Hypertrophic cardiomyopathy (HCM) is a genetic disease that is present in 0.2% of the general population and is defined by the presence of an increased left ventricular (LV) wall thickness (with or without right ventricular [RV] hypertrophy) or mass that is not solely explained by abnormal loading conditions.1 Current international guidelines define HCM in adults by the presence of an LV wall thickness ≥15 mm in any myocardial segment, while lesser degrees of LV wall thickness (13–14 mm) require additional clinical and electrocardiographic criteria to set the diagnosis. In children, an increase in LV wall thickness over two SDs than the predicted mean (z-score >2) sets the diagnosis of HCM.
However, this definition has several issues that may lead to over+ or underdiagnosis of HCM. First, this definition was derived from echocardiographic studies using M-mode, which neglects the fact that the LV hypertrophy may be asymmetric and not captured by the M-mode interrogation.2,3 Second, this definition introduces a potential bias since it does not take into consideration the effect of age, sex and body size on normal cardiac dimensions.4 Finally, there is a reported 2:1 male:female prevalence ratio in HCM, despite it being a primarily autosomal dominant disease, suggesting underdiagnosis in female patients due to the cut-off value of myocardial wall thickness.5 In addition, lower thresholds of myocardial wall thickness have also been proposed in Asian populations.6
A recent large-scale population-based study has challenged this definition of HCM by proposing demographic-based personalised LV hypertrophy thresholds for HCM.5 Shiwani et al. reported artificial intelligence-generated wall thickness measurements from cardiac magnetic resonance (CMR) in more than 2,000 patients with HCM, more than 5,000 individuals without comorbidities and more than 43,000 individuals from the UK Biobank.5 The study evaluated the impact of age, sex, height and weight on the range of myocardial wall thickness. When applying the cut-off value of ≥15 mm to the UK Biobank population, 4.3% would have been classified as having HCM with a significant sex skew (89% male), values that were reduced when applying demographic-adjusted LV hypertrophy thresholds (10–17 mm; 2.2% ascertainment and 56% male).5 Among patients with a diagnosis of HCM, the use of demographic LV hypertrophy thresholds improved the sensitivity in hypertrophy classification in female patients (from 73% to 93%) and in male patients (from 82% to 85%).5 This study emphasised the need for accurate measurements to mitigate demographic biases and provided nuanced context for myocardial wall thickness interpretation.
The diagnosis of HCM also includes other clinical, imaging, genetic and molecular markers. The vast majority of genes and mutations underlying HCM encode sarcomere proteins or sarcomere-associated proteins. The clinical presentation of the disease is highly heterogeneous and can present in all age groups. Most affected individuals will achieve a normal life expectancy without disability, but some patients with HCM can present significant complications, including sudden cardiac death (SCD), heart failure and AF. ICDs, heart failure therapies, septal reduction therapies and catheter ablation can alter the natural history of the disease.
More recently, the advent of inhibitors of cardiac myosin has provided an effective therapy for patients with symptomatic obstructive HCM.7,8 The selection of patients for the best therapeutic approach requires accurate diagnosis and phenotyping of the disease, including the characterisation of the mechanisms of LV outflow tract (LVOT) obstruction, diastolic function and tissue characterisation. In addition, differential diagnosis with other entities that can present with LV hypertrophy (i.e. hypertensive heart disease, cardiac amyloidosis and athlete’s heart, along with infiltrative storage diseases such as mitochondrial disease, Anderson-Fabry disease and Danon disease) is key to prescribing the most appropriate therapy.
Echocardiography is the imaging technique of first choice to initially set the diagnosis of LV hypertrophy and provides important key features that suggest the presence of HCM. However, additional imaging modalities such as CMR and nuclear imaging provide important additional information for risk stratification and diagnosis of other causes of LV hypertrophy that mimic HCM. CT has become an important imaging modality to diagnose additional abnormalities (such as coronary artery disease) and plan interventions for septal reduction in patients with obstructive HCM.
This review provides a practical overview of how to use the various imaging modalities to enhance accuracy for better diagnosis and management of patients with HCM.
Role of Multimodality Imaging in the Diagnosis of Hypertrophic Cardiomyopathy
Echocardiography is the imaging technique of first choice for the diagnosis and follow-up of patients with HCM. Echocardiography provides a comprehensive evaluation of the features that permit the diagnosis of HCM and differentiate it from HCM mimics. LV wall thickness, the location of the most hypertrophic segments, presence of dynamic LV obstruction (at the level of the LVOT or mid ventricular level) and systolic anterior motion of the mitral valve are key features that need to be assessed. Other abnormalities such as LV apical aneurysms, mitral valve anomalies and left atrial dilatation need to be assessed, particularly for management purposes. Assessment of LV diastolic function and myocardial mechanics with strain imaging are also important parameters for differential diagnosis and risk stratification. Accordingly, transthoracic echocardiography is recommended in patients with HCM at the first evaluation and it should be performed every 1–2 years in clinically stable patients.1
The measurement of maximum LV wall thickness with echocardiography is typically performed on the parasternal long-axis view, carefully avoiding the interference of the moderator band of the RV, as this could overestimate the thickness of the basal anterior septum. Although hypertrophy can occur in any LV myocardial segment, it is most commonly observed in the basal anteroseptal region. It is also advisable to measure the LV wall thickness on the parasternal short-axis views (basal, midventricular and apical levels) since these views help identify the segments with the greatest wall thickness.
Different patterns of LV myocardial hypertrophy have been correlated with genotype.9,10 Mid-septal hypertrophy has been associated predominantly with myosin binding protein C3 variants, while an increased septum-to-posterior wall thickness ratio correlated with variants of the myosin heavy chain 7. The apical form of HCM has been associated more frequently with mutations of the alpha kinase 3 genes while mutations of the titin and obscurin were associated with more homogeneous distribution of the myocardial hypertrophy in the LV. Subsequently, assessment of presence and location of LV dynamic obstruction should be assessed at rest and with provocation manoeuvres that alter the preload, afterload and contractility of the LV. Obstructive HCM is defined by the presence of an obstruction to flow in the LV (most commonly in the LVOT) with a peak pressure gradient of at least 30 mmHg at rest. LVOT obstruction occurs in 75% of patients with obstructive HCM and is a result of the combination of the septal hypertrophy and altered flow kinetics that cause systolic anterior motion of the mitral valve towards the septum (Figure 1 ).11 Other structural abnormalities that can favour the LVOT obstruction include redundant mitral leaflets, aberrant muscle bundles or chordal attachments and hypermobile bifid papillary muscles.
The parasternal long-axis view and the apical three-chamber view are useful for identifying the systolic anterior motion of the mitral valve, whereas 3D echocardiography allows the acquisition of a full volume of the mitroaortic unit and the assessment of the exact segments of the mitral valve that cause the LVOT obstruction. In addition, continuous wave Doppler with the ultrasound beam along the LVOT provides the typical spade shape of the outflow jet with a late systolic peak (Figure 1 ). This anterior motion of the mitral valve may cause malcoaptation of the leaflets and eccentric mitral regurgitant jet directed towards the posterior wall. Other forms of obstruction at the midventricular level causing complete systolic emptying of the LV can also be observed and may be associated with the presence of apical aneurysms. These forms of HCM may be considered non-obstructive because the midventricular obstruction causes complete emptying of the ventricular cavity and cessation of the flow.12
If there is no flow, Doppler echocardiography cannot detect a high velocity and, per simplified Bernoulli’s equation, no significant pressure gradient. In contrast, when evaluated with catheterisation, the pressure gradients are significantly higher compared with echocardiography. The aneurysms form apically from where the systolic complete emptying occurs with the subsequent apical trapping of blood. In addition, the supply–demand ischaemia is more pronounced apical of the midventricular complete emptying and the presence of akinesia on echocardiography and transmural scar on CMR supports this underlying pathophysiological mechanism. Furthermore, in one-third of patients, end-systolic retrograde flow can be observed, when blood is propelled backwards to the aneurysm due to the midventricular obstruction. This phenomenon occurs if the aneurysm shows transmural scar and is completely akinetic.
Finally, the papillary muscles of patients with midventricular obstructive HCM are more hypertrophic and displaced towards the base of the ventricle (closer to the mitral valve). Provocation manoeuvres that alter the loading conditions, reducing the preload, are important to unmask the presence of ventricular obstruction. If bedside manoeuvres fail to increase the gradient through the LVOT ≥50 mmHg, exercise echocardiography is recommended in symptomatic patients. In contrast, pharmacological stress echocardiography is not indicated.
Other parameters that need to be evaluated include LV systolic function by means of ejection fraction and diastolic function with a multiparametric approach. The role of these measurements is more prognostic rather than diagnostic and they need to be included in every echocardiographic report. In addition, LV global longitudinal strain is a measure of LV systolic function that has been researched in patients with HCM.13 Detection of early dysfunction in patients carriers of sarcomeric mutations in whom the overt phenotype is not present can be achieved with the measurement of LV global longitudinal strain.14,15 Impaired LV global longitudinal strain has been associated with worse outcomes and its association with SCD is still debated.16 In addition, some patterns of LV global longitudinal strain have been used for the identification of phenocopies (i.e. cardiac amyloidosis), although those alterations can also be observed in HCM.17,18
CMR provides better visualisation of the wall thickness and its estimation in the 16 cardiac segments on short-axis planes at the basal, mid and apical levels of the LV (Figure 2). CMR allows for more precise measurement of the LV myocardial mass compared with echocardiography.19 However, in patients with mild to moderate wall thickening, the LV mass may be within the normal limits. Similar to echocardiography, structural abnormalities of the mitral valve apparatus, presence of ventricular obstruction and the presence of apical aneurysms should also be evaluated. Additionally, the wall thickness of the RV should be evaluated, as it may be increased in certain phenocopies. However, tissue characterisation capability is the characteristic that strengthens the value of CMR in the assessment of patients with HCM. Myocardial fibrosis detected by late gadolinium enhancement (LGE) is present in 33–84% of patients and typically shows a patchy mid-wall distribution with preference for the areas of hypertrophy and the anterior and posterior insertion points of the RV (Figure 3).20
The LGE pattern may suggest specific aetiologies of LV hypertrophy. Accordingly, CMR has become a pivotal imaging modality to differentiate phenocopies of HCM.21 Sequences of T1 mapping allow evaluation of the presence of diffuse reactive fibrosis. The extracellular matrix expansion due to the deposition of collagen can be detected by the presence of long native T1 times or short T1 times after administration of gadolinium contrast agent. The difference between native and post-contrast T1 times allows the estimation of the extracellular volume. In addition, T2-weighted images can be used to assess the presence of myocardial oedema. Elevated T2 times have been reported in up to one-third of patients with HCM and are associated with repetitive ischaemia or immune-mediated mechanisms.
Finally, cardiac CT is commonly used in patients with HCM to rule out the presence of obstructive coronary artery disease or to assess the geometry of the LV to guide strategies for performing septal reduction techniques (mainly surgically). Nuclear imaging modalities have a role in the differential diagnosis of phenocopies of HCM such as cardiac amyloidosis.
Role of Multimodality Imaging in the Differential Diagnosis of Hypertrophic Cardiomyopathy
Diagnosing the precise aetiology of LV hypertrophy demands the use of various imaging modalities. Table 1 summarises the main aetiologies that can lead to LV hypertrophy and the various imaging characteristics that differentiate them.
Systemic arterial hypertension is probably the most frequent cause of LV hypertrophy that can lead to an erroneous diagnosis of HCM.22 The differential diagnosis is critical and it should be kept in mind that, given the prevalence of both pathologies, a considerable proportion of patients may present with both pathologies. While HCM is characterised by myocyte disarray around central cores of collagen (replacement fibrosis), in hypertensive heart disease the cardiomyocytes show hyperplasia and are normally arranged on a structured interstitial fibrosis that support the increased afterload.23 Therefore, tissue characterisation with CMR techniques is key to differentiating these two entities. LGE can be present in up to 50% of patients with hypertensive heart disease and follows a non-specific, non-subendocardial pattern and generally to a lesser extent compared with HCM. Extracellular volume and T1 times are slightly increased in hypertensive heart disease and can be used to differentiate this aetiology of LVH from HCM. Texture analysis and/or radiomics applied on T1 mapping sequences have been demonstrated to be useful in the distinction between hypertensive heart disease and HCM.23,24 Texture analysis captures disease-specific myocardial patterns, reflecting differences in the spatial distribution and heterogeneity of fibrosis – more focal in HCM and more diffuse in hypertensive heart disease.
Other forms of physiological adaptation to altered loading conditions of the LV that can lead to LVH and resemble HCM are the athlete’s heart and aortic stenosis. Almost 2% of white athletes and 13% of black athletes may present LV wall thickness of 13–16 mm.25 Usually, the LV cavity is larger (end-systolic diameter ≥45 mm) than that of patients with HCM (end-systolic diameter <45 mm) and there are no other associated abnormalities observed in HCM, such as mitral valve abnormalities or unusual implantation of the papillary muscles. Tissue characterisation with CMR usually shows normal values of extracellular volume and T1 and T2 times in the athlete’s heart.26 In contrast, severe aortic stenosis leads to pathological LVH response to the pressure overload. The presence of calcified, restrictive motion of the aortic valve leaflets and acceleration of the flow through the valve are the hallmark features of aortic stenosis.27 In addition, the LV myocardium can present replacement fibrosis with a non-ischaemic mid-wall distribution and the values of native T1 mapping increase with worsening of the severity of the aortic stenosis and symptoms.28
In patients presenting with LV hypertrophy and progressive renal, cardiac and cerebrovascular disease, Anderson–Fabry disease should be suspected (Figure 4).19 This is an X-link inherited metabolic disease that causes accumulation of glycosphingolipids in various organs and currently it can be reversed by appropriate recombinant enzyme replacement therapy. Therefore, it is crucial to differentiate this entity from other causes of LV hypertrophy. CMR is key in the diagnosis of Anderson–Fabry disease, showing the characteristic basal inferolateral mid-wall fibrosis in 50% of patients and the lipid accumulation in the myocardium causes typically short T1 times.29
Danon and Pompe diseases are also storage disorders that cause extreme hypertrophy of the LV. The CMR pattern in Danon disease is usually characterised by prominent, multifocal LGE with sparing of the septal myocardium and the T1 values are regionally elevated, matching the areas of replacement fibrosis.30 Pompe’s disease with an early infantile-onset presents with severe LV hypertrophy, increased extracellular volume and cardiac and respiratory failure.31 In contrast, late-onset Pompe’s disease does not show specific CMR characteristics that can differentiate the disease from other aetiologies, the presence of LGE is not common and, if present, it usually shows a non-ischaemic distribution in the basal inferoposterior wall.32
Finally, advances in cardiac imaging and the development of effective therapies have led to increased awareness and diagnosis of cardiac amyloidosis becoming probably the number one entity to be differentiated from HCM.33 Cardiac amyloidosis usually presents with concentric hypertrophy of the LV and RV, thickened valvular and subvalvular apparatus, characteristic hypertrophy of the interatrial septum as well as dilatation of both atria and ground-glass appearance of the myocardium on 2D echocardiography (Figure 4).19 The LV longitudinal shortening is characteristically reduced (as measured, e.g. with the mitral annulus plane systolic excursion) and using 2D speckle tracking techniques, there is an apical sparing of the myocardial shortening while the basal and mid ventricular segments appear markedly impaired (also known as cherry on the top pattern).34 On CMR, the deposition of the amyloid protein in the extracellular space leads to abnormal kinetics of the gadolinium, characterised by increased uptake by the myocardium and poor myocardial nulling due to the lack of relatively normal myocardium.19 The blood pool appears dark and the LGE is usually concentric, subendocardial and is commonly described as tramline or zebra pattern. The native T1 values and the extracellular volume are usually very high. Furthermore, differentiating the type of cardiac amyloidosis needs the assessment of specific blood and urine tests, bone scintigraphy and sometimes cardiac or extracardiac biopsies.
Role of Multimodality Imaging in Decision-making in Patients with Hypertrophic Cardiomyopathy
The advent of effective medical therapy to reduce LVOT obstruction and alter the natural history of the disease, as well as new less invasive interventional septal reduction techniques, has changed the management of patients with HCM, becoming more personalised and taking into consideration the genotype and phenotype.35 Improvement of symptoms is the main focus of medical and interventional therapy; therefore, the first step is to characterise the presence and magnitude of LVOT obstruction. Echocardiography with provocative manoeuvres, such as Valsalva manoeuvres, exercise or even after large carbohydrate-rich meals is key to determine the presence of LVOT obstruction.35,36
Non-dilating β-blockers are first-line therapy for symptomatic obstructive HCM and have a class 1 recommendation in the European Society of Cardiology (ESC) and American College of Cardiology (ACC) and American Heart Association (AHA) guidelines.1,37 These guidelines also recommend non-dihydropyridine calcium channel blockers in symptomatic patients unable to receive β-blockers and disopyramide for patients who remain symptomatic despite first line therapy (class 1).1,37
Cardiac myosin inhibitors have been demonstrated to improve symptoms and exercise capacity, have favourable effects on cardiac remodelling and reduce the need for septal reduction therapy.35 The ACC/AHA guidelines recommend cardiac myosin inhibitors in patients with obstructive HCM who remain symptomatic despite first-line therapy.37 In contrast, the ESC guidelines provide a class 2a recommendation for these therapies in addition to β-blockers or calcium channel blockers or in monotherapy when β-blockers, calcium channel blockers or disopyramide are not tolerated and before considering septal reduction therapy.1 This discrepancy stems from the design of the various trials, which have included patients who received cardiac myosin inhibitors while being maintained on the other therapies.35 The potential for development of heart failure under cardiac myosin inhibitors is one of the main concerns of these therapies, making frequent echocardiographic surveillance mandatory for patients on stable doses.35 In addition, the efficacy of these therapies in non-obstructive HCM is currently under research. Furthermore, the antifibrotic effects of cardiac myosin inhibitors has not been demonstrated.
Septal reduction therapies with surgery or alcohol septal ablation are reserved for patients with favourable anatomy who remain symptomatic and with pressure gradients through the LVOT ≥50 mmHg who have not responded to medical therapy.1,37 Interventricular septum thickness, location of the obstruction, additional mitral valve anatomical anomalies and coronary artery anatomy with septal perforator branches amenable to ablation are the main criteria to consider (Figure 5 ).38–40 Echocardiography is the first-choice imaging technique to evaluate most anatomical and functional characteristics to select patients for septal reduction therapies. The use of echocardiographic contrast injected directly on perforator septal branches allows delineation of the basal septal area that will be targeted during the alcohol septal ablation.39 In addition, it allows the identification of aberrant perforator septal branches that can drain directly into the LV cavity, contraindicating the alcohol septal ablation. Cardiac CT provides the highest spatial resolution for planning the surgical septal myectomy. Recent minimally invasive techniques have been developed, demonstrating safety and efficacy in reducing the LVOT obstruction without the need for extracorporeal circulation.40 To demonstrate the efficacy of the septal reduction therapy, transoesophageal echocardiography with provocation of obstruction (such as use of dobutamine infusion) is recommended.
Role of Multimodality Imaging in the Risk Stratification of Patients with Hypertrophic Cardiomyopathy
Once HCM is diagnosed, the patient should be followed-up for the occurrence of symptoms and surveillance should include echocardiography and ambulatory electrocardiographic monitoring every 1–2 years and CMR and stress testing every 3–5 years. Any change in symptomatic status should prompt clinical evaluation as soon as possible. It has recently been shown that the annual mortality of patients with HCM is similar to that of the general population with currently available therapies.41 However, the earlier the HCM is diagnosed, the higher the lifetime burden of complications such as SCD, heart failure and AF. The ICD is the only therapy that has the potential to change the natural history of patients with HCM. Therefore, identification of patients with HCM who are at risk of SCD is the main objective of imaging modalities. Contemporary practice incorporates formal risk scores to estimate the risk of SCD in patients with hypertrophic cardiomyopathy. The HCM Risk-SCD score (endorsed by the ESC) and the major risk factor algorithm (endorsed by the ACC/AHA) are the main risk scores.1,37 In addition, several parameters derived from imaging techniques have been reported to be associated with the occurrence of AF (and its potential clinical complications such as stroke), progression to LV dilatation and heart failure or restrictive filling pattern and heart failure with preserved ejection fraction.
Current calculators to estimate the risk of SCD include maximum LV wall thickness ≥30 mm, left atrial diameter and presence of LVOT obstruction as parameters that can be assessed with imaging techniques.1,37 These parameters should be considered within a clinical framework that includes age, family history of SCD at young age, presence of non-sustained ventricular tachycardia and syncope. Additionally, the presence of apical aneurysms and extensive fibrosis on CMR have also been associated with an increased risk of SCD.
In a meta-analysis of several studies comprising nearly 3,000 individuals with HCM, the presence of myocardial fibrosis on CMR was associated with 2.32-fold increased risk of SCD/aborted SCD/appropriate ICD therapy.42 Current ESC guidelines recommend the use of CMR to assess the presence of myocardial fibrosis to decide the indication of an ICD in individuals with HCM who have low to intermediate risk of SCD based on available calculators. The guidelines consider an extension of LGE of ≥15% as significant to be included in the shared decision-making with patients for the use of prophylactic ICD.
Other imaging parameters that have been associated with progression to overt heart failure and occurrence of AF and stroke are left atrial volume, left atrial reservoir strain and left atrioventricular coupling measured with echocardiography.43–47 Left atrial volume was independently associated with progression to heart failure in a cohort of 236 patients with HCM.44 In addition, a left atrial volume index of ≥37 ml/m2 and a left atrial reservoir strain of ≤23.4% were independently associated with the occurrence of new-onset AF.45 Left atrioventricular uncoupling based on a cut-off value of ≥40% was associated with increased risk of new-onset AF in a cohort of 373 patients with HCM.46 Increasing values of native T1 and extracellular volume were independently associated with heart failure-related death and the composite end point of heart failure-related death or heart failure hospitalisation in a cohort of 663 patients with HCM.47 Interestingly, T1 values and extracellular volume were not associated with the occurrence of SCD. Machine-learning approaches have demonstrated that specific CMR features may enhance the prediction of major adverse cardiac events including arrhythmic events, SCD, heart failure and AF-related stroke. In particular, the extent of LGE (≥11.6%), and the impairment of global radial strain (<25.8%) and circumferential strain (<17.3%) were associated with increased risk of major adverse cardiac events.48 It is important to note that those imaging parameters were derived mainly from retrospective studies and their implementation in clinical practice will depend on the reproducibility of the results in prospective series.
Conclusion
Cardiovascular imaging plays a central role in the diagnosis of HCM. Differentiating HCM from other entities, guiding the therapeutic management and evaluating the risk of adverse cardiovascular events are the main goals of using cardiovascular imaging to appropriately manage patients with HCM (Figure 6).