To aid in the differential diagnosis of LVH, the clinician should keep in mind a focused approach, considering age at first presentation, symptoms, personal and family history, and specific clinical markers on physical examination (“red flags”) (Table 1). The primary investigative step in adults exhibiting LVH involves screening for frequent etiologies, notably pressure overload conditions, like chronic AH and AS, or physiological adaptations associated with athletic training. Individuals with LVH may be asymptomatic or exhibit nonspecific symptoms, such as exertional dyspnea, fatigue, chest discomfort, palpitations, syncope, and/or presyncope. The investigation of LVH is often precipitated by incidental findings identified during an ECG or ECHO, which are often conducted for other screening objectives. Conversely, a variety of noncardiac symptoms and signs may occasionally be indicative of specific diagnoses.

Table 1

	Hypertrophic Cardiomyopathy	Fabry Disease	Cardiac Amyloidosis	Danon Disease	Pompe Disease	PRKAG2	RASopathies	Friedreich’s Ataxia
Genetics	• Autosomal dominant inheritance • Great variety of gene mutations, most prevalent: MYH7(cardiac myosin heavy chain beta) - 30-50%, MYBPC3 (Myosin binding protein C) -20-40%, TNNT2(Cardiac troponin T -5-20%	• X-linked inheritance • Mutation in GLA gene	• Hereditary ATTR (mutant or familiar): an autosomal-dominant disease with variable penetrance • Mutation in transthyretin (TTR) gene	• X-linked inheritance • Mutations in the lysosome-associated membrane 2(LAMP2) gene	• Autosomal recessive lysosomal storage disorder • Mutations in the GAA gene	• Autosomal dominant inheritance • Mutations in thePRKAG2 gene	• Autosomal dominant inheritance • Mutations in the RAS/MAPK signaling pathway	• Autosomal recessive inheritance • Mutations in the Frataxin gene (FXN)
Epidemiological Clinical aspects	• Most common LVH among genetic causes • Young and older patients (broad age spectrum) • History of syncope	• Corneal opacity • Angiokeratoma • Hypohidrosis • Albuminuria • Acroparesthesia	• Adults > 55 years old • Bilateral carpal tunnel syndrome • Biceps tendon rupture. • Peripheral polyneuropathy • Sensory involvement, autonomic dysfunction • Skin bruising	• Male individuals from 10-20 years old • Intellectual disability • Muscle weakness • Hepatomegaly • Women with almost exclusive cardiomyopathy	• Children (at birth and first year of life) / Adolescents • Muscle weakness • Macroglossia • Pigmentary retinitis	• Young patients(I-IV decade) • Myalgia • Epilepsia • Early onset arterial hypertension • Ventricular preexcitation(pseudo Wolff-Parkinson White)	• Children /Adolescents and young patients < 20 years old • Facial dysmorphism • Multiple lentigines • Pectus carinatum • Deafness • Kyphosis • Hypertelorism	• > 15 years old • Symmetric gait ataxia. • Kyphoscoliosis • Sensory neuropathy • Dysarthria • Deafness • Vertigo

Concerning the onset age, an elevated prevalence of glycogen storage diseases (e.g., Pompe disease) and RASopathies (including Noonan syndrome) is noted as underlying etiologies for unexplained LVH in children and adolescents. Conversely, in adults aged over 55 years, cardiac amyloidosis (CA) can be found at a higher frequency, and awareness of the possible diagnosis of this treatable disease is very important.⁴ HCM represents the most common etiology for LVH among genetic causes across a broad age spectrum, spanning from young to elderly patients.⁴

Severe LVH observed at birth or during the first year of life, coupled with muscle weakness, macroglossia, and pigmentary retinitis, should prompt clinical suspicion of Pompe disease. In male individuals aged between 10 and 20 years presenting with substantial LVH, intellectual disability, muscle weakness, and ventricular pre-excitation, an evaluation for Danon disease is warranted. Similarly, up to the age of 20, the presence of facial dysmorphism, multiple lentigines, pectus carinatum, deafness, kyphosis, and hypertelorism should alert clinicians to the possibility of RASopathies, such as Noonan syndrome and Noonan syndrome with multiple lentigines. In individuals over 15 years old, the co-occurrence of neurological symptoms like ataxia, imbalance, and alterations in gait may indicate Friedreich’s ataxia. Additionally, mitochondrial diseases, alongside LVH, often manifest with sensorial abnormalities as well as neurological and myopathic symptoms. In individuals aged between 30 and 40 years, Fabry disease and PRKAG2 cardiomyopathy (CM) should be included in the differential diagnosis.⁵ The manifestation of gastrointestinal symptoms, neuropathic pain, angiokeratomas, hypohidrosis, cornea verticillata, proteinuria, conduction disturbances, juvenile or cryptogenic transient ischemic attack or stroke, and hearing loss, coupled with a history of X-linked hereditary transmission, prompt to the investigation of Fabry disease.⁶ In patients aged over 55-60 years, CA (either light chain or wild-type transthyretin) should be considered, particularly in the presence of clinical indicators such as carpal tunnel syndrome, spontaneous biceps tendon rupture (Popeye’s sign), back pain (indicative of spinal stenosis), polyneuropathy (manifesting as neuropathic pain, ambulatory difficulties, or frequent falls), intolerance to antihypertensive or heart failure medications due to postural hypotension, disproportionate low voltage QRS in ECG to LV mass, heart failure with preserved ejection fraction (HFpEF), and bradyarrhythmia.⁷

When a genetic etiology is suspected, it is crucial to conduct a detailed inquiry into the three-generation family history, focusing on the diagnosis of HCM, presence of sudden death, arrhythmia, intracardiac device implantation, and reports of early stroke.⁵ HCM and PRKAG2 mutations are typically associated with autosomal dominant inheritance. An X-linked pattern should prompt consideration of Fabry or Danon disease, whereas an autosomal recessive pattern suggests Friedreich’s ataxia⁸(Table 1). During the physical examination, the presence of signs indicative of dynamic LV outflow tract obstruction (LVOT), such as a systolic murmur that increases in standing position or bifid pulse, may suggest intraventricular obstruction caused by HCM. A history of pacemaker implantation, numerous affected family members, and the presence of Wolff-Parkinson-White syndrome lend support to the diagnosis of PRKAG2, with Fabry disease as a potential alternative diagnosis.⁹

Clinical data alone, while informative, is insufficient for the differentiation of the etiology of LVH, and additional diagnostic tests are essential for confirming the underlying cause. Nonetheless, a comprehensive clinical judgment and a tailored assessment of each patient are critical in guiding the judicious selection of appropriate diagnostic methodologies.

In summary, based on the aforementioned criteria, three principal findings should prompt suspicion of, and initiate the investigation for HCM mimics:

Electrocardiographic anomalies may manifest years before the development of a hypertrophic phenotype. While ECG changes are generally non-specific, they can provide diagnostic hints, especially when interpreted in conjunction with other clinical and laboratory findings and correlated with multimodality imaging (Figure 2). HCM may exhibit a wide range of patterns, including left ventricular strain and ST- and T-wave abnormalities, although, in some cases, the ECG can be normal.¹⁰ Deep negative T-waves in precordial leads may suggest apical HCM. An extreme LVH pattern is suggestive of Danon, Pompe, and PRKAG2 cardiomyopathies. Low QRS voltage (absolute or relative, e.g., disproportionate QRS voltage to LV wall thickness), atrioventricular block and a pseudoinfarction pattern are hallmarks of CA. A short PR interval/ventricular pre-excitation (notably in younger patients) and atrioventricular blocks (in adult patients) are observed in Fabry, Danon, and PRKAG2 diseases. Bifascicular blocks may also point to Fabry disease as a possible diagnosis.¹¹

Figure 2

Patients with LVH may experience a wide range of arrhythmias, from asymptomatic atrial and/or ventricular premature beats to life-threatening ventricular arrhythmias (VAs). Atrial fibrillation (AF) is a common complication in the clinical progression of HCM, Fabry disease, and amyloidosis. Similarly, sarcomeric HCM, Danon, and PRKAG2 cardiomyopathies are associated with a risk of life-threatening VAs.⁸

Within the framework of a hypertrophic phenotype and its clinical manifestations, the application of routine and targeted laboratory investigations can provide indications for specific diagnoses. Although non-specific, disproportionately high levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and minor elevations in serum troponin may point to a diagnosis of amyloidosis or specific forms of sarcomeric HCM. Sustainedly high serum creatine kinase (CK) levels could indicate Pompe disease, neuromuscular diseases or athlete’s heart. Liver dysfunction, characterized by raised serum levels of hepatic transaminases, may be observed in Pompe, Danon, and PRKAG2 cardiomyopathies. The finding of light-chain immunoglobulin in serum and urine immunofixation assays and an abnormal free-light-chain ratio are consistent with a diagnosis of AL amyloidosis.⁷ For Fabry disease, the “dry spot test” is a useful screening tool in males, in whom the diagnosis is established through the assessment of alpha-galactosidase A (α-GalA) activity and lyso-Gb3 measurements. In female patients, genetic testing is typically required to confirm the diagnosis.

ECHO plays a pivotal role in the diagnosis and management of LVH, not only due to its broad availability, non-invasive nature, and relative affordability but predominantly because of the comprehensive information it provides. This includes anatomical visualization of structures (LVH phenotype, thickness of LV walls, and geometric distribution of hypertrophy), assessment of left and right ventricular (RV) function, and hemodynamic evaluations (such as LV end-diastolic pressure, pulmonary artery systolic pressure, stroke volume, and vena cava collapsibility). ECHO is also valuable for identifying fixed obstructions, like AS, or dynamic LV obstructions, like obstructive HCM.¹²

Recent advances in echocardiographic techniques, particularly in myocardial deformation analysis, have enhanced our understanding of pathophysiology, myocardial mechanics and myocardial function beyond ejection fraction. Speckle-tracking echocardiography (STE) has emerged as a sensitive tool for the early detection of myocardial disease, as global longitudinal strain (GLS) often deteriorates before LV ejection fraction (LVEF) decreases in various clinical contexts, with the advantage of being less load dependent. It is important for diagnosing subclinical cardiac diseases in genotype-positive relatives of patients with HCM, Friedreich’s ataxia, and CA, as well as for monitoring patients with metabolic, infiltrative, or myocardial storage diseases. STE helps in characterizing myocardial involvement patterns, acting as a sort of visual “fingerprint” and serving as an echo-based “tissue characterization tool” (Figure 3).¹³ There is a strong correlation between GLS values and late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR), pointing to myocardial fibrosis and higher risk of mortality and malignant VAs in patients with HCM.^14,15 This parameter also has prognostic value in infiltrative diseases like CA.¹⁶

Figure 3

Myocardial work has been developed as a new promising echocardiographic tool for the evaluation of myocardial mechanics, incorporating afterload (arterial blood pressure) as an estimate of LV pressure and using longitudinal strain (LS) for the construction of a “pressure x strain” loop, generated by a specific software.¹⁷ The additional value of this technique over conventional echocardiographic parameters for the evaluation of cardiomyopathies is still to be proved in larger studies. Still, some data are showing prognostic value for evaluation of HCM¹⁸ and CA¹⁹ for example.

While still not universally available, three-dimensional echocardiography (3DE) has become a valuable tool for assessing myocardial diseases, particularly for direct volumetric measurements of cardiac chambers. It provides accurate EF and LV mass values, correlating well with the gold standard CMR.²⁰ 3DE also enables 3D myocardial strain measurement, is less affected by technical limitations like out-of-plane movement, and allows for the simultaneous evaluation of the entire LV, which is useful for synchronization analysis.

Contrast echo using ultrasound-enhancing agents is important for LV border delineation, especially in patients with suboptimal acoustic windows. It increases sensitivity in detecting conditions like apical HCM and apical aneurysms and differentiating intracavitary thrombus from other structures such as tendons or trabeculations.²¹

CMR has assumed an unquestionable role in the evaluation of LVH, mainly by assessing cardiac morphology, function, and tissue characterization.⁸ Although CMR may give essential clues for the final diagnosis in entities with extreme abnormalities in tissue characterization, such as CA or Fabry disease, the significant overlap of imaging findings in many entities makes necessary a comprehensive integration of imaging findings in the clinical context. No imaging finding should be interpreted in isolation, without integration of clinical history, electrocardiographic data and family history.²²

Beyond the anatomical and functional evaluation of the LV, the main advantage of CMR compared to ECHO is the possibility of tissue characterization. Parametric mapping techniques that measure the T1 and T2 relaxation times have been increasingly incorporated in acquisition protocols, allowing for the quantitative evaluation of intracellular and extracellular components.²³LGE imaging can identify replacement fibrosis and has well-established prognostic value, although it is less sensitive to detect diffuse interstitial collagen deposition than T1 mapping techniques.²⁴

Despite the existence of established gender-specific normal reference values for LV mass in clinical guidelines,²⁵ technical challenges can introduce variability and difficulties in the echocardiographic measurement of LV wall thickness. Suboptimal acoustic window, incorrect measurements (oblique or foreshortening, use of apical window – poor lateral resolution), and inclusion of confounding structures may affect accuracy. Some structures, such as a prominent RV moderator band, tricuspid valve apparatus, crista supraventricularis or LV fibromuscular false tendons inserted in the interventricular septum, may erroneously be interpreted as part of the septum, overestimating septal thickness. In pediatric patients, Z-scores, which represent the number of standard deviations from mean values, are used as reference standards. These scores adjust LV mass and wall thickness according to the child’s age and body size, providing a more tailored assessment in this population.³ Thresholds for carriers of genetic pathogenic variants may be lower¹² and some presentations may cause confusion and misdiagnosis, such as late and already dilated phenotypes.²⁶ To ensure an accurate diagnosis, it is essential to correlate these measurements with the clinical background, the presence of other associated structural cardiac diseases, GLS values, and diastolic function. In certain cases, CMR may be necessary to confirm the diagnosis.

HCM is defined by an increased LV wall thickness of ≥ 15mm, or ≥ 13mm (in individuals with a positive genotype or relatives of HCM patients), in the absence of conditions that would justify secondary LVH such as severe AH, AS, or aortic coarctation, and excluding any infiltrative systemic diseases.²⁷ It is crucial to recognize that HCM is not merely a myocardial disease; other features supporting the diagnosis include MV and subvalvular apparatus abnormalities like mitral leaflet elongation, papillary muscle hypertrophy, abnormal secondary MV chords, and muscle bundles (Figure 4).^8,28,29

Figure 4

Asymmetric septal LVH is the most classic pattern of HCM. Still, other phenotypic expressions like apical, concentric, lateral wall, midventricular, and less typical presentations involving any segment of the LV are common. The classical diagnostic criteria for diagnosing HCM, which are the same for both ECHO and CMR,⁸ have recently been brought into question (“one size fits all”) and in the future, probably gender, body surface and race will be considered for the definition of new thresholds. In particular, these criteria may not be reached in the apical variant, characterized by the loss or reversal of usual apical myocardial tapering. For instance, new cut-off values and diagnostic criteria were recently suggested for the detection of apical HCM, being the upper limit of normal apically 11 mm or 5.6 mm/m². ^22,30

RV hypertrophy is also frequent in HCM patients, found in 30-44% of cases, usually alongside LVH.^31,32 RV dynamic obstruction may occur, either intraventricular or in the RV outflow tract.³³ Conventional echocardiographic indices of RV systolic function, such as tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and tissue Doppler velocities, are typically normal. Still, subclinical systolic dysfunction may be identified through alterations in RV-LS.^34,35

ECHO has also played an important role in the risk assessment and stratification of HCM patients,³⁶ with studies showing higher mortality in HCM patients with LV septal thickness ≥ 30mm, apical aneurysm, or LV dysfunction (LVEF <50%).^3,37 2D LV GLS strongly correlates with fibrosis in HCM patients. Absolute GLS values and mechanical dispersion have a good correlation with the percentage of LGE and are independent predictors of VAs.¹⁵ In the study of Reant et al.,¹⁴ GLS absolute values < 15,4% were associated with heart failure, death and hospital admissions in a cohort of HCM patients. The parametric 2D LS bull’s eye plot derived from 2D STE may offer an intuitive visual overview of the global and regional LV myocardial deformation in HCM and is characterized by severely reduced segmental strain values in the most hypertrophied walls, usually more pronounced than other etiologies such as hypertensive or LVH secondary to AS.³⁸

Hemodynamic evaluation to identify those with LVOT obstruction is crucial for treating HCM patients. Approximately one-third of HCM patients have rest LVOT obstruction (> 30 mmHg), with another third showing latent obstruction, revealed through bedside provocative maneuvers (Valsalva, standing, squatting-elevation, amyl nitrite inhalation) or exercise echocardiography.³⁹Mitral regurgitation is a common finding in patients with HCM, especially in patients with systolic anterior mitral movement (SAM), and can be a major determinant of symptoms. It is very important to highlight that SAM is not a result solely of septal asymmetric hypertrophy (LVOT high velocities and Venturi effect). In fact, primary abnormalities of the MV apparatus, such as hypertrophy and anterior displacement of papillary muscles, leaflet elongation, and alteration in chordal insertion, may have a great role in LVOT obstruction (Figure 5).^28,40

Figure 5

HCM typically presents with normal or increased LVEF, the classic phenotype of HFpEF, associated with diastolic dysfunction in various degrees. Some patients may exhibit apical aneurysms and progressive LV dysfunction, which may lead to end-stage cardiac disease or the “burned-out” HCM variant, associated with a worse prognosis.^41,42

CMR also allows for a detailed anatomical characterization regarding the pattern of LVH, variations in MV apparatus and their contributions to LVOT obstruction.⁴³Considering this detailed evaluation, CMR plays an important role in planning septal reduction therapies.⁴⁴

Regarding tissue characterization, native T1 and ECV correlate with diffuse fibrosis, elevated even in areas without LGE.^45,46 Typical replacement fibrosis with a midwall pattern, more frequent in hypertrophic areas, is well depicted by LGE, with a well-recognized prognostic value.⁴⁷Using recent advances, diffusion tensor acquisition allows the study of myocyte disarray, a premature marker of the disease,⁴⁸ and stress perfusion CMR allows the study of microvascular dysfunction.^49,50

PRKAG2 CM, an autosomal dominant glycogen storage disease that primarily affects the heart muscle and conduction system, presents with a unique clinical profile and prognosis. PRKAG2 CM is characterized by LVH, Wolff-Parkinson-White syndrome, and progressive conduction system disease.⁸⁴HCM in patients with PRKAG2 gene mutations typically emerges in the teenage years or adulthood, with few cases reported in infancy. PRKAG2 CM is associated with worse outcomes compared to sarcomeric HCM, with patients potentially experiencing early cardiac failure and sudden death.⁸⁵ The echocardiographic phenotype often shows concentric LVH, preserved LVEF, diastolic dysfunction, and, less commonly, RV hypertrophy^86,87 (Figure 8). LVOT obstruction is rare in these patients, compared to patients with sarcomeric HCM. A study showed that patients with PRKAG2 CM may have more preserved GLS, associated with bradycardia, although having similar LV mass and thickening of ventricular walls.⁸⁸

Figure 8

Friedreich’s ataxia is an autosomal recessive degenerative disease, affecting the frataxin gene, leading to mitochondrial iron storage and affecting glucose metabolism, the nervous system and the heart.⁸⁹ Cardiac disease usually manifests as an HCM phenotype that may evolve into dilated cardiomyopathy, the most important cause of death.⁹⁰Myocardial involvement may be detected subclinically before the development of LVH or LVEF reduction, either by STE⁹¹or CMR.⁹²

Echocardiographic typical features are concentric LVH without LVOT or midventricular obstruction (although asymmetric hypertrophy may also occur), with LV dysfunction (reduced EF) and heart failure in advanced disease⁹³with altered perfusion reserve.⁸ The morphological aspect of LVH in these patients may resemble CA, even with a sparkling granular texture of myocardium. Still, usually, there is no bi-atrial enlargement, pericardial effusion or severe diastolic dysfunction in patients with Friedreich’s ataxia.⁹⁴

Danon disease is a rare X-linked dominant genetic disease that manifests with the clinical triad of cardiomyopathy, skeletal myopathy, and intellectual disability. It is caused by mutations in the lysosome-associated membrane 2 (LAMP2) gene. Danon cardiomyopathy is progressive and typically manifests as a hypertrophic phenotype, with alterations in radial, circumferential, and longitudinal strain in early stages, with preserved ejection fraction (HFpEF). With the progression of fibrosis, these patients may evolve with a decline in ejection fraction, worsening of symptoms and a dilated phenotype, particularly in male patients.⁹⁵ The extent and severity of cardiomyopathy is the major prognostic factor. Most patients are asymptomatic during childhood, progressing to a symptomatic stage during adolescence and culminating in fulminant heart failure and sudden death in adulthood.⁹⁶ CMR findings have a pivotal role in the diagnosis of this disease and typically include marked LVH, which may be concentric or asymmetric, and distinct patterns of LGE that differ from other forms of hypertrophic cardiomyopathy. LGE often spares the mid-septum and exhibits a base-to-apex gradient with the involvement of the apex.^97,98 Furthermore, cardiac MRI can reveal elevated native T1 and ECV, suggesting myocardial fibrosis.^98,99