Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a genetic condition characterized by left ventricular hypertrophy that is not caused by other cardiac or causative systemic diseases. Patients can be asymptomatic or have chest pain, dyspnea, dizziness, or syncope. Sudden cardiac death may occur. The diagnosis can be established with a resting ECG and echocardiography. Management for all patients involves lifestyle changes and possibly AICD placement, and for symptomatic patients, medical or surgical therapy is indicated. The goals of therapy are to decrease the heart rate to allow for improved left ventricular filling and to reduce LV outflow tract 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 (LVOTO) that is dynamic (see “Pathophysiology” for further details)

• Second most common cardiomyopathy
• Two types are distinguished: ^[1]
  • Obstructive type/hypertrophic obstructive cardiomyopathy (HOCM): ∼ 70% of cases
  • Nonobstructive type: ∼ 30% of cases
• Alongside myocarditis, HCM is one of the most frequent causes of sudden cardiac death in young patients, especially young athletes.

Epidemiological data refers to the US, unless otherwise specified.

• HCM is a genetic condition characterized by otherwise unexplained left ventricular hypertrophy. ; ^[1][2]
  • 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 ^[3]

Nonobstructive and obstructive HCM ^[4]

• 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 ^[3][5]

• 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)

• Symptoms: worsen with exercise, dehydration, and use of certain drugs (e.g., diuretics, hydralazine, ACEIs/ARBs, digoxin) ^[6]
  • Frequently asymptomatic (especially the nonobstructive type)
  • Exertional dyspnea
  • Angina pectoris
  • Dizziness, lightheadedness, syncope
  • Palpitations, cardiac arrhythmias
  • Sudden cardiac death (particularly during or after intense physical activity)
• Physical examination ^[6]
  • Systolic ejection murmur (crescendo-decrescendo)
    • Increases with Valsalva maneuver, standing, inotropic drugs (e.g., digitalis)
    • Decreases with:
      • Hand grip, squatting, or passive leg elevation
      • Drugs that decrease cardiac contractility (e.g., beta blockers)
  • Possible holosystolic murmur from mitral regurgitation
  • Sustained apex beat
  • S4 gallop
  • 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 an important cause of sudden cardiac death in young patients!

Echocardiography is the best initial and confirmatory test. Other investigations (e.g., ECG, CXR, cardiac MRI, exercise testing, and screening for coronary artery disease or genetic diseases) can be done on a case-by-case basis.

Diagnostic criteria ^[5][7]

Both of following are required 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 ^[5]

• Indications
  • Initial assessment of patients with suspected HCM
  • Repeat testing in patients with a new cardiovascular event or change in clinical status
• Findings in patients with HCM
  • Wall thickness
    • Asymmetrically thickened left ventricular wall,; (≥ 15 mm), typically involving the septum ^[8][9]
    • LV wall thickness ≥ 30 mm is associated with a high risk of sudden death. ^[5]
  • Outflow tract abnormalities
    • Systolic anterior motion of the mitral valve ^[10]
    • Mitral regurgitation
    • ↑ LVOT pressure gradient via Doppler echocardiography
  • Other findings
    • Left atrial enlargement ^[8]
    • Systolic function typically normal ^[10]
    • Diastolic dysfunction
• Findings more specific to HOCM
  • Asymmetrically thickened interventricular septum
  • Dynamic LVOT obstruction due to contact between the septum and mitral valve during systole

The following findings are more specific to obstructive HCM: asymmetrical septal thickening, dynamic LVOT obstruction by the mitral valve during systole, and LVOT pressure gradient ≥ 30 mm Hg.

ECG findings in HCM ^[11]

• Indication: all patients with suspected HCM
• Classic findings: commonly seen in obstructive 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 ^[11]
• Other supportive findings
  • Nonspecific ST segment and T-wave changes ^[7]
  • P wave changes indicating left atrial enlargement (e.g., P mitrale) ^[11][12]
  • LBBB
• Associated dysrhythmias: Ventricular tachycardia, atrial fibrillation, or atrial flutter

A normal ECG should prompt further evaluation, as it is only seen in 5–10% of cases. ^[11]

Chest x-ray

• Indication: considered for patients presenting with dyspnea or chest pain of unknown etiology
• Suggestive findings
  • The heart can be normal or enlarged.
  • Left atrial enlargement is commonly seen in mitral regurgitation.
  • Possibly signs of pulmonary congestion (e.g., pulmonary edema) in severe forms of CHF

Exercise testing ^[5]

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

• Exercise echocardiography ^[5]
  • Indications: to confirm and quantify dynamic LVOT obstruction in patients with inconclusive TTE ^[5]
  • Findings: LVOT obstruction and/or mitral regurgitation
• Treadmill exercise testing ^[5]
  • Indications
    • Assessment of functional capacity and response to therapy
    • Addition of ECG and blood pressure monitoring for SCD risk stratification
  • Findings
    • Clinical observation for development of symptoms (e.g., dyspnea, palpitations)
    • Blood pressure monitoring: hypotension
    • ECG tracings with arrhythmias and/or signs of ischemia

Cardiac MRI (cMRI)

• Indications ^[5]
  • Evaluation of ventricular morphology if echocardiographic findings are inconclusive
  • Patients with known HCM if additional findings in MRI may require a change in management approach
  • Consider in patients with inconclusive risk stratification for sudden cardiac death.
  • 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

• Genetic testing and family screening: All patients should be assessed for familial inheritance and receive genetic counseling. ^[5]
  • Indications for genetic testing ^[5][12]
    • Considered reasonable 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 genetic counseling from someone who is knowledgeable about genetic cardiovascular diseases. ^[5][12]
• Assessment for coronary artery disease
  • Indicated for patients with chest discomfort for whom a diagnosis of CAD would impact HCM management ^[5]
  • Includes coronary angiography with levocardiography
    • 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. ^[5]
  • Indications
    • Initial assessment of patients with confirmed HCM to identify candidates for implantable cardioverter defibrillator (ICD) therapy
    • Patients with palpitations or lightheadedness
    • Repeat testing every 1–2 years for patients without prior evidence of VT.
  • Findings
    • Ventricular tachyarrhythmias
    • Atrial fibrillation or atrial flutter ^[5][11]

General approach

• All patients
  • Counsel regarding lifestyle changes.
  • Risk stratify for sudden cardiac death and consider AICD placement.
  • Treat cardiovascular comorbidities.
• Asymptomatic patients: No pharmacological or invasive treatment is needed. ^[5]
• Symptomatic patients
  • Administer pharmacological therapy as first line.
  • Consider invasive treatment for symptoms refractory to medical therapy.
  • Manage complications (e.g., shock, atrial fibrillation, CHF and ventricular arrhythmias).

All patients ^[5][7]

Lifestyle changes

• Avoidance of dehydration
• Maintaining a healthy body weight
• Avoidance of excessive alcohol intake
• Avoidance of strenuous exercise and situations that will likely cause vasodilation (e.g., environmental factors such as high temperatures)

Automated implantable cardioverter defibrillator (AICD)

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

• Absolute indication: known prior history of ventricular fibrillation, sustained ventricular tachycardia, or cardiac arrest
• Relative indications
  • Syncope of unknown cause
  • Family history of SCD in a first-degree relative
  • LV wall thickness ≥ 30 mm
• Risk stratification: for sudden cardiac death (e.g., documented NSVT)

Symptomatic patients ^[5][7]

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

Recommended pharmacotherapy ^[13][14]

• Initial therapy: for all symptomatic patients with obstructive or nonobstructive HCM
  • First-line: Beta blockers (e.g., propranolol OR atenolol OR nadolol ) ^[15]
    • Titrate to goal resting heart rate < 60–65/minute
  • Second-line: Nondihydropyridine CCBs
    • Consider in patients who do not tolerate or respond to beta blockers
    • Verapamil is preferred, but should be avoided if there is hypotension or dyspnea at rest.
    • Diltiazem may be considered in patients with an intolerance or contraindications to verapamil.
• Additional therapy: to consider adding to beta-blocker or CCB if symptoms are persistent
  • Obstructive HCM: Disopyramide ^[16]
  • Obstructive HCM, or nonobstructive HCM with LVEF > 50%): Oral diuretics, e.g., furosemide

These medications should be used with caution due to their potential for provoking dysrhythmias (e.g, AV block, QT prolongation) and worsening LVOT obstruction in specific situations (e.g., hypovolemia). Cardiology consultation is advised.

Pharmacotherapy to avoid

The following are relative contraindications and may not apply to all patients, e.g., those with acute complications such as heart failure or atrial fibrillation.

• Medications to be avoided in LVOT obstruction
  • High-dose diuretics
  • Digoxin
  • Spironolactone ^[13][17][18]
  • ACE inhibitors and ARBs ^[19]
  • Dihydropyridine CCBs (e.g., nifedipine)
  • Vasodilators (e.g., nitrates and PDE-5 inhibitors)
  • Positive inotropes (e.g., dopamine, dobutamine, norepinephrine)
• Medication to be avoided in nonobstructive HCM
  • Digoxin (except in atrial fibrillation with an 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!

Invasive therapy

These are generally indicated for symptoms that are refractory to medical therapy.

• Septal reduction therapy
  • Indication: severe symptoms (e.g., dyspnea or chest pain, often NYHA III or IV, exertional syncope or presyncope) due to LVOT obstruction (LVOT gradient ≥ 50 mm Hg) ^[20]
  • Procedures
    • Surgical septal myectomy (Morrow procedure) is preferred for most patients; involves thinning the hypertrophic muscular intraventricular septum to widen the left ventricular outflow tract
    • Transcoronary ablation of septal hypertrophy (alcohol septal ablation) when surgery is considered too high risk or is contraindicated
• Dual-chamber pacemaker: Consider for patients who are poor candidates for septal reduction therapy.
• Heart transplant: Consider in end-stage nonobstructive HCM when LVEF ≤ 50%.

The following complications can be very challenging to manage and required a specialized approach. Cardiology consultation is advised.

• Hypotension: ICU and cardiology consultation required
  • Management typically involves fluids and vasopressors with purely vasoconstricting effects and no inotropic effects, e.g., phenylephrine. ^[5][21]
  • In patients with severe LVOTO who have cardiogenic shock with pulmonary edema, vasoconstrictors may need to be combined with beta-blockers, e.g., esmolol. ^[7]
• Heart failure
  • May require medications, e.g., ACEIs, that are typically avoided in uncomplicated HOCM
  • May require discontinuation of negative inotropic medication, e.g., nondihydropyridine CCBs
• Atrial fibrillation ^[5][7][22]
  • Typically requires anticoagulation and either rate control or rhythm control
  • May also require medications, e.g., digoxin, that are typically avoided in uncomplicated HCM
• Ventricular dysrhythmias ^[7]
  • AICD placement
  • Some patients may benefit from antiarrythmic medication and radiofrequency ablation of arrhythmogenic foci.

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

• One-Minute Telegram 76-2023-2/3: Hypertrophic hearts can still flex

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