Hypertrophic cardiomyopathy: state of the art on diagnosis and current therapeutic approach

Abstract

Background

Hypertrophic cardiomyopathy is the most common genetic cardiomyopathy and is characterized by unexplained myocardial hypertrophy. This condition exhibits marked clinical and prognostic heterogeneity. Advances in cardiovascular imaging techniques and genetic testing have significantly improved the diagnostic accuracy, phenotypic characterization, and prognostic assessment.

Main body of the abstract

Hypertrophic cardiomyopathy can present with a broad spectrum of genetic substrates and clinical presentations, ranging from asymptomatic individuals to those with heart failure, arrhythmias, and even sudden cardiac death. The first-line method for diagnosis, risk stratification, and follow-up of these patients is echocardiography, but additional techniques, such as cardiac magnetic resonance imaging, provide complementary information, such as quantification of fibrosis, and more accurate measurements. Genetic testing contributes to etiological diagnosis and family screening. Treatment options include both pharmacological therapy (such as beta-blockers, calcium channel blockers, and disopyramide), which is the first-line therapy, and septal reduction techniques (alcohol septal ablation, surgical myectomy), which should be reserved for selected patients. Recently, cardiac myosin inhibitors have emerged as a novel therapeutic option, demonstrating significant reductions in left ventricular outflow tract obstruction and improvement in symptoms.

Conclusion

Hypertrophic cardiomyopathy has evolved considerably with advances in imaging techniques, genetic evaluation, and targeted therapies. This review examines the primary diagnostic and management strategies, both established and emerging, for hypertrophic cardiomyopathy.

Graphical Abstract

Background

Hypertrophic cardiomyopathy (HCM) is a widely recognized, common inherited heart disease with a global presence and a prevalence of 1 in 200 to 1 in 500 in the general population [1]. With advances in modern cardiovascular imaging, particularly echocardiography and cardiac magnetic resonance (CMR), as well as new pharmacological treatments such as myosin inhibitor drugs, interest in the identification and management of HCM has increased.

The definition of HCM differs slightly between major societies. According to the European Society of Cardiology (ESC), HCM is defined broadly as the presence of unexplained increase in Left Ventricle (LV) wall thickness [with or without right ventricle (RV) hypertrophy] or mass, thereby encompassing a range of phenocopies presenting with a 'thick heart' phenotype. In contrast, the American Heart Association (AHA) provides a narrower definition, considering HCM a primary genetic myocardial disease characterized by left ventricular hypertrophy not explained by other cardiac, systemic, or metabolic conditions. In both frameworks, HCM is identified by the presence of left ventricular hypertrophy (LVH) with wall thickness ≥ 15 mm in any myocardial segment when no other cause or abnormal loading condition explains the hypertrophy [2, 3].

The often-asymmetric nature may help to discriminate HCM from other causes of LVH, such as aortic valve stenosis or systemic arterial hypertension, although concentric phenotypes may also occur. In first-degree relatives of affected patients, a wall thickness of the LV greater than 13 mm is diagnostic. In the pediatric age group, the diagnosis of HCM requires a LV wall thickness greater than two standard deviations from the predicted value [4, 5].

Pathogenic or likely pathogenic variants in sarcomeric genes are identified in approximately 30–60% of patients with HCM, depending on the population studied and the extent of genetic testing [2, 3].

The mortality rate is four times higher in patients with severe LVH compared with the US general population and ≥ three-fold higher in patients with HCM who were 50 to 69 years old. These findings of excess mortality remained comparable when patients with HCM cared for at non-US sites were included in analyses [6].

Significant risk factors are a significant fibrotic component (≥ 15% [as assessed by late gadolinium enhancement (LGE)] of LV mass), left atrial (LA) dilation, a family history of sudden cardiac death (SCD), syncope, episodes of non-sustained ventricular tachycardia, and atrial fibrillation (AF) [7, 8].

This review highlights the rapid progress in our understanding of HCM, its varied clinical presentations, and areas in diagnosis and treatment where uncertainty and debate still exist.

Histopathology

Donald Teare first described the myocardial arrangements in HCM in 1957, illustrating a case series and showing the high variability of this disease [9]. He described and beautifully illustrated the following: “a localized and diffuse hypertrophy of the interventricular septum,” “bizarre arrangement of bundles of muscle fibers running in different directions and separated by connective tissue and clefts,” “hypertrophy of individual muscle fibers,” “hypertrophy of the right atrium and ventricle,” and “distortion of the mitral valve” [9].

Although histopathological assessment can provide valuable data, it is rarely performed in clinical practice for HCM.

As Teare pointed out, histopathological features of patients with HCM include a wide range of anomalies. The essential histopathological aspects of HCM are:

1. Hypertrophy and disorganization (disarray) of cardiomyocytes. Disarray can involve entire muscle bundles or individual myocytes. It is not exclusive to HCM, and it becomes a diagnostic feature for HCM when it affects at least 5% of the surface area. Cardiomyocyte hypertrophy features irregular shapes and disorganized intercellular connections [10, 11].

2. Fibrosis is widespread among muscle bundles and individual myocytes [12]. There are two types of fibrosis: a) interstitial fibrosis, marked by a general increase in collagen bands within the pericellular, intercellular, and fascicular spaces; and b) replacement fibrosis, which involves microscopic or macroscopic scars, results from cardiomyocyte death caused by multifactorial mechanisms [12].

3. Microvessel disease of small arterial vessels is characterized by hypertrophy of the medial layer with several disorganized elastic fibers and hyperplasia of the intimal layer [13].

Genetic

Approximately 30–60% of HCM patients carry a pathogenic or likely pathogenic variant in a sarcomeric gene, depending on the population studied and the extent of genetic testing performed [2, 3]. Inheritance is autosomal, mostly dominant, and characterized by high genetic and allelic diversity, incomplete age-related penetrance, and variable expressivity [14, 15]. Due to incomplete penetrance and variable expressivity, identifying carriers of a pathogenic variant within a family can often be challenging. The same variant that runs in a family can cause different phenotypes, displaying variable expression, which is also likely influenced by environmental factors [16, 17]. Genetic analyses on patients with HCM and their family members have identified over 1,400 pathogenic variants (mostly missense) and minor structural variants across numerous genes [2, 15]. Given that de novo variants occur across all Mendelian cardiomyopathies, and that an apparently negative family history does not exclude a genetic etiology, careful genetic evaluation is warranted even in sporadic presentations. Moreover, in a minority of cases, biallelic variants in recessive genes may also be responsible for the phenotype, further supporting the need for comprehensive genetic assessment [2]. Currently, the primary genetic test for determining the etiology of cardiomyopathies is multigene panel analysis using Next Generation Sequencing (NGS). Due to the significant genetic diversity of these diseases, the gene panels include, in addition to genes associated with HCM, those strongly linked in the literature to dilated cardiomyopathy and arrhythmogenic cardiomyopathy, which are clinically similar.

With the advent of Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS), previously unobservable variants, such as variants in non-coding regions and intragenic variants, have been identified, providing potentially valuable information on new candidate genes in early-onset cardiomyopathies, including hypertrophic cardiomyopathy [18].

However, the diagnostic yield of WES and WGS is comparable to that of multigene panels, which remain the gold standard for the molecular diagnosis of cardiomyopathies [2]. Being primarily a disease of the sarcomere, hypertrophic cardiomyopathy is mainly associated with genes that encode sarcomeric proteins, which are the protein components of the thick and thin contractile myofilaments of the sarcomere or the nearby Z-disc [15, 19].

However, in approximately 40% of patients with hypertrophic cardiomyopathy, no variants in sarcomeric genes are identified [14]. Some studies have observed pathogenic variants that cause HCM in genes encoding non-sarcomeric proteins [19]. These data are shown in Table 1.

Table 1.

Genes involved in the etiology of HCM

Gene symbol	Gene name	% of cases
MYBPC3	Myosin binding protein C3	40–45%
MYH7	Myosin heavy chain 7	15–25%
TNNT2	Troponin T, type2	1–5%
TNNI3	Troponin I, type3
ACTC1	Actin α-cardiac muscle 1	1–2%
MYL2	Myosin light chain 2
MYL3	Myosin light chain 3
TPM1	Tropomyosin 1
ACTN2	α-Actinin 2	< 1%
ALPK3	α-Kinase 3
CSRP3	Cysteine and glycine rich protein 3
FHOD3	Formin homology 2 domain containing 3
FLNC	Filamin C
PLN	Phospholamban
TNNC1	Troponin C, type 1

The genetic and allelic heterogeneity in these diseases further complicates predicting a specific phenotype, making it challenging to establish a clear link between the genetic variant and the patient's disease. Indeed, variants in the same gene can cause different phenotypes, and sometimes a single variant can lead to either dilated cardiomyopathy in one person or hypertrophic cardiomyopathy in another [20]. If a syndromic form is suspected, it is appropriate to analyze other genes, as shown in Table 2 [21].

Table 2.

Genes involved in the etiology of hypertrophic cardiomyopathy phenocopies

Gene symbol	Gene name	Disease
GAA	Alpha Glucosidase	Pompe disease
GLA	Galactosidase Alpha	Fabry disease
LAMP2	Lysosomal-associated membrane protein 2	Danon disease
PRKAG2	Protein kinase AMP-activated non-catalytic subunit-γ 2	Wolff-Parkinson-White syndrome
TTR	Transthyretin	Transthyretin amyloidosis

In selected familial cohorts undergoing comprehensive genetic testing, including analysis of single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy-number variants (CNVs), a causal genetic variant can be identified in up to ~ 85% of cases [22]. A small percentage of cases of hypertrophic cardiomyopathy in which no SNVs are identified in the significant genes, can be explained by the presence of pathogenic variants in “minor” genes or by the presence of CNVs [23]. The role of CNVs in HCM has been examined in a limited number of studies [22], which have identified CNVs in genes associated with hypertrophic cardiomyopathy, mainly in MYBPC3 and TNNT2. Consequently, comprehensive genetic analysis that includes the search for SNVs, small indels and CNVs could identify the cause of the disease in nearly 90% of cases [22–24].

When HCM is newly diagnosed, the evaluation should extend beyond the individual patient to encompass the family. Detailed family history, genetic counselling, including discussion of reproductive implications, and clinical screening with ECG, echocardiography, and CMR where appropriate are all recommended for first-degree relatives [2]. Genetic testing of the proband should be offered using phenotype-driven gene panels. If a pathogenic or likely pathogenic (P/LP) variant is found, cascade testing can be extended to at-risk relatives; variants of uncertain significance (VUS), on the other hand, do not justify cascade testing and should prompt clinical surveillance alone. Given that variants may be reclassified over time, periodic re-evaluation of genetic findings is advisable [2].

The management of mutation carriers without phenotypic expression depends on age, since penetrance increases over time. Those under 60 should be reviewed every 1–3 years; those 60 or older every 3–5 years. Relatives who are both genotype- and phenotype-negative can be discharged from active surveillance, with re-evaluation only if the clinical picture changes. In apparently sporadic cases where no variant has been identified, discontinuation of follow-up may be reasonable in relatives past the age of 50 [2].

A negative genetic result in the proband does not absolve the clinician of the responsibility to screen the family. HCM can still emerge in relatives even when no causative variant has been found, a pattern particularly evident in familial forms, and clinical surveillance should therefore continue at intervals guided by family history and clinical findings [2]. Separately, a genotype-negative result should always prompt consideration of phenocopies. Conditions such as cardiac amyloidosis, Fabry disease, glycogen storage disorders, mitochondrial diseases, and RASopathies can all produce an HCM-like phenotype, and each carries specific therapeutic implications that make accurate diagnosis essential. Inheritance pattern, phenotype, and multimodality imaging together guide the workup [2, 5, 12]

Diagnosis

Clinical scenarios

While HCM generally presents a stable and benign clinical profile that does not require primary intervention, symptomatic LV outflow tract obstruction (LVOTO) refractory to medical therapy requires invasive septal reduction to lower or eliminate the subaortic gradient [12, 25, 26]. For patients at higher risk of arrhythmic sudden death, implanting a cardioverter-defibrillator (ICD) should be considered; advanced therapies should be used when the disease reaches its end-stage. However, only 10% of HCM patients experience more than one of these adverse scenarios.

At the initial assessment, the patient’s symptoms, including exertional dyspnea, fatigue, syncope, chest pain, and prolonged palpitations, are critical factors that should be thoroughly evaluated. Notably, signs and symptoms of HCM do not necessarily match the extent or severity of LVOTO or the level of heart failure (HF), and many young patients with HCM remain pauci- or asymptomatic for a long time. The development of HF can be caused by intravascular volume depletion, impaired filling, arrhythmia, or reduced myocardial function secondary to ischemia (oxygen supply–demand mismatch) and small-vessel coronary artery disease. LVOTO, worsened by systolic anterior motion and mitral valve regurgitation, may lead to acute or intermittent HF symptoms [14].

Arrhythmias, including AF and ventricular tachycardia, may be the first symptoms before the onset of HF. It has been estimated that 1 in 3 to 1 in 5 patients with HCM have AF, which is a well-known risk factor for thromboembolic stroke. LA dilation, remodeling, and mutated proteins are potential mechanisms that sustain AF in HCM. Anticoagulation is recommended in the setting of atrial fibrillation, regardless of the CHA₂DS₂-VA score. [3, 14, 27] Given the poor haemodynamic tolerance of AF in HCM, particularly in obstructive forms, a rhythm-control strategy is generally preferred over rate control [2, 3].

SCD, caused by ventricular fibrillation, is the most feared complication. Table 3 displays some of the risk markers for SCD that have been identified.

Table 3.

Identified risk markers for SCD

Established markers	Description	Image
LV wall thickness	Maximal LV thickness (≥ 30 mm), although the relationship between LV thickness and SCD is continuous [2, 3]
Late gadolinium enhancement	LGE ≥ 15% of LV mass, with a continuous relationship to SCD [2, 3]
LVOT obstruction	LVOT peak gradient ≥ 30 mmHg at rest or with physiological provocation according to ESC guidelines [2], or ≥ 50 mmHg according to ACC/AHA guidelines [3]
LV apical aneurysm	Larger aneurysm size (e.g. ≥ 2 cm in diameter) further increases SCD risk [28]

Electrocardiography

The 12-lead Electrocardiogram (ECG) is a cornerstone in the diagnosis and evaluation of patients with HCM, because it is widely accessible and highly cost-effective. Typical ECG findings in patients with HCM are: narrow Q-waves in the inferior and lateral leads, reflecting septal hypertrophy rather than myocardial necrosis; deep S-waves in V1–V3 or tall R-waves in V4–V6 with T-wave inversion or ST-T segment depression; signs of left atrial enlargement [29]. Giant symmetric negative T-waves in V3–V5 are typical of the apical form, while a pseudo-STEMI pattern, anterior ST elevation in the absence of Left Bundle Branch Block (LBBB), should not be misinterpreted as an acute coronary syndrome [29]. The ECG is abnormal in 94–96% of affected adults and in more than 97% of paediatric cases [29]. Electrocardiographic abnormalities often precede the detection of hypertrophy on imaging, so, usually, a normal ECG in the presence of significant LVH should prompt consideration of alternative diagnoses [29].

Specific ECG patterns may also be observed in different phenocopies (Figure 1). In Fabry disease a short PR interval is observed in up to 40% of patients, as well as other findings as prolonged QRS, right bundle branch block (including incomplete forms), inferior ST depression, or deep T-wave inversion in lateral leads [2, 29]. In cardiac amyloidosis, a disproportionate QRS voltage and LVH on imaging are well-established red flags; additional features include a pseudo-infarction pattern with Q-waves in inferior and anterior leads, Atrio-Ventricular (AV) block, sinus node dysfunction, and atrial fibrillation [2, 29]. In glycogen storage disorders such as Danon disease and PRKAG2 cardiomyopathy, massive LVH on imaging could be associated with a Wolff-Parkinson-White (WPW) pattern and AV block [2, 29].

Fig. 1.

Electrocardiogram in hypertrophic phenotype cardiomyopathies: A Storage and mitochondrial disease. B Cardiac amyloidosis. C Fabry disease. D Sarcomeric HCM E) Apical HCM

Artificial Intelligence (AI)-based ECG algorithms represent a promising development in HCM detection. Convolutional neural network models have achieved AUC values of 0.96–0.98 for HCM identification from standard 12-lead ECGs, with false positive rates as low as 13.5% [30, 31]. Real-world implementation across different healthcare systems identified previously undiagnosed HCM in diverse population, supporting the potential of AI-ECG for broad screening [32]. AI-ECG may also detect early electrical abnormalities in genotype-positive/phenotype-negative relatives before overt hypertrophy develops [30–32].

Echocardiography

Transthoracic echocardiography (TTE) remains the first step imaging method for screening, diagnosing, prognostic stratification, and long-term monitoring of patients with affected hearts [21, 33]. As an initial diagnostic approach, TTE allows comprehensive visualization of the morphological and functional features of HCM, including ventricular hypertrophy, global systolic function, mitral valve anatomy, systolic anterior motion (SAM), and LVOTO [34]. Specifically, the first step involves evaluating LVH. Current diagnostic criteria include a LV wall thickness of ≥ 15 mm in at least one myocardial segment, or ≥ 13 mm in patients with a first-degree relative with confirmed HCM, in the absence of abnormal loading conditions or other causes of LVH [35]. Asymmetric hypertrophy, defined as a septal-to-free wall thickness ratio of ≥ 1.3 (or ≥ 1.5 in hypertensive patients), may be suggestive of HCM but is not a specific finding [36]. Hypertrophic cardiomyopathy, in fact, encompasses a wide range of morphological phenotypes, from sigmoid septal configuration and reverse septal curvature to concentric, mid-ventricular, and apical forms of hypertrophy [34].

Classic 2D TTE images of HCM are shown in Fig. 2.

Fig. 2.

Transthoracic echocardiography in hypertrophic cardiomyopathy: A long axis and B short axis. LV = left ventricle; LA = left atrium

LV wall thickness should be measured in end-diastole across all LV segments, preferably using 2D parasternal short-axis views [2]. This approach enables precise identification of the hypertrophy pattern, which may involve the basal ventricular septum (most commonly), the mid-septum (described as reverse septal curvature), the apex, or the midventricular region. If the extent of LVH is uncertain, especially at the apex, contrast-enhanced imaging is recommended, as it also helps detect apical aneurysms and thrombi [37]. Compared to CMR, TTE may over- or underestimate wall thickness depending on hypertrophy location, overestimation occurs in over 50% of cases, while underestimation is less common and typically seen with apical, anterolateral, or focal hypertrophy [38–40].

Right ventricular hypertrophy (RVH) is also common, present in over 50% of patients with HCM [39]. McKenna et al. classified RVH as mild (6–8 mm), moderate (9–12 mm), and severe (> 12 mm) [40]. In contrast, Maron et al. defined RVH as an end-diastolic thickness of the anterior, free, or apical right ventricular wall ≥ 5 mm, with values ≥ 10 mm indicating extreme or severe RVH [41].

Combining 2D transthoracic echocardiography with 3D imaging improves LVH diagnosis by providing more accurate and detailed visualization of the LV, reducing errors common in 2D alone [42]. A strong correlation between 3D echocardiography and CMR has been demonstrated for evaluating LVH, highlighting the superior performance of this technique [43].

AI represents an emerging frontier in echocardiographic analysis of HCM, too. Deep learning models were trained across multiple institutions using a federated approach, enabling model training without data sharing, demonstrated excellent discrimination of HCM from other causes of LVH, outperforming cardiologists in sensitivity at a comparable specificity [44]. Another approach, complementary radiomics-based, in which quantitative myocardial texture features were extracted from standard echocardiographic images, has shown promising accuracy in differentiating HCM from cardiac amyloidosis and hypertensive heart disease in external validation [45].

Myocardial strain

Concerning LV systolic function, although it is typically normal or even hyperdynamic in HCM patients, significant reductions in both longitudinal and circumferential strain are observed, particularly in hypertrophic areas. Global longitudinal strain (GLS) has emerged as a key marker of subclinical LV dysfunction, with values less negative than –10% being associated with worse outcomes in HCM [46]. Haland et al. demonstrated that HCM patients with more impaired GLS had a history of ventricular arrhythmias, emphasizing its potential usefulness in arrhythmic risk assessment [47]. Additionally, the GLS pattern plays a key role in evaluating ambiguous LVH, offering valuable diagnostic insights [48]. In classic sarcomeric HCM, strain impairment predominates in the hypertrophied septal region, whereas hypertensive heart disease more typically involves the basal-to-mid ventricular segments, and cardiac amyloidosis is characterized by the well-known apical-sparing pattern. Fabry disease may show early inferolateral basal wall impairment, often preceding overt hypertrophy. In apical HCM, a distinctive "blueberry-on-top" pattern has been described on the strain polar map, characterized by apical GLS impairment with paradoxically advanced time to peak strain at the apex, the inverse of the amyloid pattern, with sensitivity approaching 100% and specificity of 93% for this variant [49, 50].

Mechanical dispersion is typically increased in HCM in relation to interstitial fibrosis and sarcomere disarray and can be quantified by echocardiographic strain analysis. This appears to be an indicator of the risk of ventricular arrhythmias [47].

Systolic anterior motion and LVOT obstruction

A hallmark of HCM is the SAM, which contributes to LVOT obstruction [36]. Although it has traditionally been linked to the Venturi effect, it is now understood that it depends on the length of both leaflets, especially the posterior one, which during systole creates a “sailing effect” that pushes both leaflets anteriorly as shown in Fig. 3.

Fig. 3.

Systolic anterior motion mechanism in HCM: A Still frame image of 2D TTE showing the characteristic SAM. B-C Still frame images depicting the posterior leaflet (blue line) and anterior leaflet (red line) pushed anteriorly by left ventricular pressure due to a kind of “sailing effect” (arrow). This mechanism causes obstruction

Other mechanisms involve abnormal insertion of papillary muscles and a steeper angle between the LV and the aortic root, as shown in Figure 4.

Fig. 4.

Abnormal papillary muscle insertion and LVOTO: A 2D TTE four-chamber view showing a massive papillary muscle arising from the anterolateral wall (arrow). B Same case. CMR cine image in long-axis view showing a papillary muscle in the middle of the left ventricle, obstructing the LVOT. C Same case. 2D TTE two-chamber view showing the same massive papillary muscle arising also from the anterior wall. D Same case. CMR cine image in four-chamber view showing the same massive papillary muscle

SAM typically distorts the mitral leaflets, resulting in an eccentric mitral regurgitation (MR) jet directed posteriorly and laterally [34]. This case is depicted in Figure 5.

Fig. 5.

Systolic anterior motion and associated mitral regurgitation on TEE: A 2D TEE still frame image, long-axis view. The arrow indicates the SAM. B Same image with color Doppler showing a massive mitral regurgitation. C Same case. Still frame image of the 2D TOE four-chamber view. The arrow points at the SAM. The same case with color Doppler reveals massive regurgitation

LVOTO, estimated with continuous wave (CW) echo-Doppler, which is dynamic in nature, is considered clinically relevant when the peak gradient reaches ≥30 mmHg at rest or during provocation; in the latter case, the condition is referred to as labile or latent obstructive HCM. Valsalva-induced peak gradients are unreliable for ruling out obstruction, as they are positive in only ~50% of patients with exercise-provocable gradients [35].

The dynamic obstruction mainly occurs in mid-to-late systole, coinciding with systolic anterior motion of the mitral valve. Asymmetric hypertrophy of the basal interventricular septum contributes to the pathogenesis of dynamic LVOT obstruction by structurally narrowing the outflow tract [2, 3, 27].

This pattern is described as “dagger-shaped” or “sickle-shaped,” differentiating from a bell-shaped profile of mitral regurgitation, as appreciable in Fig. 6 [33, 34].

Fig. 6.

CMR and Doppler findings in obstructive HCM: A CMR image of an HCM in late systole. B the classic “dagger shape appearance of CW gradient, with a velocity increase at the mid-systole (arrow). The asterisk points to the reduction of the Doppler signal at the end-systole (see text). LA = left atrium; LV = left ventricle

In some situations, direct CW Doppler interrogation of the LVOT could be suboptimal. The LVOT gradient can be estimated indirectly, using a derivation of the modified Bernoulli equation from the mitral regurgitation jet velocity: LVOT gradient = LVSP − SBP, where LVSP = 4 × (peak MR velocity) ² + LA pressure (estimated at 10–15 mmHg). [LVSP: Left ventricular systolic pressure; SBP: Systolic Blood Pressure].

Exercise echocardiography

Exercise echocardiography is the preferred method for provoking LVOTO, but is also recommended in patients without resting obstruction, as it enables the evaluation of functional capacity and the detection of inducible ischemia [35, 51].

The test provides a comprehensive evaluation of left and right ventricular systolic function, diastolic function through E/e′, and peak tricuspid regurgitation velocity, and can detect significant MR induced by exercise. LVOTO assessment is performed at peak exercise and during the early phase of recovery, when preload decreases and afterload increases [52].

When it is not possible to provoke a gradient through the Valsalva manouvre or exercise testing, postprandial stress echocardiography, performed shortly after a modest meal followed by treadmill exercise, may unmask LVOT obstruction in a clinically significant proportion of patients; in one series, this protocol identified a gradient ≥ 50 mmHg in 35.7% of patients otherwise classified as non-obstructive, with more than half of those treated with invasive or enhanced drug therapies having only postprandial LVOTO [3, 53].

Right ventricular obstruction

Obstruction can also occur at the level of the right ventricle in HCM, with a reported prevalence ranging from 15 to 92% in catheterization studies. Three potential sites have been identified: the outflow tract, the apex, and the mid-to-basal segments [21]. Right ventricular outflow tract obstruction (Fig. 7) is defined by varying pressure gradient thresholds in the literature, with the cutoff of greater than 25 mmHg at rest being the most commonly used [54].

Fig. 7.

CMR findings in right ventricular outflow tract obstruction: CMR imaging shows myocardial wall thickening involving septal, anterior and lateral wall of left ventricle and right ventricular outflow tract (panels A-B); panels C-D show midwall Late Gadolinium Enhancement with patchy distribution involving thickened right ventricular outflow tract wall. Ultrasound has confirmed no evidence of LVOTO but detected moderate RVOT gradient

Diastolic dysfunction and left atrium

Regarding the assessment of diastolic dysfunction (DD) in HCM, the 2025 diastolic function guidelines recommend using the same multiparametric Doppler and tissue Doppler indices applied in the general algorithm, noting, however, that transmitral velocities correlate poorly with LV filling pressures in HCM with preserved LVEF. Specific indicators of elevated filling pressures in HCM include average E/e' > 14, Ar-A duration ≥ 30 ms, peak Tricuspid Regurgitation (TR) velocity > 2.8 m/s, and LA maximum volume index > 34 mL/m² [55].

The evaluation of DD is crucial, as it represents an early and central mechanism of HF in HCM, primarily related to LVH and fibrosis [34].

In the context of DD in HCM, a comprehensive approach should include LA evaluation, as progressive remodeling and dilation often occur due to impaired LV filling and structural atrial changes. Additionally, traditional parameters such as LA volume, left atrial diameter, and LA strain, along with the emerging marker of left atrioventricular coupling index (LACI), have been linked to heart failure, onset of AF, and risk stratification of SCD [21, 56, 57].

Left Atrial Reservoir Strain (LARS) has been proposed as an index for grading LV diastolic dysfunction in HCM, where conventional Doppler parameters are often discrepant or inconclusive. Using cut-offs of ≥ 35%, 24–35%, 19–24%, and < 19% for grades 0 to 3, respectively, LARS-based grading was independently associated with incident heart failure and showed incremental prognostic value over conventional diastolic parameters, with 10-year HF-free survival of 100%, 91.6%, 84.1%, and 67.5% across grades 0 to 3 [56].

The role of cardiac magnetic resonance

CMR is essential for diagnosing, risk-stratifying, and monitoring patients with HCM over time. CMR has some crucial capabilities, such as:

1. It enables accurate measurement of wall thickness and myocardial mass using cine steady-state free precession (SSFP) imaging, which provides detailed observation of cardiac structures without limited views, and

2. It has the unique and essential capability of tissue characterization by using late LGE sequences to identify myocardial fibrosis [58].

3. Additional tissue characterization by parametric mapping may shed additional insight into other causes of LVH, e.g. low native T1 signal in Fabry disease [59].

The 2023 ESC guidelines recommend CMR (class of evidence I; level of evidence B) as a key tool in the initial assessment of HCM. CMR should also be considered during follow-up to observe disease progression and aid in risk stratification and management (Class of Evidence IIa; Level of Evidence C) [2].

Assessment of wall thickness, myocardial mass, and LV volumes

CMR provides a precise evaluation of LV hypertrophy, particularly in detecting apical and anterolateral hypertrophy, apical aneurysms, and apical thrombi. It is also sensitive in identifying early disease markers in patients with sarcomeric gene mutations, such as myocardial crypts and abnormalities of the papillary muscles, revealing dysfunction even before wall thickening becomes apparent in individuals with a genetic predisposition. Additionally, CMR precisely measures LA dimensions, which, as mentioned above, are key prognostic markers in HCM [60].

CMR also allows evaluation of hypertrophy distribution beyond simple wall thickness measurements. Aquaro et al. proposed the standard deviation of wall thickness across all 17 myocardial segments (SD-WT) as a quantitative index of hypertrophy heterogeneity in sarcomeric HCM, showing in a post-mortem CMR study that a cut-off of SD-WT > 2.4 mm distinguished HCM from other causes of LVH with high accuracy (AUC 0.95), even higher in women (AUC 0.998), a finding relevant given women's tendency to present with less pronounced hypertrophy [61].

Tissue characterization

CMR helps identify myocardial fibrosis, thus revealing patients at higher risk of adverse cardiac outcomes events, including SCD. LGE is present in approximately 65% of HCM patients and typically appears as a mid-wall, patchy pattern in hypertrophied segments and at the right ventricular insertion points [21]. In advanced disease, full-thickness LGE with wall thinning contributes to increased stiffness and adverse remodeling [21]. Also, the increase in LGE overtime is associated with adverse outcomes [62]. Increased native T1 times in HCM correlate with areas of hypertrophy and help differentiate HCM from conditions like hypertensive heart disease, Fabry disease, and cardiac amyloidosis [63]. Extra cellular volume (ECV) quantification provides a measure of diffuse fibrosis and interstitial expansion, offering additional prognostic value beyond LGE [63]. Increased T2 signal intensity indicates edema or inflammation and may be associated with disease activity and a higher risk of SCD. The ongoing studies aim to refine HCM risk stratification by integrating CMR-derived parameters such as LGE, T1, and T2 mapping. Overall, CMR provides unparalleled tissue characterization, enhances risk stratification, and refines the differential diagnosis in HCM [21, 35].

The role of cardiac computed tomography

Cardiac computed tomography (CCT) complements the evaluation of HCM by providing high-resolution images for accurate assessment of wall thickness, chamber size, and volumes. While it is not the primary modality for diagnosing HCM, it can be helpful in patients who cannot undergo CMR (Class IIa, Level of Evidence C). It is mainly used in patients with suspected cardiomyopathy to exclude coronary artery disease (CAD), either as an alternative diagnosis or as a comorbid condition affecting clinical presentation and disease progression. Additionally, CCTAngiography (CCTA) should be considered for ruling out congenital or acquired cardiovascular anomalies (Class IIa, Level of Evidence C) that may be associated with myocardial hypertrophy, such as anomalous coronary origin, cardiac shunt, or aortic valve anomalies [34].

CCTA is recommended to exclude obstructive CAD in patients with chest pain (Class IIa—ESC [2] and AHA [3]), and is the preferred tool for characterizing myocardial bridging [2, 3] (Fig. 8). Photon-counting CT (PCD-CT) may extend the role of cardiac CT to myocardial tissue characterisation. In patients with HCM, PCD-CT-derived extracellular volume fraction showed excellent agreement with CMR for fibrosis quantification. It correlated well with functional biomarkers, offering a potential single-session imaging alternative for patients with CMR contraindications [64].

Fig. 8.

Cardiac CT angiography in a patient with hypertrophic cardiomyopathy: A Volume-rendered 3D reconstruction of the heart (B) Curved MPR of the LAD demonstrating an intramyocardial course of the distal segment. C Curved MPR of the CX, without significant stenosis. D Curved MPR of the RCA, without significant stenosis. E Longitudinal MPR of the LAD with cross-sectional reference images, illustrating the intramyocardial course of the distal segment consistent with myocardial bridging (measured length 17.0 mm). LAD = left anterior descending artery; CX = circumflex artery; RCA = right coronary artery; MPR = multiplanar reconstruction

Medical therapy

Medical therapy for obstructive HCM (oHCM)

Conventional therapy

Beta-blockers are the most commonly used drugs in HCM, with a preference for non-vasodilatory agents such as atenolol, nadolol, bisoprolol, and metoprolol.

Non-dihydropyridine calcium channel blockers can be used as an alternative when beta-blockers are ineffective or not tolerated.

Disopyramide is a drug used in oHCM primarily for its negative inotropic effect, which contributes to the reduction of the left ventricular outflow tract gradient. It is usually administered in combination with beta-blockers or non-dihydropyridine calcium channel blockers, with evidence of efficacy primarily on the resting gradient [65]. The mechanism of action involves a sarcomere-dependent and sarcomere-independent negative inotropic effect, mediated by the inhibition of multiple ion channels and improvement of intracellular calcium homeostasis [65]. Disopyramide is classified as a class Ia antiarrhythmic agent and has been extensively studied in patients with HCM, showing antiarrhythmic effects on cardiomyocytes such as suppression of early and late afterdepolarizations and restoration of repolarization homogeneity [65, 66]. QTc interval should be monitored during dose up-titration and the dose reduced if it exceeds 500 ms [2].

Cardiac myosin inhibitors

A significant advance in treating HCM is the development of a new class of drugs, cardiac myosin inhibitors, which have been shown to notably improve symptoms and functional capacity in patients with substantial LVOT obstruction (baseline or provoked obstructive gradient > 50 mmHg) in multiple clinical trials [67, 68]

In the randomized Phase 3 EXPLORER-HCM clinical trial, the myosin inhibitor Mavacamten was tested in patients with obstructive HCM and NYHA functional class II-III who were treated with beta-blockers (BBs) or non-dihydropyridine calcium channel blockers, but not disopyramide. The study achieved its primary endpoint with a highly significant result, demonstrating the high efficacy of Mavacamten in improving patients' functional capacity, along with a reduction in symptoms and LVOT obstruction, the latter already evident after 4 weeks of treatment [67].

In the VALOR-HCM trial, after 16 weeks of Mavacamten treatment, there was a 60% reduction in patients eligible for septal reduction therapy (SRT) based on the AHA/ACC guidelines criteria [69]. Sustained freedom from SRT was observed at 128 weeks, with nearly 90% of patients remaining on long-term Mavacamten [70]. Therefore, the ESC guidelines recommend using Mavacamten as a second-line alternative to disopyramide in patients with significant LVOTO who remain symptomatic despite treatment with beta-blockers or non-dihydropyridine calcium channel blockers (class IIa) [2]. Unlike the North American guidelines, the ESC guidelines also consider using Mavacamten as monotherapy in patients intolerant to BBs or calcium channel blockers [2, 3].

Aficamten is a second-generation cardiac myosin inhibitor that has demonstrated safety and efficacy across multiple clinical trials. Compared with mavacamten, aficamten has a shorter half-life, a more predictable pharmacokinetic–pharmacodynamic relationship, particularly regarding its effect on LVEF, and is metabolized through multiple cytochrome P450 pathways, resulting in fewer drug–drug interactions. In indirect comparisons, aficamten also appears to have a more favorable safety profile, with lower rates of heart failure events, atrial fibrillation, and treatment interruptions due to LVEF reductions. These observations should be interpreted cautiously, as follow-up in aficamten studies remains shorter than in mavacamten trials [71].

The MAPLE-HCM trial further expanded the evidence base by directly comparing aficamten monotherapy with metoprolol in patients with obstructive HCM. Participants discontinued beta-blockers and calcium channel blockers before randomization. Aficamten proved superior to metoprolol in reducing LVOT gradients and improving symptoms, supporting its potential role as an alternative to conventional negative inotropes in oHCM [72].

Cardiac myosin inhibitors require regular echocardiographic follow-up, with treatment interruption if LVEF falls below 50% [2, 3]. When systolic dysfunction is already present or in non-responders, septal reduction therapy is the appropriate next step [2, 3].

The choice between the two strategies should be guided by the underlying anatomy and obstruction mechanics. Myosin inhibitors are preferred when obstruction is predominantly dynamic, and no structural features require correction [26]. Septal reduction is indicated when anatomical contributors are present, such as anomalous papillary muscle insertion, accessory muscle bundles, intrinsic mitral valve disease, or concomitant surgical indications such as multivessel CAD or aortic stenosis [3].

Medical therapy for non-obstructive HCM (nHCM)

In patients with nHCM, symptom management generally follows the therapeutic principles applied to Heart Failure with preserved Ejection Fraction (HFpEF), as endorsed by both the ESC and AHA/ACC guidelines. The primary goals are to reduce left ventricular filling pressures and improve diastolic function. Beta-blockers remain the preferred first-line therapy to slow the heart rate and enhance diastolic filling, while verapamil or diltiazem serve as alternatives in patients who do not tolerate or respond to beta-blockers [2, 3].

When congestion is present, low-dose loop diuretics may be used cautiously to relieve symptoms while avoiding excessive preload reduction.

For patients experiencing angina-like discomfort in the absence of coronary disease or dynamic obstruction, beta-blockers or non-dihydropyridine calcium channel blockers are appropriate options. Short-acting nitrates can be considered, but only when LVOTO has been reliably excluded, as both European and American guidelines warn against their use in patients at risk of dynamic obstruction [2, 3].

Ranolazine is an antianginal medication that inhibits the late sodium (Na1) current in myocytes. In cases of persistent chest pain due to suspected microvascular ischemia, ranolazine may be considered, although supporting evidence remains limited. In vitro studies using human tissue from myectomy surgery have indicated that an enhanced late Na1 current contributes to abnormal intracellular calcium (Ca2 +) handling, suggesting that inhibiting the channel might be a therapeutic target [65]. A small HCM study showed symptom improvement with ranolazine, but a larger trial found no benefit in function or quality of life [73–75].

N-acetylcysteine (NAC), a glutathione precursor that inhibits oxidative stress, reversed diastolic dysfunction and hypertrophy in HCM mouse models. However, a human trial showed minimal impact on hypertrophy, fibrosis, mass, strain, and functional capacity [76].

Non-medical therapy

If symptoms are not controlled with maximal pharmacological therapy or if the drugs are not tolerated or are contraindicated, patients may be candidates for surgical myectomy or septal ablation.

Surgical approach

Myectomy is a cardiac surgery procedure that, through a transaortic approach, allows for remodeling of the ventricular anatomy by resecting hypertrophic areas as appreciable in Fig. 9.

Fig. 9.

Specimens of interventricular septum after surgical myectomy: A and endocardial fibrosis of the interventricular septum to trauma caused by systolic anterior motion of the mitral valve anterior leaflet B

It enables correction of outflow gradient contributors, including papillary muscle remodeling, mitral valvuloplasty, and removal of fibrotic trigones and redundant chordae as shown in Figure 10.

Fig. 10.

Surgical view: A left ventricle outflow obstruction and the bulging of the interventricular septum after aortic valve leaflet retraction (left and right); B diseased mitral valve secondary cordae and papillary muscles after surgical myectomy

Myectomy is therefore a precision procedure that requires careful preoperative planning, including TTE and CMR imaging, and an intraoperative transesophageal echocardiogram to best plan the procedures to be performed and verify the success of the surgery. Sometimes, minimally invasive approaches such as minithoracotomy or ministernotomy may be used. Myectomy, performed in experienced, high-volume centers, carries a low complication risk, such as pacemaker implantation (10% of cases Postoperative 30-day mortality is very low (<1%), and the 10-year all-cause mortality rate is 8% [77].

In the absence of intrinsic mitral valve disease, SAM-related obstruction and regurgitation typically resolve after adequate septal resection [78]; anterior mitral leaflet elongation (≥30 mm) does not independently predict the need for concomitant repair [79]. Leaflets prolapse, chordal rupture, or severe calcific stenosis represent the main indications for direct mitral surgery at the time of myectomy. When repair is required, it is strongly preferred over replacement, offering superior long-term survival and lower thromboembolic risk. Leaflet plication and edge-to-edge techniques are the most employed approaches, with or without concomitant myectomy, depending on the degree of septal hypertrophy. MV replacement should be reserved for anatomy not amenable to repair [78, 80].

Alcohol septal ablation

Alcohol septal ablation (ASA) involves injecting absolute ethanol into a suitable septal perforator branch, causing confined septal necrosis and thereby reducing septal thickness and the outflow tract gradient. ASA, less invasive but with higher pacemaker risk and residual gradient, is reserved for older or high-risk patients, while myectomy remains the preferred treatment [3, 81].

Transcatheter edge-to-edge repair (TEER)

As mentioned above, HCM may be associated with MR due to SAM. Since the obstruction is due to a “sailing effect” of intraventricular pressure, which pushes A2 and P2 towards the hypertrophied septum, a reasonable strategy is to implant a clip on the A2-P2 segments. A case series of five HCM patients with SAM-induced MR demonstrated symptomatic improvement by reduction of SAM and MR [82].

More recently, The TRANSPARENT registry subsequently reported outcomes in 35 high-surgical-risk patients with obstructive HCM and moderate-to-severe SAM-related MR: technical success was achieved in 94%, MR < 2 + in 97%, and LVOT gradient decreased from 62 to 16 mmHg with sustained benefit at a median follow-up of 523 days; NYHA class I/II improved from 31 to 88% [83]. These findings support TEER as a feasible option in selected high-surgical-risk patients or those ineligible for alcohol septal ablation, pending confirmation in prospective studies.

Alternative and investigational approaches to septal reduction

Parallel to surgical myectomy and alcohol septal ablation, percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) has emerged as a promising minimally invasive option for the treatment of oHCM. The procedure is performed with the patient in the left lateral decubitus position under general anesthesia and continuous vital signs monitoring. A temporary pacing wire is positioned in the right ventricle before the intervention. Under real-time TTE guidance, a radiofrequency needle is introduced transapically into the hypertrophied septum, with the tip generally advanced to the basal septum approximately 8–10 mm below the aortic valve. Radiofrequency energy is delivered through the needle tip, generating temperatures above 80 °C and inducing controlled coagulative necrosis of septal tissue and occlusion of small intramural vessels; the energy delivery automatically pauses when tissue impedance rises to 150% of baseline. Initial power is typically set at 60 W and can be increased up to 100 W if required, with individual applications lasting up to 12 min. After each application, the needle is withdrawn by about 10 mm to create a contiguous ablation line. To avoid injury to the conduction system, lesions are placed 3–5 mm from the endocardium. Procedural efficacy is assessed by TTE, including evaluation of hyperechoic ablation zones and contrast-perfusion defects, and ablation is considered complete when the peak LVOT gradient is reduced to < 30 mmHg or when a necrotic area measuring approximately 30–40 mm in length and width and involving two-thirds of septal thickness is achieved. After ablation, local compression ensures hemostasis, and a final TTE assessment is performed before transfer to a monitored setting for at least 24 h [84, 85].

In symptomatic patients with oHCM who remain refractory to medical therapy, PIMSRA has demonstrated sustained reductions in peak LVOT gradients and improvements in functional status at medium-term follow-up, with low procedural morbidity and mortality. Until larger controlled studies become available, the technique should still be considered investigational; however, PIMSRA represents an intriguing future direction in the field of septal reduction strategies [85].

An alternative approach is endocardial radiofrequency ablation (ERFA). This technique is performed under local anesthesia with continuous vital signs monitoring. A 4-mm irrigated-tip ablation catheter (30 mL/min) is positioned against the hypertrophied septum using either a retrograde transaortic LV approach. Radiofrequency energy (40–60 W) is applied for 60–180 s per lesion, strictly targeting the proximal septal segments adjacent to the LVOT. TTE and fluoroscopy confirm stable catheter–septum contact throughout the procedure. To minimize the risk of complete heart block, the catheter is kept away from the His region, identified by a dedicated His catheter or electroanatomic mapping. Anticoagulation is maintained to an activated clotting time of 300–350 s. The goal is to create a controlled septal lesion of approximately 2 cm². Procedural success is defined as a reduction of at least 50% in the LVOT gradient, measured invasively and by TTE before the end of the procedure [86, 87]. ERFA allows significant and sustained gradient reduction and symptomatic improvement of patients with severe HOCM [87]. Although technically feasible, ERFA is supported by more limited evidence and carries a higher theoretical risk of atrioventricular conduction disturbances.

Other septal reduction approaches have been described in small patient series, including non-alcohol embolization techniques (such as coil deployment, polyvinyl alcohol particle injection, and cyanoacrylate-based occlusion) as well as methods involving direct endocavitary or intramyocardial tissue destruction (cryotherapy) [2]. These strategies have not been systematically compared with established septal reduction therapies, and data on long-term outcomes and safety remain insufficient.

Advanced heart failure therapies

Among patients with HCM, 5–7% progress to advanced heart failure (AHF), a condition defined by medically refractory disease and severe functional impairment [88]. This represents the endpoint of a gradual and often insidious process, unfolding over 9–14 years, which, according to the staging framework proposed by Olivotto et al., passes through a phase of adverse remodeling (Stage III, LVEF 50–65%) to reach a stage of overt dysfunction (Stage IV) [88, 89]. At this final stage, the disease presents as either a hypokinetic-dilated or a hypokinetic-restrictive phenotype [88, 89].

An accurate characterization of AHF-HCM requires both invasive hemodynamic evaluations, through right heart catheterization (RHC), and functional assessment, including cardiopulmonary exercise test (CPET). RHC provides direct quantification of filling pressures, cardiac output, and pulmonary vascular resistance, and is indispensable to exclude irreversible precapillary pulmonary hypertension, a contraindication to heart transplantation [88]. CPET is recommended in patients with non-obstructive HCM and NYHA class III–IV symptoms despite guideline-directed medical therapy (Class I, Level of Evidence B) [2, 3]: pVO₂ and VE/VCO₂ slope represent the strongest independent predictors of death or transplantation irrespective of LVEF [88, 90]. It should be noted that a mismatch between pVO₂ and clinical symptom burden may arise in this population, and CPET results alone should not drive transplant exclusion decisions [88]. When combined with simultaneous exercise stress echocardiography (ESE), the CPET-ESE protocol offers additional hemodynamic insight by unmasking exercise-induced abnormalities not detectable at rest [91].

Once the patient with AHF-HCM has been identified and irreversible pulmonary hypertension or other contraindications have been excluded, heart transplantation is the preferred treatment (Class I) [2, 3], with one-year survival exceeding 90%, on par with other advanced heart failure etiologies [88]. The central challenge lies in the timing of referral: irreversible precapillary pulmonary hypertension, found in approximately 8% of excluded candidates in published series, can develop silently, making serial hemodynamic monitoring and early referral to experienced centers a clinical priority [88]. The hypokinetic-restrictive phenotype deserves particular attention in this regard, as its tendency to preserve LVEF despite significant hemodynamic impairment makes late recognition more frequent [88, 89]. For patients in whom transplantation is not feasible or being pursued, left ventricular assist device (LVAD) support may be considered, although its applicability in HCM is inherently constrained by the small LV cavity, residual hypertrophy, and the attendant risks of inflow cannula obstruction and suction events [88]. Available registry data suggest that satisfactory outcomes are confined to patients who have undergone sufficient LV remodeling toward a dilated phenotype; an LV end diastolic diameter below 5.0 cm consistently identifies those at markedly higher risk [92]. The hypokinetic-restrictive phenotype is poorly suited to LVAD support [88, 92].

For patients who reach the advanced stage at an age or with comorbidities precluding any of the above therapies, heart failure accounts for 74% of HCM-related mortality, with most deaths occurring beyond the age of 65 [93]. In this group, early integration of palliative care is recommended, consistent with current guidelines for the management of advanced heart failure [94].

Limitations and outstanding questions

Principal limitations of this review (and of the available evidence base) are related to:

• Evidence is dominated by non-randomized and referral-center cohorts, limiting causal inference and generalizability; event rates are low and disease progression is often slow, making conventional RCT designs challenging in HCM [3, 95].

• Marked clinical and methodological heterogeneity across studies (phenotype definitions, composite endpoints, follow-up duration, and protocol variability—particularly for exercise testing and imaging) constrains pooling and weakens cross-study comparability [90, 95].

• Inconsistent diagnostic and biomarker measurement standards (e.g., fibrosis quantification on CMR; advanced echo/CMR techniques such as GLS, mapping, ECV) remain incompletely validated for routine prognostic use, limiting firm conclusions about incremental clinical value [37].

• Genetic evidence is limited by variant interpretation uncertainty and incomplete molecular ascertainment, with a substantial proportion of patients remaining “genotype-elusive,” and with ancestry-related misclassification concerns affecting external validity [96].

• Underrepresentation of key populations (pediatrics, non-White ancestries, and genotype-positive/phenotype-negative cohorts with long follow-up) restricts applicability of conclusions to the full spectrum of HCM [3, 97].

There are also several outstanding questions that concern:

• Disease initiation and progression (true disease modification remains unproven): there are still no established preventive or disease-modifying therapies, largely due to incomplete understanding of the biology linking genotype to phenotype emergence and progression [3].

• Genotype-positive/phenotype-negative management: penetrance is variable and not reliably predictable, the prognostic meaning of subtle “early” imaging/functional abnormalities is unclear, and robust models to predict phenotypic conversion and outcomes are lacking [37, 96].

• Risk stratification remains imprecise: current sudden cardiac death (SCD) prediction approaches have limited positive predictive value, and additional validated markers (including imaging and physiologic measures) are still needed—particularly in children and other under-studied groups [3].

• Imaging biomarkers need standardization and outcome validation: the field lacks universally accepted, standardized fibrosis quantification methods and definitive evidence that newer metrics (e.g., GLS, mapping/ECV, microvascular ischemia assessment, AI-derived markers) improve decision-making and outcomes beyond current models [37].

• Non-obstructive HCM remains a major therapeutic unmet need: symptom mechanisms are complex and trial evidence is comparatively limited; even in the era of myosin inhibitors, subgroup-specific effectiveness and long-term outcome effects (mortality/SCD/HF progression) require longer follow-up and dedicated study [3, 98].

• Mechanisms beyond the sarcomere: multiple observations (microvascular dysfunction, mitral valve and intramural coronary abnormalities, fibrosis biology, and emerging immune-fibrotic pathways) are not fully explained by a purely sarcomeric model, supporting broader mechanistic frameworks that still require human validation [97].

Conclusions

Hypertrophic cardiomyopathy (HCM) remains a highly heterogeneous disease in which major advances in imaging, genetics, and targeted therapy coexist with substantial unresolved questions, particularly around early disease, risk prediction, and disease modification. Current guidelines and recent consensus documents consistently emphasize that much of HCM care is still built on observational evidence and expert opinion, reflecting the paucity of adequately powered randomized trials and the slow, variable natural history of the condition. Currently, thanks to the evolution of advanced imaging techniques—such as 2D and 3D echocardiography and CMR—HCM can be identified with much greater accuracy and at earlier stages, allowing for a significant increase in diagnoses across a wide range of clinical settings. Early and precise detection is especially important in the current era, where the introduction of targeted therapies has transformed the management of HCM, leading to marked reductions in both mortality and morbidity and improving overall patient outcomes.

Abbreviations

ACTC1

Actin α-cardiac muscle 1

ACTN2

α-Actinin 2

AF

Atrial Fibrillation

AHA

American Heart Association

AHF

Advanced Heart Failure

AI

Artificial Intelligence

ALPK3

Α-Kinase 3

ASA

Alcohol Septal Ablation

AV

Atrio-Ventricular

CAD

Coronary Artery Disease

CCTA

Cardiac Computed Tomography Angiography

CMR

Cardiac Magnetic Resonance

CNVs

Copy-Number Variants

CPET

Cardiopulmonary Exercise Test

CSRP3

Cysteine And Glycine Rich Protein 3

CW

Continuous Wave

CX

Circumflex Artery

DD

Diastolic Dysfunction

ECG

Electrocardiogram

ECV

Extra Cellular Volume

ERFA

Endocardial Radiofrequency Ablation

ESC

European Society Of Cardiology

ESE

Exercise Stress Echocardiography

FHOD3

Formin Homology 2 Domain Containing 3

FLNC

Filamin C

GAA

Alpha Glucosidase

GLS

Global Longitudinal Strain

HCM

Hypertrophic Cardiomyopathy

HF

Heart Failure

HFpEF

Heart Failure With Preserved Ejection Fraction

ICD

Implantable Cardioverter-Defibrillator

LA

Left Atrium

LACI

Left Atrioventricular Coupling Index

LAD

Left Anterior Descending Artery

LAMP2

Lysosomal-Associated Membrane Protein 2

LARS

Left Atrial Reservoir Strain

LBBB

Left Bundle Branch Block

LGE

Late Gadolinium Enhancement

LV

Left Ventricle

LVAD

Left Ventricular Assist Device

LVH

Left Ventricular Hypertrophy

LVOTO

Left Ventricle Outflow Tract Obstruction

LVSP

Left Ventricular Systolic Pressure

MPR

Multiplanar Reconstruction

MR

Mitral Regurgitation

MYBPC3

Myosin Binding Protein C3

MYH7

Myosin Heavy Chain 7

MYL2

Myosin Light Chain 2

MYL3

Myosin Light Chain 3

NAC

N-Acetylcysteine

NGS

Next Generation Sequencing

noHCM

Non-Obstructive Hypertrophic Cardiomyopathy

NYHA

New York Heart Association

oHCM

Obstructive Hypertrophic Cardiomyopathy

P/LP

Pathogenic Or Likely Pathogenic

PCD-CT

Photon-Counting Computed Tomography

PIMSRA

Percutaneous Intramyocardial Septal Radiofrequency Ablation

PLN

Phospholamban

PRKAG2

Protein Kinase AMP-Activated Non-Catalytic Subunit-Γ 2

RCA

Right Coronary Artery

RHC

Right Heart Catheterization

RV

Right Ventricle

RVH

Right Ventricular Hypertrophy

SAM

Systolic Anterior Motion

SBP

Systolic Blood Pressure

SCD

Sudden Cardiac Death

SD-WT

Standard Deviation Of Wall Thickness

SNVs

Single-Nucleotide Variants

SRT

Septal Reduction Therapy

SSFP

Steady-State Free Precession

STEMI

ST-Segment Elevation Myocardial Infarction

TEER

Transcatheter Edge-To-Edge Repair

TNNC1

Troponin C, Type 1

TNNI3

Troponin I, Type3

TNNT2

Troponin T, Type2

TPM1

Tropomyosin 1

TR

Tricuspid Regurgitation

TTE

Transthoracic Echocardiography

TTR

Transthyretin

US

United States

VUS

Variants of Uncertain Significance

WES

Whole Exome Sequencing

WGS

Whole Genome Sequencing

WPW

Wolff-Parkinson-White

Authors’ contributions

Authors' contributions: Eluisa La Franca, Francesca Parisi, Alessandro Lucchino, Elif Leyla Sade, Tim Wong, Italia Loddo, Luigi Alioto, Giovanni Gentile, Michele Pilato, Manlio Cipriani, and Francesco Fulvio Faletra all contributed equally to the conception, drafting, and critical revision of the manuscript, and approved the final version.

Funding

This study is supported by the Italian Ministry of Health-Ricerca Corrente.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.