OBJECTIVE. We present a two-part review about the use of MRI in patients with hypertrophic cardiomyopathy (HCM). This article, Part 1, focuses on the MRI appearances of HCM.
CONCLUSION. MRI has proven to be an important tool for the evaluation of patients suspected of having HCM because it can readily diagnose those with phenotypic expression of the disorder and can potentially identify the subset of patients at risk of sudden cardiac death.
Cardiovascular MRI is now accepted as a valuable tool in the initial assessment and follow-up of many acquired and congenital disorders. In particular, assessment of cardiomyopathies with MRI has been successful owing to its unique ability to depict different enhancement patterns in diseased myocardium on inversion recovery delayed gadolinium-enhanced images. We present a two-part review about the use of MRI in hypertrophic cardiomyopathy (HCM). Part 1 of the review focuses on the MRI appearances of HCM. Part 2 of the review covers the differential diagnosis, risk stratification, and posttreatment MRI follow-up appearances in these patients .
HCM is defined as a primary disease of the cardiac sarcomere that leads to cardiac hypertrophy. It is the most common inheritable cardiac disorder, with an estimated prevalence of 1:500 [2–5]. HCM is characterized by left ventricular hypertrophy (LVH) with occasional involvement of the right ventricle. Familial disease with autosomal dominant inheritance predominates . There is a broad range of phenotypic expressions with asymmetric involvement of the interventricular septum being the most common pattern. MRI has proven to be an important tool for the evaluation of patients suspected of having HCM because it can readily diagnose those with phenotypic expression of the disorder and can potentially identify the subset of patients at risk of sudden cardiac death.
HCM is the most common inheritable cardiac disorder with an estimated prevalence of 1:500. The mode of inheritance is autosomal dominant in approximately 50–60% of the cases. Currently, 10 genes have been implicated and more than 150 mutations have been characterized, all relating to the cardiac sarcomere [2–5]. These mutations typically cause an increase in myocyte stresses and impaired function that eventually lead to hypertrophy and fibrosis . Not surprisingly, the disease has a wide variability in penetrance and in phenotypic expression leading to a great variability in imaging appearances.
Most cases of HCM are phenotypically expressed in adolescence or early adulthood; however, research has shown age-related penetrance with certain phenotypes in which the delayed and de novo emergence of LVH occurs in midlife or even later [7, 8].
Most of the clinical manifestations of the disease involve either diastolic or systolic dysfunction, left ventricular outflow tract (LVOT) obstruction, arrhythmias, and sudden cardiac death.
The heterogeneity of HCM is well appreciated by reviewing its wide variation in morphologic expression. Asymmetric involvement of the interventricular septum is the most common form of the disease. Other variants include symmetric, apical, and masslike LVH and an end-stage form, known as the “burned out phase,” that is characterized by progressive wall thinning and systolic dysfunction. Right ventricular involvement occurs in approximately 17.6% of all cases of HCM, most commonly involving the mid to apical portion of the right ventricle [4, 9]. A more in-depth discussion of the various gross appearances of HCM is included later in this article.
In HCM, myocytes show hypertrophy and disarray, with bizarre enlarged nuclei, hyperchromasia, and pleomorphism. The histologic criteria for the diagnosis of HCM require disarray of at least 5–10% of the myocytes within the interventricular septum . Diagnostic pitfalls include patchy myocardial involvement that leads to false-negative biopsies (sampling errors).
Determination of which myocardial segments are involved before biopsy may provide the interventional cardiologist with the ability to perform a targeted biopsy, thus potentially improving sampling. Unfortunately, myocyte disarray is not specific for HCM and may be seen in many common cardiovascular diseases and even in the normal heart, where it is usually found at the points at which the right ventricle interdigitates with the left ventricular septum. In these locations, the normal disarray is accompanied by increased interstitial adiposity [3, 4].
HCM also affects small intramural coronary arteries. Typical appearances include reduced arteriolar density and intimal and medial smooth-muscle hyperplasia, with many vessels showing dense perivascular collagen deposition [3, 4].
How to Image
Although echocardiography is an excellent technique to use for the assessment of patients with HCM, it is occasionally limited by poor acoustic windows, incomplete visualization of the left ventricular wall, and inaccurate evaluation of left ventricular mass [10, 11].
MRI has the ability to evaluate wall thickness and the distribution of disease better than echocardiography, especially in the anterolateral wall of the left ventricular myocardium [11, 12]. MRI's ability to more accurately assess left ventricular wall thickness is important in evaluating myocardium greater than 30 mm , a key prognostic indicator that we discuss later in this article.
MRI also has the ability to more accurately evaluate left ventricular mass, volumes, and function than echocardiography and to assess for areas of regional wall motion abnormalities, aneurysms, and foci of delayed enhancement [10, 11].
At our institution, imaging begins with acquisition of an abbreviated set of ungated localizer images in all three planes. From these images, the imaging planes for the left ventricle are determined. Vector ECG-gated steady-state free precession (SSFP) pulse sequences are used to assess the heart as a stack of contiguous images in the short-axis oblique, four-chamber, vertical long-axis, and LVOT imaging planes. Fast cine phase-contrast imaging is then performed in the LVOT plane. After that sequence, gadolinium is administered and delayed imaging of the myocardium is performed in the short-axis oblique, four-chamber, and vertical long-axis planes.
Postprocessing and Image Analysis
Left ventricular wall thickness should be calculated during end-diastole, preferably in the short axis for assessment of the mid to basal thirds of the left ventricular myocardium. The vertical and horizontal long-axis planes are useful in evaluating wall thickness at the left ventricular apex. Measurements of thickness in these planes, however, should be made with care. Images chosen for measurement should be cross-referenced with another view to avoid obliquity because only a slice that perpendicularly transects the left ventricular wall will yield accurate measurements . Care should also be taken to exclude free muscle bundles when measuring wall thickness.
Measurements of left ventricular volumes, function, and mass are derived from an SSFP pulse sequence in the left ventricular short-axis oblique plane. Techniques for performing these measurements have been well described previously [14–16]. The decision to either include or exclude papillary muscles in measurements of left ventricular end-diastolic volume, end-systolic volume, or mass differs among institutions.
Assessment of regional wall motion abnormalities is generally made by visual inspection alone. In some centers, research protocols may include complementary spatial modulation of magnetization (CSPAMM), which is otherwise known as “myocardial tagging,” to assess for regional wall motion. Although fractional shortening can be formally measured, these measurements are not performed routinely in most clinical practices .
Asymmetric disease is the most common morphologic presentation of HCM with the anteroseptal myocardium being the most commonly hypertrophied segment [10, 12]. Clinically, patients may be asymptomatic or may present with dyspnea, presyncope or syncope, or angina .
Asymmetric septal wall hypertrophy causes obstruction of the LVOT in 20–30% of the cases [3, 4, 17]. This obstruction may be present when the patient is at rest or may be latent (provocable) or labile (variable) . The severity of the obstruction can be affected by ventricular afterload (systolic blood pressure), preload, and contractility . Sudden standing, eating a large meal, or drinking alcohol, for example, may cause a drop in afterload .
Although previously subject to periodic controversy, a gradient of 30 mm Hg or more is now generally recognized to be of pathophysiologic and prognostic importance [18, 19]. Peak outflow tract gradients can be estimated using phase-contrast MRI; however, these gradients are currently better assessed using echocardiography because of its higher temporal resolution when measuring peak instantaneous velocities. Efforts to improve flow measurements on MRI are focused on both improving the temporal resolution of phase-contrast imaging and developing new techniques, such as real-time Fourier velocity encoding .
Evaluation of left ventricular functional parameters shows that mass measurements may not necessarily be greater in patients with asymmetric HCM than in those with a normal heart. Although the left ventricular ejection fraction (LVEF) is typically preserved in asymmetric HCM, subtle evidence of regional wall hypocontractility that can be quite variable may be present . The results of a study by Sipola et al.  suggest that impaired contractility may precede findings of hypertrophy, with a progressive decline in systolic function accompanying more marked LVH.
Delayed enhancement of the left ventricular myocardium occurs in up to 80% of all patients with HCM and is usually patchy and mid wall in location [21, 22]. We discuss this topic separately later in this article.
Abnormalities of the mitral valve may occur because of a primary abnormality of the valve itself or as a result of an LVOT obstruction. Systolic anterior motion of the mitral valve is due to the portion of the anterior mitral leaflet distal to the coaptation point being displaced into the LVOT by venturi or drag forces (Figs. 1, 2A, 2B, 2C, 2D, 3A, 3B, 3C, 3D). Over time, the systolic anterior motion of the mitral valve leads to a subaortic mitral impact lesion on the septum, which undergoes fibrosis; thickening of the anterior mitral leaflet and chordae from the resultant trauma; a posteriorly directed mitral regurgitant jet into the left atrium; and a systolic gradient along the LVOT [3–5]. If the mitral regurgitant jet is either anteriorly or centrally placed, other structural abnormalities such as prolapse or leaflet restriction should be excluded [3, 5]. These other abnormalities of the mitral valve occur in approximately 20% of patients with subaortic obstruction and include abnormal insertion of the papillary muscles, mitral valve prolapse, or excessive fibrotic thickening of the anterior mitral valve leaflet .
Diastolic Dysfunction and the Left Atrium
Diastolic dysfunction is thought to occur secondary to abnormal dissociation of actin and myosin filaments during the active phase of relaxation in early diastolic filling and to left ventricular myocardial properties that affect passive characteristics of late diastole, such as the widespread increased volume of the intercellular collagen network . This dysfunction may also result in a restrictive picture. Mitral regurgitation from systolic anterior motion or from morphologically abnormal mitral valve leaflets may also contribute to left atrial dilatation . Patients with left atrial enlargement may then subsequently develop atrial fibrillation . Stretch and distention of the atrial appendage have been shown to perhaps be related to the onset of atrial fibrillation due to an increase in the dispersion of the atrial effective refractory period .
Tani et al.  found that an increase in left atrial volume and, to a lesser extent, in left atrial diameter correlated well with the presence of paroxysmal atrial fibrillation. They concluded that left atrial enlargement may be used to help predict which patients with HCM will likely develop atrial fibrillation. This distinction among HCM patients is important because the presence of atrial fibrillation reduces left ventricular pre-load and may lead to cardiac failure and systemic thromboembolism .
Symmetric HCM is said to occur in up to 42% of HCM cases . This entity should be evaluated closely to differentiate it from other causes of symmetric left ventricular thickening, which we discuss in more detail in Part 2.
Apical HCM was originally described in individuals of Asian descent but is now being increasingly diagnosed in Western populations [4, 5]. Reports of the rate of occurrence of apical HCM vary in the literature, ranging from 25% of all patients with HCM in Japan to fewer than 2% of HCM patients in Western countries . Wigle  reported an incidence of 9% in an HCM population in a clinic in Toronto.
ECG findings of giant negative T waves in the precordial leads raise initial suspicion of apical HCM in up to 50% of cases in some studies [5, 26] (Fig. 4). The diagnosis of apical HCM can occasionally be difficult on echocardiography. MRI plays an important role in the diagnosis and exclusion of other diseases and abnormalities that mimic apical HCM on echocardiography .
Diagnostic criteria for apical HCM reported in the literature include an absolute apical wall thickness of > 15 mm or a ratio comparing apical left ventricular and basal left ventricular wall thicknesses of ≥ 1.3–1.5 [27, 28]. More subjective criteria for the diagnosis of apical HCM include obliteration of the left ventricle apical cavity in systole and failure to identify a normal progressive reduction in left ventricular wall thickness toward the apex (Figs. 5A, 5B and 6A, 6B).
Moon et al.  found that 10 patients with a history of ECG abnormalities (i.e., antero-lateral T wave inversion) and negative findings for apical HCM on echocardiograms had positive MRI findings for apical HCM, with one patient having a left ventricular wall thickness of 28 mm on MRI. They found no evidence of a correlation between the extent of repolarization abnormality and the degree of morphologic severity .
The characteristic spadelike configuration of the left ventricular cavity initially described in angiographic studies is well appreciated on left ventricular vertical long-axis views on MRI [26, 28] (Fig. 5A, 5B).
Concomitant apical involvement of the right ventricle is also commonly seen (Fig. 6A, 6B).
Other common findings include apical aneurysm formation with delayed enhancement, which is sometimes referred to as a “burned out apex”  (Fig. 7A, 7B, 7C, 7D). This process is thought to be due to ischemia that results from reduced capillary density, hyperplasia of the arterial media, increased perivascular fibrosis, and myocardial bridging . This process usually occurs in the presence of normal epicardial coronary arteries.
HCM with Midventricular Obstruction
This variant of asymmetric HCM, predominantly involving the middle third of the left ventricle, may result in severe midventricular narrowing and obstruction. HCM with midventricular obstruction may be associated with the formation of an apical aneurysm, which is thought to result from the generation of increased systolic pressures within the cardiac apex from the midventricular obstruction. A similar appearance may be due to a burned out apex, as is seen in the apical variant [4, 5] (Fig. 7A, 7B, 7C, 7D).
Patients with HCM occasionally present with a masslike thickening of the left ventricle. This scenario may cause difficulties in diagnosis. In theory, a true mass will have no contractile portion to it, whereas HCM will show variable degrees of contractility. MR tagging by spatial modulation of magnetization has been used to assess for tag displacement and deformation. Tag deformation should be identified in hearts with HCM but should not be noted in neoplastic masses . This technique has yet to be thoroughly investigated, however, and care should be made to distinguish minimal contraction from scant residual normal myocardium in the setting of infiltrative processes such as lymphoma, amyloid, or sarcoid.
Perhaps more useful than this tag deformation is signal characterization of the myocardium with double inversion recovery or spin-echo imaging using varying tissue weighting and observing perfusion of the area with first-pass perfusion and delayed enhancement techniques. Masslike HCM more precisely parallels the homogeneous signal characteristics and perfusion of adjacent normal myocardium (Fig. 8A, 8B, 8C, 8D, 8E, 8F), whereas tumors often show varying degrees of signal heterogeneity before and after gadolinium administration and show perfusion characteristics that differ from those of the remainder of the left ventricle.
Burned Out Phase
The burned out phase occurs in up to 10% of patients with HCM and severe cardiac symptoms. It is characterized by left ventricular dilatation and by loss of myocardium and replacement fibrosis, which are thought to be due to small-vessel ischemia [4, 30, 31].
The burned out phase may present as a localized process with an appearance similar to that of a myocardial infarct but with normal epicardial coronary arteries, as seen in Figure 7A, 7B, 7C, 7D, or as a more diffuse end-stage process with an appearance similar to that of a dilated cardiomyopathy. Little has been written in the literature regarding the cardiac MRI appearances of diffusely burned out end-stage HCM.
It has been well established that delayed enhancement of the myocardium using a segmented inversion recovery pulse sequence can differentiate between normal and infarcted myocardium or fibrosis . Delayed enhancement is thought to occur in areas of abnormal myocardium secondary to expansion of the extracellular space, alterations in the extracellular matrix composition, and altered distribution kinetics [32–34].
Delayed enhancement occurs in up to 80% of patients with HCM [21, 22]. The most common form of hyperenhancement in HCM is patchy and mid wall in location. Teraoka et al.  found delayed enhancement in 75% of patients with HCM, 89% of whom had patchy mid-wall-type enhancement (Figs. 2A, 2B, 2C, 2D and 9).
The various proposed histologic correlates of enhancement in HCM include plexiform fibrosis (fibrosis seen in HCM in areas of myocyte disarray), expanded interstitial spaces, and microscopic replacement fibrosis due to ischemia [22, 27–39]. However, Mahrholdt et al.  have suggested that areas of visually detected delayed enhancement are most likely explained by macroscopic replacement fibrosis and that enhancement secondary to diffuse interstitial processes, such as plexiform fibrosis, is less likely to cause recognizable differences in regional signal intensity.
In a case study, Moon et al.  compared the MRI findings and histology results of an explanted heart with HCM and found that an increased percentage of histologic collagen correlated directly with increased delayed enhancement of the myocardium. Those researchers also found that increased enhancement was associated with an increased incidence of regional wall motion abnormalities . Other studies have also shown a significant decrease in global and regional cardiac function in patients with increasing volumes of delayed enhancement [21, 35, 41, 42].
Delayed enhancement tends to involve the interventricular septum, particularly the anteroseptal mid to basal segments. These segments are also the most commonly thickened segments in patients with asymmetric HCM [35, 42, 43]. If abnormal enhancement occurs elsewhere outside the interventricular septum, it also tends to occur in areas of maximal left ventricular thickness.
As we mentioned earlier, delayed enhancement that occurs in areas of hypertrophy tends to be mid wall and patchy in distribution. Another interesting feature of delayed enhancement in HCM is a predilection for enhancement to occur at the anterior and posterior right ventricular insertion points (Figs. 2A, 2B, 2C, 2D and 9). An exception to this is in areas of burned out myocardium where the left ventricular wall is typically thinned and enhancement is full thickness  (Fig. 7A, 7B, 7C, 7D).
Delayed enhancement in areas of burned out myocardium bares striking similarity to delayed enhancement in patients with chronic myocardial infarction secondary to coronary artery disease. This type of enhancement however may not necessarily conform to a particular vascular territory. The postulated causes of ischemia in patients with HCM and normal epicardial coronary arteries include reduced capillary density; hyperplasia of the arterial media; increased perivascular fibrosis, leading to reduced coronary vasodilator reserve; and myocardial bridging .
Investigators have noted that in patients without LVH there is usually no enhancement. Lack of enhancement in this population suggests that regions of delayed enhancement occur only after the development of LVH, although this theory has yet to be proven across all the many genotypic variants of LVH .
Despite the low yield for discovering delayed enhancement in patients with only minimally thickened left ventricular myocardium, administration of gadolinium remains useful in differentiating other causes of thickened left ventricular myocardium that show characteristic patterns of enhancement. Examples include cardiac involvement by amyloid and Fabry's disease, both of which are discussed in Part 2 .
The presence of delayed enhancement and its relationship to patients with an increased risk of sudden cardiac death as established by traditional risk factors [21, 22, 34, 44] are elaborated on in Part 2  also.
This section completes Part 1 of this two-part review on MRI of HCM. This article focuses on the abnormalities and imaging characteristics of HCM, along with a discussion about its various morphologic subtypes and the all-important topic of delayed enhancement. The significance of delayed enhancement imaging in HCM is emphasized in Part 2 , which addresses the topics of sudden cardiac death and risk stratification. Part 2 also deals with the differential diagnosis and posttreatment follow-up of this disorder.
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