Hypertrophic cardiomyopathy

Definition

Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes and a non-dilated left ventricle with preserved or increased ejection fraction.

In adults, HCM may be diagnosed by the presence of left ventricular end diastolic wall thickness >13 mm on an echocardiogram or other imaging technique.

The European Society of Cardiology guidelines recommend using a left ventricular wall thickness of ≥15 mm in the diagnostic criteria

Epidemiology

HCMP occurs at a rate of 1:500 in the general adult population.

Etiology

The most frequent causes of HCM are listed in Image 1.

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Types of HCM (Image 2)

Johan Martijn Bos, Michael J. Ackerman,Chapter 7 - Hypertrophic Cardiomyopathy in the Era of Genomic Medicine,Editor(s): Geoffrey S. Ginsburg, Huntington F. Willard,Genomic and Precision Medicine (Third Edition),Academic Press,2018,Pages 103-126.

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‍Pathophysiological consequences

The main functional consequences of HCM are listed in Image 3.

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Clinical manifestation

Image 4 Main clinical presentations of HCM

Adapted from: Camm, J. A., Lüscher, T. F., & Serruys, P. (2020). The ESC Textbook of Cardiovascular Medicine (3rd ed.). Wiley-Blackwell.

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Diagnostic approach

The diagnosis of HCM is based on the detection of increased LV wall thickness by an imaging modality

The disease phenotype also includes myocardial fibrosis, morphologic abnormalities of the mitral valve apparatus, abnormal coronary microcirculatory function and electrocardiographic abnormalities.

Due to the diverse etiology of the disease, detection of increased LV wall thickness that is unexplained by loading conditions should prompt a systematic search for its underlying cause. In many patients, this work-up should include specialized laboratory testing and genetic analysis.

In an adult, HCM is defined by a wall thickness ≥15 mm in one or more LV myocardial segments- measured by echocardiography, cardiac magnetic resonance imaging, or computed tomography that is not explained solely by loading conditions.

‍Genetic and non-genetic disorders can present with lesser degrees of wall thickening (13–14 mm). In these cases, the diagnosis of HCM requires evaluation of other features including family history, non-cardiac symptoms and signs, ECG abnormalities, laboratory tests and multi-modality cardiac imaging.

In children the diagnosis of HCM requires an LV wall thickness more than two standard deviations greater than the predicted mean.

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Echocardiographic findings

Echocardiography is used to diagnose and monitor HCM.

In most patients, hypertrophy involves the interventricular septum in the basal LV segments but often extends into the lateral wall, the posterior septum and LV apex, but it can be found at any location (including the right ventricle).

1. Assessment of left ventricular wall thickness

The single most relevant parameter is the maximum LV wall thickness at any level. Measurements of LV wall thickness should be performed at end-diastole and it is best seen in short-axis views.

In patients with known or suspected HCM it is essential that all LV segments from base to apex be examined at mitral, mid-LV and apical levels.

Video 1  Hypertrophic cardiomyopathy with significant dynamic obstruction - maximum of hypertrophy at midventricular (IVS 23 mm) and apical level (IVS 25mm), where the obstruction occurs (midventricular LVOT gradient 20/12 mmHg and apical 17/12 mmHg, rising to 81/41 mmHg with Valsalva maneuver). The left atrium is slightly enlarged.  Systolic anterior motion (SAM) of the mitral valve is present and causes mild mitral regurgitation. 

Video 2  Hypertrophic cardiomyopathy - PSAX view of the hypertrophied myocardium of left ventricle

Image 5 Hypertrophic cardiomyopathy - measurement of the LV wall thickness in PSAX view shows severely thickened myocardium

Video 3 Hypertrophic cardiomyopathy with severely thickened septum - A4C view, the septum is severely hypertrophied at its whole length with diameter up to 30 mm, hypokinesis of the septum with reduced longitudinal contraction (MAPSE 10mm) and thickened walls of LV.

‍Video 4  Hypertrophic cardiomyopathy with severely thickened septum, PLAX view - despite the size of the hypertrophy, no obstruction is present.

Image 6 Hypertrophic cardiomyopathy with severely thickened septum, PLAX measurement of diameters - IVS 30 mm

Video 5  Hypertrophic cardiomyopathy with dynamic obstruction of LVOT and SAM - hypertrophic septum (IVS 22mm) and severely enlarged left atrium with aneurysm of interatrial septum. Note the systolic anterior motion (SAM) of the mitral valve  = anterior leaflet hits the IVS during systole, causing moderate mitral regurgitation.

Video 6  Hypertrophic cardiomyopathy sparing the basal part of the septum (basal IVS 11mm), A4C - hypertrophy prevails in the apical ⅔ of the heart. Apical squeezing with a gradient 31/17 mmHg at rest. Note the “kissing” of the papillary muscles. SAM is also present.

Video 7  Asymmetric hypertrophic cardiomyopathy without obstruction - severely thickened basal part of the IVS up to 30mm. No dynamic obstruction or SAM. Note the ICD electrodes in the right heart, the patient has a history of cardiac arrest.

Video 8 Asymmetric hypertrophic cardiomyopathy without obstruction, PLAX view - severely hypertrophied basal part of the interventricular septum.

Image 7 Asymmetric hypertrophic cardiomyopathy without obstruction, 2D measurements in PLAX view of wall thickness

Video 9  Apical form of hypertrophic cardiomyopathy, A4C view - severely hypertrophied apical ⅓ of the heart with walls thickened to 20-22 mm and midsystolic obstruction. Global longitudinal strain was significantly reduced (- 9,5%).

Video 10 Left ventriculat hypertrophy in a patient with Fabry disease

2. Assessment abnormalities of the mitral valve and left ventricular outflow tract

Systolic anterior motion (SAM) of the mitral valve nearly always results in failure of normal leaflet coaptation and leads to mitral regurgitation.

It is typically mid-to-late systolic and inferolaterally oriented. 

SAM of the mitral valve leaflets also results in obstruction to the LV outflow tract.

LVOTO is defined as an instantaneous peak Doppler LV outflow tract pressure gradient ≥30 mm Hg at rest or during physiological provocation such as Valsalva manoeuvre, standing and exercise.

A gradient of ≥50 mm Hg is usually considered to be the threshold at which LVOTO becomes hemodynamically important.

The gradient usually rises in hypovolemia, exercise, medication (nitroglycerine, dobutamine) and with the Valsalva maneuver.

Systematic 2D and Doppler echocardiography is usually sufficient to determine the mechanism and severity of LVOTO.

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3. Assessment of latent obstruction

It is recommended in all patients to perform 2D and Doppler echocardiography during a Valsalva manoeuvre in the sitting and semi-supine position- and then on standing if no gradient is provoked.

Exercise stress echocardiography is recommended in symptomatic patients if bedside manoeuvres fail to induce LVOTO ≥50 mm Hg. 

Video 11  Systolic anterior motion (SAM) of the anterior leaflet of the mitral valve - septal hypertrophy causes drag forces and Venturi effect. When the LV contracts, the anterior leaflet (the one closest to the IVS) is pushed against the IVS. This is SAM and it causes obstruction of LVOT.

Video 12  SAM with systolic obstruction, A3C view, colour Doppler - flow acceleration across the LVOT

Image 8  CW Doppler across LVOT measurement in a patient with hypertrophic CMP at rest - the CW Doppler is measured first at rest. The concentric hypertrophy of LV with SAM of the anterior MV leaflet causes a significant 50/23 mmHg LVOT gradient at rest in this patient. Note the “dagger shape” of the signal that is typical for dynamic obstruction that occurs in mid to late systole, associated with SAM and hypertrophic CMP.

Image 9  LVOT CW Doppler measurement during Valsalva maneuver of the same patient - after the measurement at rest, the patient was asked to perform the Valsalva maneuver. This led the gradient rise to 152/78 mmHg. 

4. Left atrial enlargement

The most common mechanism for developing LA enlargement is SAM-related mitral regurgitation and elevated LV filling pressures.

Video 13 Severely enlarged left atrium (LAVi 51.2 cm3/m2) in a patient with obstructive hypertrophic cardiomyopathy.

Image 10 Severe biatrial dilatation on TTE in a patient with Fabry disease

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5. Assessment of diastolic function

Patients with HCM often have diastolic dysfunction and the assessment of LV filling pressures can help in the evaluation of symptoms and disease staging.

It is recommended to evaluate pulsed Doppler of mitral valve inflow, tissue Doppler velocities at the mitral annulus, pulmonary vein flow velocities, pulmonary artery systolic pressure, and measurement of LA size and volume.

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6. Systolic function

Strain and strain rate derived from Doppler myocardial imaging or speckle tracking techniques can evaluate myocardial longitudinal velocities and deformation parameters. These parameters are often reduced despite a normal EF and may be abnormal before the development of increased wall thickness.

Myocardial longitudinal deformation is often  reduced at the site of hypertrophy.

Video 14  Global longitudinal strain (GLS) quad format, hypertrophic cardiomyopathy - the GLS is -15,3% and is reduced especially in the severely thickened basal parts of the septum (IVS 27 mm). Note the lighter colour in this segment.

Image 11  Global longitudinal strain (GLS) Bull’s eye plot, decreased GLS to -15,3% - the Bull’s eye format shows the reduced strain in the septal part of LV (lighter colour) typical for this type of hypertrophic cardiomyopathy.

7. Transesophageal echocardiography

Transoesophageal echocardiography should be considered in patients with poor transthoracic echo windows.

It is particularly useful in patients with LVOTO if the mechanism is unclear, when assessing the mitral valve apparatus before a septal reduction procedure, and when severe mitral regurgitation caused by intrinsic valve abnormalities is suspected. 

In patients undergoing septal myectomy, perioperative TOE should be used to guide the surgical strategy and to detect surgical complications (ventricular septal defect and aortic regurgitation) and residual LVOTO.

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8. Magnetic resonance

CMR provides high-fidelity morphologic information and can diagnose echocardiographically occult HCM variants.

CMR provides excellent demarcation between the myocardium and blood pool, allowing the most accurate calculation of LV mass and volumes. Velocity-encoded imaging can provide severity assessments of LVOT gradient and MR.

CMR also adds additional prognostic information that can be improved depending on the presence and extent of LGE.

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Management

Initial assessment

Echocardiography is essential in diagnosis and clinical decision-making and determines the extent and location of hypertrophy, concomitant structural and functional abnormalities (valvular dysfunction, systolic/diastolic dysfunction,..).

Main two groups of patients are divided by presence of dynamic LVOT obstruction.

Table below show recommendations for initial echocardiographic assessment and follow up  according to patient’s symptoms and history (Image 12):

Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020 Dec 22;142(25):e533-e557. doi: 10.1161/CIR.0000000000000938. Epub 2020 Nov 20. PMID: 33215938.

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Genetic testing

In the majority of cases, hypertrophic cardiomyopathy is inherited as an autosomal dominant trait, with 50% risk of the same genetic variant transmission to offspring. Genetic testing is therefore an important part of diagnosis and management.

Genetic counselling is recommended in all patients when HCM cannot be explained solely by a non-genetic cause.

Family history of HCM and sudden death events should be assessed preferably across at least 3 generations.

Algorithm below sums up management of patients and their family members (Image 13):

Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020 Dec 22;142(25):e533-e557. doi: 10.1161/CIR.0000000000000938. Epub 2020 Nov 20. PMID: 33215938.

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Lifestyle changes

For optimal management of HCM, the patient should adopt lifestyle modifications from optimal hydration, avoidance of caffeine and alcohol to evaluation of sports participation and occupation restrictions. 

The HCM is often associated with increased risk of SCD - abrupt increases in catecholamines are thought to be a trigger for SCD, in moderate- to high-intensity competitive sports, but may be reasonable with comprehensive evaluation of the patient. 

Image 14 Recommendation for sports activity in HCM

Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020 Dec 22;142(25):e533-e557. doi: 10.1161/CIR.0000000000000938. Epub 2020 Nov 20. PMID: 33215938.

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‍SCD risk assessment

The HCMP is regarded as the most common cause of SCD in young people and is a devastating complication of this disease.

‍Image 15 Sudden cardiac death risk calculator

ESC calculator - http://www.hcmrisk.org

‍Image 16 Algorithm showing patient selection for ICD implantation

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Management of patients with obstructive HCM (Image 17)

Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020 Dec 22;142(25):e533-e557. doi: 10.1161/CIR.0000000000000938. Epub 2020 Nov 20. PMID: 33215938.

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Pharmacologic therapy

Therapy is targeted to symptom relief caused by the dynamic left ventricular obstruction.

The success is measured by the patient’s symptoms and response, not by measured gradient across the LVOT. 

First-line therapy: non-vasodilating beta-blockers

• beta-blockers increase diastolic filling and decrease contractility

Verapamil or diltiazem - calcium channel blockers, are reasonable alternatives to beta-blockers if those are not effective or contraindicated.

Disopyramide - advanced therapy in patients who do not respond to  ≥1 of previous drugs

• reduces LV contractility and subaortic gradient, reduced afterload and slows LV ejection acceleration

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Invasive therapy of HCM (Image 18)

Invasive therapy is reserved for patients with severe symptoms despite optimal medication, usually NYHA III and IV class.

Surgical septal myectomy

During this procedure, part of the septum causing the systolic anterior movement (SAM) of the mitral valve is resected in an open heart surgery.

When performed in experienced centers the mortality is 0,3%.

Septal myectomy is most often performed via transaortic approach, but transmitral, transapical or their combination may be performed.

Successful myectomy eliminates or reduces SAM-mediated MR and leads to a reduction in left atrial size and a small degree of LV reverse remodeling

Alcohol septal ablation

Direct infusion of 98% ethanol into a target septal perforator supplying the left ventricular side of the basal septum where systolic contact with the mitral valve is occurring causes controlled infarction of hypertrophic septum.

Procedural mortality is low (<1%), but is associated with greater risk of conduction block requiring a permanent pacemaker and greater need for repeated intervention because of residual obstruction (7-20%), compared to surgical myectomy.

On the other hand, alcohol septal ablation avoids sternotomy and has significantly shorter convalescence.

It also offers treatment to frailty or polymorbid patients who are not indicated for surgical myectomy.

Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020 Dec 22;142(25):e533-e557. doi: 10.1161/CIR.0000000000000938. Epub 2020 Nov 20. PMID: 33215938.

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‍Management of patients with nonobstructive HCM (Image 19)

Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020 Dec 22;142(25):e533-e557. doi: 10.1161/CIR.0000000000000938. Epub 2020 Nov 20. PMID: 33215938.

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New specific treatment of obstructive HCM

Mavacamten is a first-in-class cardiac myosin inhibitor that directly targets the underlying pathophysiology of HCM and restores the heart’s normal function.

In early clinical trials, treatment with mavacamten led to significant improvements of symptoms, physical function, exercise capacity, and quality of life, and reduced LVOT obstruction in patients with obstructive HCM (Image 20).

Spertus JA, Fine JT, Elliott P, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2021 Jun 26;397(10293):2467-2475. doi: 10.1016/S0140-6736(21)00763-7. Epub 2021 May 15. PMID: 34004177.

References

1. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults.Circulation. 1995; 92:785–789.

2. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the task force for the diagnosis and management of hypertrophic cardiomyopathy of the european society of cardiology (ESC).Eur Heart J. 2014; 35:2733–2779. doi: 10.1093/eurheartj/ehu284.

3. Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020 Dec 22;142(25):e533-e557. doi: 10.1161/CIR.0000000000000938. Epub 2020 Nov 20. PMID: 33215938.

4. Spertus JA, Fine JT, Elliott P, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2021 Jun 26;397(10293):2467-2475. doi: 10.1016/S0140-6736(21)00763-7. Epub 2021 May 15. PMID: 34004177.

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