Abstract
This chapter is devoted to the macroscopic and microscopic appearance of myocardial ischaemia and includes discussion of regional myocardial infarction and of papillary muscle rupture. Coronary atherosclerosis can occur, albeit rarely, in the child, and this is discussed particularly in relation to hypercholesterolaemia. Antiphospholipid syndrome and haemolytic-uraemic syndrome are also discussed.
6.1 Introduction
Most injury leading to necrosis or infarction of the myocardium in children is hypoxic or ischaemic in origin. The fetal heart is more resistant to hypoxic cell death than the adult heart because of its ability to increase glycolysis [1]. It is even possible that low oxygen tension in the developing fetus is necessary for normal heart formation and maturation [2]. Myocardial necrosis and infarction can occur in the neonate and infant, and are associated with congenital heart disease [3], coronary artery abnormalities [4–6], perinatal asphyxia [7, 8], myocarditis [9, 10] and tumours [4]. In some cases no underlying cause can be identified [11–16]. Studies show myocardial necrosis with a frequency of up to 29% of autopsy cases in neonatal intensive care populations [16], accounting for 0.18% of infant autopsies over 15 years in one large series [17]. In that series myocardial necrosis was present to some degree in around 10% of infant autopsies and was much more common in deaths occurring in the neonate and early infant than those occurring later in infancy. Myocardial necrosis in infants is most common in areas of the heart that are most sensitive to hypoxia: the subendocardial region and papillary muscles of the atrioventricular valves.
The frequency of myocardial necrosis in the hearts of infants with various forms of congenital heart disease coming to autopsy is shown in Table 6.1. The link is not a simple one, and multiple factors are involved.
Table 6.1 Types of congenital and acquired structural heart disease by European Association for Cardio-Thoracic Surgery/Society of Thoracic Surgeons (EACTS-SCS) diagnosis category identified in 105 infants with histologically proven myocardial necrosis and structural cardiac abnormalities
| Category | Number | % |
|---|---|---|
| Atrial septal defect | 52 | 49.5 |
| Patent arterial duct | 33 | 31.4 |
| Ventricular septal defect | 28 | 26.7 |
| Coronary artery anomalies | 24 | 22.9 |
| Aortic valve disease | 17 | 16.2 |
| Tricuspid valve disease and Ebstein’s anomaly | 12 | 11.4 |
| Pulmonary atresia | 12 | 11.4 |
| Transposition of the great arteries | 11 | 10.5 |
| Hypoplastic left heart syndrome | 10 | 9.5 |
| Mitral valve disease | 10 | 9.5 |
| Pulmonary valve disease | 9 | 8.6 |
| Coarctation of aorta and aortic arch hypoplasia | 8 | 7.6 |
| Atrioventricular septal defect | 7 | 6.7 |
| Hypoplastic right ventricle | 6 | 5.7 |
| Truncus arteriosus | 5 | 4.8 |
| Total anomalous pulmonary venous connection | 4 | 3.8 |
| Tetralogy of Fallot | 4 | 3.8 |
| Interrupted arch | 2 | 1.9 |
| Pulmonary venous stenosis | 2 | 1.9 |
| Double outlet right ventricle | 2 | 1.9 |
| Double inlet left ventricle | 2 | 1.9 |
| Double outlet left ventricle | 1 | 1.0 |
| Dextrocardia | 1 | 1.0 |
The clinical presentation of myocardial infarction in the infant and child is with chest pain. There is ST segment depression in subendocardial ischaemia and ST elevation in transmural ischaemia. Measurement of levels of the enzymes cardiac troponin T and I and creatine kinase MB isoenzyme shows good sensitivity and specificity for myocardial damage. Their blood levels rise within two hours of injury. The creatine kinase level peaks at 24 hours whereas troponins persist for longer.
6.2 Macroscopic Appearance
6.2.1 Subendocardial Necrosis
Regional infarction, so commonly seen in the adult practice, is rare in children. The commonest form of myocardial necrosis is subendocardial necrosis (Figure 6.1), and a subgroup of this is necrosis of the papillary muscles of the atrioventricular valves. The tissue may be haemorrhagic, or at least hyperaemic with telangiectasia. In cases with jaundice, the necrotic myocardium may take on a green-yellow tinge. The atria may be affected, and the interventricular septum high on the base near the conduction system is frequently involved, as well as the atrioventricular junctions.
(A) Sudden collapse in a 13-year-old. A short-axis cut through the ventricular myocardium shows subendocardial necrosis on the left ventricular aspect of the interventricular septum and in the anterior left ventricular wall (including the anterior papillary muscle of the mitral valve). The affected area is identifiable by focal haemorrhage. Histologically the necrotic myocardium showed a neutrophilic infiltrate in keeping with a date of several days duration. The appearances suggest re-perfusion following a period of non-perfusion, and the myocardial injury is almost certainly secondary to the collapse rather than its cause.
(B) A 5-week-old who died 24 hours after resuscitation following collapse of unknown cause. The myocardium shows extensive necrosis particularly beneath the endocardium of the interventricular septum and the left ventricle. The short-axis cut
(C) shows the circumferential distribution of the haemorrhagic necrosis and its confinement to the inner part of the ventricular wall. Histologically, the necrotic myocardium showed loss of nuclei with intense eosinophilia of the myocyte cytoplasm and contraction bands. A few leucocytes only were present in the interstitium.
6.2.2 Papillary Muscle Rupture
Ischaemic necrosis of the papillary muscles may result in their rupture and this may cause intractable heart failure and even death. The muscles of the mitral valve are usually involved (Figure 6.2), but the tricuspid valve papillary muscles may also be affected (Figure 6.3) [18]. Papillary muscle rupture has been described in older children following blunt chest trauma, usually in road traffic accidents [19]. In many instances no explanation of the rupture is identified, but rupture of the chordae tendineae has been attributed to maternal anti-SSA antibodies [20].
(A) The mitral valve is viewed from the left atrium. The chordae have become detached from the anterior papillary muscle, and their distal ends are haemorrhagic and twisted and have prolapsed into the atrium.
(B) A section of the anterior papillary muscle shows coagulative necrosis of the centre of the muscle extending to its apex from where the chordae have detached. The non-necrotic myocardium is vacuolated.
Figure 6.2 Rupture of attachment of anterior leaflet of mitral valve. Eight-week-old boy with trisomy 21 with oesophageal atresia without fistula. Two weeks before death he developed increasing dyspnoea. Echocardiograhy showed a large arterial duct. He collapsed acutely and echocardiography showed flail anterior leaflet of mitral valve. At post-mortem there was rupture of the anterior papillary muscle of the mitral valve at the insertion of the chordae, and there was a flail segment with a loose attachment that had become distorted and prolapsed into the left atrium.
Figure 6.3 Ruptured papillary muscle of tricuspid valve. An infant born at term who suffered respiratory distress and cyanosis in the first hours of life. Enlarged liver with tricuspid regurgitation on echo. Arrested on transfer for surgery. Ruptured anterior papillary muscle of the tricuspid valve on echo. The picture shows an area of black discolouration of the anterior papillary muscle with a raw area at the site of rupture. The more distal part of the papillary muscle is attached to the chordae attached to the anterosuperior leaflet of the tricuspid valve. Similar, smaller areas of necrosis are scattered in the right and left ventricular myocardium. No anatomical abnormality to account for the necrosis was identified, but the histological appearances suggest the necrosis has occurred within the previous 24 hours. Rupture of the papillary muscles of the tricuspid valve is a rare occurrence, and most cases have been attributed to perinatal hypoxia.
6.2.3 Regional Infarction
Extensive myocardial infarction may be found in the absence of coronary artery lesions. Focal coronary artery abnormalities, nonetheless, may cause regional infarction. Infarction may complicate origin of the left coronary artery from the pulmonary trunk, and in these cases the distribution of the necrosis is in the territory of the left coronary artery [21]. Similarly, in Kawasaki disease [22] or fibromuscular dysplasia [23] the area of necrosis may have a regional distribution. Extensive infarction can occur in hypertrophic cardiomyopathy (Figure 6.4) [24]. It is also worth keeping in mind that the severe chronic allograft vasculopathy in cardiac transplantation results in severe chronic ischaemic damage to the myocardium above that caused by the cellular component of rejection, albeit frank regional infarction is rare.
Figure 6.4 Myocardial infarction in hypertrophic cardiomyopathy. A fifteen-year-old with MHY7 mutation causing hypertrophic cardiomyopathy who underwent orthotopic heart transplant following collapse with heart failure. The explanted heart shows extensive haemorrhagic infarction of the hypertrophied myocardium of the free wall of the left ventricle. The coronary arteries were normal.
6.2.4 Coronary Artery Atherosclerosis
Coronary atherosclerosis, although very rare, does occur in children, usually in the setting of familial hypercholesterolaemia. Familial hypercholesterolaemia is an autosomal dominant disease with a risk of premature coronary artery disease in early adulthood. About 80% of cases are accounted for by mutation in the LDLR gene on chromosome 19 that results in absent or deficient low-density lipoprotein (LDL) receptors on the liver cells. The receptor defect leads to reduced uptake and metabolism of LDL by the hepatocytes with consequent increase in circulating LDL cholesterol [25].
Other genes, mutation in which cause familial hypercholesterolaemia, are APOB (apolipoprotein B) accounting for about 5% of cases and PCSK9 (proprotein convertase subtilisin/kexin type 9) accounting for only 1% of cases.
A rare autosomal recessive form (LDLRAP1) occurs, and the remainder of cases are due to mutation in unknown genes or are polygenic. Heterozygous familial hypercholesterolaemia results from inheritance of the mutation from one parent and is a common defect with a prevalence of about 1:300.
Inheritance of a mutation from both parents causes homozygous familial hypercholesterolaemia with a prevalence in European populations of 1:160 000 to 1:300 000. Untreated individuals have very high circulating levels of LDL cholesterol, and are at high risk of coronary artery disease in childhood and adolescence (Figure 6.5) [26].
Figure 6.5 Familial hypercholesterolaemia. Thirteen-year-old with familial hypercholesterolaemia and mixed valvar and supravalvar aortic stenosis who underwent aortic stenosis repair. A section through the thickened excised aorta shows a fibrous cap with underlying numerous foam cells with focal calcification in keeping with atheromatous plaque.
Coronary artery calcification is rare before adolescence in homozygous familial hypercholesterolaemia, although it does develop in the teenage years in many cases [27].
In homozygous familial hypercholesterolaemia there is massive accumulation of cholesterol in the aortic valve and supravalvar aorta resulting in aortic stenosis and regurgitation and coronary artery ostial stenosis [28]. Heterozygous familial hypercholesterolaemia tends to involve the more distal coronary artery tree.
6.3 Microscopic Appearance
The first tissue change that is evident by light microscopy is that the myocytes become hypereosinophilic (Figure 6.6) [29]. This change takes 6–8 hours to develop from the onset of the insult. The cross striations may become blurred, and there may be clumping of the cytoplasm. Contraction bands are frequently present (Figure 6.7). There is nuclear change, with blurring and loss of staining. Intercellular oedema develops and then infiltration by neutrophil polymorphs, usually by 12–24 hours. There is capillary dilatation, and often this may be the alerting sign to the presence of necrosis. Infant myocardium in particular has a propensity to calcify and may do so within a day of the insult, sometimes massively (Figure 6.8).
Figure 6.6 Early myocardial necrosis. Term infant who died 48 hours after emergency caesarean section for fetal distress. A representative section from the right ventricular myocardium shows hypereosinophilia of the myocytes with intense capillary engorgement and loss of myocyte nuclei. There is margination of neutrophils in capillaries, but, as yet, no infiltration of the interstitium.
Figure 6.7 Contraction band necrosis. Two-week-old infant with tetralogy of Fallot who died of viral encephalitis. The myocardium of the right ventricle was hypertrophied and showed scattered small foci of contraction band necrosis. The Masson’s trichrome stained section shows myocytes with clumping of the filaments causing thick transverse bands in the cytoplasm, the so-called contraction bands. There is associated nuclear loss.
Figure 6.8 Myocardial calcification. A 4-month-old with transposition and VSD repaired. The infant developed pulmonary hypertension, and an attempt to close a residual VSD resulted in going on to extracorporeal membrane oxygenation (ECMO). They died shortly afterwards. The cut surface of the myocardium shows linear pale areas in the subendocardium representing necrotic and calcified myocytes.
6.3.1 Dating of Injury
Dating of hypoxic/ischaemic injury in adults is based on classical studies from many years ago [29] that need to be interpreted in the light of recent therapeutic interventions [30]. In particular reperfusion can markedly affect the appearance and histology of infarcted myocardium [31]. In children these dating schemes need even greater caution in their use, and the insult may have been present for longer than it appears. Inflammatory cell infiltration is usually not so prominent as in older individuals.
After myocardial infarction, there is activation of tissue matrix metalloproteinases that degrade the existing extracellular matrix and vasculature. This degradation declines after the first week because of a rise in tissue metalloproteinases. Neutrophils contribute to the proteolytic digestion, and macrophages contribute to phagocytosis. The inflammatory response peaks at weeks 1–2 post infarction and usually disappears by 3–4 weeks by apoptosis.
Fibrosis begins with activation of TGF-β1with subsequent synthesis of collagen types 1 and III [32]. Eventually there is fibrous scarring in the distribution of the original necrosis (Figure 6.9).
