Differential diagnosis of thickened myocardium: an illustrative MRI review
The purpose of this article is to describe the key cardiac magnetic resonance imaging (MRI) features to differentiate hypertrophic cardiomyopathy (HCM) phenotypes from other causes of myocardial thickening that may mimic them.
Many causes of myocardial thickening may mimic different HCM phenotypes. The unique ability of cardiac MRI to facilitate tissue characterisation may help to establish the aetiology of myocardial thickening, which is essential to differentiate it from HCM phenotypes and for appropriate management.
• Many causes of myocardial thickening may mimic different HCM phenotypes.
• Differential diagnosis between myocardial thickening aetiology and HCM phenotypes may be challenging.
• Cardiac MRI is essential to differentiate the aetiology of myocardial thickening from HCM phenotypes.
KeywordsCardiac magnetic resonance Hypertrophic cardiomyopathy Myocardial thickening Myocardial hypertrophy Cardiomyopathies
Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disorder worldwide, with a prevalence of 1 in 500 in the general population . It is characterised by an unexplained left ventricular (LV) hypertrophy in the absence of other disease entities that may lead to inappropriate myocardial wall thickening caused by pressure/volume overload, infiltrative disorders, athlete’s heart or neoplastic infiltration [2, 3, 4, 5]. For HCM diagnosis, international guidelines advocate using a wall thickness cut-off of 15 mm in one or more myocardial segments, measured by any imaging technique [6, 7].
Echocardiography is the most commonly used imaging modality in the evaluation of HCM. When the HCM phenotype is fully expressed, echocardiography generally allows a reliable and unequivocal diagnosis. Occasionally, however, the differential diagnosis among the broad range of phenotypic expressions of HCM and other causes of myocardial thickening may be challenging. Tissue characterisation, which is limited with echocardiography, could provide additional diagnostic information .
Cardiac magnetic resonance imaging (MRI) has evolved into a multiparametric imaging modality allowing a truly comprehensive picture of HCM, providing information regarding various phenotypes, their functional and haemodynamic consequences, presence and extent of microvascular dysfunction and myocardial fibrosis . The tissue characterisation capabilities of cardiac MRI may help to differentiate HCM from other causes of myocardial thickening and to determine an appropriate treatment strategy [4, 5, 8, 9].
The aim of this article is to illustrate and review the contributions of cardiac MRI to the differential diagnosis among HCM phenotypes and other causes of myocardial thickening.
There is a broad range of phenotypic expressions of HCM. Asymmetric involvement of the interventricular septum is the most common pattern (60–70%), followed by symmetric or concentric myocardial hypertrophy (up to 40%) and the less common apical variant [4, 8].
Summary of most common differential diagnosis of HCM phenotypes
MRI clues suggesting HCM
Mild wall hypertrophy
Increased ventricular volume
Normal diastolic function
Absence of LGE
Detraining can regress the hypertrophy and ventricular volume
Asymmetric wall hypertrophy
Small/normal ventricular size
Diastolic LV dysfunction
LGE can be present
Mild wall hypertrophy
Elevated indexed LV mass
Increased ventricular volume
Uncommon mid-wall LGE
Regression of LV hypertrophy after systolic blood pressure control
Asymmetric wall hypertrophy
Normal indexed LV mass
Small/normal ventricular size
Patchy LGE most common
Mild/moderate wall hypertrophy
Turbulent flow jet across aortic valve
Diffuse subendocardial or mid-wall LGE
Normal aortic root and valve
Subaortic turbulent flow jet in obstructive HCM
Patchy and extensive LGE most common
Marked wall thickness
Dilatation of both atria
Thickening of atrial free wall, interatrial septum and valves
Difficult to find the optimal inversion time for nulling the normal myocardium
Diffuse, subendocardial or transmural LGE
Asymmetric wall thickness
Left atrial dilatation
Spared atrial wall, interatrial septum and valves
Endocardial LGE is rare
Basal septal thinning
Aneurysms and ventricular dysfunction
Myocardial oedema at T2-w
T2 mapping: early detection and follow-up during treatment
Basal septal and lateral epicardial LGE
Myocardial oedema at T2-w is uncommon
Patchy mid-wall or RV insertion points of ventricular septum LGE
Delayed-enhancement image: very dark thrombus
Delayed-enhancement image: greyish myocardium
Patchy mid-wall or RV insertion points of ventricular septum LGE
Apical and mid-wall trabeculations with spared of interventricular septum
Non-compacted end-diastolic thickness > 2.3 compacted thickness
Cine SSFP images: high signal intensity of intertrabecular recess
Apical myocardial thickening
Cine SSFP images: endocardial smooth surface
Obliteration of the apical cavity
Subendocardial and triple-layered LGE
Apical myocardial thickening
Patchy mid-wall LGE
Concentric LV thickening
HCM with concentric LV hypertrophy should be differentiated from other causes of symmetrical myocardial hypertrophy, including mild (athlete’s heart) and mild or moderate (hypertensive heart disease and aortic stenosis) and from other causes of myocardial thickening (cardiac amyloidosis).
The term ‘athlete’s heart’ refers to a clinical picture characterised by two distinct and specific cardiac effects induced by a sustained and regular physical training programme, namely, slow heart rate and enlargement of the heart. Increased of LV size and LV hypertrophy are generated in order to normalise LV wall stress. The need for reliable methods to differentiate physiological from pathological LV hypertrophy are brought into focus by the rare but prominent cases of sudden death in elite athletes and the young .
Patients with HCM have LV hypertrophy with diastolic dysfunction from increased muscle stiffness leading to impaired myocardial relaxation; the ventricular volumes are frequently reduced and the hyperkinetic appearance of systolic contraction translates into a normal or supernormal ejection fraction until the end stage of the disease [1, 4, 15]. Unlike HCM, LV diastolic function is normal in athlete’s heart [10, 11].
Late gadolinium enhancement (LGE) is typically absent (Fig. 1c). Although studies have described small spots of LGE in the septum at the right ventricle (RV) insertion site in athlete’s heart [16, 17], attributed to repetitive myocardial microtrauma, pulmonary artery pressure overload with dilated RV, genetic predisposition and silent myocarditis . On the contrary, the presence of LGE would be suggestive of HCM rather than athletic adaptation .
Recent studies have shown that native T1 values and myocardial extracellular volume (ECV) by T1 mapping can be used in the differential diagnosis between HCM and 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) .
Practical recommendations: As a general rule, the development of physiological LV hypertrophy in the context of athlete’s heart is consistently associated with an LV cavity—a difference from HCM. When the differential diagnosis remains still unresolved, serial echocardiography or cardiac MRI after exercise detraining (3 months) may show regression of LV hypertrophy and reduction in LV end-diastolic volume in most athletes.
Hypertensive heart disease
Arterial hypertension is the most common cause of cardiovascular death. It may lead to hypertensive heart disease and it isthe most common cause of increased afterload that leads to heart failure, ischaemic heart disease and LV hypertrophy .
Cardiac MR provides a comprehensive non-invasive evaluation of hypertensive heart disease, including accurate and reproducible assessment of global and regional biventricular function, valvular disease and myocardial fibrosis [21, 22].
In hypertensive heart disease, compensatory LV hypertrophy in response to increased afterload is usually concentric and mild (≤ 13 mm) with an increased indexed LV mass, increased chamber volumes and normal or reduced ejection fraction [5, 21, 23]. Diastolic dysfunction and/or heart failure with preserved ejection fraction due to remodelling of the extracellular matrix and increase in LV filling pressures are common in concentric LV hypertrophy [21, 24]. Myocardial fibrosis plays an important role in the development of diastolic dysfunction. Mid-wall LGE has been documented in patients with hypertensive heart disease, although its prevalence is lower than in HCM patients .
The absence of LGE does not equate to the absence of myocardial fibrosis because this LGE identifies focal replacement fibrosis but fails to demonstrate diffuse fibrosis. T1 mapping techniques provide quantification of the myocardial intra and extracellular compartments, and native T1 has demonstrated increased diffuse myocardial interstitial fibrosis at an early stage in hypertensive heart disease patients who do not yet exhibit LGE abnormalities. These abnormalities are associated with decreased LV global function and LV remodelling [25, 26].
Practical recommendations: Independent predictors of hypertensive heart disease rather than HCM are elevated indexed LV mass, absence of myocardial LGE or less pronounced patchy myocardial LGE in hypertensive heart disease than seen in HCM.
Aortic stenosis causes a LV pressure overload leading to structural, functional and molecular changes in the process of myocardial hypertrophy. Untreated hypertrophy leads over a longer period of time to ventricular dysfunction that is irreversible and is associated with advanced remodelling .
Typically, aortic stenosis presents with mild or moderate concentric hypertrophy because of LV pressure overload with normal LV ejection fraction; however, recent studies have also demonstrated the existence of asymmetrical patterns . Progressive myocardial fibrosis drives the transition from hypertrophy to heart failure in aortic stenosis. Myocardial fibrosis detected by LGE is common and is usually seen in the basal segments, in a diffuse subendocardial or mid-wall distribution. It is irreversible following valve intervention in aortic stenosis and is considered a direct marker of the LV decompensation .
Practical recommendations: Aortic stenosis is readily evaluated on phase-contrast cardiac MRI, and evidence of this finding should be sought when imaging patients for suspected HCM.
Cardiac amyloidosis is a rare but important phenocopy of HCM characterised by extracellular deposition of monoclonal light chain or transthyretin amyloid and symptoms of heart failure with preserved ejection fraction. Cardiac involvement in amyloidosis significantly worsens prognosis of the disease. Endomyocardial biopsy is considered the “gold standard” in the diagnosis of cardiac amyloidosis. However, the relatively high risks and clinical complications may hinder its widespread use in clinical settings .
Cardiac MRI with LGE provides unique information regarding myocardial tissue characterisation and it is extremely helpful in differentiating cardiac amyloidosis from HCM. Due to interstitial expansion from amyloid deposition, LGE is seen in 69–97% of all cardiac amyloidosis patients [5, 32].
Alterations in gadolinium kinetics in the blood and myocardium are common and can be useful in differentiating cardiac amyloidosis from HCM . The high tissue uptake and faster washout of gadolinium from blood and myocardium may result in perceived difficulties in selecting an appropriate inversion time to null the myocardial signal on the delayed enhancement imaging pulse sequence [32, 35]. At 4 min after gadolinium administration, the inversion time of myocardium affected by amyloid is shorter than normal and lengthened with time. T1 values of subendocardium and subepicardium are similar between 8 and 10 min after gadolinium administration owing to altered contrast agent kinetics and therefore imaging must be performed earlier than usual and completed quickly  (Fig. 5).
In cardiac amyloid disease, the deposition of the abnormal protein typically occurs in a circumferential manner starting in the endocardium and then extending to the myocardium in a transmural fashion. Characteristic patterns of myocardial enhancement include global, subendocardial and, less often, patchy or diffuse LGE distribution within the LV (Fig. 4d, e) [32, 33, 36, 37]. Recently, lower LGE in the apical myocardial segments compared to the basal segments has been reported .
Practical recommendations: Late imaging with inversion recovery should be performed at 4 min and completed quickly to identify myocardial amyloid deposition.
Asymmetric LV thickening
Asymmetric LV hypertrophy is the most common phenotypic expression of HCM, which typically involves the basal ventricular septum. Infiltrative cardiomyopathies usually cause symmetrical LV wall thickening; however, occasionally cardiac sarcoidosis may manifest as asymmetric LV wall thickening simulating HCM.
Sarcoidosis is a multisystem disorder of unknown aetiology that is characterised histopathologically by non-caseating granulomatous infiltration. Cardiac involvement is common (50%), but only 5% of patients are symptomatic and may initially manifest with arrhythmias or even sudden cardiac death .
Disease may involve either the left or right ventricle but more commonly involves the LV, usually the basal septum; nevertheless, involvement of RV free wall, atrium, pericardium and endocardium can also be seen [39, 40].
Abnormalities of cardiac sarcoidosis tend to be non-specific and variable; interventricular thinning (particularly basal) is the most typical feature of cardiac sarcoidosis . There may be other abnormalities, such as aneurysms, LV and/or RV diastolic and systolic dysfunction, regional wall motion abnormalities, LGE and myocardial oedema [39, 40].
The appearance of sarcoidosis at cardiac MRI largely depends on the timing of imaging. In the acute phase of disease, myocardial inflammation or oedema manifests as myocardial thickening and patchy increased signal intensity on T2-weighted images and T2 mapping. Recent studies have shown that T2 mapping seems to serve as a novel quantitative biomarker to detect myocardial inflammation in systemic sarcoidosis and during the follow-up of the disease. T2 values are higher in cardiac sarcoidosis than in patients without cardiac involvement and decrease in response to anti-inflammatory treatment. .
LGE MR images in patients with sarcoidosis typically show a patchy mid-myocardial, subepicardial or epicardial pattern that is not in a vascular distribution, most often seen in basal segments (particularly of the septum and lateral wall) and typically in the epicardium and mid myocardium . In chronic disease, nodular foci of LGE indicative of fibrosis and scar formation without corresponding T2-weighted signal intensity may be present [39, 41, 42].
Practical recommendations: T2 mapping can be useful for early detection of cardiac involvement in systemic sarcoidosis and for monitoring the activity of myocardial inflammation during the follow-up of the disease.
Apical LV thickening
The differential diagnosis of apical HCM includes mural thrombus, hypertrabeculation or non-compaction and endomyocardial fibrosis. These entities may be diagnosed on MRI using steady-state free precession (SSFP) imaging techniques and LGE imaging.
Practical recommendations: Late imaging with inversion recovery should be performed with a long inversion time (500–600 ms). At this time, the signals of thrombi are very dark.
Patients may have no symptoms or may present with heart failure, atrial and ventricular arrhythmias, thromboembolic events and sudden cardiac death .
Although a “gold standard” for the diagnosis of LV non-compaction continues to be lacking, cardiac imaging criteria provide the best tool currently available . Imaging diagnostic criteria are based on the relationship between the thicknesses of the non-compacted and compacted layers. An end-systolic ratio between non-compacted and compacted layers greater than 2 in the short-axis view is considered diagnostic on echocardiography .
Advances in cardiac MRI have resulted in superior image quality and increased sensitivity in the detection of myocardial trabeculations. Moreover, cardiac MR can also reveal the presence of LGE, a marker of myocardial fibrosis that represents the substrate for potentially lethal arrhythmias . Higher prevalence of LGE is associated with disease severity and LV systolic dysfunction .
On cardiac MRI, diagnosis of LV non-compaction is supported if the end-diastolic thickness of the non-compacted layer is greater than 2.3 times that of the compacted one . This relationship should be measured in short-axis images when compacted and non-compacted myocardium is located in the mid-cavity and basal segments. When myocardial trabeculations are located at the apex, the four-chamber or long-axis views are preferred [47, 49].
The diagnosis of LV non-compaction can be challenging due to the lack of universally validated diagnostic criteria [47, 52]. Diagnosis is also complicated by the fact that there is a complex genetic background responsible for isolated LV non-compaction development that is in part shared with hypertrophic and dilative cardiomyopathy [47, 53].
Left ventricular non-compaction shares morphological features with HCM that can mimic isolated LV non-compaction . A true overlap may exist, as reported in genotyped families expressing both HCM and LV non-compaction phenotypes, and both diseases can occur in the same patient [47, 54].
Practical recommendations: The intertrabecular recesses that communicate with the LV cavity and that are characteristic of LV non-compaction are easily demonstrated by the high signal intensity of the blood pool on cine SSFP MR images.
Practical recommendations: Mural thrombus and subendocardial LGE in endomyocardial fibrosis are most useful findings to differentiate this entity from apical HCM.
In summary, familiarity with the spectrum of myocardial thickening mimickers allows consideration of the differential diagnosis of HCM. Understanding relevant clinical features, the myocardial thickening location and distribution patterns of late gadolinium enhancement facilitates the recognition of key cardiac MRI features, which can allow identification of those causes of myocardial thickening that may mimic the various HCM phenotypes.
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 L. Monserrat are part of a cardiovascular research network CIBER in Cardiovascular Diseases (CB16/11/00425).
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