Left Ventricular Hypertrophy: Evaluation With Cardiac MRI

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Left Ventricular Hypertrophy: Evaluation with Cardiac MRI Karen G Grajewski , Jadranka Stojanovska , El-Sayed H Ibrahim , Mohamed Sayyouh , Anil Attili PII: DOI: Reference:

S0363-0188(19)30207-5 https://doi.org/10.1067/j.cpradiol.2019.09.005 YMDR 760

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Current Problems in Diagnostic Radiology

Please cite this article as: Karen G Grajewski , Jadranka Stojanovska , El-Sayed H Ibrahim , Mohamed Sayyouh , Anil Attili , Left Ventricular Hypertrophy: Evaluation with Cardiac MRI, Current Problems in Diagnostic Radiology (2019), doi: https://doi.org/10.1067/j.cpradiol.2019.09.005

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Left Ventricular Hypertrophy: Evaluation with Cardiac MRI

Authors

Karen G Grajewski University of Michigan Hospital and Health Systems Department of Radiology Division of Cardiothoracic Imaging 1500 E. Medical Center Drive, TC B1 132 Ann Arbor, MI 48109 Office: (734) 936-8769 Fax: (734) 936-0013 [email protected]

Jadranka Stojanovska University of Michigan Hospital and Health Systems Department of Radiology Division of Cardiothoracic Imaging 1500 E. Medical Center Drive, CVC 5581 Ann Arbor, MI 48109-5868 Office: (734) 232-5056 Fax: (734) 232-5055 [email protected]

El-Sayed H Ibrahim Medical College of Wisconsin Department of Radiology Division of Research MRI Research Building 8701 Watertown Plank Road Milwaukee, WI 53226 Tel no 414-955-4756 [email protected]

Mohamed Sayyouh University of Michigan Hospital and Health Systems Department of Radiology Division of Cardiothoracic Imaging 1500 E. Medical Center Drive, TC B1 132 Ann Arbor, MI 48109 Office: (734) 647-9957 Fax: (734) 936-0013 [email protected]

Anil Attili * University of Michigan Hospital and Health Systems Department of Radiology Division of Cardiothoracic Imaging 1500 E. Medical Center Drive, TC B1 132 Ann Arbor, MI 48109 Office: (734) 936-8769 Fax: (734) 936-0013 [email protected]

* Corresponding author

Disclosures: None

Abstract

Objective

Left ventricular hypertrophy (LVH) is a frequent problem in clinical practice and can be caused by diverse conditions including hypertension, aortic stenosis, hypertrophic cardiomyopathy, athletic training, infiltrative heart muscle disease, storage and metabolic disorders. Identification of the precise etiology can be challenging and is a common cause of referral for cardiac MRI (CMR). In this article, CMR findings in various causes of LVH will be reviewed with an emphasis on determination of etiology and emerging role of CMR in risk stratification.

Conclusions In patients with LVH, CMR allows precise determination of the severity and distribution of hypertrophy, evaluation of ventricular function, and tissue characterization. The information obtained from CMR enables identification of the etiology of LVH and may aid in determining prognosis and therapy.

Introduction

Left ventricular hypertrophy (LVH) is an independent predictor of future cardiovascular events regardless of its etiology [1]. In clinical practice, LVH is a commonly encountered condition and can be caused by diverse diseases and physiological states including hypertension, aortic stenosis, hypertrophic cardiomyopathy, athletic training, infiltrative heart muscle disease, storage and metabolic disorders. Determination of the precise etiology of LVH is a challenging clinical problem.

Conventional echocardiography is the first line imaging modality used to assess the extent and distribution of LVH in addition to other anatomic and functional parameters such as ventricular size, systolic and diastolic function. Echocardiography is however limited by operator dependency, acoustic windows, and inability to provide tissue characterization.

CMR enables a comprehensive and detailed evaluation of hypertrophied hearts with respect to morphology and tissue characterization. Accurate measurements of wall thickness, distribution of hypertrophy, chamber size, and systolic function can be obtained irrespective of body habitus and imaging windows. Importantly, myocardial tissue characterization by CMR allows phenotypic determination of the hypertrophied heart.

A CMR protocol for evaluation of LVH should consist of modules for evaluation of LV structure and function and tissue characterization [2]. The examination begins with the acquisition of axial, coronal, and sagittal scout images followed by an axial (8-10 mm slice thickness) set of steady state free precession (SSFP) or single-shot turbo spin echo black-blood

morphological images through the chest. Scouting images are then obtained in 2-chamber (vertical long axis) and 4-chamber plane (horizontal long axis) in either cine or single-shot mode. SSFP short-axis cine images, from the mitral valve plane through the apex are then prescribed from the previously acquired horizontal long-axis image for evaluation of ventricular volumes, structure, and function. Short-axis images are typically 6-8mm thick with a 2mm inter-slice gap and a temporal resolution < 45ms. SSFP long-axis images acquired in 2-chamber, 4-chamber, and 3-chamber (LV outflow tract) planes prescribed from the short-axis cine images complete the information required to evaluate the LV structure and function. A visual evaluation of the short- and long-axis cine images allows for qualitative evaluation of the presence and distribution of hypertrophy, ventricular size, structure, and function. Contouring of the epicardial and endocardial borders on the short axis cine images in end-diastole and end-systole allows calculation of quantitative parameters including: LV end-diastolic volume, end-systolic volume, stroke volume, mass, and ejection fraction (EF). The papillary muscles are myocardial tissue, and thus, ideally, should be included with the myocardium. Because not all evaluation tools allow for inclusion of the papillary muscle in the analysis without manually drawing contours around them, they are often included in the volume in clinical practice, which is still acceptable. However, reference ranges that use the same approach should be used and the inclusion or exclusion of papillary muscles should be mentioned in the report. LV mass is calculated on the end diastolic images as the difference between the total epicardial volume (sum of epicardial cross-sectional areas multiplied by the sum of the slice thickness and interslice gap) minus the total endocardial volume (sum of endocardial cross-sectional areas multiplied by the sum of the slice thickness and interslice gap), multiplied by the specific density of myocardium (1.05 g/ml). Estimates of left ventricular mass (LVM) are conventionally indexed to body size, yielding a

value for LVM index (LVMI) in g/m2 if corrected for body surface area (BSA) or g/m if corrected for height. Reference ranges for normal LV volumes, systolic function, and mass normalized to the influence of gender, BSA, and age have been published for CMR [3]. It must be noted that factors such as age, race, physical activity, hypertension, diabetes, and smoking history affect LVM, and different threshold values may be suitable in different populations. Recent advances in machine learning and automated CMR image analysis have shown accuracy and performance similar to expert manual tracing for ventricular volumes, LV mass and function and are likely to significantly shorten image processing times [4].

LV wall-thickness (LVWT) measured from an end-diastolic cine image in the short-axis plane is the most commonly used measurement to define and quantify LVH. Normal LV myocardial thickness is < 11 mm [5]. LVH is considered mild if it measures 11–13 mm, moderate if it measures 14–15 mm, and severe if it measures > 15 mm. LVH can also be defined and quantified in terms of absolute and BSA-indexed LV mass values, with values over the 95th percentile considered abnormal (91g/m2 in males and 77g/m2 in females) [3]. It should be noted that the LV mass may be within normal limits despite increased myocardial wall thickness, particularly when the thickening is focal.

LVH is traditionally categorized into 2 patterns based on the relative wall thickness (RWT), a ratio derived from left ventricular (LV) wall thickness and LV chamber dimension. LVH with increased RWT is classified as concentric, and when the RWT is not increased, LVH is classified as eccentric. Though widely used, this classification system has important limitations, including relying on a ratio of linear dimensions for wall thickness and chamber size, and not accounting for LV dilation in isolation, an important aspect of geometric remodeling.

More recently a 4-tiered classification of LVH based on LV end-diastolic volume (EDV) and concentricity index (a marker of wall thickness) as assessed by CMR has been proposed [6]. In this classification, eccentric hypertrophy was further divided into dilated hypertrophy and indeterminate hypertrophy based on whether the LV volume was increased. Similarly, concentric hypertrophy was divided into thick hypertrophy and both thick and dilated hypertrophy. This 4 – tiered classification of LVH accounting for increased LV wall thickness and end diastolic volume has been found to identify sub groups of patients at differential risk of cardiovascular outcomes. In particular the presence of LV dilatation was found to confer increased risk with the incidence of heart failure and cardiovascular death being higher in patients with dilated hypertrophy and thick and dilated hypertrophy.

The late gadolinium enhancement (LGE) sequence is the standard technique used for myocardial tissue characterization [2]. A 2D segmented inversion recovery gradient echo sequence is obtained starting 10 minutes after injection of 0.1-0.2mols/kg of gadolinium contrast agent with inversion time set to null the normal myocardium. In addition to conventional segmented LGE images, single-shot LGE images may be acquired as a backup for patients with irregular heart rhythm or those with breath-holding difficulty. Short- and long-axis planes are acquired using the same slice thickness and positions as used for cine imaging with an in-plane resolution of ~ 1.4-1.8mm. A T1 scout (or Look-Locker) sequence is used to determine the appropriate inversion time (TI) that nulls the myocardium signal. Phase-sensitive (PS) LGE sequences eliminate the need for precise setting of the TI and result in more consistent image quality.

CMR myocardial tissue characterization is a rapidly advancing field, and in recent years myocardial parametric imaging with T1 and T2 mapping sequences are increasingly being used for research and clinical purposes [7]. Traditional LGE images are most useful for evaluation of focal abnormalities, where normal myocardium can be used as a standard of reference and a pattern of enhancement can be detected. However, diffuse fibrosis and infiltration may go undetected in the LGE images if gadolinium uptake is uniform. In contrast, magnetization relaxometry mapping techniques allow for detection of diffuse fibrosis using native (non-contrast enhanced) T1 and T2 values, which appears to be more robust than qualitative assessment of signal intensity. Furthermore, contrast-enhanced T1 mapping, in conjunction with the hematocrit value, is useful for calculating the extracellular volume fraction (ECV), a measure of the proportion of extracellular space within the myocardium. An increased ECV is a marker of myocardial remodeling and is most often due to excessive collagen deposition (in the absence of amyloid or edema). The MOLLI (modified look locker) and ShMOLLI (shortened modified look locker) sequences are the most commonly used techniques for acquisition of T1 mapping values. Less applicable in the context of LVH are T2-weighted sequences, which can be used for acquisition of T2 mapping values. Absolute T1 and T2 values for normal LV myocardium vary across different MRI systems and manufacturers. Furthermore, several studies have shown that numerous factors can affect the native T1 relaxation time, including the implemented imaging pulse sequence, magnetic field strength (T1 values increase with increasing field strength), acquisition plane (e.g two-chamber vs four-chamber); region of myocardium being sampled, and the patient’s heart rate, age, and sex. In general, a large native myocardial T1 value is encountered in various disease states that result in edema or fibrosis, and in amyloid deposition. Reduced native T1 relaxation time can be seen in siderosis, Anderson-Fabry disease, and fat

deposition. T2 relaxation times are increased in disease states associated with myocardial inflammation and edema. Examples of specific diseases and the value of magnetization relaxometry mapping techniques for differentiating between various causes of LVH are discussed later in this article.

Hypertrophic Cardiomyopathy

HCM is the most common genetic heart disease and is a leading common cause of sudden death in young people with an estimated prevalence between 1:500 to 1:200 [8].

HCM is a clinically and genetically heterogeneous disorder inherited as an autosomal dominant trait with over 600 mutations identified in sarcomere genes. At least 11 genes have now been identified, which primarily encode more than 1,500 cardiac sarcomere and sarcomererelated single-nucleotide mutations, critical for the basic contractile function of the heart. Cardiac β-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) are the two most common sarcomere gene mutations accounting for the majority of HCM. In adults, HCM is defined by a wall thickness ≥ 15 mm in one or more LV myocardial segment, as measured by an imaging technique (echocardiography, CMR, or CT), that is not solely explained by loading conditions [9].

CMR with its high spatial resolution and tomographic capabilities is an important complementary imaging technique to echocardiography for both diagnoses of the HCM

phenotype and risk stratification. CMR can precisely characterize the location, distribution, and extent of LVH, and it is superior to echocardiography for identification of segmental hypertrophy in areas not easily recognized by echocardiography. These areas include the LV apex, basal anterior wall, anterior lateral wall, and the inferior septum. HCM is varied in its morphology (Figure 1) with the asymmetric septal pattern of hypertrophy being the most common phenotype. Other variants include apical (Video 1), concentric, mid ventricular, mass like, and noncontiguous HCM. The most common location for increased LV wall thickening in HCM, as shown by CMR, is the confluence of the basal anterior septum with the contiguous anterior free wall [10]. The next most common region for increased wall thickness is the inferior septum at the mid LV level. The majority of HCM patients have diffuse hypertrophy, involving more than 50% of the LV myocardium. A substantial minority of HCM patients have focal or regional areas of increased wall thickness involving only one or two LV segments, most commonly the basal anterior septum, but also the anterior lateral free wall, inferior septum, and apex. In one study, an important subset of patients with HCM was ultimately diagnosed with the disease only after LVH was recognized in the anterior lateral wall by CMR [11]. In apical HCM, there is obliteration of the LV cavity at the apex, giving a characteristic spade like configuration to the cavity as seen in long-axis views. An apical wall thickness of > 15 mm or a ratio of apical-tobasal LV wall thickness ≥ 1.3-1.5 is characteristically present. CMR is particularly helpful for identifying apical HCM, which may be missed by echocardiography because of its inability to accurately define the endocardial and epicardial borders and near-field artifacts [12].

Approximately one-third of patients with HCM have resting systolic anterior motion (SAM) of the mitral valve leaflets that results in obstruction of the LV outflow tract (Video 2), while another third have latent obstruction only during maneuvers that change loading conditions

and LV contractility. Systolic anterior motion of the mitral valve nearly always results in failure of normal leaflet coaptation and mitral regurgitation, which is typically at mid-to-late systole and is inferolaterally oriented. Velocity-encoding flow mapping sequences can be used to determine the peak velocity of blood flow through the LV outflow tract in patients with LV outflow tract obstruction (LVOTO); nevertheless, proper alignment of the imaging plane to obtain the highest flow velocities is time-consuming and prone to error. Intra-voxel dephasing and signal loss because of phase offset errors also make accurate quantification of turbulent flow difficult. Further, LV outflow gradients can only be measured at rest. For these reasons, Doppler echocardiography is the modality of choice for quantification of LVOTO [9]. In addition to LVH, phenotypic abnormalities in HCM may involve the right ventricle (RV), mitral valve, papillary muscles, and myocardial architecture, as seen by CMR.

Morphological RV abnormalities are present in a substantial proportion of patients with HCM, including increased RV wall thickness (≥ 8mm) in over a third and an increase in RV wall mass [13]. Areas of increased RV wall thickness are most commonly seen at the junction of the insertion of the RV wall into either the anterior or inferior septum, although involvement of the entire RV may also occur. In addition to RV hypertrophy, CMR can also identify prominent RV muscle structures such as the crista supraventricularis. On the basal short-axis images, this RV structure is situated adjacent to the ventricular septum and may result in overestimation of the septal thickness if incorrectly included in measurements.

Mitral valve abnormalities in HCM may represent a primary phenotypic expression of the disease independent of a number of HCM disease variables including age, LV thickness, and the presence of LVOTO [14]. Mitral valve leaflet lengths are increased in many HCM patients,

including over one third with substantially elongated anterior (≥ 30mm) or posterior mitral valve leaflet lengths ( ≥ 17mm). Elongated mitral valve leaflets also contribute substantially to the mechanisms responsible for sub-aortic gradients, particularly in patients in whom mitral leaflet lengths exceed 2- fold the transverse dimension of the outflow tract at end-systole.

Abnormalities of the papillary muscles are common in HCM, including an increase in the number of papillary muscles, papillary muscle hypertrophy, apical displacement of the papillary muscles, and anomalous insertion of the papillary muscle directly into the anterior mitral valve leaflet with short or absent chordae tendinae [15]. Abnormalities of the mitral valve and papillary muscles may contribute to dynamic LVOTO and have important implications for pre-operative surgical myectomy planning in selected candidates with LVOTO and symptoms refractory to medical management. In such patients, additional procedures on the mitral valve or papillary muscles may be considered [16].

Myocardial crypts are discrete clefts or fissures in otherwise compacted myocardium of the LV. Recent reports suggest higher prevalence of crypts localized predominantly to the basal inferior septum and LV free wall in patients with phenotype positive HCM and also within samples of genotype-positive phenotype-negative HCM [17].

Sarcomere protein mutations in HCM may induce subtle cardiac structural changes before the development of LVH. In a multicenter study, the presence of crypts (particularly multiple), anterior mitral valve leaflet elongation, abnormal trabeculae, and a smaller LV systolic cavity indicated the presence of sarcomere gene mutations in genotype-positive phenotypenegative HCM patients [18]. Virtually, any wall thickness even within normal limits can be consistent with an HCM causing mutant gene. When LVH is mild (wall thickness = 13-15mm),

additional morphological abnormalities, such as crypts, mitral valve elongation, and abnormal papillary muscle architecture can help make the diagnosis of HCM (Figure 2).

Isolated focal hypertrophy of the basal inter-ventricular septum can be seen in up to 10% of cardiac patients without HCM, being more prevalent in the elderly and hypertensive patients Limited data suggests that individuals with this form of ventricular remodeling are less likely to have familial disease or mutations in cardiac sarcomere genes [9].

Sudden cardiac death (SCD) remains the most devastating consequence of HCM. SCD in HCM occurs most commonly in young patients and significantly less in patients of advanced age (≥ 60 years old), and is often the initial clinical manifestation of HCM. The mechanism of SCD is primary ventricular tachycardia/fibrillation (VT/VF) originating from an unstable electrophysiological substrate, which includes an abnormal arrangement of hypertrophied myocytes, with an expanded extracellular space composed of interstitial fibrosis and replacement scar resulting from bursts of silent microvascular ischemia. Implantable cardiac defibrillators (ICDs) have proven benefit in preventing SCD in HCM, making risk stratification essential. Several non-invasive risk markers are used to identify HCM patients at highest risk of potentially life threatening VT/VF [19]. These risk factors include: (1) family history of premature HCM related SCD in close or multiple relatives, (2) unexplained syncope judged non neurocardiogenic, particularly if recent and in young patients, (3) non-sustained VT on serial ambulatory ECG, particularly when bursts are multiple, repetitive or prolonged, (4) hypotensive or attenuated blood pressure response to exercise, and (5) extreme/massive LVH (wall thickness ≥ 30mm). Secondary prevention with an ICD is indicated in patients with a history of prior cardiac arrest or spontaneous, sustained VT. Risk for SCD is increased in proportion to the

absolute number of risk factors. However, a single risk factor may be sufficient to increase the risk enough in a HCM patient for that individual to be considered for life saving therapy with primary prevention ICD, particularly in a patient with one of the three strongest risk markers: massive LVH, family history of SCD, or recent syncope. More recently, the European Society of Cardiology has promoted a novel score for risk stratification, which takes into account many clinical variables, some of which are not considered in the ACC/AHA guidelines, including assessment of outflow tract obstruction and left atrial diameter by echocardiography [9].

Although non-invasive clinical risk markers have proved to be highly effective in identifying many HCM patients at increased risk of SCD who would benefit from primary prevention ICD, the HCM risk algorithm is incomplete. For example, SCD risk in patients without conventional risk markers is 0.5% per year, meaning that a minority of patients remain unrecognized with current risk stratification algorithm. In addition, nearly half of clinically identified HCM patients have one or more risk factors; therefore, a substantial proportion of HCM patients could be considered at risk, leading to over-treatment with ICDs in some patients. Furthermore, high-risk status remains ambiguous in a subgroup of patients (particularly those with one risk factor) making decision making about ICDs complex. These observations underscore the need for additional strategies to improve risk prediction for SCD in HCM.

LGE can identify areas of myocardial fibrosis where potentially life threatening arrhythmias in HCM originate. Several observations, including histological analysis of myectomy specimens and explanted hearts in HCM support the observation that LGE represents the arrhythmogenic substrate of myocardial fibrosis in HCM. Areas of LGE can be quantified and expressed as a percentage of the total LV mass. Approximately 50% of HCM patients

demonstrate signal hyper-enhancement in LGE images, which when present, occupies on average 10% of the overall myocardial volume. Signal hyper-enhancement can be observed at any location or distribution in HCM, although most frequently in the ventricular septum and free wall [20]. A significant, but modest, relationship is present between LGE and the severity of hypertrophy in HCM.

Several prospective outcome studies have demonstrated an association between the presence of LGE and a combined end-point of adverse HCM related events [20-23]. When data from these studies was combined, LGE was more common in patients who experienced SCD or had an appropriate ICD discharge than those who did not, resulting in a significant, but weak, association between the presence of LGE and the risk for SCD [24]. An important point in establishing clinical relevance of LGE is the relationship between presence versus extent of LGE with respect to outcome. Most studies have reported only an association between the presence of LGE and SCD in HCM. However, the reported prevalence of LGE is greater than 50%, hence LGE alone would not qualify as a practical risk marker because too many HCM patients would be identified for primary prevention ICD. In a large multicenter international prospective study of nearly 1,300 patients the extent of LGE emerged as a strong predictor of future SCD in HCM [25]. A continuous relationship was present between the amount of LGE and SCD risk, with substantial LGE (≥ 15% of LV mass) associated with a 2-fold greater risk of SCD compared to patients without LGE, even in patients without conventional risk factors. On the other hand, patients without LGE had a relatively benign course and a low risk of adverse events. In addition, when the results of LGE images were used in conjunction with the traditional SCD risk factors, the extent of LGE strengthened the current SCD risk model by providing information that improved the ability to identify high-risk patients. Similarly in a more recent large single

center study of low-/intermediate-risk adult patients with HCM (including obstructive, myectomy, and nonobstructive subgroups) with preserved systolic function, LGE ≥ 15% was significantly associated with a higher rate of composite endpoint ( SCD and appropriate ICD discharge), providing incremental prognostic utility [26].

Published studies on LGE in HCM and prognosis are limited by selection and referral bias, incomplete risk assessment, low event rates, and differences in scanning protocols and LGE quantification. Generally, the extent of LGE has some utility in predicting cardiovascular mortality, but current data does not support the use of LGE as an independent predictor of SCD risk [9]. Extensive LGE by contrast-enhanced CMR may help identify high-risk patients who have none of the traditional risk markers and help resolve complex ICD decision making in patients whose high-risk status remains uncertain after assessment with the traditional risk markers ( Figure 3).

LV EF is typically normal or increased in patients with HCM. End-stage HCM with systolic dysfunction may develop in a small subgroup of HCM patients as a result of accelerated myocardial fibrosis leading to adverse LV remodeling. The end-stage of HCM is associated with an increased risk of SCD and progressive symptoms of heart failure (HF)[27]. Extensive LGE (≥ 20% of LV mass) has also emerged as a marker to prospectively identify HCM patients with preserved systolic function who are at increased risk of future progression and development of the end-stage phase of HCM [25].

HCM patients with LV apical aneurysms (Figure 4) constitute an additional high-risk subgroup at increased risk of SCD, HF, and thromboembolic events. LV apical aneurysms are associated with mid-ventricular hypertrophy and are underdiagnosed by echocardiography

compared to CMR. CMR can identify LV apical aneurysms (particularly when small in size) when not detected by echocardiography, in addition to the presence and extent of fibrosis contained within the aneurysm and in adjacent areas of the myocardium [28].

Massive LVH of 30mm or more demonstrated anywhere in the LV chamber identifies patients with HCM at highest risk who potentially need an ICD therapy for primary prevention of SCD (Figure 5). Therefore, accurate measurement of maximal wall thickness is an essential part of the evaluation of HCM patients. In this regards, measures of LV wall thickness may be underestimated by echocardiography compared to CMR (particularly when confined to the anterior lateral free wall) with important management implications [29]. CMR-derived LV mass represents the most accurate marker of the overall extent of LVH. However, LV mass may be normal in patients with HCM, particularly when LVH is focal, asymmetric, and has not emerged as an independent predictor of adverse events [30].

Hypertension

Hypertension (HTN) remains a major public health problem associated with considerable morbidity and mortality. Hypertensive heart disease is a constellation of abnormalities that include LVH, systolic and diastolic dysfunction, and their clinical manifestations including arrhythmias and symptomatic heart failure. The incidence of LVH is directly related to the level of systolic blood pressure (BP). Although a linear relationship to BP is observed, BP does not fully account for the variability in LVM. Factors other than BP, including age, sex, race, body mass index (BMI), and neurohormonal stimulation, are operative in determining who among the

hypertensive population develops LVH. An LV mass increase was documented in a much higher percentage of hypertensive women than men—57% compared with 31%, a difference which parallels the higher contribution of hypertension to overall HF risk in women [31]. In African Americans, the prevalence of LVH is increased 2- to 3-fold compared with White Americans with similar BP elevations [32]. The prevalence of LVH increases markedly with age, an effect which is greater in women compared with men. Other coexistent factors such as coronary artery disease (CAD), diabetes, and obesity influence the extent and pattern of LVH in HTN.

With pharmacological control of BP, LV mass decreases and is associated with reduced risk of clinical events including cardiovascular death, myocardial infarction, and stroke [33].

CMR provides a comprehensive assessment of hypertensive heart disease. In less than an hour, ventricular dimensions, LV mass, function, and tissue characterization can obtained with high accuracy and reproducibility. The pathophysiological consequences of hypertension can be assessed and several quantitative parameters can be obtained with high reproducibility and accuracy that can be of use in the follow-up of these patients. Concurrently, several secondary causes of hypertension such as aortic coarctation and renal artery disease can be ruled out in the same study.

In clinical practice, it can be a challenge to make a differential diagnosis between hypertensive heart disease and HCM associated with systemic hypertension. Regression of LVH with treatment of HTN argues against the diagnosis of HCM, but the reverse is not necessarily true. In general, maximal LV wall thickness is greater in patients with unequivocal HCM; however, there is an overlap between the two conditions. The majority of patients with hypertensive LVH have a maximal interventricular septal thickness <15mm, but in African

American patients (particularly in the presence of chronic kidney disease), maximal interventricular septal thickness is not uncommonly between 15 and 20mm [34]. LGE signal hyper-enhancement is reported in the mid-myocardium and epicardium in both HTN ( Figure 6) and HCM, but tends to be located in the segment with the greatest wall thickness and at the RV insertion points in HCM [35]. The presence of RV hypertrophy and focal LV hypertrophy favors a diagnosis of HCM. Resting- or exercise-induced LVOTO can also be observed in hypertension (Video 3) and does not constitute a diagnostic criterion [36].

Native T1mapping has been investigated to discriminate between HCM and hypertensive heart disease [37]. Native T1 and ECV values were significantly higher in HCM compared with patients with HTN, including in subgroup comparisons of HCM subjects without evidence of LGE signal hyper-enhancement, as well as of hypertensive patients with LV wall thickness >15 mm. Native T1 was an independent discriminator between HCM and HTN, over and above ECV fraction, LV wall thickness, and indexed LV mass.

Athlete’s heart

In some highly trained athletes, the thickness of the LV wall may increase as a consequence of exercise training and resemble that found in cardiac diseases associated with LVH, such as HCM. The degree of LVH in an athlete is determined by several factors including sport type and training intensity (greater in isometric or strength-based exercise vs isotonic or endurance-based exercise), age (older), sex (male), body size (larger), and ethnicity (greater in African American ).

Echocardiography is the first-line modality used to differentiate athlete’s heart from pathological LVH. When echocardiography cannot provide a clear diagnosis CMR is performed [38]. In elite athletes, LVH involves typically all myocardial segments, and the maximal septal thickness is usually ≤12 mm. An LV wall thickness ≥13mm is very uncommon in highly trained athletes, virtually confined to athletes with high endurance training such as rowing sports, and associated with an enlarged LV cavity (55-63mm in end diastole) and preserved systolic function [39]. In contrast, LV end-diastolic diameter becomes larger (>55 mm) than the normal limits only in end-stage HCM patients when LV EF is <50%. In an echocardiographic study of 28 athletes free of cardiovascular disease compared with 25 untrained patients with HCM, matched for LV wall thickness (13 to 15 mm), age, and gender, LV cavity <54 mm distinguished HCM from athlete's heart with the highest sensitivity and specificity [40]. In addition to LV cavity dilatation, athletic training may induce RV cavity remodeling and dilatation, and biventricular dilatation can be a clue to athlete’s heart in the presence of LVH [41]. Wall thickness ‘cut-off’ values may be helpful in distinguishing athlete’s heart from disease (HCM), as LV wall thickness >15mm should be considered pathologic until proven otherwise. A small number of healthy trained athletes demonstrate hypertrophy with LV wall thickness in the 13-15mm range ( Figure 7 and Video 4), which overlaps with that seen in phenotypically mild HCM and represents a ‘gray zone’ in which it is difficult to distinguish physiological from pathological hypertrophy [39]. The ability to reliably differentiate between HCM and athlete’s heart is important, as an incorrect diagnosis has far-reaching implications for individual athletes and their families.

Features that favor the diagnosis of HCM in elite athletes include [9] :

asymmetric septal hypertrophy (septum-to-lateral wall ratio > 1.5) or focal areas of hypertrophy SAM of the mitral valve Myocardial crypts LGE signal hyper-enhancement LV end-diastolic diameter < 55mm Left atrium diameter > 45mm, RV hypertrophy. When the distinction between athlete’s heart and HCM is still in doubt, a trial of deconditioning for 3 months may be pursued with regression of LV wall thickness of greater than 2mm supporting a diagnosis of athlete’s heart[42].

Aortic stenosis

In patients with aortic valve stenosis (AS), LVH is as an adaptive response that keeps LV wall stress close to normal, offsetting the hemodynamic load. Echocardiography is the principal non-invasive tool for initial evaluation and longitudinal monitoring of patients with AS. However, echocardiography can be limited by poor acoustic windows, and is dependent on the skill and experience of the sonographer. CMR can provide a comprehensive non-invasive assessment of valvular morphology, quantification of the severity of valvular dysfunction, determination of its etiology (e.g. bicuspid aortic valve), and assessment of effect on the heart through measurement of ventricular volumes and function, and evaluation of hemodynamic abnormalities. Additional information, such as great vessel anatomy and the presence of

coronary disease and myocardial scar, can also be obtained from CMR. There is a considerable variation in the hypertrophic response of the LV in patients with AS. In a CMR study, the degree of the hypertrophic response was independent of the severity of valve narrowing, and six distinct patterns of LV adaptation were observed, including normal ventricular geometry, concentric remodeling, asymmetric remodeling , concentric hypertrophy, asymmetric hypertrophy, and LV decompensation [43]. Asymmetric patterns of LVH involving the septum at the base- and midcavity levels may occur in a significant number of patients, particularly amongst the elderly and those with HTN, which display a considerable overlap in appearance (wall thickness (mean ± standard deviation) = 17±2mm) with HCM. Higher LV mass at baseline is independently associated with increased cardiovascular mortality and morbidity in both symptomatic severe AS and asymptomatic mild-to-moderate AS.

Myocardial fibrosis occurs in aortic stenosis as part of the hypertrophic response. It can be detected by LGE which has been shown to occur in both an infract pattern and mid-wall pattern in AS. The presence of LGE signal hyper-enhancement indicating focal fibrosis or unrecognized infarct by CMR is an independent predictor of mortality in patients with AS undergoing aortic valve replacement (either surgical or percutaneous catheter valves) and may provide additional information in the pre-operative risk evaluation in these patients [44].

Cardiac Amyloidosis

The term amyloidosis describes a group of rare diseases characterized by extracellular deposition of fibrillary proteins. Cardiac amyloidosis results from progressive accumulation of amyloid in the myocardial interstitium and is associated with increased wall thickness and mass, which results in diastolic and, ultimately, systolic dysfunction. The majority of patients with cardiac amyloidosis have either immunoglobulin light-chain amyloidosis (AL) associated with a plasma cell dyscrasia, or transthyretin amyloidosis (ATTR). ATTR amyloidosis may be acquired, associated with wild type transthyretin (previously known as senile systemic amyloidosis), or hereditary, associated with variants in the transthyretin gene. In patients with AL, disease progression and prognosis are much worse than in those with ATTR; however, in both forms, myocardial involvement is the main driver of prognosis.

Typical morphological features of cardiac amyloidosis (Figure 8 and Video 5) include LV wall thickening, RV wall thickening, thickening of the interatrial septum, valvular thickening, and pericardial and pleural effusion [45]. LVH is concentric in the majority of patients with cardiac amyloidosis; however, asymmetric LVH affecting the interventricular septum may also occur [46]. The LV end-diastolic volumes are slightly reduced and LV EF is near normal, though may be decreased, in end-stage disease. Echocardiography is the most commonly used imaging test in the diagnostic workup, but characteristic findings such as ventricular hypertrophy and restrictive filling pattern are not specific for cardiac amyloidosis and may be insensitive for early disease. The morphological features are better evaluated by CMR compared to echocardiography due to the higher spatial resolution, tissue contrast, and lack of

limitation by body habitus. Coexisting RV free wall or atrial septal thickening strongly suggests an infiltrative cardiomyopathy because these are rarely seen in association with true LVH.

An important contribution of CMR to the diagnosis of cardiac amyloidosis relies on tissue characterization: LGE signal hyper-enhancement, abnormally increased T1 times (before or after contrast), and ECV expansion.

In patients with cardiac amyloidosis, LGE occurs in characteristic patterns (Figure 9). Global transmural or sub-endocardial LGE in the LV is most common, but suboptimal myocardial nulling and focal patchy LGE are also observed [47-49]. Diffuse LGE in the atrial wall and RV may also be seen in cardiac amyloidosis. On the basis of the gold standard, endomyocardial biopsy, noninvasive CMR can be used to diagnose or rule out cardiac amyloidosis with good sensitivity and excellent specificity in the clinical routine setting [49]. LGE imaging may detect early cardiac abnormalities in patients with amyloidosis with normal LV wall thickness [48]. The presence and pattern of LGE is strongly associated with clinical, morphologic, functional, and biochemical markers of prognosis [48]. Gadolinium kinetics are abnormal in cardiac amyloidosis, with a faster washout of gadolinium from the myocardium and blood pool when compared with that in non-amyloid control subjects [47]. A difficulty of nulling of myocardial signal in the LGE images, despite the use of a T1 scout, may suggest underlying amyloid (especially if the blood pool is unusually dark, indicating rapid contrast sequestration) rather than suboptimal image quality. White et al [50]studied patients with suspected cardiac amyloidosis and compared them to HTN controls with LVH using a quick visual assessment with a standard pulse sequence typically acquired in a CMR study to find the optimal TI for LGE imaging using the T1 scout sequence. Following completion of the first pass of gadolinium,

normal myocardium will have a considerably lower concentration of contrast than blood and, therefore, should have a far longer T1. A shorter (or similar) T1 indicates abnormal myocardium with increased gadolinium retention. If the myocardial tissue crossed the null point (i.e., became black) at an earlier or at the same TI as blood, the T1 of that tissue was considered abnormally short and if >50% of the LV myocardium on either the short- or long-axis images had abnormally short T1 in an area that was not in a typical coronary artery distribution, then diffuse LGE signal hyper-enhancement was considered present. This method was reasonably efficient for identifying patients with cardiac amyloidosis, especially those at higher risk for death.

Native (pre-contrast) T1 mapping techniques have been studied in AL [51] and ATTR [52] cardiac amyloidosis using the ShMOLLI pulse sequence. This is important because many patients with amyloidosis have concomitant renal involvement and severe renal dysfunction and may not be candidates for gadolinium administration. Although there was an overlap, the native T1 times in patients with AL cardiac amyloidosis (1130±68 ms) and ATTR cardiac amyloidosis (1097±43 ms) were significantly increased when compared with HCM (1026±64 ms; P<0.0001) and normal subjects (967±34 ms; P<0.0001) [52]. Non-contrast T1 mapping has high diagnostic accuracy for detecting cardiac amyloidosis ( Figure 10), correlates well with markers of systolic and diastolic dysfunction, and is potentially more sensitive for detecting early disease than LGE imaging [51].

Precise diagnosis of the subtype of cardiac amyloidosis is crucial given the role of chemotherapy in AL type and with novel therapies for ATTR type currently in development. There are limited studies examining the role of CMR in differentiating between AL and ATTR amyloid [53, 54]. Compared to patients with AL amyloid , patients with ATTR amyloid have

been found to have a greater LV mass, more extensive LGE including a greater proportion of patients with transmural LGE and RV LGE [53]. ECV has been found to be higher (mean ± SD = 0.58 ± 0.06 vs 0.54 ± 0.07; P = 0.001) in patients with ATTR than in those with AL cardiac amyloidosis, reflecting the presence of more amyloid [54]. Despite a lower ECV (i.e, less amyloid), the native T1 value was higher in patients with AL than in those with ATTR (mean = 1126 ms vs 1101 ms; P < .05), which suggests an additional pathologic process in AL amyloidosis, possibly edema.

Scintigraphy is a valuable alternative and complementary to CMR, particularly for patients with ATTR amyloidosis due to its very high sensitivity. The [99mTc]-labelled bisphosphonate compounds pyrophosphate (PYP) and 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), and hydroxydiphosphonate (HDP) (which are routinely used as bone scintigraphy agents) bind through unknown mechanisms to amyloid protein. All have proven very sensitive for detecting cardiac involvement in ATTR amyloidosis with reported sensitivities up to 100% on late phase planar scintigraphy [55, 56]. However, in AL amyloidosis, cardiac uptake was found in less than half of the patients and is generally less intense. In a recent study, using 99mTc-PYP, while patients with AL had some uptake, the visual score was significantly less than in patients with ATTR, allowing the differentiation between ATTR and AL amyloidosis with 97% sensitivity and 100% specificity [55]. Cardiac ATTR amyloidosis can be reliably diagnosed in the absence of histology, provided that an echocardiogram or CMR is suggestive of amyloidosis, cardiac uptake is present on scintigraphy, and there is an absence of a detectable monoclonal gammopathy [57].

Fabry’s disease

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disease caused by the inappropriate accumulation of globotriaosylceramide in tissues due to a deficiency in the enzyme α-galactosidase A (α-Gal A). Men are predominantly affected and experience the most severe clinical phenotype, while (heterozygous) women may represent symptomatic or asymptomatic carriers of this disease. The systemic nature of AFD may lead to multi-organ involvement with renal failure, corneal deposits, and nervous, gastrointestinal, and cutaneous manifestations. Heart disease is a major contributor to death in patients with AFD and is characterized by progressive LVH leading to HF, valvular heart disease, and arrhythmias [58].

AFD accounts for at least 3% of unexplained LVH in middle aged men [59]. Most patients (male and female) with AFD develop LVH. LVH is typically concentric (Figure 11 A), though asymmetric septal hypertrophy, indistinguishable from that seen in sarcomeric cardiomyopathies, accounts for 5% of cases [60]. Dynamic LV outflow obstruction is rare, but may occur.

LGE shown by histological correlation to represent focal fibrosis in Fabry disease, is most often observed in a distinctive mid-wall pattern in the basal inferolateral LV wall ( Figure 11B and 11 C) and is detectable in up to 50% of Fabry disease patients [61] . LGE has shown potential to identify early cardiac involvement in Fabry disease and allows targeted enzyme therapy and improved risk stratification. Moreover, the presence of progressive fibrosis determined by LGE is an important prognostic determinant for malignant ventricular arrhythmias and cardiac outcome in Fabry disease.

Lipid is known to shorten myocardial T1 values, and non-contrast T1 mapping has a unique role in the evaluation of AFD and differentiation from other forms of LVH [62].Compared with healthy volunteers, septal T1 was lower in AFD and higher in other diseases including HTN, HCM, AS, and cardiac amyloidosis (AFD versus healthy volunteers versus other patients, 882+/-47, 968+/-32, 1018+/-74 milliseconds; P<0.0001). In patients with LVH, T1 discriminated completely between AFD and other diseases with no overlap.

Other lysosomal and storage disorders

Like Fabry disease, Danon disease is a rare X-linked disorder due to primary deficiency of lysosome associated membrane protein 2 [63]. It affects men at an early age (in the teens) and women in later years (in the 20’s). Affected men typically present with a triad of HF, skeletal myopathy, and mental retardation. Danon cardiomyopathy is progressive and typically manifests a hypertrophic phenotype, with preserved EF and normal cavity dimensions early in the course of disease and later progression to dilated features in 11-12% of males [63]. Hypertrophy can be extreme with ventricular septal thickness of up to 65mm reported. Danon disease should be strongly suspected in young males presenting with pre-excitation and moderate to severe cardiac hypertrophy. CMR findings have been reported in a limited number of patients with Danon disease [64]. The phenotypic pattern is typically symmetric HCM with LGE signal hyperenhancement involving the anterior wall, inferior wall or more frequently the lateral wall with a subendocardial, intramyocardial or transmural distribution. A subendocardial pattern of LGE signal hyper-enhancement not confirming to a coronary artery distribution has most often been described.

LVH may be a feature of other lysosomal storage disorders including Pompes disease, mucopolysaccharidosis and sphingolipidosis (Gauchers disease) with onset in infancy and childhood [65]. Valve disease and CAD may also occur in these conditions due to infiltration. Diagnosis is made by a thorough clinical examination, enzyme assays, and genetic testing.

PRKAG2 cardiac syndrome is an autosomal dominant inherited glycogen storage cardiomyopathy characterized by LVH, progressive conducting abnormalities and ventricular pre-excitation (Wolff-Parkinson-White [WPW] syndrome). PRKAG2 cardiac syndrome may present with eccentric distribution of LVH, involving focal mid-inferolateral pattern in the early disease stage, and more diffuse pattern, but focusing on interventricular septum, in advanced cases [66]. LGE signal hyper-enhancement may be present in a patchy mid wall distribution predominantly in the hypertrophied segments.

Miscellaneous causes of LVH

Obesity is associated with LVH typically concentric LV remodeling as measured by CMR without a change in EF [67].

LV non-compaction may mimic an infiltrative cardiomyopathy with apparent LVH on echocardiography due to the inability to clearly resolve the details of myocardial architecture. CMR with its high contrast and spatial resolution clearly shows the 2 layered myocardial structure with spongy non-compacted myocardium along the endocardial aspects (Figure 12). A ratio of non-compacted to compacted myocardium greater than 2.3 at end-diastole has been proposed as a diagnostic criterion for non-compaction on CMR [68].

Cardiac sarcoidosis may rarely present with LVH, including asymmetrical septal hypertrophy, apical hypertrophy, and localized septal hypertrophy particularly in the basal septum [69].

Conclusion

The correct identification of the etiology of unexplained LVH is of critical importance. Accurate diagnosis relies on integration of information available from history, clinical examination, imaging, and in some cases biochemical and genetic analysis. LVH is most often discovered initially on echocardiography, which remains the first-line imaging modality for assessing cardiac structure and function. CMR provides accurate 3D evaluation of cardiac anatomy and precise evaluation of wall thickness and LV mass. CMR tissue characterization by LGE and the newer methods of non-contrast myocardial mapping allows detection of fibrosis and infiltration in the myocardium. Comprehensive evaluation by CMR allows differentiation of various causes of LVH and provides guidance on therapy and prognosis. CMR findings in the major causes of LVH and differentiating features are summarized in Table 1.

Table 1

CMR Findings Structure and function

HTN

HCM

Concentric LVH rarely exceeding 15mm. Preserved systolic function

Diagnosed by LVH > 15mm in one or more segment in the absence of known causes of LVH. Asymmetric septal hypertrophy commonest, concentric, apical, mid cavitary and focal masslike forms exist. Other morphologica l abnormalities such as elongated mitral valve . leaflets, crypts, papillary muscle abnormalities may exist. Hyperdynami c LV function, small LV cavity. SAM. Dilated LA

Athlete’s heart Symmetric LVH < 13mm. LV cavity dilatation. Normal systolic function. Balanced cardiac remodeling including RV dilatation may be a clue

Cardiac Amyloidosis Concentric LVH and RVH. Biatrial dilatation. Thickened valves and interatrial septum. Pericardial effusion. Systolic function and EF preserved in early stages

Fabry’s disease Typically concentric LVH

Aortic stenosis Symmetric concentric LVH

Tissue characterizati on

Mid-wall LGE signal hyperenhancement may occur in the hypertrophied areas

Mid-wall non ischemic pattern of LGE signal hyperenhancement typically in the interventricul ar septum at the junction points of the LV and RV

Typically no LGE signal hyperenhancement

Circumferenti al subendocardial LGE signal hyperenhancement, patchy diffuse LGE signal hyperenhancement or inability to null the myocardium. Myocardium suppresses before or at the same time as the blood pool on inversion time (TI) finder sequences. Increased T1 times on mapping sequences

Mid-wall or sub-epicardial LGE signal hyperenhancement in the inferior lateral wall. Decreased T1 times

Nonspecific LGE signal hyperenhancement; patchy diffuse or midwall septal LGE signal hyperenhancement

Figure and Video legends

(a)

(b)

(c)

(d)

(e) Figure 1- HCM phenotypes: A). Asymmetrical septal HCM B). Concentric HCM C). Apical HCM D). Focal mass like HCM (asterix showing the focal mass like area of thickening in the anterior septum and adjacent right and left ventricular walls) E). Midcavitary HCM

(a)

(b)

Figure 2. Preclinical HCM in a genotype positive individual. Maximal septal thickness is 13 mm and is associated with a crypt in the inferior wall of the LV (Arrow in Figure 2A) and elongated mitral valve leaflets (Figure 2B)

(a)

(b)

(c)

(d)

(e) Figure 3. 49-year-old Male with HCM. Asymmetrical septal hypertrophy measuring a maximum of 26mm (Figure 3 A and B in short axis and 3 chamber planes respectively). Nonsustained VT on holter monitor and no other clinical risk factors for SCD. On LGE imaging (Figures C-E) there is extensive enhancement > 15% of LV mass. ESC risk calculator showed the SCD risk was 4.9% (intermediate risk). Given the extensive LGE and intermediate risk of SCD a decision to implant an ICD was made. This case illustrates the role of CMR as an arbitrator when risk stratification by conventional clinical methods is indeterminate.

(a)

(b)

(c) Figure 4. Midcavitary HCM in a 65-year-old male with apical aneurysm- 3 chamber views in diastole (Figure 4A) and systole (Figure 4B). LGE imaging (Figure 4 C) shows subendocardial enhancement in the aneurysm.

(a)

(b)

(c)

(d)

Figure5. Massive LVH over 30mm thickness of the interventricular septum in a 31-year-old male with HCM in short axis (Figure 5A) and 3 chamber planes (Figure 5B). There is a large amount of delayed enhancement/scar quantified over 15%. 4 chamber delayed enhancement (Figure 5C) and short axis delayed enhancement (Figure 5D) are shown. The patient subsequently underwent an ICD placement for prevention of sudden death.

(a)

(b)

(c) Figure 6. LVH from HTN in a 60 year old male. Concentric LVH upto 20 mm seen on short axis (Figure 6A) and 4 chamber views (Figure 6B). There is a non-ischemic pattern of patchy enhancement in the hypertrophied LV myocardium most evident in the lateral wall (Arrow in Figure 6C)

(a)

(b)

Figure 7. Athletes heart. Concentric LVH upto 13mm in a 24-year-old weight trained collegiate wrestler shown in short axis (Figure 7A) and 4 chamber planes (Figure 7 B)

(a)

(b)

Figure 8. Morphological features of cardiac amyloidosis shown on bright blood cine imaging in 4 chamber (Figure 8A) and short axis (Figure 8B) planes. Note concentric LVH, RV wall thickening, thickening of the interatrial septum, dilated atria, pericardial effusion and pleural effusions

(a)

(b)

Figure 9. LGE patterns in Cardiac amyloidosis. Global subendocardial enhancement in Figure 9A in a case of AL amyloid and diffuse myocardial enhancement in Figure 9B in a case of ATTR amyloid

(a)

(b)

(c) Figure 10. T1 mapping in cardiac amyloidosis. Concentric LVH and pericardial effusion seen on short axis cine imaging (Figure 10A). Global sub endocardial enhancement on LGE (Figure 10B). Native pre contrast T1 was 1120 ms (Figure 10C). Case courtesy of Dr. Steve Leung, Gill heart center, University of Kentucky

(a)

(b)

(c) Figure 11. Fabrys disease in a 51-year-old male presenting with arrhythmia and neurological symptoms. Note concentric LVH (Figure 11A in short axis plane) and mid wall enhancement (shown by arrows ) in the basal inferior lateral wall on LGE shown in short axis ( Figure 11 B) and 4 chamber planes ( Figure 11 C).

(a)

(b)

(c) Figure 12. Non compaction cardiomyopathy. Hypertrabeculated non compacted 2-layer structure of the myocardium with the ratio of non-compacted to compacted myocardium exceeding 2.3 in diastole shown in short axis (Figure 12 A and 12 B) and 4 chamber planes (Figure 12 C).

Video 1- Apical HCM shown in 3 chamber (1 A) and short axis apical (1 B) and basal level (1 C). Note the preferential thickening of the apical segments and spade like left ventricular cavity configuration.

Video 2- Asymmetrical septal variant of HCM in 3 chamber (2 A), 4 chamber (2 B) and short axis planes ( 2 C) . Note the systolic anterior motion of the mitral valve and subaortic obstruction.

Video 3. LVH from HTN in a 60-year-old male. There is septal hypertrophy upto 20 mm and LVOT obstruction at rest. The patient underwent a myectomy for symptomatic obstruction.

Video 4. Athletes heart in a 24-year-old weight trained collegiate wrestler. LVH upto 13 mm shown in short axis (4 A) and 4 chamber planes (4 B).

Video 5. Morphological features of cardiac amyloidosis in 4 chamber (4 A) and short axis (4 B) planes. There is concentric LVH, biatrial dilatation, a small pericardial effusion and pleural effusion. Note the thickening of the free wall of the right ventricle.

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