Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common hereditary heart disease. HCM is characterized by unexplained hypertrophy of the left ventricle, which leads to diastolic dysfunction. It is a leading cause of sudden cardiac death (SCD) in young athletes. While many patients are asymptomatic, common symptoms include exertional dyspnea and syncope, which are often exacerbated by exercise. Physical examination may reveal a systolic ejection murmur that increases with maneuvers that decrease preload (e.g., the Valsalva maneuver) and an S4 gallop. Diagnosis is confirmed with echocardiography, which typically shows an asymmetrically thickened left ventricular wall, particularly the septum. Management consists of SCD prevention in high-risk individuals, and pharmacological treatment (e.g., beta blockers, nondihydropyridine calcium channel blockers) indicated only for symptomatic patients. Invasive management, including septal reduction therapy, may be required for refractory obstructive HCM. It is crucial to avoid medications that reduce preload or afterload, such as nitrates and ACE inhibitors in patients with obstructive HCM, as they can worsen the obstruction.

• Nonobstructive HCM: Hypertrophic cardiomyopathy without obstruction of the left ventricular outflow tract (LVOT)
• Hypertrophic obstructive cardiomyopathy (HOCM): HCM with left ventricular outflow tract obstruction that is dynamic (see “Pathophysiology” for further details)

• Second most common cardiomyopathy
• ♂ = ♀ ^[1][2]
• Two types are distinguished: ^[3]
  • Obstructive type, i.e., hypertrophic obstructive cardiomyopathy (HOCM): ∼ 70% of cases
  • Nonobstructive type: ∼ 30% of cases
• One of the most frequent causes of sudden cardiac death in young patients, especially young athletes ^[1]

Epidemiological data refers to the US, unless otherwise specified.

• HCM is a genetic condition characterized by otherwise unexplained left ventricular hypertrophy. ; ^[3][4]
  • Most common hereditary heart disease
  • Autosomal dominant inheritance with varying penetrance
  • Most commonly caused by mutations of the sarcomeric protein genes (e.g., myosin heavy chain, myosin binding protein C) → disorganization of myocyte architecture characterized by myofibrillar disarray and fibrosis
    • MYH7 gene: gene on the long arm of chromosome 14 that codes for the beta-myosin heavy chain, which forms a part of type II myosin in skeletal and cardiac muscle cells
    • MYBPC3 gene: gene on the short arm of chromosome 11 that codes for cardiac myosin binding protein C, which prevents the breakdown of thick filaments in cardiac sarcomeres
  • Less commonly due to a mutation in cardiac sarcomeric proteins such as troponin and tropomyosin
• Other conditions that are associated with left-ventricular hypertrophy include the following:
  • Chronic hypertension (most common cause of left ventricular hypertrophy)
  • Aortic stenosis
  • Friedreich ataxia, Fabry disease, Noonan syndrome
  • Amyloidosis

HCM is characterized by hypertrophy of the left ventricle; ; most commonly occurs with asymmetrical septal involvement, which leads to diastolic dysfunction (impaired left ventricular relaxation and filling) → reduced systolic output volume → reduced peripheral and myocardial perfusion.; → cardiac arrhythmia and/or heart failure and increased risk of sudden cardiac death ^[5]

Nonobstructive and obstructive HCM ^[6]

• Typical features include:
  • Increased LV wall thickness with septal predominance , no dilation of left ventricle
  • Myofibrillar disarray, interstitial fibrosis, and myocyte hypertrophy
  • Concentric hypertrophy: a form of cardiac remodeling characterized by parallel duplication of sarcomeres that leads to thickening of the ventricular wall
    • In HOCM, concentric hypertrophy is caused by genetic mutations (see “Etiology”).
    • Concentric hypertrophy can also occur secondary to the following diseases, then potentially mimicking HCM:
      • Hypertension and aortic valve stenosis; (due to chronic pressure and volume overload): Chronic hypertension → increased afterload → increased myocardial wall tension → changes in myocardial gene expression → sarcomeres laid down in parallel → increased left ventricular thickness → decreased left ventricular size → diastolic dysfunction
      • Storage disorders (e.g., Fabry disease, amyloidosis) and hereditary syndromes; (e.g., Friedreich ataxia, Noonan syndrome)

HOCM ^[5][7]

• Pathomechanism: LVOT obstruction → increased LV systolic pressure → prolongation of ventricular relaxation → increased LV diastolic pressure → exacerbation of HCM with further reduction of cardiac output
• Mechanisms of obstruction
  • Systolic anterior motion (SAM) of the mitral valve, results in mitral-septal contact during mid-to-late systole ; caused by either or both:
    • Venturi effect: accelerated blood flow through ventricular outflow tract creates negative pressure that pulls the mitral valve towards the septum → increased outflow tract obstruction
    • Ejection against an elongated and distorted mitral valve; causes leaflets to get pulled into the outflow tract → potential secondary mitral regurgitation
  • Muscular obstruction
    • Encroachment of the LVOT by the hypertrophic septum
    • Hypertrophy or anomalous insertion of papillary muscles → increased left ventricular apical pressure → ↑ risk for development of apical ventricular aneurysms
• LVOT obstruction is dynamic
  • The following factors can increase the degree of obstruction: ↑ LV contractility, ↓ preload, and ↓ afterload
  • Clinically exacerbating factors
    • Physical exercise/stress
    • Dehydration
    • Pharmacologic provocation (e.g., diuretics, ACEIs/ARBs, digoxin, hydralazine)
    • Valsalva maneuver (strain phase)

Clinical features ^[1]

HCM is frequently asymptomatic; , especially if nonobstructive. The following features may be present:

• Exertional dyspnea
• Angina pectoris
• Syncope, dizziness, lightheadedness
• Palpitations, cardiac arrhythmias
• Sudden cardiac death (particularly during or after intense physical activity)
• Symptoms of HCM may worsen with exercise, dehydration, and certain medications (e.g., diuretics, hydralazine, ACEIs, ARBs, digoxin). ^[1]

Physical examination ^[1]

• Systolic ejection murmur (crescendo-decrescendo):
  • Cause: subvalvular dynamic LVOT obstruction due to asymmetrically thickened myocardium
  • Location: best heard at the cardiac apex or the left lower sternal border and Erb's point (cardiology)
  • Radiation: to the axilla if there is concomitant mitral regurgitation; no radiation to the neck
  • Response to maneuvers and medications (see “Maneuvers and their effects on murmurs")
    • Increases with Valsalva maneuver, standing, inotropic medications (e.g., digitalis).
    • Decreases with:
      • Hand grip, squatting, or passive leg elevation
      • Drugs that decrease cardiac contractility (e.g., beta blockers)
• S4 gallop
• Possible holosystolic murmur from mitral regurgitation
• Sustained apex beat
• Paradoxical split of S2
• Pulsus bisferiens: LV outflow obstruction causes a sudden quick rise of the pulse followed by a slower longer rise (biphasic pulse).

HOCM is a common cause of sudden cardiac death in young patients.

Transthoracic echocardiography (TTE) with Doppler is the primary imaging modality in most patients. Additional studies (e.g., ECG, cardiac MRI, exercise testing, and screening for CAD or genetic diseases) can be done on a case-by-case basis. ^[1][8]

Diagnostic criteria ^[1]

Both criteria must be met to make the diagnosis:

1. Left ventricular nondilated hypertrophy (usually ≥ 15 mm in adults)
2. Absence of other cardiac or systemic diseases that could explain hypertrophy (e.g., long-standing hypertension or aortic stenosis)

Transthoracic echocardiography with Doppler ^[1][8]

• Indications
  • Initial assessment for suspected HCM
  • Repeat testing in patients with a new cardiovascular event or change in clinical status
• Findings
  • Wall thickness
    • Asymmetrically thickened left ventricular wall,; (≥ 15 mm), typically involving the septum ^[1]
    • LV wall thickness ≥ 30 mm is associated with a high risk of sudden cardiac death. ^[1]
  • Outflow tract abnormalities
    • Systolic anterior motion of the mitral valve
    • Mitral regurgitation
    • ↑ LVOT pressure gradient via Doppler echocardiography
  • Other findings
    • Left atrial enlargement ^[9]
    • Systolic function typically normal
    • Diastolic dysfunction
• Findings more specific to HOCM ^[1]
  • Asymmetrically thickened interventricular septum
  • Dynamic LVOT obstruction due to contact between the septum and mitral valve during systole
  • Obstruction is considered present if peak LVOT gradient is ≥ 30 mm Hg. ^[1]
  • Hemodynamically significant obstruction is considered if LVOT pressure gradient is ≥ 50 mm Hg.^[1]

Asymmetrical septal thickening, dynamic LVOT obstruction by the mitral valve during systole, and LVOT pressure gradient ≥ 30 mm Hg are findings more specific for HOCM.^[1]

ECG findings in HCM ^[1][10]

• Indication: all patients with suspected HCM
• Classic findings: commonly seen in HCM
  • ECG signs of LVH (see Sokolow-Lyon criteria)
  • Deep Q waves, particularly in the inferior (II, III, and aVF) and lateral (I, aVL, V4–6) leads
  • Giant inverted T waves in the precordial leads ^[10]
• Other supportive findings
  • Nonspecific ST segment and T-wave changes
  • P wave changes indicating left atrial enlargement (e.g., P mitrale)
  • LBBB
• Associated arrhythmias: ventricular tachycardia, atrial fibrillation, or atrial flutter

A normal ECG in patients with HCM is rare (5–25% of cases) and should prompt further evaluation . ^[1]

Chest x-ray

• Indication: considered for patients presenting with dyspnea or chest pain of unknown etiology
• Findings
  • The cardiac silhouette can be normal or enlarged.
  • Left atrial enlargement is commonly seen in mitral regurgitation.
  • Signs of pulmonary congestion (e.g., CXR findings in pulmonary edema) may be present in severe CHF.

Exercise testing ^[1]

Provocation tests (e.g., exercise testing) are obligatory if no obstruction is discernible at rest.

• Stress echocardiography ^[1]
  • Indications: to confirm and quantify dynamic LVOT obstruction if inconclusive TTE
  • Findings: LVOT obstruction and/or mitral regurgitation
• Cardiac exercise stress test ^[1]
  • Indications
    • Assessment of functional capacity and response to therapy
    • Addition of ECG and blood pressure monitoring for sudden cardiac death risk stratification
  • Findings
    • Development of symptoms (e.g., dyspnea, palpitations)
    • Blood pressure monitoring: hypotension
    • ECG: arrhythmias and/or signs of ischemia (e.g., ECG changes in STEMI, ECG changes in NSTEMI/UA)

Cardiac MRI (cMRI) ^[1][8]

• Indications
  • Evaluation of ventricular morphology if echocardiographic findings are inconclusive
  • Patients with known HCM and additional findings in MRI may require a change in management approach.
  • Consider if risk stratification for sudden cardiac death is inconclusive.
  • Evaluation of alternative diagnoses
• Advantages
  • Better visualization of segmental left ventricular hypertrophy located in the anterolateral wall or apex compared to echocardiography
  • Better detection of apical aneurysms compared to echocardiography
  • Identification of myocardial fibrosis with late gadolinium enhancement (LGE)

Additional studies ^[1]

• Genetic testing and family screening: All patients should be assessed and receive genetic counseling.
  • Indications for genetic testing
    • Considered in index patients to identify first-degree family members who may be at risk of HCM
    • Index patients with an atypical presentation or for whom another genetic cause is suspected
  • First-degree relatives: Screen by clinical assessment (with or without genetic testing).
  • Patients who undergo genetic testing should receive counseling from a knowledgeable professional with expertise in genetic cardiovascular diseases. ^[7][11]
• Assessment for coronary artery disease ^[1]
  • Indicated for patients with chest discomfort for whom a diagnosis of CAD would impact HCM management
  • Includes coronary angiography with evaluation of the left side of the heart
    • Gold standard for identifying epicardial coronary stenoses
    • Used to measure LVOT gradient and hemodynamics
    • Considered in patients with an intermediate or high likelihood of CAD§
• Ambulatory ECG monitor (e.g., 24-hour Holter monitor, 48-hour Holter monitor, or event recorder) ^[1]
  • Indications
    • Initial assessment of confirmed HCM to identify candidates for implantable cardioverter defibrillator (ICD) therapy
    • Palpitations or lightheadedness
    • Risk factors for atrial fibrillation
  • Findings
    • Ventricular tachyarrhythmias
    • Atrial fibrillation or atrial flutter ^[1][10]
  • Repeat testing every 1–2 years for patients without prior evidence of VT.

Approach^[1]

• All patients
  • Refer to a cardiologist or HCM specialist.
  • Counsel on lifestyle changes.
  • Risk stratify for sudden cardiac death and consider AICD placement.
  • Treat cardiovascular comorbidities (e.g., diabetes, obesity, hypertension, hyperlipidemia).
• Asymptomatic patients: Pharmacological and surgical interventions are not indicated. ^[1]
• Symptomatic patients
  • Pharmacological treatment is the first choice for all patients with obstructive or nonobstructive HCM.
  • Invasive treatment is indicated for symptoms refractory to pharmacological treatment.
  • Manage complications (e.g., shock, atrial fibrillation, CHF and ventricular arrhythmias).

All patients ^[1]

Lifestyle changes

• Avoidance of dehydration
• Maintaining a healthy body weight
• Avoidance of unhealthy alcohol use
• Mild or moderate-intensity physical activity
• Avoidance of situations that will likely cause vasodilation (e.g., high temperatures)

Patients with HCM may participate in strenuous physical activities after careful assessment by an HCM specialist with experience managing athletes. ^[1]

Automated implantable cardioverter defibrillator (AICD) ^[1]

An AICD is considered for primary or secondary prevention of sudden cardiac death in patients with HCM who are at high risk.

• Absolute indications: history of ventricular fibrillation, sustained ventricular tachycardia, or SCD
• Relative indications
  • Syncope of unknown cause (≥ 1 episode)
  • History of SCD in a first-degree relative
  • LV wall thickness ≥ 30 mm ^[1]
  • LV apical aneurysm with transmural scar
  • LVEF < 50% ^[1]
  • Other risk factors to consider
    • Documented nonsustained ventricular tachycardia
    • Younger age ^[1]
    • Extensive late gadolinium enhancement on CMR
• Specific considerations
  • Single-chamber transvenous ICD or subcutaneous ICD are recommended for most patients.
  • Dual-chamber ICD may be considered for:
    • Need for atrial or AV sequential pacing
    • Comorbid paroxysmal atrial tachycardia or atrial fibrillation
    • Symptomatic patients ≥ 65 years old with HOCM ^[1]

Symptomatic patients ^{[1] [8]}

The goal is to alleviate symptoms of HCM by slowing the heart rate and LVOT.

Pharmacological treatment ^[1][8]

Cardiology consultation is advised before starting treatment.

• Initial therapy: for all symptomatic patients with obstructive or nonobstructive HCM
  • First-line: beta blockers (e.g., propranolol OR atenolol OR nadolol ) ^[12]
    • Titrate to goal resting heart rate < 60-65/minute ^[1]
  • Second-line: nondihydropyridine CCBs
    • Consider in patients with HOCM who do not tolerate or respond to beta blockers.
    • Verapamil is preferred, but should be avoided if there is hypotension or severe dyspnea at rest.
    • Diltiazem may be considered if there is intolerance or contraindications to verapamil.
• Additional agents: The following may be added to beta blockers or CCBs if symptoms are persistent.
  • Obstructive HCM
    • Disopyramide ^[1][13]
    • Mavacamten: for patients with NYHA II-III HOCM ^[1]
  • Obstructive HCM or nonobstructive HCM with LVEF > 50%: Oral diuretics, e.g., furosemide

Medications for HCM may cause arrhythmias (e.g, AV block, QT prolongation) or worsen LVOT obstruction symptoms in specific situations (e.g., hypovolemia).

Medications to avoid ^[1]

The following are relative contraindications. A risk-benefit assessment should be performed for each patient (e.g., considering acute complications such as heart failure or atrial fibrillation).

• To be avoided in LVOT obstruction
  • High-dose diuretics
  • Digoxin
  • ACE inhibitors and ARBs ^[14]
  • Dihydropyridine CCBs (e.g., nifedipine)
  • Vasodilators (e.g., nitrates and PDE-5 inhibitors)
  • Positive inotropes (e.g., dopamine, dobutamine, norepinephrine)
• To be avoided in nonobstructive HCM
  • Digoxin (except in atrial fibrillation with LVEF ≤ 50%)

Positive inotropic and afterload-reducing or preload-reducing drugs (e.g., digoxin, nitrates, dihydropyridine CCBs, ACEIs) are contraindicated in patients with obstructive HCM. ^[1]

Invasive treatment ^[1]

These may be indicated for symptoms refractory to pharmacological treatment.

• Septal reduction therapy
  • Indications: severe symptoms (e.g., dyspnea or chest pain, often NYHA III or IV, exertional syncope or presyncope) due to LVOT obstruction ^[1][15]
    • LVOT obstruction demonstrated to be due to mitral valve apposition with the hypertrophied septum
    • LVOT gradient ≥ 50 mm Hg at rest or with provocation
  • Procedures
    • Surgical septal myectomy (Morrow procedure): preferred for most patients; it consists of partial resection of the hypertrophic muscular intraventricular septum to widen the left ventricular outflow tract.
    • Transcoronary ablation of septal hypertrophy (alcohol septal ablation): if surgery is contraindicated
• Heart transplantation: Consider in nonobstructive HCM with heart failure NYHA III– IV refractory to GDMT.

• Hypotension
  • Consult ICU and Cardiology.
  • Management typically involves IV fluid resuscitation and vasopressors with purely vasoconstricting effects and no inotropic effects (e.g., phenylephrine). ^[1]
  • In severe LVOTO and cardiogenic shock with pulmonary edema, vasoconstrictors may need to be combined with beta-blockers (e.g., esmolol). ^[1]
• Heart failure ^[1]
  • GDMT for heart failure
  • Medications that are typically avoided in uncomplicated HOCM (e.g., ACEIs) may be required.
  • Discontinuation of negative inotropic medication (e.g., nondihydropyridine CCBs) may be required.
• Atrial fibrillation ^[1]
  • Anticoagulation is recommended (DOACs are preferred)
  • Rate control is key.
  • Rhythm control may be considered based on patient factors.
  • Medications (e.g., digoxin) that are typically avoided in uncomplicated HCM may be required.
• Ventricular arrhythmias ^[1]
  • AICD placement
  • Some patients may benefit from antiarrhythmic medication and radiofrequency ablation of arrhythmogenic foci.

We list the most important complications. The selection is not exhaustive.

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