupted and replaced by pale bluish mucoid material. This appearance is commonly referred to as “cystic medial degeneration”. Inflammatory cell infiltration is lacking (Fig. 2.77).
Fig. 2.77: Photomicrograph from the aorta showing large pools of mucinous material in the media (cystic medial necrosis)
The aetiopathogenesis of this condition is related to two major factors: (i) weakening of the vessel wall, and (ii) hypertension which is associated in over 90 per cent cases. Weakening of the wall of aorta is attributed to the change in the media known as cystic medial necrosis or Erdheim's medial degeneration. The causes of cystic medial necrosis are not known. But similar morphologic changes in the muscular elastic tissue of the media are characteristic of Marfan's syndrome, an autosomal dominant disorder of connective tissue formation in which mutation of the gene encoding fibrillin-1 on chromosome 15 has been recognised. Fibrillin is one of the components of the extracellular matrix found in periosteum, corneal stroma, suspensory ligament, aortic media and other tissues. This defect in part may explain various manifestations in Marfan's syndrome. It is likely that cystic medial necrosis also represents a biochemical defect in the collagen, elastin and proteoglycans that leads to weakness of the connective tissue of the aorta.
Rupture of a dissecting aneurysm leading to haemorrhage is the usual cause of death. Rupture may occur into the pericardial cavity resulting in cardiac tamponade and sudden death. It may rupture into the mediastinum, left pleural space and the retroperitoneum. Extension of dissection into the coronary artery may result in massive myocardial infarction and involvement of arch vessels causes cerebral insufficiency. As is understandable, most of these events are fatal. Mortality and morbidity is much reduced by prompt recognition and management of this condition.
DISEASES OF VEINS
Veins have a much thinner wall as compared with arteries, and are therefore more prone to extrinsic compression, inflammation and invasion by tumours. Unlike in the arteries three layers of the vein are not clearly demarcated and no internal and external elastic laminae are recognised. The intima is thin and lined by endothelial cells with little subendothelial connective tissue. Media is composed of few smooth muscle cells seperated by collagen fibres. Most veins possess valves which are best developed in the legs. These prevent back flow of venous blood. Veins also show some changes of ageing wherein eccentric or concentric thickening of the intima develops. Luminal narrowing is uncommon. In the initial stages prominent fibromuscular tissue is seen in the intima which undergoes hyalinisation. This change is also termed as phlebosclerosis.
Phlebothrombosis and/or thrombophlebitis and varicose veins are important diseases of the veins.
Phlebothrombosis and Thrombophlebitis
Phlebothrombosis is primary thrombosis of the vein with none or very mild inflammation. Thrombophlebitis on the other hand is primarily inflammation of the vein with subsequent thrombus formation. Both these conditions, however, usually coexist. Important factors implicated include endothelial damage, changes in the blood constituents and vascular stasis. Some of the clinical conditions that predispose to thrombosis include congestive heart failure, prolonged bed rest or immobilisation of the limbs, pregnancy, postoperative states and malignancy.
The vast majority of venous thrombosis affects the calf veins deep vein thrombosis (DVT) which have associated thrombophlebitis and phlebothrombosis. Embolism is a dreaded complication of leg vein thrombophlebitis and in about 95 per cent cases pulmonary thromboemboli originate from the veins of the leg. Phlebitis may result when veins get trapped in a suppurative inflammatory focus as in the large veins in the skull and dural sinuses in middle ear infections or bacterial meningitis, uterine veins in puerperal sepsis or infections in the abdominal cavity which may lead to portal pylephlebitis. The veins show inflammation and undergo thrombosis with suppuration. These infected thrombi may fragment and enter either the circulation to produce pyaemia or get impacted in a blood vessel and cause septic infarcts and abscesses in the affected organ.113
Varicose Veins
Varicose veins is an abnormal dilatation and tortuosity affecting either a small group of veins or a diffuse dilatation of the entire venous system of the leg. Any vein in the body may undergo dilatation, but the most common site is the superficial veins of the leg particularly the long saphenous vein and its tributaries. Varicose veins develop in about 10 to 20 per cent of the general population. Incidence increases with age the peak occurrence being in the fourth and fifth decades of life beyond which age, it may affect 50 per cent of individuals in varying severity. Beyond the third decade of life women are affected four to five times more often than men particularly women who have gone through pregnancies. Pressure of the gravid uterus on the iliac veins favours venous stasis in the leg veins.
Varicose veins is known to have a familial tendency due to a possible hereditary structural weakness of the wall of the vein and/or venous valves. Obesity is another factor that contributes to the increased incidence of varicosity. The most important factor in the formation of varicose veins is increased intraluminal pressure in the leg veins which is directly related to the posture. Even normally the pressure in the veins is several times greater in the erect posture than in the recumbent position. Prolonged standing without much muscular movement causes dilatation of veins and consequently incompetence of the venous valves and thus marked increase in the intraluminal pressure.
On examination affected veins are dilated, stretched, tortuous and nodular. Due to the prolonged stretching and dilatation, the venous valves not only become incompetent but are also fibrosed and atrophic. There is irregular thinning and atrophy of wall of the vein resulting in tortuosity. In later stages fibrosis of the wall and the venous valves develops. Thrombosis is common. Organisation of thrombi and their incorporation into the wall produce intimal fibrous plaques or calcification. Microscopically, variation in the thickness of the wall is present. Prominent smooth muscle is seen in the thickened areas while in the dilated segment the wall is thin and shows few atrophic muscle and elastic fibres and fibrosis. Intima is thickened due to subintimal fibrosis and incorporation of thrombi into the wall. Prolonged venous stasis of the leg veins leads to congestion, oedema and thrombosis. The overlying skin suffers ischaemia and dermatitis and ulceration may follow.
Oesophageal Varices
These are tortuous and dilated veins at the lower end of the oesophagus and cardia of the stomach. These are a complication of portal hypertension of any aetiology particularly cirrhosis of the liver. High portal pressures lead to distension and opening up of anastomoses between the systemic veins and the portal system at the lower end of the oesophagus. Rupture and haemorrhage from oesophageal varices is one of the common causes of mortality in cirrhosis.
Haemorrhoids
Haemorrhoids are varicosities of the haemorrhoidal venous plexuses. These may be located inside (internal haemorrhoids) or outside (external haemorrhoids) of the anal sphincter. The former is a result of varicosity of the submucosal internal haemorrhoidal venous plexus that drains into the portal venous system while the latter are varicose veins of the inferior haemorrhoidal plexus which empties into the internal iliac vein. As in varicosities elsewhere, these also result from venous obstruction caused by increased intra-abdominal pressure as in pregnancy, rectal tumours, portal hypertension, constipation and straining over stools. Haemorrhoids may bleed extensively. Other complications include thrombosis and ulceration.
Varicocele
Varicocele is varicosity of the pampiniform plexus of veins of the spermatic cord and is consequent to venous stasis aided by gravity forces and prolonged standing.114
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In addition, it may also, result from increased pressure on the spermatic veins as in intra-abdominal tumours or any lesion which exerts pressure on the inferior vena cava or the renal vein into which the testicular veins drain.
TUMOUR AND TUMOUR LIKE CONDITION OF BLOOD VESSELS (Table 2.19)
Tumour Like Conditions of Blood Vessels
Arteriovenous Aneurysm (Fistula)
An arteriovenous aneurysm or fistula is an abnormal communication between an artery and a vein. This communication exists either as a developmental anomaly or is acquired when there is injury or in inflammatory necrosis of an adjacent artery and vein. Sometimes the arteriovenous communication may consist of a complex of tortuous and dilated arteries and veins with multiple interconnections present as a large pulsatile swelling. This is commonly termed as circoid or racemose aneurysm.
Berry Aneurysm (Fig. 2.74C)
Berry aneurysm is the most common type of aneurysm encountered in the cerebral arteries of the circle of Willis particularly at the branching sites. Their rupture leads to subarachnoid haemorrhage which is often fatal. Berry aneurysm possibly represents a developmental structural defect in the wall of the atery.
Vascular Ectasias (Telangiectatic Conditions)
Vascular ectasias represent a group of vasoproliferative conditions possibly congenital in origin (hamartomatous) presenting most commonly as focal red lesions in the skin and mucous membranes and rarely also associated with visceral involvement.
Naevus Flammeus
Naevus flammeus is a cutaneous telangiectatic, reddish coloured lesion commonly known as “port-wine” stain. It usually manifests in early childhood and increases in size gradually with age. Microscopically, prominent dilatation of vessels is present in the dermis.
Hereditary Haemorrhagic Telangiectasia
Hereditary haemorrhagic telangiectasia also known as Osler-Weber-Rendu or Osler's disease is a rare disorder transmitted as an autosomal dominant trait of high penetrance. It is characterised by multiple telangiectasia of the skin, mucous membrane and viscera that are present at birth. The lesions are superficial punctate spots present in the skin and mucosa of oral cavity, lips, gastrointestinal, respiratory and urinary tracts and in the liver, spleen and brain. The usual clinical presentation is bleeding from 115the involved sites which increases in frequency and severity with age. Microscopically, prominent dilated blood vessels are seen in the affected tissues. Arteriovenous fistula develops in some cases.
Angiomatosis (Multiple Hemangiomatous Syndromes)
Angiomatosis includes a heterogeneous group of rare disorders comprised by multiple, diffuse haemangiomatous lesions associated with other congenital malformations.
von Hippel-Lindau syndrome is a rare autosomal dominant disorder in which haemangioblastomas are present in the cerebellum and retina along with cysts in the pancreas, kidney or liver.
Sturge-Weber syndrome an uncommon entity and is also known by the name encephalotrigeminal angiomatosis. It is characterised by naevus flammeus on one side of the face in the distribution of the trigeminal nerve along with ipsilateral retinal and leptomeningeal angiomatosis. These lesions are often associated with hemiplegia, epilepsy, and mental retardation.
The Maffucci syndrome is a rare congenital disorder in which angiomatoses are associated with dyschondroplasia and skeletal deformities.
Benign Tumours
Haemangiomas
Hemangiomas are common tumours of infancy and childhood and constitute about 7 per cent of all benign tumours. These are generally superficial having a predilection for the head and neck region. However, they may occur in any location including visceral organs.
Capillary haemangioma
It is the most common type of haemangioma and is composed of a mass of blood vessels. They are usually well defined and occur as single or multiple, small or large, flat or slightly raised bright red to purple lesions of variable size. The common sites of location are the skin, subcutaneous tissue and mucous membranes of the oral cavity and lips. Internal viscera may also be affected. Microscopically, capillary haemangiomas are well circumscribed and composed of a dense branching network of capillaries which have prominent endothelial cell lining. Groups of endothelial cells may exist as solid masses with none or very little attempt at formation of lumen (Figs 2.78 and 2.79). Haemosiderin pigment when present represents bleeding due to rupture of these vessels.
Fig. 2.78: Capillary haemangioma. Notice the numerous vascular slits amidst groups of mesenchymal cells
Juvenile haemangioma (strawberry angioma)
It represents a type of capillary haemangioma that occurs in newborns. They grow rapidly in the first few months of life, begin to decrease in size at 1 to 3 years of age and completely regress over a period of few years in 75 to 90 per cent of cases. Histologically, the early lesions are highly cellular along with moderate mitotic activity. Plump endothelial cells line vascular spaces. Regression is marked by diffuse interstitial fibrosis.
Cavernous haemangioma
This type of haemangioma is characterised by large thin walled vascular spaces (cavernous), separated by thin and scanty fibroconnective tissue. These are most commonly located in the skin and/or subcutaneous tissue of the face, neck and extremities. They may also be found in viscera namely liver, bones, stomach and the small intestine.116
Lesions may be single or multiple and have a purple or dark red and spongy appearance. Microscopically, large thin endothelium lined blood-filled spaces separated by thin connective tissue are characteristic of this type of haemangioma. Due to the large sized blood spaces, thrombosis, fibrosis and haemorrhages may occur.
Epithelioid haemangioma
Also known as angiolymphoid hyperplasia with eosinophilia and histiocytoid haemangioma is a lesion that occurs in the second to fourth decade of life and is distributed in the head and neck region predominantly in the vicinity of the ear. The lesion is circumscribed and located mostly in the dermis or subcutaneous tissue. It is characterised by vascular structures lined by plump endothelial cells that appear epithelial like and an inflammatory infiltrate rich in eosinophils. Lymphoid aggregates with germinal centres can also be seen (Fig. 2.80).
Glomus Tumour (Glomangioma)
Glomus tumour is an uncommon benign tumour of the glomus body. Latter is comprised by small arteriovenous anastomoses, modified smooth muscle cells with abundant nerve supply. Normally glomus bodies are distributed throughout the skin but are particularly frequent in the distal portions of the fingers and toes. The tumour is most commonly located in the fingers beneath the nailbeds and is typically associated with paroxysms of severe pain. These lesions are small and range from 2 mm to 1 cm in diameter. Other sites include the palm, wrist, forearm and foot. It has also been reported in unusual sites including areas where normal glomus body is lacking. Glomus tumour appears as a rounded, firm, redblue painful nodule. Microscopically varying proportion of vascular channels, smooth muscle and glomus cells are present. Glomus cells are uniform round to oval cells having a rim of eosinophilic cytoplasm which have features typical of smooth muscle on electron microscopy (Fig. 2.81). Non-myelinated nerve fibres are also present frequently. Depending on the predominant histologic component these may be categorised as glomangioma, glomangiomyoma and glomus tumour.
Fig. 2.80: Angiolymphoid hyperplasia. Numerous blood vessels lined by plump endothelial cells are seen surrounded by an infiltrate of lymphocytes and eosinophils
Intermediate-Grade Tumours
Haemangioendothelioma
Haemangioendotheliomas are vascular neoplasms believed to have an intermediate biologic behaviour between haemangioma and angiosarcoma.117
Fig. 2.81: Glomus tumour. Groups of uniform round to polyhedral cells arranged around thin vascular spaces are seen. Hyalinised stroma is present in between the groups of cells
These are most often located in the skin, subcutaneous tissue, but may also affect the spleen and liver. Different types of haemangioendothelioma have been recognised.
Epithelioid haemangioendothelioma
It is a rare neoplasm arising from the medium and/or large sized blood vessels of any age group and rarely in children. This tumour is comprised by small groups and/or cords of plump or slightly spindle-shaped epithelioid or histiocytoid endothelial cells interspersed with vascular channels in a hyaline or myxoid stroma. In foci these characteristic cells may be seen to line well-formed vascular channels. Small intracellular lumina seen as clear spaces or vacuoles can be recognised in some tumour cells. In a small proportion of cases nuclear atypia, mitotic activity and necrosis can also be seen. Metastasis has been reported in cases with atypical features.
Due to the morphologic appearance of the plump endothelial cells, epitheliod haemangioendothelioma can often be mistaken for a metastatic carcinoma. Similar tumour has been reported in the lung, bone and the liver where they are often multifocal. In the lung epithelioid haemangioendothelioma closely simulates intravascular bronchiolo-alveolar carcinoma. Awareness of the lesion along with ultrastructural and immunohistochemical evaluation confirm the endothelial nature of the tumour cells. The lesion may follow a benign or a malignant clinical course. Most tumours are cured by excision, however, recurrence and metastases have been documented in some cases.
Spindle cell haemangioendothelioma
This lesion is well documented as a low-grade angiosarcoma with features of both cavernous haemangioma and Kaposi's sarcoma. Additionally, epithelioid endothelial cells are present which differentiates this lesion from Kaposi's sarcoma. Though locally recurrent it is a non-metastasising lesion.
Endovascular papillary angioendothelioma
It is a rare vascular tumour described by Dabska. It occurs in skin or subcutaneous tissues of mostly infants and young children. The tumour is comprised by large vascular spaces lined by cuboidal to columnar cells. In foci the endothelium is thrown into papillary folds which have a hyaline core. The tumour cells often show vacuoles in their cytoplasm. A characteristic feature is the presence of lymphocytes both within the tumour and the perivascular spaces. Tumour cells express factor VIII-related antigen and UEA-markers for endothelial cells. This tumour is known to metastasise but despite this it has a good prognosis.
Malignant Vascular Tumours
Angiosarcoma (Haemangiosarcoma; Malignant Endothelioma)
Angiosarcoma is a rare malignant tumour of the endothelial cells. These may occur at any age and both sexes are equally affected. Angiosarcomas may occur anywhere in the body, however, they are most frequently located in skin, subcutaneous tissue, liver, breast and bone. Grossly, the early lesions may be small, painless reddish nodules which may progress to large, ill-defined fleshy tumour masses often with extensive areas of haemorrhage and necrosis.118
Pathology
Microscopically, varying degrees of differentiation may be seen. While in some areas capillary haemangioma-like appearance is seen in other foci vascular channels lined by plump anaplastic endothelial cells are present. In still other areas, poorly differentiated lesions comprised by solid clusters of polyhedral cells or spindle-shaped cells resembling malignant connective tissue tumours with indistinct vascular channels may be encountered (Fig. 2.82). In the latter foci, pleomorphism, anaplasia, abundant mitoses, haemorrhage and necrosis are frequent. In such lesions, endothelial origin of the tumour needs to be confirmed by ultrastructural examination and immunohistochemical staining for endothelial cell markers namely factor VIII-related antigen or ulex europaeus agglutinin I (UEA). Angiosarcomas are highly malignant tumours showing both local invasion and distant metastases.
Angiosarcoma of the liver is of some interest due to its documented association with exposures to arsenic (pesticide), thorium dioxide or thorotrast a radioactive contrast material which was used prior to 1950, and vinyl chloride which is used in the production of plastics. A long latent period between the exposure to these agents and a cause and effect relationship in the development of angiosarcoma is well documented. Tumours are often multicentric and may occur concomitantly in the liver and spleen. The gross and microscopic appearances and biological behaviour of hepatic angiosarcoma is identical to that described in the preceding section.
Angiosarcoma of the breast is a rare tumour but it deserves a mention because although it is a highly malignant tumour the histological appearance may be totally bland and bear a close resemblance to capillary haemangioma. A high index of suspicion and extensive sampling will reveal features of a malignant neoplasm.
Haemangiopericytoma
Haemangiopericytoma is a rare neoplasm arising from the pericytes which are located in the basement membrane of the wall of the capillaries, arterioles and venules. The tumour may occur at any age, in either sex and in any site. However, haemangiopericytoma is most commonly located in the lower extremities and the retroperitoneum. The size of the tumour is variable measuring either less than 1cm in diameter or attaining large proportions. Histologically, tumour consists of thin vascular channels surrounded by tightly packed spindle-shaped or polyhedral cells arranged in a flowing fashion in between the vascular channels. Mitoses is variable and their number is a useful prognostic criterion. Four or more mitotic figures per 10 high-power fields usually indicate a fast growing tumour. Electron microscopic studies of these tumours have revealed their origin to be from the pericytes. Most of the large sized tumours not only recur but metastasise frequently to the lungs, bone, liver and lymph nodes.
Fig. 2.82: Photomicrograph of an angiosarcoma showing round to polyhedral cells filling a space. Nuclear pleomorphism is present
Kaposi's Sarcoma (KS)
Kaposi's sarcoma is a malignant lesion of endothelial cells presenting as plaques and nodules in the skin of the lower extremities. Involvement of the mucosal surfaces and viscera is also well documented. Several forms of the disease having specific features have been recognised: (i) classic Kaposi's sarcoma, (ii) lymphadenopathic Kaposi's 119sarcoma, (iii) transplantation-associated Kaposi's sarcoma, and (iv) AIDS-related Kaposi's sarcoma.
Classic Kaposi's sarcoma also known as the European or sporadic form occurs in elderly men (sixth or seventh decade). Multiple cutaneous lesions consisting of dark reddish plaques or nodules develop in the lower extremities. Involvement of internal viscera in the absence of skin lesion is uncommon. Classic Kaposi sarcoma is commonly associated with a second malignant tumour such as leukaemia, lymphoma or multiple myeloma.
Lymphadenopathic Kaposi's sarcoma In contrast to the classic variety this type occurs predominantly in young adults and children and is characterised by generalised lymphadenopathy, involvement of multiple viscera and an aggressive clinical course.
Transplantation-associated Kaposi's sarcoma Kaposi's sarcoma is one of the aftermaths of organ transplantation who are on prolonged immunosuppression therapy. Its occurrence in renal transplant patients is well documented. Both skin and internal organs are involved. Reduction of immunosuppressive therapy leads to some degree of regression of lesions.
AIDS-related Kaposi's sarcoma The human immunodeficiency virus (HIV-I) produces immunodefeciency and increased risk of developing various opportunistic infections and tumours. Kaposi's sarcoma has been found to occur in an epidemic form in young homosexual men. Besides skin, gastrointestinal tract and other internal organs may be affected.
Pathology
Regardless of the clinical type of Kaposi sarcoma, the histological appearances, are identical. The earliest stage is characterised by thin walled vascular channels along with infiltration by lymphocytes and plasma cells. At this stage the lesion closely simulates a capillary haemangioma and caution needs to be exercised during interpretation. Infiltration by lymphocytes and plasma cells is also seen. As the lesion progresses to the plaque stage, the extent of vascular profliferation is increased and may occupy the entire dermis. The vascular channels are interspersed with spindle-shaped cells arranged in fascicles that resemble a fibrosarcoma. Slit-like spaces are interspersed within the spindle cells. Extravasation of red blood cells and haemosiderin is frequently observed. In some cases hyaline globules may also be seen both intracellularly and extracellularly (Figs 2.83 and 2.84).
Fig. 2.83: Kaposi's sarcoma. Tumour cells are arranged in flowing bundles. Groups of polyhedral cells are enclosed
Fig. 2.84: Kaposi's sarcoma. Several capillaries are enclosed within the tumour. Extravasation of red blood cells is noted
Clinical behaviour of Kaposi's sarcoma is quite variable. However, AIDS-associated Kaposi's 120sarcoma has a rapidly progressive clinical course and high mortality.
SUPPORT READING
- Anderson RH, MaCartney, FJ, Shinebourne EA et al (Eds): Paediatric Cardiology Churchill Livingstone: London 1987.
- Braunwald E: Heart Disease: A Textbook of Cardiovascular Medicine (5th ed) Prism Books: Bangalore, 1997.
- Burke A, Farb A, Virmani R: Atlas of Cardiovascular Pathology WB Saunders: Philadelphia, 1996.
- Burke A, Virmani R: Atlas of Tumour Pathology: Tumours of the Heart and Great Vessels AFIP: Washington DC, 1996.
- Donald C Fyler (Ed): Nadas’ Pediatric Cardiology Jaypee Brothers: New Delhi, 1992.
- Freedom RM, Beneox LN, Smallhorn JF (Eds): Neonatal Heart Disease Springer Verlag: London 1992.
- Robertson WB, Anderson RH, Becker AE: The cardiovascular system—general consideration and congenital malformation. In Symmers W-StC (Ed): Symmers Systemic Pathology Churchill Livingstone: Edinburgh, 10 (A): 1993.
- Silver MD: Cardiovascular Pathology (2nd ed) Churchill Livingstone: New York, 1991.