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Abnormal Morphologic Features of
Hypertrophic Cardiomyopathy

Jamshid Shirani, MD

Departments of Medicine (Division of Cardiology) and Pathology,
Albert Einstein College of Medicine, Bronx, New York, USA

INTRODUCTION
   The first detailed description of HCM was published by Teare in 1958 who noted "asymmetric hypertrophy of the heart" in several family members who died suddenly (1). Teare also observed abnormal arrangement and variable size of cardiac muscle fibers in the ventricular septum (1). In the following years, obstruction to LV outflow tract was considered the principal clinical manifestation of the disease leading to its designation as "idiopathic hypertrophic subaortic stenosis" (2). The last two decades have witnessed major contributions to the understanding of HCM, now considered a primary and genetically transmitted cardiac disease with extremely heterogeneous clinical and morphologic profile (3). In recent years, an increasing number of mutations in genes encoding cardiac sarcomeric proteins (Table 1) have been identified in individuals and families expressing the cardiac disease phenotypes (4, 5). These mutations are thought to be responsible for some of the prominent and characteristic structural alterations in HCM, such as cardiac myocyte hypertrophy and disorganization (6). Other frequently found cardiac morphologic abnormalities in patients with HCM, such as myocardial fibrosis (7) and abnormalities of intramural coronary arteries (8) involve the connective tissue rather than cardiac myocytes. In addition, other cardiac morphologic abnormalities, such as direct insertion of papillary muscle into mitral leaflet and solitary papillary muscle, have been reported in association with HCM (9). Table 2 lists the most prominent gross and microscopic cardiac morphologic abnormalities reported in individuals with HCM. In the following sections, each particular cardiac morphologic abnormality is discussed and the interrelation of these morphologic findings and the clinical presentation of HCM explored.


DEFINITION
   HCM is classically defined as "hypertrophied and non-dilated left ventricle in the absence of any other cardiac or systemic disease capable of producing the degree of left ventricular hypertrophy present in that patient" (3). However, marked heterogeneity in cardiac morphologic features and clinical presentation of HCM has made it difficult, if not impossible, to provide an all-inclusive definition of the disease. This is further complicated by the observations that: i) age, sex, and other environmental, hormonal as well as genetic modifying factors significantly alter the disease phenotype; ii) none of the gross and histomorphologic features of the disease are in fact specific for HCM. Rather, they are present in greater proportions than found in other cardiac diseases; and 3) as previous studies unavoidably have focused on patients with the most dramatic presentation of the disease, the full spectrum of cardiac morphologic abnormalities of HCM has not been unraveled (10). In addition, the diagnosis of HCM poses a special problem in infants (11), children (12), elderly (13), competitive athletes (14) and in patients with systemic hypertension (15). Finally, the definition of the disease requires broadening in order to address those with the disease genotype in whom clinically recognizable cardiac morphologic abnormalities are absent or only mild.

CARDIOMEGALY AND LEFT VENTRICULAR HYPERTROPHY
   Heart weight, as measured at necropsy, is increased in most patients (>95%) with HCM and at times may exceed 1,000 grams. Normal heart weight in HCM is more often found in i) asymptomatic young patients with the disease genotype who have not yet expressed the phenotypic characteristics of the disease (16), or ii) in those who die suddenly in the absence of known cardiac symptoms during life (17).

   The primary gross morphologic feature of HCM is hypertrophy of LV walls and often the right ventricle (18). However, echocardiographic and necropsy studies have demonstrated marked variations in the extent and patterns of LVH in HCM (19,20). In most patients LVH is diffuse although the magnitude of segmental hypertrophy often differs significantly among various regions. The ventricular septum usually shows the greatest magnitude of hypertrophy followed by large portions of the anterolateral LV free wall. The posterior LV free wall is the least affected region in HCM. Asymmetric septal hypertrophy (defined as a septal to posterior wall thickness ration exceeding 1.3) is observed in up to 90% of patients with HCM (Figure 1). In these patients, septal hypertrophy may be limited to the basal most portion of the septum (in 25% of the patients), may extend down to the level of papillary muscles (in another 25%), or may involve the entire ventricular septum (in the remaining 50%). When the entire ventricular septum is thickened, the hypertrophy often extends to regions of the anterolateral LV free wall. Nevertheless, segmental LV hypertrophy in HCM may be confined to the anterior or posterior septum, anterolateral free wall, posterior free wall or even the most apical portion of the LV (19, 21-23). The latter, called apical HCM, is often associated with deep, symmetrically inverted T waves in precordial leads of surface 12-lead electrocardiogram in its early stage (24). However, gradual LV dilation, apical wall thinning and even aneurysm formation have been reported in some patients with apical HCM in association with loss of inverted T waves, reduction in R wave amplitudes, and development of Q waves presumably due to apical scarring (25). A distinct subtype of patients with HCM shows hypertrophy limited to the LV papillary muscles (26).

Figure 1. Gross photograph of the heart if a patient with hypertrophic cardiomyopathy demonstrating marked asymmetric left ventricular (LV) hypertrophy with preferential wall thickening in the ventricular septum (VS) and anterior free wall.

   The magnitude and distribution of LVH in HCM often determine the clinical features of HCM. Asymmetric, marked hypertrophy of the basal septum is a prerequisite for development of dynamic LV outflow tract (subaortic) obstruction whereas HCM patients with mid-LV cavity obstruction show marked symmetric (concentric) LVH especially at the papillary muscle level. Systolic mid-LV cavity obstruction results from complete apposition of the hypertrophied walls and papillary muscles, leads to separation of the apical and basal LV regions and may be associated with apical ischemia, scarring and even aneurysm formation (27, Figure 2). Patients with milder concentric LVH often show LV cavity obliteration due to increased ejection fraction without focal intracavitary or outflow tract obstruction. Marked LVH has been identified as a risk factor for sudden death in HCM (28). However, LV diastolic dysfunction and presence of symptoms of CHF do not closely parallel the severity of LVH in this disease (29,30). In some patients with HCM, asymmetric hypertrophy of the infundibular region may result in right ventricular outflow tract obstruction.

Figure 2. Gross photograph of the heart in a patient with midventricular obstruction and left ventricular apical aneurysm (A). LA=left atrium;PW=posterior wall;VS=ventricular septum.

CARDIAC MYOCYTE DISORGANIZATION
   Histologic examination of myocardial biopsy samples and necropsy material has revealed marked disorganization of myocardial fibers (involving at least 5% of the tissue surface) in about 95% of patients with HCM (6,20). This cellular disarray involves >25% of myocardium in 50% and >50% of the tissue in 25% of the patients and is characterized by oblique and perpendicular arrangement of adjacent muscle fibers (6, Figure 3). Myofiber disorganization in HCM is not necessarily confined to the most hypertrophied LV segments. Indeed, there is little correlation between wall thickness and extent of cellular disorganization (31). Thus, cellular disorganization involves an average of 40% of the ventricular septum and 33% of the LV free wall despite differences in the magnitude of hypertrophy in these regions (31,32). The extensive cellular disorganization in HCM is in contrast to other cardiac diseases such as aortic and mitral valve disease, hypertension, and congenital lesions where myocyte disarray involves <5% of the LV wall (6).

Figure 3. Photomicrograph of a section of left ventricular myocardium in HCM demonstrating marked myocyte hypertrophy and disorganization. Hematoxylin and eosin X200.

   Patients with HCM who die suddenly often have extensive areas of cardiac myofiber disorganization (33). It has been speculated that the widespread myofiber disorganization may function as a substrate for abnormal electrical conduction and thus contribute to the genesis of ventricular arrhythmias (34).

   It has also been noted that the degree of cellular disorganization is significantly less in the hearts of patients with end-stage, dilated phase of HCM in whom progressive wall thinning has occurred. It has been speculated that regions of LV with cellular disorganization may more selectively undergo scarring and thus contribute to the development of systolic dysfunction. Cellular disorganization may also contribute to impaired LV diastolic function (35).

ABNORMAL INTRAMURAL CORONARY ARTERIES
   Abnormal intramural coronary arteries have been reported in as many as 80% of patients with HCM studied at necropsy, and are seen most commonly in the ventricular septum (8,36, Figure 4). The walls of these intramural vessels are thickened by cellular hyperplasia (both intimal and medial) and increased amounts of collagen, elastic fibers and mucoid deposits. The lumen frequently appears significantly narrowed (8, 36). Abnormalities of coronary microcirculation have been implicated in the pathogenesis of myocardial ischemia (37) and sudden death (38-40) in patients with HCM and normal epicardial coronary arteries. This is supported by the observation that increased numbers of clusters of abnormal intramural arteries are often observed within or at the margins of sizable areas of fibrosis including regions of transmural infarction (41). In addition, clinical studies have demonstrated evidence of impaired coronary vasodilator reserve (42, 43), and reversible or irreversible thallium-201 perfusion defects (37-39) in patients with HCM and normal epicardial coronary arteries. The severity of impairment in coronary vasodilator reserve has been shown to correlate with the severity of microvascular abnormalities in endomyocardial biopsy samples from patients with HCM (44). Mechanisms other than "small vessel disease" have also been also implicated in pathogenesis of myocardial ischemia in HCM. These include reduced capillary density relative to muscle mass (43), subendocardial ischemia secondary to reduced coronary perfusion pressure (45), systolic compression of septal perforator coronary artery (46, 47), and intramyocardial course ("bridging") of major epicardial coronary arteries (48)

Figure 4. Photomicrograph of a section of left ventricular myocardium in HCM showing abnormal intramural coronary arteries with thickened walls and apparently narrowed lumens. Dense perivascular collagen (shown in red) surrounds the vessels. Collagen can also be seen within the wall of the vessels. Picrosirius red X200.

MITRAL VALVE ABNORMALITIES
   Primary abnormalities of the mitral valve and the subvalvular apparatus are characteristics of many patients with HCM (49,50). Roughly two-thirds of patients with HCM show abnormalities of size, shape or morphology of mitral valve at necropsy (49). The most common abnormality is an increase in mitral leaflet surface area largely due to leaflet elongation without evidence for myxomatous degeneration. In addition, the papillary muscles may show distinct abnormalities including direct insertion into anterior mitral leaflet (50). The latter may result in midcavitary LV obstruction (51). Occasional patient with HCM may have associated mitral valve prolapse (52) or rupture of chordae tendineae (53).

COLLAGEN MATRIX AND MYOCARDIAL FIBROSIS
   The cardiac collagen matrix, the fibrillar collagen network comprising the interstitium of the heart, is substantially expanded and morphologically abnormal in patients with HCM (7, Figures 5 and 6). The calculated volume fraction of interstitial collagen is about eight times greater than that of normal controls and three times greater than that of patients with systemic hypertension (7). Interstitial collagen comprises about 15% of ventricular septal tissue and thus, contributes to LV wall thickness in HCM (7). This expansion in matrix collagen is independent of other clinical and morphologic features of HCM, including age, sex, heart weight, segmental wall thickness and degree of regional myofiber disorganization (7). Qualitative assessment of matrix collagen in HCM demonstrates marked increase in number and size of transverse struts, pericellular weaves and intercellular perimysial coils. The perimysial coils also appear to be stretched. Substantial disorganization of collagen fibers is evident in myocardial regions with myofiber disorganization. Dense perivascular collagen often surrounds intramural coronary arteries and extends into the media of these vessels. These observations indicate that pathologic remodeling of collagen matrix is independent of cardiac muscle cell abnormalities in HCM. In addition, collagen matrix remodeling may contribute to LV diastolic dysfunction, small vessel disease, myocardial ischemia and sudden death in HCM.

Figure 5. Photomicrograph of a section of left ventricular myocardium demonstrating markedly expanded matrix collagen (in red) encasing myocytes. Picrosirius red X100.

Figure 6. Photomicrograph of a section of left ventricular myocardium in HCM viewed at high power (X1000) showing markedly thickened and stretched matrix collagen fibers among hypertrophied myocytes. Picrosirius red.

   In roughly two-thirds of patients with HCM a distinct mural plaque (composed primarily of dense fibrous tissue) is seen in the LV outflow tract. This is the result of repeated contact between mitral valve leaflet and septal mural endocardium. Although all patients with subaortic obstruction demonstrate this mural plaque at necropsy or on myectomy specimens, it may occur in those with non-obstructive HCM due to diastolic contact between septum and mitral leaflet.

   Myocyte necrosis and replacement fibrosis are also frequently found in the hearts of HCM patients who die suddenly. In addition, LV wall thinning with progression to end-stage, dilated-phase of cardiomyopathy has been observed in about 10% of patients with HCM (54). Necropsy studies have demonstrated extensive myocardial fibrosis in the hearts of such patients (55-59, Figures 7 and 8). Some of these patients have been successfully managed by cardiac transplantation (60).

Figure 7. Transverse sections of the explanted heart of a patient with end-stage, dilated-phase of HCM showing dilated and hypertrophied left and right ventricles with diffuse gross myocardial fibrosis (whitish patches).

Figure 8. Photomicrograph of left ventricular myocardial section in a patient with end-stage, dilated-phase of HCM demonstrating abnormal intramural coronary arteries and dense replacement fibrosis. Movat pentachrome X40.

   In addition to myocyte necrosis, ongoing loss of cardiac myocytes by apoptosis has been hypothesized as contributing to the progression of myocardial dysfunction in HCM. Indirect evidence for the role of apoptosis is provided by observations that: i) cardiac myocytes are able to recruit their genetic program of apoptosis (61), ii) stretch of adult mammalian myocardium (that resembles hemodynamic load) induces myocyte apoptosis in vitro (62), and iii) evidence for myocyte apoptosis is present in LV of patients with chronic CHF (63,64). Widespread myocyte apoptosis has been observed in the heart of a 16-year-old boy with HCM who had progressed from a non-dilated to dilated phase of the disease over a 10-year period (65). Interestingly, persistent elevation on cardiac enzymes had been documented during life in this patient. In a more recent study (66) extensive myocyte apoptosis was reported in endomyocardial biopsy samples obtained from 14 patients with HCM.

CONCLUSION
   HCM is a primary and genetically transmitted cardiac disease with heterogeneous clinical and morphologic profile. Numerous mutations involving the genes encoding cardiac sarcomeric proteins have been identified in individuals and families with HCM. The clinical presentation of the disease is quite variable but does closely parallel the extent and distribution of several characteristic cardiac morphologic abnormalities. Although some general tendencies, in regards to clinical presentation and cardiac morphologic features, have been noted in individuals with the same genetic defect, a firm relation between the two has not been established yet. A systematic search for environmental and genetic modifiers of HCM phenotype appears warranted.

Abbreviations:
CAD: Coronary Artery Disease
CHF: Congestive Heart Failure
HCM: Hypertrophic Cardiomyopathy
LV: Left Ventricle (Ventricular)
LVH: Left Ventricular Hypertrophy

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