Phenotypes of hypertrophic cardiomyopathy. An illustrative review of MRI findings
The purpose of this article is to review how cardiac MRI provides the clinician with detailed information about the hypertrophic cardiomyopathy (HCM) phenotypes, assessing its morphological and functional consequences.
An understanding of cardiac MRI manifestations of HCM phenotypes will aid early diagnosis recognition and its functional consequences.
• The phenotypic variability of HCM expands beyond myocardial hypertrophy, to include morphological and functional manifestations, ranging from subtle anomalies to remodelling of the LV with progressive dilatation and thinning of its wall.
• The stages of HCM, which are based on the clinical evidence of disease progression, include subclinical HCM, the classic HCM phenothype, adverse remodelling and overt dysfunction, or end-stage HCM.
• Cardiac MRI provides the clinician with detailed information regarding the HCM phenotypes and enables the assessment of its functional consequences.
KeywordsHypertrophic cardiomyopathy Phenotypes Magnetic resonance Heart
Implantable cardioverter defibrillator
LV outflow tract
Magnetic resonance imaging
Positron emission tomography
Systolic anterior motion
Sudden cardiac death
Single photon emission computed tomography
Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disease, defined by an increase in the left ventricular wall thickness (end-diastolic left ventricular wall thickness ≥ 15 mm or the equivalent relative to the body surface area in children) that is not solely explained by abnormal loading conditions. Lesser degrees of wall thickness (13–14 mm) can also be diagnostic of HCM, particularly when it is identified in family members [1, 2, 3]. In up to 60% of adolescents and adults, this disorder is an autosomal dominant trait caused by mutations in cardiac sarcomere protein genes [2, 4, 5].
The microscopic findings of HCM are characteristic with hypertrophy of the myocardial fibres, disorganisation of muscular bundles, interstitial fibrosis and dysfunction of the coronary microvasculature with increased wall thickening that leads to luminal narrowing, silent myocardial ischaemia, and myocardial injury and fibrosis .
HCM is characterised by diverse phenotypic expressions and a variable natural progression, which may range from dyspnoea and/or syncope to sudden cardiac death (SCD). HCM is the most common cause of SCD in young athletes [2, 3, 7, 8].
The phenotypic variability of HCM is not limited to only myocardial hypertrophy, but rather includes a set of morphological and functional manifestations, ranging from subtle anomalies to remodelling of the left ventricle (LV) with progressive dilatation and thinning of its wall that evolves to heart failure simulating a restrictive or dilated cardiomyopathy [8, 9, 10, 11, 12]. It is important to look for each of these phenotypic expressions to establish the diagnosis and define the importance of the disease [2, 8].
Cardiac MRI has emerged as an imaging modality particularly well-suited to characterise the phenotypic expression of HCM, providing more accurate wall thickness measurements and identifying patients with an increased risk for ventricular arrhythmias and thromboembolic stroke, as well as abnormalities that contribute to LV outflow tract (LVOT) obstruction and differentiating HCM from other causes of LV hypertrophy [3, 8, 13].
Additionally, contrast-enhanced cardiac MR with late-gadolinium enhancement (LGE) has the ability to identify areas of myocardial fibrosis/scarring that may be at increased risk for SCD, and it has implications for management strategies, such as primary prevention implantable cardioverter defibrillator (ICD) therapy [3, 8, 13, 14, 15].
The stages of HCM, which are based on the clinical evidence of disease progression, were previously defined by Olivotto et al. . These clinical stages include subclinical HCM, the classic HCM phenothype, adverse remodelling and overt dysfunction, or end-stage HCM.
Cardiac MR characteristics of different stages of HCM
Cardiac MR imaging
Late-gadolinium enhancement (LGE)
Morphological and functional features
% / LV mass
Normal/borderline myocardial hypertrophy
Mitral valve leaflets elongation
Normal LA diameter
Normal LV EF
LVOT obstruction (70%)
Mid or moderate LA dilatation
LV EF > 65%
Adverse remodelling (15–20%)
Progressive LV wall thinning
Reduction/loss of LVOT
Moderate/severe LA dilatation
LV EF: 50–65%
LV EF < 50%
Subclinical HCM refers to the detection of subjects who carry any stigmata of HCM causing gene mutation but who are without LV hypertrophy (genotype-positive, phenotype-negative subjects). In these patients, the risk for SCD is exceptional .
When genetic testing is negative or ambiguous (30 to 40% of patients), cardiac MR can demonstrate a degree of LV hypertrophy that is not fully appreciated by echocardiogram  and other abnormalities, such as myocardial crypts, elongated mitral valve leaflets and apical myocardial trabeculations [8, 9, 10, 11, 12, 13], expanded extracellular space (with T1 mapping) and LGE [17, 18]. These individuals should be periodically followed for the development of an increased LV wall thickness [4, 5, 19].
Myocardial clefts or crypts are congenital abnormalities related to myocardial fibre or fascicle disarray and have been described in healthy volunteers, as well as those with classic HCM (< 5%) [8, 20, 21].
These myocardial crypts should be differentiated from trabeculations characteristic of LV noncompaction, congenital LV diverticula and aneurysms.
Unlike crypts, trabeculations of LV noncompaction are parallel to the endocardial border and do not penetrate the normal compacted myocardium .
Congenital LV diverticula are characterised by an outpouching that contains endocardium, myocardium, and pericardium, and they are a narrow connection to the cavity and collapse at end-systole. The primary diagnostic feature to differentiate diverticula from crypts is that the congenital diverticula extend outside the epicardial border while crypts remain confined inside the myocardial margin .
Congenital LV aneurysm represents an outpouching containing endocardium, epicardium and thinned myocardium that shows akinetic or dyskinetic motion. A thinned myocardium shows LGE without pericardial enhancement [23, 24].
Mitral valve leaflets elongation
Other recent studies suggest that mitral valve elongation does not constitute the primary phenotypic expression of HCM and that the elongation of mitral valve leaflets in HCM seems to be associated with body size and left ventricular remodelling .
Left ventricular non-compaction is a genetically heterogeneous disorder and shares genetic mutations with HCM. Both entities can coexist and have been described as being associated with mutations in different sarcomeric genes .
The development of fibrosis is an important step in the LV remodelling process of HCM. Recent studies have demonstrated that HCM genotype-positive and phenotype-negative patients have increased levels of biomarkers of collagen deposition. This finding indicates that increased levels of profibrotic markers are also found in patients without ventricular hypertrophy, suggesting that hypertrophy is preceded by the fibrosis process. In genotype-positive, phenotype-negative HCM subjects, several cardiac MR studies found that the myocardial mid-wall LGE consistent with fibrosis was attributed to episodes of myocardial ischaemia due to coronary microcirculation remodelling . Other studies have shown that both native T1 values and extracellular volume (ECV) fraction obtained after gadolinium administration can detect diffuse interstitial fibrosis and are elevated in regions without LGE in subjects with a mutation known to cause HCM without sufficient phenotypic expression to diagnose the disease based on current imaging criteria .
Native T1 mapping and the ECV fraction could be used at the initial phase of HCM for the early detection of interstitial diffuse myocardial fibrosis in these patients and to monitor disease progression, as well as to evaluate novel disease-modifying therapy, targeting interstitial fibrosis [8, 17].
The diagnosis of mild HCM in young competitive athletes may be challenging when the LV wall thickness is between 13 and 15 mm (or 12 and 13 mm in women), which identifies the “grey-zone” of overlap between the physiological adaptations to training and mild phenotypic expression of the disease. In such instances, the diagnosis can often be resolved by applying noninvasive markers. HCM is favoured with the identification of a pathogenic sarcomere mutation or a family history of HCM, an abnormal LV filling/relaxation, small/normal size LV, myocardial crypts or LGE on contrast cardiac MR and response to detraining [30, 31].
Recent studies have shown that native T1 values and myocardial ECV by T1 mapping can be used in the differential diagnosis between HCM and an athlete’s heart. While the ECV fraction increases with increasing LV hypertrophy in HCM (due to extracellular matrix expansion and myocardial disarray), the ECV fraction reduces in athletes with an increasing wall thickness (due to an increase in the healthy myocardium by cellular hypertrophy) .
The classic and most common HCM phenotype (75%) consists of a hypertrophied, nondilated and hyperdynamic LV (ejection fraction > 65%), which arises during adolescence and is usually complete by young adulthood, though the onset of its phenotype may occur at virtually any age, including in utero and in those older than 60 years .
Distribution of hypertrophy
Left ventricular hypertrophy
The most common location of LV hypertrophy is the confluence of the basal anterior septum with the contiguous anterior free wall (70%) (Fig. 4b) [3, 8, 35]. The next most common segment with increased wall thickening is the posterior septum at the mid-LV level [27, 35].
The extent of hypertrophy is focal (involving fewer than three segments), intermediate (3–7 segments) or most common diffuse (more than seven segments) (Fig. 4a). Patients with LVOT obstruction shows hypertrophy of more segments . Massive hypertrophy is considered when the LV wall thickness is > 3 cm and it has important prognostic considerations. However, in approximately 20% of HCM patients, the LV mass index values are normal on cardiac MRI [8, 19].
Mid-ventricular HCM shows predominant hypertrophy at the mid-ventricular level. Patients with this type of HCM constitute an unusual and important group of patients because severe mid-ventricular HCM can cause ventricular arrhythmia, myocardial necrosis, and systemic embolism secondary to dynamic obstruction associated with apical aneurysm (Fig. 4c) [3, 36]. Contrast-enhanced cardiac MR has demonstrated that the aneurysm rim in these patients is composed predominantly of fibrosis that extends from the aneurysm rim into the septum and free wall (Fig. 4d) and serves as nidus for ventricular tachycardia .
Apical HCM (5–25%) shows a predominant apical distribution of hypertrophy with a characteristic spade-like configuration of the LV cavity and is usually associated with giant inverted anterolateral T-waves on the electrocardiogram (Fig. 4e) . The apical extension of LV hypertrophy is found in 10% of classic septal HCM patients, suggesting that both phenotypic expressions may coexist .
Right ventricular hypertrophy
Hypertrophy of the RV wall and RV muscle structures, such as that of the crista supraventricularis are common (Fig. 4f). Most HCM patients (53%) have diffuse RV hypertrophy involving all three segments of the RV, but a conspicuous proportion (47%) demonstrate RV hypertrophy confined to only the segments contiguous with the ventricular septum .
In HCM, reduced ventricular volumes are frequent and the hyperkinetic appearance of systolic contraction translates into a normal or supernormal ejection fraction (EF) (> 65%) until the end-stage of the disease . EF is, therefore, considered inadequate to evaluate the indication for medical treatment and cardiac transplantation .
Doppler parameters are accurate in evaluating diastolic function in HCM. Accurate measurements of transmitral and transpulmonary vein flow parameters using phase-contrast cardiac MRI are lower than those echocardiography, which is probably due to the lower temporal resolution of the breath-hold phase-contrast sequence. A new semi-automated, three-dimensional model-based analysis of the LV fillings curve showed a similar agreement with Doppler parameters .
In addition, myocardial tagging [39, 40] enables the quantification of cardiac strain evolution during late diastole, which can be used to assess diastolic myocardial dysfunction . However, despite recent advances of myocardial tagging methods, the fading of taglines due to T1 relaxation is a common inherent limitation of all existing methods, which also requires prolonged imaging acquisition and post-processing times .
Mitral valve apparatus
Abnormalities in the morphology and function of the mitral valve apparatus are now considered a phenotypic expression of HCM that is independent of the hypertrophy distribution .
LV outflow tract obstruction
LVOT obstruction is present in 70% of classic HCM phenotype patients and is associated with an increased risk for heart failure-related death [2, 8]. The mechanisms responsible for LVOT obstruction are related to complex anatomical relationships between the basal septum, LVOT, mitral valve, and papillary muscles [8, 41].
An elongated anterior mitral leaflet (Fig. 5a) is considered an important determination of LVOT obstruction, particularly in patients in whom the mitral leaflet length exceeds the transverse dimension of the outflow tract at end-systole 2-fold [3, 8, 11]. Systolic anterior motion (SAM) of the mitral valve refers to the paradoxical movement of the anterior leaflet and/or chordae toward the interventricular septum during systole. The precise mechanism of SAM in HCM remains unclear. Many investigators hypothesise that anterior mitral leaflet elongation and thickening and hypertrophy with anterior displacement of the papillary muscles contribute to the development of SAM. The resultant flow forces during systolic anterior motion pulling the leaflets into the LVOT in mid- and late-systole also result in reduced leaflet coaptation and a posteriorly directed mitral regurgitant jet (Fig. 5b) [25, 26].
Echocardiography remains the technique of choice to evaluate LVOT obstruction. However, cardiac MR-derived planimetry at the rest of the LVOT area during systole can identify obstructive HCM. A cutoff value of 2.7 cm2 has been reported as having an accuracy of 100% to differentiate obstructive from non-obstructive HCM . Moreover, cine MRI in a long-axis cine view can provide a more accurate evaluation of the mechanism of outflow tract obstruction, demonstrating turbulent flow generated by systolic movement of the anterior mitral leaflet, chordae, and papillary muscle toward the interventricular septum  (Fig. 6).
Left atrial size
The left atrium (LA) is often enlarged in HCM patients, and its size provides important prognostic information. An enlarged LA is related to an increased morbidity and mortality in cardiovascular patients, and it is considered a marker for risk for SCD and potentially lethal arrhythmic events among HCM patients [44, 45, 46].
Volumetric MR quantification is the best approach to assess the LA size, but it may be too time-consuming. An area ≧ 15 cm2/m2 and a transverse diameter ≧ 2.8 cm/m2 in the four-chamber view are valuable alternatives to identify LA enlargement .
The cause of LA enlargement is multifactorial, but the most common mechanisms are SAM-related mitral regurgitation and elevated LV filling pressures . Mild or moderate LA dilatation is common and is related to LV diastolic dysfunction . Severe LA dilattion is common when mitral regurgitation is associated with LVOT obstruction [8, 41].
Atrial fibrillation is the most common arrhythmia in HCM (20%) and LA remodelling is the strongest predictor of atrial fibrillation independent of age and functional class .
The hallmarks of HCM include LV hypertrophy, fibrosis and microvascular ischaemia, and whether there is a causative link between these features has not been determined to date .
Microvascular ischaemia in HCM, which is attributed to increased oxygen requirements due to hypertrophy, impaired ventricular relaxation, microvascular dysfunction of intramyocardial arterioles, and LVOT obstruction, is associated with chest pain, clinical deterioration, diastolic dysfunction, and an adverse prognosis [50, 51]. It is most pronounced in the hypertrophied segments and in gene-positive HCM patients .
Although microvascular dysfunction may precede clinical deterioration for several years and is present in all stages of HCM, it is not associated with evidence of permanent ischaemic damage and replacement fibrosis [16, 19].
The presence and severity of myocardial ischaemia and reduced myocardial blood flow can be diagnosed using non-invasive imaging modalities, including positron emission tomography (PET) , single photon emission computed tomography (SPECT)  and first-pass perfusion cardiac MR sequences [8, 54]. Myocardial perfusion defects are usually found at subendocardium (most common) or at mid-wall, and it correlates with the areas of maximal wall thickness .
Myocardial fibrosis in HCM is histopathologically diffuse in both the replacement and interstitial forms, and it is assumed to be a substrate for tachyarrhythmias and SCD. LGE essentially shows the focal distribution of fibrosis on cardiac MR, is present in less than half of those with the classic HCM phenotype and occupies a small percentage of the LV mass (median value: 2%) [16, 55], suggesting that collagen deposition at this stage reflects an exaggerated activation of the matrix rather than a reparative process .
Systemic hypertension can lead to concentric LV hypertrophy, and discriminating between HCM and hypertensive heart disease is a frequent dilemma in clinical practice. Unlike HCM, the LV wall thickness in hypertensive heart disease rarely exceeds 16 mm, and usually, there is no LGE .
Hypertrophy in amyloidosis is usually moderate and relatively concentric, involving both ventricles, atria, inter-atrial septum and valves. Amyloidosis displays a specific pattern of global or segmental subendocardial LGE and frequently atrial enhancement as well . In addition, the typical markedly elevated native T1 values contribute to differentiating amyloidosis from HCM .
Although SCD is infrequent in classic HCM (0.5–1%/year), the risk stratification for SCD should be performed in all patients with HCM due to the efficacy of the ICD in preventing SCD in this disease [1, 2, 44].
The major risk factors for SCD in HCM include a family history of SCD, age (< 40 years), unexplained syncope, an abnormal blood pressure response to exercise, nonsustained ventricular tachycardia, a maximal LV wall thickness > 30 mm, a LVOT gradient ≥ 30 mmHg at rest and the LA diameter [1, 2, 44]. Although current risk factor models, such as the American algorithm  and European Society of Cardiology HCM Risk-SCD calculator  are highly effective in identifying many patients with HCM who will benefit from ICD, some patients without conventional risk markers nevertheless remain at risk for SCD .
Currently, neither American guidelines nor the HCM Risk-SCD calculator incorporate LGE [1, 44]. However, multiple studies have demonstrated that LGE is correlated with areas of myocardial fibrosis as the arrhythmogenic substrate for ventricular tachyarrhythmias [27, 46, 67] and might be considered a potential risk modifier, particularly when it is seen in extensive areas of the myocardium (LGE ≥ 15% of the LV myocardium) [13, 14, 66, 68]. It has been postulated that T1 mapping may prove to be superior to LGE for risk stratification in HCM. However, to date, there has been no link between T1 mapping and cardiovascular outcomes within HCM .
Another imaging feature with a potential impact on the current risk stratification models could be the myocardial high T2 signal intensity areas. These areas have been related to markers of adverse disease progression, such as LGE, elevated troponin and non-sustained ventricular tachycardia  and they have been recently implicated as a potential tool for the prediction of SCD .
The diagnosis of adverse remodelling is important because it can alter management strategies including the consideration of prophylactic ICD, and timely evaluation for heart transplantation, before symptoms develop .
A small distinctive group of HCM patients (5–10%) will develop the high-risk phenotype of end-stage disease, which is characterised by progressive LV wall thinning, LV dilatation, a decrease or disappearance of LVOT gradients and LV systolic (EF < 50%) and diastolic dysfunction [8, 16, 62, 73].
Most end-stage HCM patients show mid-wall or transmural LGE (75–100%) [8, 14]. The extent of LGE often exceeds that observed in any other cardiovascular disease (>25% of the LV mass) , and it is more extensive in those with ventricular remodelling and the LA is larger in those with a normal ventricular size [8, 27, 72].
The phenotypic expression of HCM includes a wide variety of morphological and functional manifestations that may lead to severe left ventricular wall remodelling.
Cardiac MRI provides the clinician with detailed information regarding the HCM phenotypes and enables the assessment of its functional consequences elucidating the causes and site of hypothetical dynamic obstruction, the presence and extent of myocardial perfusion abnormalities and the existence of fibrosis.
This review was presented in part as an educational exhibit at the 2016 RSNA Scientific Assembly, Chicago IL as: Cristina Méndez, Susana A Otero Muinelo, Tania Pérez Ramos, Rafaela Soler, Esther Rodríguez, Roberto Barriales Villa, Juan Pablo Ochoa, Lorenzo Montserrat Iglesias. MRI of Hypertrophic Cardiomyopathy: Phenotypes and Phenocopies. Abstract available at: archive.rsna.org/2016/16013821.html
R. Barriales-Villa and Lorenzo Monserrat are part of a cardiovascular research network CIBER in Cardiovascular Diseases (CB16/11/00425).
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