Hypertrophic cardiomyopathy: an autopsy analysis of 14 cases.
RS Phadke, P Vaideeswar, B Mittal, J Deshpande
Department of Pathology, Seth G. S. Medical College and K. E. M. Hospital, Mumbai, India. , India
R S Phadke
Department of Pathology, Seth G. S. Medical College and K. E. M. Hospital, Mumbai, India.
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is one of the less common forms of primary cardiomyopathies. There is little data available on HCM in Indian literature. AIMS: To assess the incidence and analyse the clinicopathological features of HCM. SETTINGS: Analysis of data of 15 years from a tertiary care centre. METHODS AND MATERIAL: The clinical and pathological data in fourteen cases of HCM with respect to their gross and microscopic features and clinical presentation were reviewed. RESULTS: Incidence of HCM amongst the autopsied primary cardiomyopathies (N = 101) was 13.9% (n=14). Males were affected more. Common presenting symptoms were exertional dyspnoea, angina and palpitations. Concentric and asymmetric hypertrophy was equally seen. Obliterative small vessel disease was noted in 50% of the cases. Although significant myofibre disarray (>5%) was seen in all fourteen cases, it could be demonstrated in only 40- 50% of an average of twenty sections studied. Type IA myofibre disarray was the commonest. Six of the fourteen patients died suddenly. Cardiac failure was the commonest cause of death. CONCLUSIONS: Myofibre disarray is a highly sensitive and specific marker for HCM only when considered in a quantitative rather than a qualitative fashion. In this context, the rationale for performing endomyocardial biopsy is to rule out mimics of HCM.
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Phadke R S, Vaideeswar P, Mittal B, Deshpande J. Hypertrophic cardiomyopathy: an autopsy analysis of 14 cases. J Postgrad Med 2001;47:165-70
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Phadke R S, Vaideeswar P, Mittal B, Deshpande J. Hypertrophic cardiomyopathy: an autopsy analysis of 14 cases. J Postgrad Med [serial online] 2001 [cited 2021 Apr 21 ];47:165-70
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Hypertrophic cardiomyopathy (HCM) represents one of the less common forms of primary cardiomyopathies. The condition is being increasingly recognised in India and yet, there is little data available regarding the incidence and the rates of mortality. The main purpose of this study has been to analyse the clinical presentations and the pathological features in fourteen patients with HCM diagnosed at autopsy. We have critically analysed the role of myofibre disarray as a diagnostic marker for the disease. Our aim was also to elucidate the importance of histological examination in making or ruling out the diagnosis of HCM, especially in the setting of sudden death.
In a fifteen-year period (1985-2000), primary cardiomyopathy was diagnosed in 101 cases at autopsy [Table:1]. There were fourteen cases of HCM. In all cases, congenital heart disease, ischaemic heart disease, valvular deformities or hypertension were ruled out. The clinical and pathological data were reviewed from clinical and autopsy records in these cases. All the hearts were examined in detail with specific attention to heart weight, chamber size, the type (symmetric or asymmetric) and degree (mild, moderate or marked) of hypertrophy, degree of fibrosis, status of cardiac valves and epicardial coronary arteries. In the nine hearts that were available for re-examination, in addition to the existing sections, additional tissue blocks were taken from full thickness of the ventricular septum, left ventricular and right ventricular free walls in the transverse plane. Junctional sites between the septum and ventricular free walls where disarray occurs naturally were excluded. This gave an average of twenty sections per heart (range fifteen to thirty). In the remaining five hearts, the existing slides (five per heart) were retrieved and studied. Features studied on histology were myofibre disarray, hypertrophy and degeneration, fibrosis, inflammation and presence of obliterative small vessel disease. Myofibre disarray was identified and classified as per the criteria described by Maron and Roberts as follows: IA, where cardiac muscle cells are aligned obliquely or perpendicularly to each other forming tangled masses or pinwheel configurations, IB, where myofibres are arranged in relatively broad bundles aligned obliquely or perpendicularly; individual cells within the bundles being normally arranged, IIA with relatively narrow (one to two cell wide) longitudinally cut bundles of cells interlaced in various directions among larger groups of transversely cut cells and IIB which is similar to IIA except that the longitudinal bundles are more linear. Abnormally arranged myofibres were not read as disarray if present in or at the edges of fibrosis, at the points of convergence of major muscle bundles or adjacent to interstitial spaces containing blood vessels. We measured myofibre disarray in a semi quantitative fashion. The number of sections showing disarray were noted and expressed as a percentage of the total number of sections examined per heart.
The fourteen cases of HCM accounted for 13.9% of the cases of cardiomyopathy. HCM was seen in all age groups. The youngest patient was a day old while the oldest was sixty-five years old. Overall, males were affected nearly twice as commonly as females. Two among the fourteen, both elderly, were diagnosed cases of HCM on regular follow-up with a history of exertional dyspnoea of one to three years duration. Both died suddenly following acute dyspnoea. Two patients were neonates who presented with birth asphyxia. The remaining ten patients were adults. Four of them died suddenly and were asymptomatic during life. Cardiac arrhythmia was documented as being the terminal event in three of them. The six other patients presented chiefly with exertional dyspnoea lasting from eight months to four years. Four of them also complained of angina and palpitations. The heart weight was increased in all cases [Figure:1]. Amongst adults, it ranged from 400 grams to a maximum of 750 grams (mean 514 grams). It weighed 225 grams in a thirteen-year-old male. The two neonatal hearts weighed 30 grams and 45 grams (mean 37.5 grams). In all cases, the left ventricular free walls and septum were hypertrophied. Asymmetric [Figure:2] and concentric symmetric hypertrophy [Figure:3] was seen in seven cases each [Table:2]. In asymmetric hypertrophy, localisation and degree of the hypertrophy were variable. The ventricular free wall thickness varied from 1.1 centimetres to 1.5 centimetres (average 1.2 centimetres) whereas the septal thickness varied from 1.3 centimetres to 3.2 centimetres (average 1.7 centimetres) in these cases. Both neonatal hearts showed concentric symmetric hypertrophy. Accompanying mild to moderate right ventricular hypertrophy was present in ten cases. Although not a feature of HCM, mild to moderate chamber dilatation was present in over 50% of cases, since these patients were in cardiac failure at presentation. Streaky myocardial fibrosis was seen in four cases. Septal endocardial thickening in the form of a mirror image of the anterior mitral leaflet in the subaortic region of the left ventricular outflow tract was seen in three cases, with corresponding thickening of the anterior mitral leaflet [Figure:4]. Striking myofibre hypertrophy was present in all 14 cases. Affected myofibres showed a three to five fold increase in their transverse diameters with nuclear enlargement and hyperchromasia. Typical box and cigar shaped nuclei with perinuclear clearing were often seen. Significant myofibre disarray (> 5%) was present in all cases. However, disarray could be demonstrated in only 40- 50% of an average of twenty sections studied. Type IA was the commonest [Figure:5], comprising 60% to 75% of the disarray. Type IB was the next most common [Figure:6], comprising 15% to 30% of the disarray while types IIA and IIB made up for about 10%. The extent of disarray was variable. In one case it chiefly involved the septum. In six cases, it involved the septum and the right and left ventricular free walls. In the remaining seven cases, it involved the septum and either one of the ventricular free walls. In four cases, the epicardial coronaries showed uncomplicated atherosclerotic changes, none of which had critical luminal narrowing. Obliterative small vessel disease was noted in seven cases, intimately associated with areas of scarring. The intramural coronaries showed smooth muscle proliferation and collagen deposition in both the media and intima, resulting in abnormal thickening of the walls and luminal narrowing. Other features seen were degeneration, scarring and inflammation. Myofibre degeneration was present in the form of waviness, smudging and vacuolation. Scarring was commonly interstitial, interfibrillar and less often perivascular. Inflammation was focal, sparse, interstitial and composed of mononuclear cells.
HCM represents a diastolic disorder that is characterised by idiopathic cardiac hypertrophy and restriction to ventricular filling. HCM is increasingly being recognised in India, though there is little data available regarding the incidence. In the present series, fourteen cases of HCM comprised 13.9% of all cardiomyopathy cases [Table:1]. Recent studies indicate that the disease is familial in 50% to 60% of cases and sporadic in the remainder.
As documented in other series, the chief presenting symptoms were dyspnoea, angina and palpitations. Sudden death, inarguably one of the most unpredictable and devastating complications of the disease was seen in six of the fourteen patients. It is said to occur more often in young patients, especially those with a family history. More recently, Maron et al, in a study of a prospectively assembled, regionally based and predominantly unselected patient cohort found that sudden deaths in HCM were not just confined to adolescents and young adults, but also extended to later phases of life. Only one of our six patients who died suddenly was young. Two of them were diagnosed cases of HCM on regular follow-up while the other four were asymptomatic during life. The mechanisms responsible for sudden death are complex and are probably not identical in all patients., Available data suggest that the most common precipitating factors of sudden death are arrhythmias., In the present study, in three of the six patients, cardiac arrhythmia was documented.
The original description of HCM by Teare highlighted the disease with asymmetric basal, septal hypertrophy, leading to obstruction of the left ventricular outflow at the subaortic level. The condition thus became known as hypertrophic obstructive cardiomyopathy or asymmetric septal hypertrophy. Following the development of M-mode echocardiography, several clinical and autopsy studies over the years have highlighted that HCM is much more protean in its clinical and morphologic manifestations. Echocardiographic surveys have showed that while the upper septum and anterior wall of the left ventricle was the most common site, the segment of abnormal muscle may lie in the mid-septal, lateral, posterior or apical regions of the left ventricle or in the right ventricle. Symmetric involvement of the left ventricle is another recognised variant. In their autopsy analysis of 74 hearts showing HCM, Davies and McKenna documented symmetric hypertrophy in 34% of their cases. In our study, symmetric and asymmetric hypertrophy was present equally [Table:2]. Asymmetric hypertrophy was anteroseptal in four cases, anteroseptal and lateral in two and septal in one case. Accompanying right ventricular hypertrophy was present in 10 cases. The systolic anterior motion (SAM) of the anterior mitral leaflet produces a helpful morphological feature of a patch of endocardial thickening on the septum below the aortic valve, forming a mirror image of the anterior mitral leaflet. This feature was seen in three of the fourteen cases. All three had asymmetric hypertrophy (anteroseptal) and two had documented obstruction during life. Finally cases are now being described which at autopsy do not have hypertrophy as judged by total heart weight or isolated ventricular mass, yet the clinical features and histology is that of HCM.
Ideally, there should be a single “gold standard” for the disease; the histological features seem to be an obvious candidate. Teare’s observation in 1958 that sudden death was associated with asymmetric septal hypertrophy, histologically characterised by a bizarre myofibre architecture and conspicuous interstitial fibrosis, set the scene for relating myofibre disarray to this condition. However many investigators felt that it was a non-specific feature when considered in isolation., Van Noorden and coworkers introduced a semi quantitative approach to diagnosis, which included other histological features such as the degree of hypertrophy and fibrosis along with disarray. They however encountered a substantial overlap between HCM and other hypertrophic heart diseases. Matters were further complicated when myofibre disarray was documented in normal hearts, foetal and infant hearts and in cases of congenital heart disease., The very specificity of disarray as a marker for HCM was questioned. Maron and Roberts, stated that myofibre disarray is a highly sensitive and specific marker for HCM only when considered in a quantitative rather than a qualitative fashion. Using a planimetric method to measure the percentage area of septal disorganisation, they showed that a cut point of 5% best distinguished patients with HCM from those with other cardiac diseases. It was subsequently shown that the extent of disarray does not differ much amongst sections from the septum and the ventricular free wall in patients with HCM., However, the distribution of abnormal myocardium throughout the heart is very variable. It is maximum in areas of macroscopic wall thickening but may occur focally within macroscopically normal areas and is often patchy in a given tissue section. We made similar observations. Though significant myofibre disarray (>5%) was present in all cases, it could be demonstrated in only 40- 50% of an average of twenty sections studied. The disarray was quite variably distributed throughout the myocardium and was often patchy in a given section. Also, in constant accompaniment of disarray were a constellation of histological findings such as a bizarre and uneven myocyte hypertrophy, large hyperchromatic nuclei, myocyte degeneration, interstitial and interfibrillar scarring and focal interstitial aggregates of mononuclear inflammatory cells. Obliterative small vessel disease was seen in 50% of cases. In another large series, it was seen in only 40% cases. It has been postulated to be the cause of fibrosis in histological sections. Indeed, whenever present, obliterative small vessel disease was intimately associated with areas of scarring in this study. Summarily, it appears that, as already stated by Maron, taken in association with other histological features, disarray is the pathognomonic feature of HCM, when assessed quantitatively.
An important limitation to such a quantitative approach to the diagnosis of HCM is the variable amount and extent of disarray distributed throughout the heart. This may necessitate extensive sampling to reach a quantitative diagnosis. Clear enough, this is possible only in the case of autopsy specimens. The question that arises is what is the practical value of disarray as a diagnostic marker for biopsy specimens, when the clinical diagnosis is in doubt? Biopsy in life can neither confirm nor refute the diagnosis of HCM. The chance of getting false negative findings is high due to sampling errors. This may be due to the variable amount and extent of disarray as well as due to the fact that disarray is often present deep within the septum, beyond the reach of the bioptome. The biopsy may include a focal area of disarray in a heart without HCM, leading to a false positive diagnosis. Criteria such as the histological HOCM index (HHI) were devised by Van Noorden and colleagues to distinguish HCM from other cardiac diseases in biopsies, but there was an unacceptable overlap. They concluded that biopsy could not provide more that circumstantial confirmation of the clinical opinion. Accordingly, the rationale for biopsy is not to diagnose HCM, but rather to rule out other disorders such as cardiac amyloidosis that may mimic HCM.
In conclusion, myofibre disarray as a marker for the diagnosis of HCM in biopsy specimens is not of much practical value. This is related more to the variable amount and distribution of disarray within the myocardium and the limitations of sampling. When assessed quantitatively along with other histological features, disarray is indeed pathognomonic of HCM. The importance of histological examination cannot be overemphasised especially in the setting of sudden death. It would be easier for clinicians to ascribe sudden death in the elderly to an acute myocardial infarction without resorting to autopsy confirmation. For the pathologist, the diagnosis could easily be missed without histological examination given the variable phenotype of the disease. As pointed out by Davies, to use the diagnosis as an explanation for sudden death in the absence of histological disarray serves no useful purpose and may submit the family to pointless and expensive genetic screening.
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