Abstract
This chapter deals with inflammatory disease affecting the heart, both disease confined to the heart and inflammatory disease where the heart is affected as one among many other tissues. Myocarditis and its classification and investigation are detailed. Rarer forms including eosinophilic disease and giant cell myocarditis are also included. Endocarditis, both infective and non-infective, is discussed. Systemic inflammatory disease such as lupus, systemic sclerosis, rheumatic disease and sarcoid are also illustrated. Aortic inflammatory disease including Takayasu disease is described.
8.1 Introduction
Inflammatory diseases of the myocardium are important causes of morbidity and mortality and a frequent cause of myocardial biopsy [1]. In the setting of heart transplantation infectious complications are a serious threat to the survival of the graft. Allograft rejection is itself an inflammatory reaction but will be discussed separately in Chapter 14. Inflammatory disease of the heart is rarely confined exclusively to one compartment; thus, myocarditis is frequently associated with pericarditis or involvement of the endocardium, albeit of lesser severity than in the myocardium. Pericarditis is discussed separately in Chapter 11.
8.2 Myocarditis
The term myocarditis is defined differently depending on whether it is being used clinically, radiologically or pathologically. Clinically, there is no universally accepted definition of acute myocarditis [2]. There is wide variation both in symptoms and in their severity. Symptoms may be shortness of breath, chest pain, arrhythmia, gastrointestinal symptoms, fever and myalgia. At the most severe end the disease may present with cardiogenic shock or sudden death. There may be ST and T wave changes on ECG, impaired function on echocardiography and elevated blood troponin levels.
Pathologically, myocarditis is defined as an inflammatory cell infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of the ischaemic injury associated with coronary artery disease [3]. The diagnosis can be made on endomyocardial biopsy [1] or on the whole heart at autopsy [4]. It is generally assumed to be a diffuse process, but the inflammatory infiltrates can be patchy and there is an element of chance as to whether an area of inflammation is actually biopsied [5].
There are no reliable figures for the incidence in children. There is a slight male preponderance [6]. Children are said to have a more fulminant presentation [7].
Myocarditis may be caused by drugs, toxins, infectious agents or an immunological reaction (Table 8.1). Many cases are idiopathic (approximately 50%), the cause simply being unknown. Sometimes a combination of factors is involved, as when a viral infection initiates an autoimmune reaction [2]. The inflammatory process may be confined to the heart or may be part of a more generalised inflammatory reaction, e.g. rheumatic fever or systemic lupus erythematosus. Most cases of myocarditis in which the aetiology is identified are infectious in origin with viral myocarditis being by far the commonest category [8]. During many viral illnesses there are subtle changes in ECG and there may be associated subclinical cardiac functional disturbance, sometimes with elevated troponin levels. From this it is inferred that there is a mild inflammatory reaction within the heart muscle that resolves completely. The commonest virus causing myocarditis is coxsackie B virus [9]. Infection with these viruses is particularly common in infants. Approximately 20% of cases of dilated cardiomyopathy show evidence of coxsackievirus RNA by PCR [10]. Most viruses causing disease in man have at some time or other been reported as being responsible for myocarditis. Other viruses causing myocarditis include Influenzavirus [11], human immunodeficiency virus [12], cytomegalovirus [13,14], adenovirus [15], herpes simplex virus [16] and human herpes virus 6 [17]. Cardiovascular problems associated with HIV infection, including left ventricular dysfunction and increased left ventricular mass, are common and clinically important indicators of survival for children with HIV [11]. In utero infection with parvovirus B19, while usually causing anaemia leading to hydrops, may cause myocarditis by direct infection of the myocardium with resulting hydrops and intrauterine death [18]. Parvovirus B19 infection is also increasingly being recognised as a cause of myocarditis and cardiac dysfunction in children [19,20].
| Aetiology | Cell type | Clinical type |
|---|---|---|
| Virus | Lymphocytic | Acute |
| Bacteria | Giant cell | Fulminant |
| Fungi | Eosinophilic | Chronic |
| Rickettsia | Granulomatous | |
| Spirochaetes | ||
| Protozoa | ||
| Drugs, chemicals | ||
| Allergy, autoimmune | ||
| Collagen disease | ||
| Kawasaki disease | ||
| Sarcoidosis | ||
| Unknown | ||
Clinical myocarditis depends on a complex interplay between the infecting virus and the T-cell response of the host. It is noteworthy that many cases are associated with immunosuppression [13,17]. Myocarditis may present with non-specific clinical features of progressive cardiac dysfunction or with dilated cardiomyopathy [2]. It is also a recognised cause of sudden unexpected death in both children and adults [4]. About half of all cases of sudden death due to myocarditis in children occur in infants less than 1 year of age [4].
8.2.1 Macroscopic Pathology
In fatal cases, or following transplant, the macroscopic appearance of the heart is usually described as resembling dilated cardiomyopathy; there is frequently a small pericardial effusion, the ventricles are dilated and the cut surface of the myocardium has a blotchy appearance (Figure 8.1A,B). There may be areas of frank necrosis or of epicardial or endocardial haemorrhage. In almost 40% of cases of children dying suddenly due to myocarditis, there is no macroscopic cardiac abnormality (Figure 8.2), and the heart weight is normal in the majority of cases [4]. Explanted hearts post-myocarditis may show areas of myocardial necrosis and dystrophic calcification with or without residual patchy inflammatory infiltrate (Figure 8.3). Otherwise, they resemble dilated cardiomyopathy (Figure 8.4). Where the heart appears otherwise normal, the presence of a small to moderate pericardial effusion may cause suspicion of underlying myocarditis.
(A) A ten-year-old who died on extracorporeal life support following a diagnosis of myocarditis caused by parvovirus B19. The heart is opened to display the left ventricular outflow tract. The left ventricle is dilated, and the papillary muscles and the interventricular septum have a blotchy and haemorrhagic appearance.
(B) A three-year-old boy who died suddenly following a short upper respiratory illness. There was florid myocarditis. No virus was identified. A transverse section at the mid-ventricular level of the left ventricular wall shows patchy pallor and hyperaemia.
Figure 8.2 Macroscopically normal heart in myocarditis. Female infant who was found dead. The heart is opened to display the left atrium and left ventricle. It is macroscopically normal. Histologically there was myocarditis. No virus was identified.
Figure 8.3 Explanted heart with myocarditis. An infant with Enterovirus myocarditis who underwent cardiac transplant. The explanted heart is cut in a simulated four-chamber view. There is myocardial necrosis with calcification that appears yellow in the papillary muscles of the right ventricle, the interventricular septum and the free wall of the left ventricle. The left ventricle is dilated.
Figure 8.4 Dilated cardiomyopathy post-viral myocarditis. Teenage girl with dilated cardiomyopathy after an episode of myocarditis. No specific virus was identified. She underwent heart transplantation some years later. The explanted heart, cut in a simulated four-chamber view, shows a dilated left ventricle with endocardial thickening. The blotchy pallor of the myocardium is due to fibrosis, and this pattern of abnormality is typical of myocarditis.
8.2.2 Microscopic Pathology
Histopathological features of myocarditis are an inflammatory cell infiltrate in the myocardium that may be scanty and patchy, or diffuse and heavy (Figure 8.5) [2]. Neutrophils may be prominent, particularly in early stages. Lymphocytes are the main inflammatory cell. The lymphocytes are predominantly CD3-positive T-cells with some B-cells and CD68-positive macrophages (Figure 8.6). Eosinophils, plasma cells and mast cells may also be present [21,22]. Myocyte necrosis or damage must be present to sustain the diagnosis (Figure 8.7). Occasionally, the extent of necrosis is such as to cause difficulty in differentiation from infarction [23]. The myocytes usually contain abundant intracytoplasmic lipid, if looked for, and this should not be confused with a disorder of fatty acid oxidation (Figure 8.8) [24]. The histological features in myocarditis do not permit distinction between the various viral causes.
(A) Sudden infant death due to viral myocarditis. A section of the left ventricular wall stained with antibody to CD3. It shows focal aggregates of CD3+ lymphocytes in the myocardium and also the endocardium.
(B) Endomyocardial biopsy in a case of coxsackievirus myocarditis stained with antibody to CD68. It shows a heavy concentration of macrophages around damaged myocytes.
Figure 8.6 Myocarditis – inflammatory cell immunohistochemistry.
Figure 8.7 Myocarditis – myocyte necrosis. A high-power view of left ventricular myocardium in a case of viral myocarditis. The myocytes are cut longitudinally and there is a myocyte closely surrounded by lymphocytes. It is shrunken with a hyalinised appearance and has lost its normal internal structure. The cytoplasm consists of a series of dense eosinophilic micronodules.
Figure 8.8 Myocarditis – cytoplasmic lipid in myocytes. A frozen section from a case of viral myocarditis stained with oil-red-O to demonstrate cytoplasmic lipid. There is heavy accumulation of microvesicular lipid droplets in the myocyte cytoplasm. This is a frequent finding in myocarditis and should not be taken as evidence of an underlying metabolic abnormality.
8.2.3 The Dallas Criteria
The Dallas criteria for diagnosis of myocarditis are based on histological features on endomyocardial biopsy [2]. They require inflammatory cell infiltration and myocyte damage for a definitive diagnosis of myocarditis. According to this scheme, a biopsy may show one of three patterns: myocarditis, no myocarditis or borderline. Repeat biopsy may show the myocarditis to be persisting, healing or healed.
Objections to the Dallas criteria abound [25] and include:
They were developed before the widespread use of immunohistochemistry to characterise inflammatory cell infiltrates
Infiltrates other than lymphocytes are ignored
Myocyte damage is not fully characterised
The term “borderline” is unhelpful
No account is taken of aetiological factors
Sampling affects the diagnostic yield, and increasing the number of specimens and how they are examined increases yield.
The Padova group from the Veneto region of Italy have proposed a system of grading and staging of endomyocardial biopsy in addition to the inflammatory infiltrate. They propose a value of >14 leukocytes per mm2 with >7 T-cells per mm2 [21,26].
See Table 8.2 below for a method of calculating the high-power field (HPF) area.
Table 8.2 Area of high-power field
| Area of ×40 HPF = πr² |
| Π = 3.14 |
| r = field radius (field diam. (mm) ÷ 2) |
| Eyepiece with standard 22-mm diameter and ×40 objective |
| r = eyepiece diameter (mm) (22/40 ) ÷ 2 |
| r = 0.275 |
| Area of ×40 HPF = 3.14 × (0.275)² = 0.237 mm² |
| (×4.2194 to convert to 1 mm²) |
The World Health Organisation/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies has defined inflammation in an endomyocardial biopsy by immunohistochemical detection of focal and diffuse mononuclear infiltrates (T-cells and macrophages) with >14 cells/mm2, in addition to enhanced expression of HLA class II molecules [27].
At post-mortem, small foci of lymphocytes, with or without associated small foci of fibrosis, may be seen without myocyte necrosis [28], which do not necessarily represent myocarditis (Figure 8.9).
Figure 8.9 Focal lymphocytic infiltration of myocardium. A four-year-old child who died suddenly and for whom no cause of death was found at autopsy. The heart showed a few scattered foci of lymphocytic infiltration without associated myocyte necrosis. No viral genome was identified in the myocardium. The appearances cannot confidently be ascribed to myocarditis.
Increasingly, the diagnosis of myocarditis is being made on the basis of imaging, particularly cardiac MRI. The Lake Louise Criteria have been developed in an attempt to standardise radiological diagnostic criteria (Table 8.3) [29].
Table 8.3 Lake Louise Diagnostic Criteria for suspected myocarditis on cardiac MRI
| Cardiac MRI findings are consistent with myocardial inflammation if at least two of the following criteria are present: |
| 1. Regional or global myocardial signal intensity increase in T2-weighted images |
| 2. Increased global myocardial early enhancement ratio between myocardium and skeletal muscle in gadolinium-enhanced T1-weighted images |
| 3. There is at least one focal lesion with non-ischaemic regional distribution in inversion-recovery prepared gadolinium-enhanced T1-weighted images (delayed enhancement) |
| Cardiac MRI study is consistent with myocyte injury or scar caused by myocardial inflammation if the third criterion is present. |
| A repeat cardiac MRI study between 1 and 2 weeks after the initial cardiac MRI study is recommended if: |
| 1. None of the criteria are present but onset of symptoms is very recent and there is strong clinical evidence for myocardial inflammation |
| 2. One of the criteria is present |
| 3. The presence of left ventricular dysfunction or pericardial effusion provides additional supportive evidence for myocarditis |
8.2.4 Giant Cell Myocarditis
Giant cell myocarditis [30] is a rare and fulminant myocarditis that presents with congestive heart failure, ventricular arrhythmia or heart block (Figure 8.10). About one-fifth of cases have associated autoimmune disorders. The disease is rapidly fatal. It may occur in neonates [31]. Histologically, there is widespread myocardial necrosis associated with an inflammatory infiltrate with multinucleated giant cells (Figure 8.11). Importantly, there are no granulomata. The inflammatory cell infiltrate includes lymphocytes (largely CD8+ T-cells), histiocytes and eosinophils and sometimes neutrophils (Figure 8.12) [32]. The infiltrate also involves epicardium and endocardium, but giant cells are found only in myocardium.
Figure 8.10 Giant cell myocarditis. Heart transplant for biopsy-proven giant cell myocarditis. The child had been on support with a left ventricular assist device for some weeks before transplant. The heart is cut in a simulated four-chamber view. The left ventricular cannula of the assist device is visible. The myocardium is remarkably normal looking.
(A) Low-power view of the myocardium shows extensive loss of myocytes and a patchy inflammatory cell infiltrate.
(B) Focally there are multinucleate giant cells. In this instance they appear to be of myocyte origin, but others may derive from macrophages. Significantly there are no granulomata, a point of distinction from sarcoidosis.
Figure 8.11 Giant cell myocarditis. This is the same case as Figure 8.10.
Transplantation is the treatment of choice, but the disease may recur in transplanted heart [33].
8.2.5 Eosinophilic Myocarditis
Eosinophilic endomyocarditis is rare and is characterised by infiltration of the endocardium and myocardium by eosinophils (Figure 8.13) [34]. The endocardium is thickened and mural thrombus is common. The disease may occur in isolation or be associated with peripheral eosinophilia. There may be associated drug hypersensitivity, parasitic infestation or eosinophilic leukaemia. The drugs implicated include ampicillin, furosemide, digoxin, tetracycline, methyldopa, hydrochlorothiazide, phenytoin, benzodiazepines and tricyclic antidepressants [35].
The characteristic microscopic appearance is of a mixed inflammatory cell infiltrate within the myocardium containing variable numbers of eosinophils [36]. The eosinophil density ranges from mild, with small foci of inflammatory cells containing few eosinophils, to widespread infiltrates readily appreciated at scanning magnification. The inflammatory cell infiltrate may be perivascular or interstitial (Figure 8.14). Both epicardium and endocardium may be involved. Myocyte necrosis is variable. It is common with hypereosinophilic syndrome when it is associated with extensive endocardial eosinophilic infiltration that results in endocardial fibrosis and eventual restrictive cardiomyopathy (Figure 8.15).
Figure 8.14 Eosinophilic myocarditis. A high-power view of the case in Figure 8.13 confirms the interstitial and perivascular nature of the infiltrate of eosinophils. Intravascular eosinophils can also be appreciated. There is no myocyte necrosis.
Figure 8.15 Eosinophilic endomyocardial disease. There was peripheral blood eosinophilia associated with cardiomyopathy. There was biventricular hypertrophy with endocardial thickening particularly on the right side and, there was right atrial and right ventricular thrombus. The ventricular myocardium was scarred and there was fibrosis of the endocardium. The section shows the thrombus overlying the thickened endocardium that contains eosinophils.
Myocyte necrosis is much less common in drug-associated or hypersensitivity eosinophilic myocarditis. A more severe form of hypersensitivity eosinophilic myocarditis does occur and is termed acute eosinophilic necrotising myocarditis, characterised by a heavy eosinophilic infiltrate, florid oedema and myocyte necrosis with a fulminant course [37]. Eosinophilic granulomatosis with polyangiitis (formerly Churg–Strauss syndrome) is discussed in Chapter 9.
8.2.6 Bacterial and Protozoal Myocarditis
8.2.6.1 Bacterial Myocarditis
Bacterial myocarditis in the absence of endocarditis, while rare, can occur, usually in the setting of overwhelming bacteraemia [38]. The leading bacterial pathogen is Staphylococcus aureus. There are multiple small abscesses in the myocardium, usually of the left ventricle. Disturbance of cardiac contraction or of rhythm may occur, or there may be rupture into the pericardium with development of suppurative pericarditis.
Occasionally, histological sections taken from the heart at autopsy may show blood vessels filled with bacteria, but without an inflammatory cell reaction within the myocardium (Figure 8.16). This usually occurs in the setting of a terminal bacteraemia with a delay in the performance of post-mortem such that organisms, present in the blood at the time of death, have time to multiply in the anaerobic conditions of the heart vessels after death. Naturally, the organisms are usually anaerobic; necrotising enterocolitis or other bowel pathology is a frequent source of such. If gas-forming organisms are involved, the vessels may contain gas bubbles.
Figure 8.16 A child who died of Group B streptococcal septicaemia. There was an interval of three days between death and post-mortem. A section through the myocardium shows a vessel that is distended with cocci. They are confined to the vessel, and there is no associated inflammatory cell infiltrate. The appearance is interpreted as post-mortem overgrowth of bacteria present in the vessel at the time of death.
8.2.6.2 Toxoplasma
Toxoplasma may cause myocarditis following maternal infection and transplacental passage. Myocardial necrosis, scarring and calcification have been described [39]. There are usually associated brain abnormalities. Pseudocysts may be seen in the placenta or even in the myocardium (Figure 8.17). Following heart transplant Toxoplasma and Cytomegalovirus are the most frequent causes of infections of the myocardium [40]. The presence of neutrophils in the absence of severe acute cellular rejection should raise suspicion of infection.
8.2.6.3 Chagas Disease
This disease is caused by infection with the protozoan parasite Trypanosoma cruzi and is prevalent in Southern and Latin America. It is usually transmitted by insect bite, but it can also be transmitted through infected blood transfusion and vertically from mother to infant [41]. The initial infection is usually asymptomatic, but an acute illness may arise. Most people spontaneously clear the infection, but a minority develop a chronic form with dilated cardiomyopathy, achalasia or intestinal pseudo-obstruction. Children may present with the acute form, which is manifest as fever lymphadenopathy, hepatosplenomegaly and tachycardia. Death in the acute phase is usually the result of myocarditis or meningoencephalitis. At post-mortem in these cases the heart is oedematous and shows myocarditis. The form of the organism known as amastigotes can be seen in myocytes (Figure 8.18). Although the chronic form is most often seen in adults, it may affect children [42]. Pathologically there is dilated cardiomyopathy with characteristic thinning of the ventricular apex [43]. Histological examination shows widespread destruction of myocardial cells, diffuse fibrosis, oedema, mononuclear cell infiltration of the myocardium and scarring of the conduction system [44]. Parasites are very difficult or impossible to identify [45].
Figure 8.18 Acute Chagas myocarditis. A section of the myocardium of the heart of a two-year-old boy infected with Trypanosoma cruzi. Multiple myocytes are swollen by small rounded basophilic bodies that are the amastigotes of T. cruzi. There is an associated lymphocytic infiltrate in the interstitium.
8.3 Systemic Inflammatory Diseases with Heart Involvement
There is a group of systemic inflammatory disorders with a strong autoimmune component that may involve the heart to a greater or lesser degree. This group includes rheumatic disease, lupus erythematosus, systemic sclerosis, idiopathic juvenile arthritis and sarcoidosis [46]. The heart involvement may be predominantly confined to one compartment out of the pericardium, myocardium or endocardium, or may affect any combination of the three. Endocarditis is a feature of lupus erythematosus and rheumatoid disease and rheumatic fever.
8.3.1 Rheumatic Disease
Rheumatic fever occurs in children, but is uncommon under five years of age and is exceptionally rare under the age of one year [47]. In acute rheumatic fever the valves are affected by the inflammatory process with diffuse involvement of the valve leaflet or cusp and foci of fibrinoid necrosis. Aschoff nodules are the characteristic and diagnostic granulomatous lesions of rheumatic heart disease [48]. They may occur in endocardium, myocardium or pericardium. Typically, they are present in relation to blood vessels. They consist of a central core of fibrinoid with surrounding histiocytes and scanty lymphoid cells (Figure 8.19) [49]. The characteristic histiocytes, known as Anitschkow’s cells, show a central longitudinal bar of nuclear chromatin. Giant cells (Aschoff cells) may also be present. There is formation of small verrucae along the lines of apposition of the valve leaflets, with the mitral valve being the most frequently involved. There is involvement with decreasing frequency of the valves – aortic, tricuspid and pulmonary valve. The leaflet tissue shows ingrowth of capillaries. The lesions heal by fibrous scarring with shortening and thickening of chordae. This leads to fusion of commissures and nodular thickening of the valve. These valves rarely come to the surgical pathologist in the acute phase.
