Left ventricular hypertrophy (LVH) is characterized by an increase in the mass of the left ventricle (LV), resulting from either thickening of the ventricular wall (concentric), enlargement of the ventricular cavity (eccentric), or a combination of both. The worldwide prevalence of LVH is estimated at 10–20% in adults, and LVH is more common in individuals with hypertension. Approximately 40% of people with hypertension develop LVH.1 The LV undergoes geometric changes in response to stressors such as pressure or volume overload, leading to an increase in the size of myocardial fibers.1,2 There are multiple etiologies of LVH, including systemic hypertension, aortic stenosis (AS), athletic training, hypertrophic cardiomyopathy (HCM), storage/metabolic disorders, and infiltrative cardiac diseases. Regardless of its etiology, LVH is an independent risk factor for adverse cardiovascular events.3 In this review, we discuss the etiologies, clinical approach, and role of multimodality imaging in the evaluation of LVH.
Physiological/Structural Contributors to LVH
Due to physiological and structural changes, LVH can be divided into three entities: athlete’s heart, hypertensive heart disease, and valvular heart disease (Figure 1 ). The clinical features of each of these are briefly described below.
Athletes Heart
Exercise-induced cardiac remodeling, or athlete’s heart, refers to the adaptive enlargement of the LV in response to the pressure and volume load of exercise. Historically, the Morganroth hypothesis was used to explain the physiology and consequences of athletic training on the heart based on the type of training.4 According to the hypothesis, endurance (isotonic) training, such as long-distance swimming and running, results in LV volume overload and eccentric hypertrophy (i.e. dilatation of the LV with a concomitant increase in LV wall thickness [LVWT]). In contrast, strength training, such as wrestling and weightlifting, causes pressure overload and concentric hypertrophy (i.e. increased wall thickness and normal chamber size). This hypothesis remains contentious because recent studies have failed to observe the concentric LVH traditionally associated with strength training.5 Therefore, a significant increase in wall thickness or LV mass in wrestlers or weightlifters should raise suspicion of an underlying pathology or anabolic steroid use. In athletes who participate in sports combining endurance and strength components, eccentric LV hypertrophy is common.6 The severity of LVH varies by sport played; one study showed cyclists and triathletes develop the most significant eccentric LVH, whereas canoeists and rowers have a lower degree of eccentric LVH with a major increase in LV mass.7
Hypertensive Heart Disease
The LV is the principal target for end-organ damage in hypertension. The prevalence of LVH in patients with hypertension is 36–41%.8 Although hypertensive heart disease typically manifests with concentric hypertrophy and rarely exceeds 15 mm, a wall thickness that exceeds this threshold or is asymmetric should prompt further evaluation for alternative or coexisting pathology, such as HCM. A significant diagnostic ‘gray zone’ persists in clinical practice, where LVH attributed to hypertension may mask an underlying cardiomyopathy or represent a phenotypic overlap of both conditions. For example, focal hypertrophy of the basal septum may mimic the asymmetric pattern of HCM, but is often a benign, pressure-related adaptation that regresses with antihypertensive therapy and lifestyle modifications. Notably, this regression may be attenuated in older individuals or in those with long-standing hypertension and multiple comorbidities.9 To improve diagnostic accuracy, a multimodal approach integrating clinical context with the ECG and advanced imaging findings is essential.
Aortic Stenosis
AS represents the most common valvulopathy in adults, occurring in 4% of patients older than 75 years of age.10 To compensate for the chronic pressure overload due to AS, the LV undergoes hypertrophy to normalize wall stress and preserve systolic function. However, this remodeling eventually becomes maladaptive and leads to myocardial fiber disarray and fibrosis. Critically, a high LV mass index is a predictor of worse outcomes after transcatheter aortic valve replacement.11
Clinically, AS manifests with the classic triad of chest pain, syncope, and dyspnea with exertion, with physical examination findings providing key diagnostic differentiation from HCM. Unlike the brisk, double-pulse pulsus bisferiens of HCM, AS is characterized by a weak, slow-rising carotid upstroke known as pulsus parvus et tardus. Further, the late-peaking systolic murmur in AS decreases in intensity with the Valsalva maneuver and from squatting to standing; the opposite physiological response is observed in HCM. Although valvular obstruction is most common, clinicians must also consider subvalvular or supravalvular stenosis, particularly in younger populations. For example, progressive LV outflow tract (LVOT) obstruction and concomitant aortic insufficiency should prompt evaluation for a subaortic membrane.12 Given these complexities, transthoracic echocardiography (TTE) remains the diagnostic cornerstone for staging the severity of obstruction and quantifying the degree of associated hypertrophy.
Infiltrative Diseases of the Heart
LVH can also occur due to infiltrative cardiomyopathies, where the accumulation of abnormal substances within the myocardium increases wall thickness. Unlike true myocyte hypertrophy, these diseases represent pseudohypertrophy because the increased mass is driven by interstitial infiltration.
Amyloidosis
Cardiac amyloidosis is the extracellular deposition of misfolded protein in the form of β-sheet fibrillar protein within the myocardium.13 Among the numerous proteins implicated in the development of amyloid in vivo, only nine cause significant cardiac disease. The most prevalent subtypes of amyloid are amyloid-light chain (AL) and amyloid transthyretin (ATTR). AL, which accounts for a minority of cardiac cases, is caused by a plasma cell dyscrasia that results in misfolded monoclonal immunoglobulin light chains.13 The vast majority of cases of cardiac amyloidosis are from ATTR caused by the misfolding of transthyretin. This protein acts as a carrier of thyroxine and retinol binding protein and is otherwise known as prealbumin. ATTR disease is further divided into wild-type and hereditary ATTR (ATTRwt and ATTRv, respectively) based on the presence or absence of a pathogenic genetic variant. In cardiac amyloidosis, LVH is typically associated with biventricular hypertrophy, hypertrophy of the papillary muscles, valvular thickening, enlarged atria, and hypertrophy of the interatrial septal wall. Valvular abnormalities such as concomitant aortic stenosis, mitral, and tricuspid regurgitation are common.
The clinical presentation of AL amyloidosis is often multisystemic. Renal involvement is common and manifests as nephrotic syndrome. A painful, length-dependent sensorimotor neuropathy can occur that presents with orthostatic hypotension, early satiety, or gastrointestinal dysmotility. Cardiac involvement leads to restrictive cardiomyopathy and portends a worse prognosis.14 The presence of macroglossia and periorbital ecchymosis is a rare but pathognomonic finding. Patients may also develop a bleeding diathesis due to an acquired factor X deficiency through a binding of factor X to amyloid fibrils.15 In contrast to AL amyloidosis, ATTR amyloidosis is more often predominantly cardiac, although some patients with ATTRv (e.g. those with a V30M gene variant) may present with neuropathy. Cardiac amyloidosis due to ATTR manifests as restrictive cardiomyopathy and heart failure with preserved ejection fraction. Patients may also present with AF or atrioventricular block from infiltration of the conduction system. As mentioned above, extracardiac involvement is more common in ATTRv than in ATTRwt, usually with peripheral and autonomic neuropathy. Interestingly, bilateral carpal tunnel syndrome is fairly common and may precede cardiac symptoms by years. Lumbar spinal stenosis and spontaneous biceps tendon rupture are also characteristic of ATTR and can provide valuable diagnostic clues.15
Sarcoidosis
Sarcoidosis is characterized by non-necrotic inflammatory granulomas that may develop in almost any organ of the body. Sarcoidosis is attributed to a dysregulated T cell immune response, potentially triggered by an environmental stimulus in a genetically predisposed individual. Most cases of sarcoidosis occur in patients aged 25–60 years, with a higher prevalence observed in northern Europeans, African-Americans and women.16
Cardiac sarcoidosis frequently accompanies extracardiac manifestations but may be the first or an isolated sign of sarcoidosis, which portends a poor prognosis.17 It may remain asymptomatic in as many as 25% of patients, whereas approximately 5% of patients may experience conduction abnormalities, ventricular arrhythmia, and heart failure based on the extent and location of the granulomas.17 High-grade atrioventricular block and ventricular arrhythmias are the most common initial manifestations.18 Sustained ventricular tachyarrhythmias stem from re-entrant circuits located within areas of granulomas/fibrosis, and high-grade atrioventricular block arises from extensive septal involvement.19 Heart failure with systolic dysfunction can occur due to extensive infiltration of granulomas in the myocardium or restrictive cardiomyopathy. AF is rare at presentation and occurs late in the disease course.20 Less commonly, patients may develop coronary artery disease, mitral regurgitation, or effusive/constrictive pericarditis.21
Cardiac sarcoidosis can present with a concentric pattern of LVH due to widespread infiltration of granulomas in the myocardium, although focal basal interventricular septal thickening is the most common finding. Other associated findings on TTE include ventricular aneurysms and isolated wall motion abnormalities, which occur in non-coronary distribution areas.
Hemochromatosis
Hemochromatosis is an abnormal deposition of iron in the visceral organs, leading to multiorgan dysfunction. The prevalence of hemochromatosis in the US is 0.37%, and it can be broadly categorized as hereditary or acquired.22 Hereditary hemochromatosis is classified into four types: type 1 is caused by a variant in the HFE gene, type 2 is caused by a variant in the hemojuvelin gene, type 3 is caused by a variant in the transferrin receptor-2 gene, and type 4 is caused by a variant in the ferroportin gene. Acquired hemochromatosis occurs after ingestion of massive amounts of iron or multiple blood transfusions.
Cardiac manifestations of hemochromatosis occur due to iron deposition in cardiac tissue and include cardiomyopathy, valvular heart disease, and arrhythmias.23 Patients present with heart failure, either due to underlying restrictive or dilated cardiomyopathy. AF is the most common arrhythmia, but atrioventricular block or ventricular arrhythmias also occur.24 Screening for hemochromatosis is done by measuring serum ferritin and transferrin saturation levels. Plasma transferring saturation >55% and serum ferritin >200 ng/ml in women or 300 mg/ml in men is a positive result.25
On TTE, eccentric LVH is observed and may be preceded by LV diastolic dysfunction.26 It is associated with low to normal LV ejection fraction (LVEF), and increased pulmonary artery pressure.26 Cardiac MRI (CMR) with T2* sequencing is the most accurate non-invasive method to assess myocardial iron deposition. Further, late gadolinium enhancement (LGE) can help identify the extent of cardiac fibrosis. Therapeutic phlebotomy and iron chelators are the primary management choices and may improve cardiac function.26
Primary Familial/Genetic Hypertrophic Syndromes
Genetic or familial causes of LVH include HCM, glycogen storage disease, lysosomal storage disease, PRKAG-2 deficiency, and RASopathies. HCM usually manifests with isolated cardiac involvement, whereas the rest are associated with prominent extracardiac features.
Hypertrophic Cardiomyopathy
HCM is the most common inherited cardiomyopathy, with a prevalence in the general population of between 1:300 and 1:500.27 HCM affects individuals of all races and ethnicities, and the age at diagnosis is typically in the fourth to fifth decades of life. HCM is slightly more common in men than in women.28 HCM may be asymptomatic in many patients and detected incidentally or through screening. Symptomatic patients may present with chest pain, dyspnea, palpitations, and syncope. Findings on physical examination include a harsh crescendo–decrescendo systolic murmur, prominent apical maximal impulse, and a fourth heart sound. LVOT obstruction can be evaluated by provocative maneuvers such as Valsalva and standing from a squatting position at the bedside. A three-generation family history is crucial to identify relatives with HCM or sudden cardiac death. Investigating for extracardiac features suggestive of an infiltrative or syndromic etiology of LVH is also an important part of the clinical evaluation, because HCM is a diagnosis of exclusion.
The morphology of LVH in HCM is variable and typically accompanied by small ventricular volumes. The most common location for hypertrophy is the interventricular septum, followed by hypertrophy of the mid-ventricle and apex. Septal hypertrophy is divided into three subtypes: sigmoid, reverse sigmoid, and neutral. The sigmoid pattern is seen more commonly in older individuals, whereas the reverse sigmoid pattern is seen in younger individuals and is associated with genotype-positive HCM.29 Mid-ventricular hypertrophy is characterized by a pressure gradient between the apical and basal chambers of the LV that increases the risk of apical aneurysm. LV aneurysm is associated with significant morbidity and mortality, including higher risks of stroke and sudden cardiac arrest.30,31 Apical hypertrophy occurs in the distal LV, below the papillary muscles, and is more prevalent in the Japanese population.32 Genetic testing is also helpful because typical contemporary HCM panels also include common mimics of HCM.
Glycogen Storage Disorders
Anderson–Fabry Disease
Anderson–Fabry disease is an X-linked lysosomal storage disease caused by the deficiency of α-galactosidase A, resulting in the accumulation of globotriaosylceramide in the heart and other tissues. In Anderson–Fabry disease, LVH typically manifests as diffuse and concentric hypertrophy with prominent papillary muscles and a binary endocardial layer.33 In some cases, Anderson–Fabry disease may be asymmetric and mimic HCM.34 It is crucial to differentiate LVH due to Anderson–Fabry disease from other etiologies because early identification and enzyme replacement therapy can limit disease progression.
Danon Disease
Danon disease is an X-linked lysosomal storage disease caused by a deficiency of the LAMP-2 protein, causing the accumulation of intracytoplasmic vacuoles containing glycogen in cardiac myocytes. In men, Danon disease manifests as severe LVH with a concentric pattern, whereas in women it manifests as mild LVH with an asymmetric pattern.35 Pre-excitation due to Wolff–Parkinson–White syndrome or fasciculoventricular pathways is a characteristic feature of Danon disease. Novel therapies for this condition, including gene therapy, are under investigation; in a phase I study, a single infusion of RP-A501, a recombinant adeno-associated virus serotype 9 containing the transgene LAMP2B, was safe and showed evidence of clinical improvement over 24–52 months.36
Other rare causes of LVH include PRKAG-2 deficiency and RASopathies. PRKAG-2 deficiency is characterized by glycogen accumulation in the cardiac myocytes due to increased cellular uptake of glucose. RASopathies, such as Noonan’s syndrome, are associated with germline variants associated with the RAS/mitogen-activated protein kinase pathway.37
Diagnostic Testing
12-Lead ECG
The features of HCM on an ECG include positive diagnostic criteria for LVH, pathological Q waves, ST-segment changes, and T wave abnormalities. Approximately 50% of patients with amyloid cardiomyopathy (AC) also present with a pseudo-infarct pattern in early precordial leads mimicking an anteroseptal infarct.38 The ST-T wave changes in HCM can mimic myocardial ischemia and range from isolated biphasic T waves in aVL to pronounced ST-segment elevation in anterior leads.38 Giant symmetric negative T waves (>10 mm) in anterior and/or lateral leads are characteristics of apical HCM.39 Isolated inverted T waves in inferior leads are common in athletes and are benign in nature.39
A high-voltage QRS on ECG has low sensitivity but high specificity for hypertensive heart disease.40 Low voltage on ECG relative to the degree of LV thickening on TTE is characteristic of AC and infiltrative disorders of the myocardium, but its absence does not exclude their diagnosis. True low voltage, defined as a QRS amplitude <5 mm in limb leads and <10 mm in precordial leads, is more prevalent in AL-AC than ATTR-AC. Low voltage is a relatively late finding in ATTR-AC and has limited utility in the early identification of the disease.41 ECG to TTE ratios are easily measurable and can play a supportive role in the detection of AC. A voltage-to-mass ratio <1.5 is suggestive of AC and is calculated by dividing the Sokolow–Lyon index (the sum of the amplitude of the S wave in V1 plus the R wave in V5 or V6) by the cross-sectional area of the LV wall.42 A ratio of the sum of all QRS voltages to LVWT <7.8 has high sensitivity (94%) and, when added to a model with clinical variables, improves the diagnostic accuracy for AC.43
In ATTR-AC, AF and atrioventricular blocks are more prevalent than in AL-AC.44 Atrioventricular blocks frequently present with cardiac sarcoidosis, often occurring in conjunction with left or right bundle branch block and fragmented QRS.45 Familial Wolf–Parkinson–White syndrome occurs in patients with a non-sarcomeric HCM due to variants in the PRKAG2 gene.46
Artificial Intelligence in ECG
Artificial intelligence (AI) analysis can help identify patterns and signatures on the ECG that are unrecognizable with conventional interpretation. AI-ECG models effectively identify etiologies of LVH, such as HCM, AC, hypertension, and AS, using 12-lead ECG and single-lead ECG (leads 1 and 2).47 A multimodal deep learning (DL) model combining ECG with echocardiographic data accurately differentiated HCM from hypertensive heart disease.48 Most of the available AI-ECG data are for the detection of HCM using DL with conventional neural network models. A team from the Mayo Clinic developed an AI-ECG algorithm that was later refined by combining it with a clinical variable-based ‘HCM-DETECT score’, which improved its diagnostic accuracy, particularly in patients over 40 years of age, who had a high false-positive rate with the original model.49,50 However, there is a paucity of data to support the use of AI-ECG as a screening tool for HCM currently.
Transthoracic Echocardiography
TTE is the initial imaging modality for the evaluation of LVH due to its accessibility and cost-effectiveness. To achieve optimal value from the test, a high-quality study and an increased index of clinical suspicion are required. TTE may be of limited use in patients with poor acoustic windows, which can hinder accurate visualization.
Hypertrophic Cardiomyopathy
An LVWT ≥15 mm and disproportionate to any pre-existing pressure overload state is diagnostic of HCM.51 A more lenient LVWT of 13–14 mm can be used as the cut-off value in genotype-positive individuals or in those with a family history of HCM.51 The distribution of hypertrophy is typically focal and asymmetric with involvement of non-contiguous LV segments or, less commonly, the right ventricle and papillary muscle. The basal anterior interventricular septum is typically affected, resulting in a septal/posterior wall thickness ratio >1.3, which is characteristic of HCM. Associated findings on TTE include LVOT obstruction and abnormalities of the mitral valve apparatus. LVOT obstruction is defined as a peak gradient >50 mmHg at rest or with provocation and is accompanied by a late peaking or dagger-shaped Doppler profile.52 Mid-ventricular obstruction is identified by the hourglass appearance of the LV with a paradoxical apex-to-base diastolic gradient on color Doppler.
Provocation maneuvers should be performed if resting gradients are normal. As per the 2024 American Heart Association (AHA)/American College of Cardiology (ACC) HCM guidelines, exercise stress echocardiography is the preferred method for provoking an LVOT gradient due to its ability to induce the most physiological response.49 In patients who remain equivocal after exercise stress echocardiography, cardiac catheterization with hemodynamic assessment can be helpful.49 Provocation maneuvers like Valsalva and squat-to-stand can also be performed in patients for whom accurate non-invasive estimation with exercise is limited by inconsistencies in patient instruction and effort. Postprandial exercise can be considered in patients who experience symptoms after meals.49 Pharmacological provocation with amyl nitrate, isoproterenol, or dobutamine may be used in experienced laboratories, although amyl nitrite is not widely available.49
Systolic anterior motion (SAM) of the mitral valve is characterized by the abnormal coaptation of the mitral valve leaflets into the LVOT due to push or drag forces, leading to obstruction. The structural abnormalities contributing to SAM include elongated mitral valve leaflets, chordal elongation, abnormalities of the papillary muscle, and direct insertion of an anomalous papillary muscle into the anterior leaflet. Mitral regurgitation can be primary or secondary to SAM, and the direction of the jet can be used to differentiate between them. A posteriorly directed jet should raise suspicion for SAM-related mitral regurgitation, whereas a central or anteriorly directed jet is suggestive of an intrinsic mitral valve abnormality. TTE also plays a crucial role in risk stratification for sudden cardiac death.51 High-risk features based on the recent 2024 AHA/ACC HCM guidelines, such as maximum LVWT >30 mm, LV aneurysm, and LVEF <50%, can be reliably assessed.49
Athletes Heart
It is important to distinguish between an athlete’s heart and HCM because they may present similarly. On TTE, a ‘gray zone’ of LVH exists where the LVWT falls within the upper limits of normal for athletes but remains below the diagnostic threshold for HCM. LV cavity size is regarded as the most reliable independent criterion for differentiating physiological from pathological LVH.52 In athletes heart, there is an increase in LVWT and cavity size; however, in HCM, there is an increase in LVWT with a decrease in cavity size. An LV cavity size ≥55 mm showed the highest sensitivity and specificity (both 100%; p<0.001) for athlete’s heart.53 However, it does not have the same diagnostic accuracy when the two pathologies coexist. A study by Sheikh et al. showed that 13% of athletes with HCM had an LV cavity size >54 mm.54 In healthy athletes, diastolic filling is normal or even supranormal; however, in HCM, myocardial stiffness and impaired muscle relaxation lead to abnormal filling patterns. Furthermore, although detraining often leads to the regression of LVH in athletes, it has little effect on the structural changes of HCM.55 However, it is important to note that more research is needed to determine how training or detraining affects individuals who are genotype-positive for HCM.
Aortic Stenosis
Typical features of AS are symmetric LVH, calcification, and impaired cusp mobility of the aortic valve.56 The absence of evidence of AS and SAM on TTE should raise suspicion of subvalvular stenosis. On continuous wave Doppler, an early peaking gradient indicates fixed LVOT obstruction in aortic and subvalvular stenosis. In contrast, a late peaking or dagger-shaped Doppler profile is evidence of the dynamic nature of the gradient in HCM, which typically develops in mid-late systole.
Amyloid Cardiomyopathy
Echocardiography is the initial imaging modality used for evaluating AC. Several typical features on TTE raise suspicion of cardiac amyloidosis, including concentric LVH, biatrial enlargement, valvular thickening, and interatrial septal hypertrophy.57 However, in early disease, TTE lacks specificity to distinguish AC from other etiologies of LVH. Myocardial speckling on echocardiography has low sensitivity but a high specificity of 81%.58 Diastolic dysfunction occurs early in AC, and progresses and correlates with disease severity. A restrictive filling pattern is frequently present in advanced disease.59 Early diastolic velocity (E′) measured using tissue Doppler imaging is abnormal in early and late AC. Systolic dysfunction can occur in the advanced stage in the form of reduced LVEF and is associated with a poor prognosis.
Strain and strain rate can detect early LV systolic dysfunction in AC before the clinical manifestation of heart failure. Global longitudinal strain imaging demonstrating severe impairment of the mid and basal segments with relative apical sparing (ratio of apical longitudinal strain/average longitudinal strain in mid and basal myocardial segments >1.0) is helpful in distinguishing AC from other forms of LVH.60 This has been referred to as a “cherry-on-top” pattern, given its distinctive appearance on strain mapping.
Sarcoidosis
TTE is the initial modality for screening due to its wide availability and low cost, but it has limited sensitivity (25%) for sarcoidosis.59 Features of cardiac sarcoidosis on TTE include reduced LVEF, regional wall aneurysm, basal septal thinning, and abnormal global longitudinal strain. Right ventricular systolic pressure may be increased, indicative of sarcoid-related pulmonary hypertension. Nevertheless, patients with cardiac sarcoidosis may initially have a normal echocardiogram. Therefore, CMR and fluorodeoxyglucose PET are adjunct modalities for the detection of myocardial inflammation and fibrosis.
Artificial Intelligence in Echocardiography
The application of AI, machine learning, and DL to overcome the inherent limitations of echocardiography in differentiating LVH etiologies has been an area of interest recently. One study showed that an AI model based on echocardiography–radiomics, a process of extracting data-rich features from echocardiographic images, was able to effectively distinguish different etiologies of LVH, including HCM, cardiac amyloidosis, and hypertensive heart disease.60 This approach also provided key diagnostic insights into specific features, such as myocardial texture, shape, and thickness, that were used by the model in the identification of the etiology. Although DL algorithms have been shown to improve the diagnostic process of differentiating LVH, they do not reveal the specific features used for the differentiation of LVH. One study showed that a DL-based model had a significantly higher diagnostic accuracy in differentiating HCM, cardiac amyloidosis, and hypertensive heart disease than echocardiography specialists (~92% versus ~80%, respectively).61 Another study of a DL-based model, which trained convolutional neural networks to identify HCM in patients with LVH on TTE, had a sensitivity and specificity of 68% and 99%, respectively.62 Future research should be aimed at evaluating these models in diverse populations and clinical settings, although one such model has already been approved for clinical use in the US by the Food and Drug Administration.63
Cardiac MRI
CMR provides high-definition anatomical assessment and tissue characterization that supplements the information obtained on echocardiography. It serves as a valuable tool when findings are inconclusive on TTE. The use of CMR may be limited by AF, decreased cooperation due to breath holds, advanced renal dysfunction, and incompatible cardiac devices.
Hypertensive Heart Disease
CMR may be useful in cases where it is challenging to distinguish hypertensive heart disease from HCM.64 This is observed in certain high-risk populations, such as African Americans with chronic kidney disease. In these patients, LVWT may reach up to 20 mm, where it typically does not exceed 15 mm in hypertensive disease. LGE shows a patchy, non-specific, non-subendocardial pattern in up to 50% of patients with hypertensive heart disease, similar to HCM.65 Further, the interpretation of LGE in hypertensive heart disease is difficult due to diffuse fibrosis. Because the detection of myocardial fibrosis depends on the surrounding normal myocardial tissue, the lack of a normal “baseline” makes it difficult to identify specific areas of damage. T1 mapping is a novel technique that quantifies the longitudinal relaxation time of the myocardial tissue. Patients with hypertrophic cardiomyopathy demonstrate a higher native T1 compared to those with hypertensive heart disease.66
Athlete’s Heart
CMR plays a supportive role in the evaluation of athletes with features that overlap with pathological causes of LVH. Features that are characteristic of an athlete’s heart on CMR include symmetric enlargement of both ventricles, mild interventricular hypertrophy, and low normal LVEF with a normal stroke volume index, which help differentiate it from other phenocopies.67 LGE is typically seen at right ventricle insertion points, where it is associated with elevated extracellular volume (ECV) and is generally considered a benign imaging finding due to repetitive hemodynamic stress.68
Hypertrophic Cardiomyopathy
In patients with high clinical suspicion of HCM in whom TTE is inconclusive, CMR provides additional information. CMR has high spatial resolution that enables better visualization of focal areas of LVH. Hypertrophy of the anterolateral wall of the LV may be overlooked on poor acoustic windows on TTE, which can be overcome by CMR. The LVWT, ventricular size, systolic function, and associated abnormalities of the mitral valve apparatus can be more accurately assessed. The pattern of LGE distribution is non-specific, patchy, and limited to the areas of prominent hypertrophy. Although CMR alone cannot distinguish HCM from its phenocopies, it can help identify high-risk morphological features associated with sudden cardiac death. These include LV apical aneurysm, extensive LGE involving multiple LV segments, massive LVH (defined as >30 mm), and systolic dysfunction (defined as LVEF <50%).51
Amyloid Cardiomyopathy
LGE in AC shows a diffuse subendocardial or transmural pattern that does not correlate with any coronary artery distribution. Subendocardial distribution is more commonly seen with ATTR-AC, whereas transmural distribution is seen with AL-AC. A recent meta-analysis showed that the sensitivity and specificity of LGE for diagnosing AC are as high as 86% and 92%, respectively.69 ECV, a measure of the proportion of the myocardium occupied by the extracellular space, is typically elevated in amyloidosis due to the deposition of amyloid fibrils. ECV values characteristic of AC are >30%.70 Although ECV expansion has shown greater diagnostic and prognostic utility than LGE, it does not differentiate between ATTR and AL subtypes. A recent study showed that T2 mapping, a measure of myocardial edema, may have the potential to differentiate ATTR-AC from AL-AC when used in conjunction with LGE distribution patterns.71
Sarcoidosis
The characteristic pattern of LGE in cardiac sarcoidosis is patchy, involving the subepicardial or mid-myocardial layers of the LV and right ventricle. There is prominent involvement at the ventricular insertion points, with contiguous extension across the basal interventricular septum into the right ventricle, also described as the “hook sign.” However, these LGE patterns are not specific to cardiac sarcoidosis (specificity 85%), because similar findings can be seen in inflammatory cardiomyopathies.72 Nonetheless, CMR has a high negative predictive value to help rule out cardiac sarcoidosis. In some patients, overt myocardial involvement may be absent despite high clinical suspicion, as in early or subclinical disease. In such “image-negative” cases, multiparametric CMR imaging using T2 mapping may aid in the detection of areas with inflammation or edema. For patients with low pretest probability, CMR alone may suffice, or, in patients with higher pretest probability, fluorodeoxyglucose PET along with CMR may provide additional information.72 Given all the limitations of imaging, evaluation with cardiac or extracardiac tissue sampling may still be necessary.
Artificial Intelligence in CMR
AI applied to CMR can help improve the diagnostic accuracy of CMR, especially in distinguishing between subtypes of cardiac amyloidosis. Weberling et al. showed that a trained machine learning model using semiautomated CMR imaging data and patient demographics could accurately identify cardiac amyloidosis and differentiate its subtypes.73 Another study by Hwang et al. showed that T1 mapping on CMR derived from AI automated segmentation could improve the diagnosis of cardiac amyloidosis and differentiate it from other etiologies of LVH.74 A pilot study on CMR steady-state free-precession radiomics using myocardial textural analysis showed potential in differentiating etiologies of LVH and early diagnosis.75 Although these advances are exciting, at this time, these AI algorithms are not yet available for widespread clinical use.
Genetic Testing
Genetic testing and inheritance patterns can provide additional diagnostic clues in distinguishing HCM from other causes of LVH. HCM is commonly inherited in an autosomal dominant pattern, whereas hereditary hemochromatosis is inherited in an autosomal recessive pattern. Danon and Fabry diseases are both X-linked conditions; therefore, father-to-son transmission would rule out an X-linked condition. Genes for some of these syndromes are included on clinically available HCM genetic panels, facilitating genetic testing for HCM and for systemic diseases that include LVH. Pathogenic DNA variants prevalent in HCM include those in the MYH7 and MYBPC3 genes, which encode for myosin heavy chain and myosin binding protein C, respectively.76 Fabry disease is linked to a variant GLA or α-galactosidase enzyme, whereas the LAMP2 gene is implicated in Danon disease. Accurately distinguishing HCM from its phenocopies is important because enzyme replacement therapy is available for Fabry and Pompe diseases, and anticipation for heart transplantation for Danon disease is likely warranted, which rapidly progresses to end-stage heart failure in adolescent males.
A study by Maestro-Benedicto et al. investigated the prevalence of ATTRv among elderly patients with transthyretin cardiomyopathy (ATTR-CM), finding that 5.3% of patients aged ≥70 years with ATTR-CM were diagnosed with ATTRv.77 This finding underscores the importance of considering genetic testing for ATTRv in elderly patients with ATTR-CM, because it has significant therapeutic and diagnostic implications. Specifically, the identification of ATTRv can lead to the initiation of transthyretin-specific drug treatments and genetic screening of relatives, which can identify asymptomatic carriers and guide family counseling. The AHA recommends differentiating ATTRv from ATTRwt to trigger genetic counseling and potential screening of family members, which is critical for early diagnosis and intervention.78 In addition, genetic testing allows for the identification of presymptomatic carriers, enabling timely monitoring and the administration of disease-modifying therapies before significant organ damage occurs.78 Therefore, routine genetic testing in patients with ATTR-CM, regardless of age, is essential to ensure early diagnosis, appropriate treatment, and effective family counseling, ultimately improving patient outcomes and quality of life.
The clinical consensus statement by the European Society of Cardiology (ESC) Council on Cardiovascular Genomics emphasizes the integration of genetic testing into routine diagnostic pathways for cardiomyopathies, as recommended in the 2023 ESC guidelines.79 The clinical consensus statement highlights the critical role of cardiologists in managing genetic testing, from clinical phenotyping and test prescription to interpretation and communication of results. The statement underscores the importance of multidisciplinary collaboration and the development of a genetically literate workforce to optimize genomic medicine in cardiology.
Genetic testing is crucial for diagnosing inherited cardiomyopathies such as HCM and dilated, arrhythmogenic, and restrictive cardiomyopathies. The early identification of pathogenic variants allows for the initiation of preventive strategies and tailored therapies, even in asymptomatic or presymptomatic individuals, which can significantly improve outcomes.80,81 The AHA recommends obtaining a three-generational family history and performing periodic echocardiographic screening for first-degree relatives of patients with familial cardiomyopathy.82 Variant-specific genetic testing is also advised for family members once a causative variant is identified in the index case.82 The Heart Failure Society of America emphasizes that genetic testing facilitates patient management and family screening, identifying at-risk family members who may benefit from early intervention.83 This approach can prevent sudden cardiac death and reduce hospitalizations and mortality due to heart failure.84 The 2021 ESC position statement on the management and treatment of cardiac amyloidosis includes screening recommendations aimed at facilitating early (i.e. subclinical) diagnosis of ATTRv cardiomyopathy in at-risk family members.85 In a study assessing the effectiveness of this recommendation, 25% of screened relatives were found to have ATTRv cardiomyopathy, with half already exhibiting clinical symptoms such as heart failure or conduction abnormalities.86 These findings support the utility of the 2021 ESC screening guidelines in facilitating the early detection of ATTRv cardiomyopathy in at-risk individuals. Therefore, the diagnostics in variant carriers of cardiomyopathy are vital for early detection, risk stratification, and the implementation of preventive and therapeutic measures, ultimately improving patient outcomes and enabling effective family screening.
Conclusion
In patients with LVH, the 2024 AHA/ACC HCM guidelines recommend a systematic approach on echocardiography to distinguish HCM from other systemic or physiological causes of LVH. A maximum end-diastolic wall thickness of ≥15 mm that is disproportionate to a mechanical stimulus, or 13–14 mm in patients with positive family history or genetic testing, raises the suspicion of HCM. The typical pattern of LVH observed in HCM is focal asymmetric hypertrophy, most commonly involving the basal anterior septum. In contrast, physiological LVH is characterized by concentric hypertrophy in pressure overload situations and more eccentric hypertrophy in an athlete’s heart. Systemic causes of LVH, such as infiltrative diseases, exhibit their own distinct patterns of hypertrophy. Other clues on imaging include abnormalities of the mitral valvular apparatus, such as systolic anterior motion of the mitral valve and mitral regurgitation. The presence of dynamic LVOT obstruction at rest or with provocation, defined as a gradient ≥30–50 mmHg, or mid-ventricular obstruction with apical aneurysm, further supports a diagnosis of HCM.
At the bedside, a comprehensive history and physical examination help identify a family history of HCM, assessing for symptoms and possible alternative etiologies of LVH. In younger individuals, the presence of LVH should prompt consideration of HCM or athlete’s heart and systemic diseases, such as sarcoidosis, RASopathies, and glycogen and lysosomal storage disease; in older individuals, physiological causes such as hypertension and aortic stenosis are more common, as well as infiltrative diseases like amyloidosis. A three-generation family history of HCM or sudden cardiac death is recommended as part of the initial assessment to identify familial syndromes and individuals at increased risk, and genetic testing should be routine in most cases. Extracardiac manifestations may be clinical clues for an underlying systemic disease, such as in amyloidosis, where bilateral carpal tunnel syndrome, chronic kidney disease, and polyneuropathy are commonly found in association with LVH.
In patients with LVH of an uncertain etiology, genetic testing for HCM or other genetic conditions is recommended when there is heightened suspicion. In such cases in which clinical evaluation and echocardiography are inconclusive, CMR allows for more accurate assessment of LVWT, LV chamber size, systolic function, and the distribution and extent of fibrosis with LGE, which can help identify the cause of the LVH. Therefore, when available and feasible, MRI serves as a critical diagnostic tool when the diagnosis of HCM remains ambiguous after initial evaluation. There is also a growing body of evidence regarding the use of AI to detect LVH and phenocopies based on ECG, echocardiography, and text mining of electronic health records, demonstrating significant advances in diagnostic accuracy and clinical utility.