Hypertrophic cardiomyopathy (HCM) is a familial disease with a disease-causing mutation in the genes encoding structural components of the cardiac muscle sarcomere in about 60% of cases.1 In a general population of healthy young adults, the prevalence is 1:500.2 The penetrance is incomplete and age-related with a wide clinical spectrum.1 Many patients have normal life expectancy, some die suddenly – often as adolescents or young adults – whereas only a few develop end-stage heart failure. In the total HCM population, only 25% develop significant left ventricular outflow tract obstruction.3
HCM was first described in 1958 by Teare.4 In the beginning, HCM was described as asymmetrical septal hypertrophy of the left ventricle, but it is now clear that practically any patterns of wall thickening may be observed.5,6 In large reported cohorts of HCM patients, end-diastolic septal thickness averages approximately 20–22mm; however, it may exceed 30mm, can rarely measure up to 50mm and in some patients carrying an HCM disease-causing mutation the septal thickness is in a normal dimension (pre-clinical HCM).1
The histopathological hallmarks of HCM with general myocyte hypertrophy, i.e. regions of myocyte disarray,7 different types of fibrosis8 and small-vessel disease,9 originate from several autopsy and transplant studies from HCM patients who suffered sudden cardiac death (SCD) or progression to end-stage heart failure. There are considerably fewer studies from living HCM patients with histopathological evaluation of surgical myectomy specimens or studies of endomyocardial biopsies from the right side of the interventricular septum. In this brief article, the relationship between histopathological features and clinical findings and outcome in patients with HCM will be discussed.
Myocyte disarray is characterised by regions of architectural disorganisation of hypertrophied myocytes and distinct nuclear changes. Adjacent myocytes are arranged obliquely or perpendicularly to each other around foci of interstitial collagen (plexiform fibrosis) in a pinwheel or herringbone pattern. Myocyte disarray is not specific for HCM. This architectural disorganisation of the myocytes has been found, although to a lesser extent, in patients with dilated CM, alcoholic CM, various congenital heart diseases and cardiovascular diseases (systemic hypertension, coronary artery disease and cor pulmonale) and in normal hearts.10
There is no consensus about the amount of myocyte disarray required to fulfil the criteria for the diagnosis of HCM. Early studies have suggested that 5–10% of ventricular septal myocardium should show disarray.11 In the majority of cases, myocyte disarray is extensive and >20% of the myocardium will exhibit disarray in at least two tissue blocks.12 In regions with myocyte disarray, Sepp et al. have shown in HCM patients that the intercellular junctions responsible for electromechanical coupling are dispersed over the surface of the myocytes instead of being confined to intercalated discs.13 This disorganisation of the intercellular junctions may serve as a substrate for ventricular arrhythmias. Varnava et al.14 concluded that myocyte disarray is probably a direct response to functional or structural abnormalities of the mutated sarcomeric protein (see Figure 1).
Myocyte Disarray and Clinical Findings
In another report from 2001 the same group correlated the pathological findings with cause of death and risk profile in 75 patients with HCM, and found SCD in 52%, end-stage heart failure in 37% and death from other causes in 11%.15 In the total population, myocyte disarray was greater in the young group and in those with an abnormal vascular response to exercise. High incidences of SCD are associated with some troponin T mutations.16 These HCM patients had extensive myocyte disarray and mild hypertrophy and fibrosis.
Menon et al. examined myectomy specimens of 45 children and adolescents with symptomatic obstructive HCM.17 All the specimens demonstrated severe hypertrophy, and a majority showed moderate disarray and mild fibrosis. Only myocardial disarray was found to correlate with left atrial volume index and diastolic dysfunction grade. This study did not include adult HCM patients, who commonly have more fibrosis.
Both macroscopic and microscopic scars are common findings in HCM. In a review article by Maron et al., the authors concluded that small-vessel disease leads to blunted myocardial blood flow and myocardial ischaemia during stress in the HCM population.18 Macroscopic scars, often more pronounced over the septum, range from grey or white patchy fibrosis to large white transmural scars. These scars probably represent the sequelae of an ischaemic process and correspond to histological replacement-type fibrosis.19
In 1979, Anderson et al. described different types of microscopic scar in patients with HCM: replacement-type fibrosis (scars), interfibre fibrosis, perivascular fibrosis and plexiform fibrosis.8 The vast majority of later studies have addressed the general matter of total amount of fibrosis20,21 and were largely concerned with replacement-type fibrosis.19
Normal hearts have a fibrillar collagen network that builds up the structural skeletal framework of the interstitium of the myocardium. This collagen network is composed of pericellular, intercellular and fascicular connective tissue.22 Shirani et al. used a collagen-specific staining, excluded perivascular fibrosis and endocardial fibrosis and analysed the amount, distribution and structure of the cardiac collagen network in transmural sections of the ventricular septum in children and young adults with the HCM diagnosis who suffered from SCD.23 The collagen network in the HCM group was morphologically abnormal and increased in size compared with structurally normal hearts. The authors suggested that the HCM disease process is not only confined to disease-causing mutations in genes encoding sarcomeric proteins, but also involves connective tissue elements. Perhaps these abnormalities of the connective tissue elements also play a role in the pathological process leading to enlargement and elongation of the mitral valve leaflets and medial hypertrophy of intramural coronary arteries (see Figure 2).
Fibrosis and Clinical Findings
There are indications that increasing amounts of fibrosis and ischaemia occur in the natural history of HCM. The amount of fibrosis is associated with small-vessel disease, increasing septal thickness, cardiac mass, increasing age, progression to end-stage heart failure and SCD.15,24
In a study by Blauwet et al., who examined surgical myectomy specimens from 59 HCM cases, the specimens were examined to determine the total amount of myocardial fibrosis, including pericellular, perivascular and replacement-type fibrosis.25 The results showed significantly more fibrosis in HCM patients than in controls, and the amount of fibrosis correlated with the degree of septal hypertrophy and with systolic and diastolic function.
In a prospective study of 21 symptomatic HCM patients, myocardial collagen volume fraction was histologically determined in an endomyocardial biopsy from the right side of the ventricle.26 The results showed that increased myocardial fibrosis was associated with a worse prognosis.
Cardiac imaging with delayed hyperenhancement magnetic resonance imaging (DHE-MRI) detects areas of myocardial scarring in HCM-patients in vivo.27 Areas of delayed hyperenhancement have been shown to correlate with histologically proven myocardial scar.28 The results from Known et al., who examined 60 symptomatic obstructive HCM patients with DHE-MRI before undergoing septal myectomy, showed a strong association between the degree of small-vessel disease and myocardial scarring observed on DHE-MRI.29 It is also demonstrated that scarring seen on DHE-MRI is associated with arrhythmias and disease severity.30,31
The histopathological hallmarks of HCM are general myocyte hypertrophy, regions of myocyte disarray, different types of fibrosis and small-vessel disease. Myocardial disarray is found to a greater extent in young HCM patients and is associated with SCD in these young patients. There are indications that myocardial disarray is also responsible for the early development of diastolic dysfunction in HCM patients.32 Increasing amounts of fibrosis and ischaemia occur in the natural history of HCM, and the amount of fibrosis is associated with increasing septal thickness, progression to end-stage heart failure and SCD. The aetiology of the electrical instability leading to malignant arrhythmias and SCD in HCM patients is still unknown. Myocyte disarray, acute or subacute ischaemia leading to scarring and different types of fibrosis may play an important role.