Hypertrophic Cardiomyopathy

Overview

Epidemiology

• Most commonly inherited cardiomyopathy 
• Prevalence: 1 in 200–500 adults
• Higher prevalence in men than in women
• Patients present most commonly in their 30s.
• Well-known cause of sudden cardiac death in athletes (approximately 50% of deaths occurring during or immediately after physical activity)
• Left ventricular outflow tract obstructions seen in 70%–75% cases

Etiology

Approximately 60%–70% of cases are caused by mutations affecting the thick or thin myofilament proteins of the sarcomeres (contractile components of the heart).

• Mutations leading to hypertrophic cardiomyopathy (HCM) found in 6 different genes over 4 different chromosomes 
• 50+ associated gene mutations identified
• The majority are missense mutations (single amino acid is replaced).
• Inheritance pattern most commonly autosomal dominant
• De novo (sporadic) mutations without a familial pattern may also occur.
• Penetrance and phenotypic expression vary due to a vast number of mutations and sarcomeric genes that cause HCM.

Pathophysiology

• Left ventricle (LV) becomes thickened and hypertrophied (asymmetrically with septal predominance) → left ventricular cavity becomes small/noncompliant → harder for the heart to pump blood and relax to refill during diastole
• Depending on the location and severity of wall thickening within the ventricle:
  • Left ventricular outflow tract obstruction impairs blood flow from the heart to rest of the body, especially with exertional activity:
    • Dynamic and affected by ↑ LV contractility, ↓ preload, and ↓ afterload
    • ↑ Left ventricular outflow tract obstruction → ↓ cardiac output
  • Diastolic dysfunction
  • Mitral regurgitation
  • Myocardial ischemia
  • Sudden cardiac death
• Mechanisms of left ventricular outflow tract obstruction:
  • Anterior displacement of the mitral valve during systole, also known as systolic anterior motion
  • Venturi effect: High-velocity blood flow through the left ventricular outflow tract during systole creates negative pressure, pulling the mitral valve leaflets toward the ventricular septum and pressing the leaflets against it.
  • Abnormally elongated mitral valve leaflets in patients with HCM 
  • Muscular obstruction due to a hypertrophic septum narrowing cavity space 
• Hypertrophy or anomalous insertion of papillary muscle may also occur, increasing left ventricular apical pressure and the risk of apical ventricular aneurysms.

Clinical Presentation

Many individuals affected by HCM are asymptomatic throughout their lives. For some, typically during adolescence, sudden cardiac death is the 1st symptom.

History

Symptoms:

• Shortness of breath, particularly with physical activity (most common symptom)
• Chest pain, especially upon exertion
• Fatigue
• Palpitations
• Dizziness/light-headedness
• Syncope, particularly during exercise:
  • 15%–25% of patients report at least 1 episode of syncope.
  • More common in individuals < 30 years of age
  • Unexplained syncope = ↑ risk sudden cardiac death

Family history:

• Important to determine the history of HCM to help in the diagnosis
• History of sudden cardiac death in a family member worsens prognosis:
  • Sometimes, sudden cardiac death is not known as the cause of a family member’s death.
  • Important to ask about unexplained deaths (drowning, car accidents, etc)

Physical exam

• Patients with minimal or no left ventricular outflow tract obstruction tend to have a normal exam.
• Cardiac auscultation must be performed in at least 2 different positions (sitting and standing).
• Patients with left ventricular outflow tract obstruction may present with:
  • Crescendo-decrescendo, harsh systolic murmur best heard at the apex and lower left sternal border: 
    • May radiate into axilla, but not into neck
      • Intensity ↑ with standing from sitting or lying position
      • Intensity ↑ with Valsalva maneuver
      • Intensity ↓ with squatting
    • Pansystolic murmur of mitral regurgitation is sometimes heard
    • Systolic thrill (palpable vibratory sensation) at the apex or lower left sternal border
    • Palpable left ventricular heave (upward push/motion on hand)
    • 2nd heart sound may split.
    • S3 or S4 gallop may be heard in younger patients.
    • Prominent, forceful impulse at apex
    • Double-beat (bifid) carotid or arterial pulse may be present.
    • High BP
    • Tachycardia
    • Hypotension in setting of acute hemodynamic collapse

Diagnosis

• Initial diagnosis based on history and physical examination:
  • Given the prevalence of a lack of symptoms, physical examination and screening of all athletes annually during pre-participation is essential.
  • May require further investigation:
    • Unexplained chest pain, shortness of breath on exertion, syncope, palpitations
    • Family history of HCM or sudden cardiac death at an early age
    • Systolic heart murmur
• ECG: 
  • Abnormal in > 90% of cases
  • Left-axis deviation
  • P wave abnormalities (diphasic) consistent with left-atrial or biatrial enlargement
  • Pathological Q wave abnormalities in inferior (II, III, and aVF) and lateral leads (I, aVL, V5, V6)
  • Tall R waves in lateral leads with deep S waves in V1, V2:
    • Sum in millimeters (mm) of S wave in V1 and R wave in V5 totaling > 35 mm, indicative of left ventricular hypertrophy (LVH)
  • May or may not show QRS widening 
  • ST-T wave abnormalities in lateral leads, including horizontal or down-sloping ST-segment with T wave inversions
• Echocardiography with Doppler: 
  • Assessment for:
    • Cardiac size and structure
    • Systolic and diastolic function
    • Presence and severity of left ventricular outflow tract obstruction or mitral regurgitation 
  • Findings suggestive of HCM
    • Asymmetric thickening of the left ventricular wall
    • Variable wall thickening, most commonly seen in interventricular septum
  • Diagnostic criteria:
    • LVH with a maximum wall thickness > 15 mm in adults or a z-score > 3 in children
    • In case of positive family history of HCM or pathogenic sarcomere variant, LVH with a maximum wall thickness of > 13 mm supports diagnosis 
  • The majority of patients have normal left ventricular ejection fraction (LVEF).
• Exercise stress testing: 
  • Treadmill stress test preferred over pharmacological intervention → gives better idea of functional capacity and cardiovascular changes with physical activity
  • Should be performed in conjunction with echocardiography 
• Ambulatory monitoring (Holter monitor): 
  • Should be performed for 24–48 hours
  • Used to evaluate for atrial and ventricular arrhythmias
• Cardiac MRI with gadolinium: provides more advanced and reliable assessment of cardiac structure, anatomy, and function than echocardiography
• Coronary angiography and/or cardiac catheterization is reserved for patients in whom coronary artery disease needs to be ruled out.
• Genetic testing: only if familial HCM suspected

Management

Treatment

No pharmacological treatment is known to improve prognosis.

Goals of treatment:

• Reduce symptoms.
• Reduce left ventricular outflow tract obstruction.
• Control HR to ↑ filling time (with caution to avoid bradycardia)
• Maintain atrial contractions.
• Manage/correct any conduction disturbances.
• Avoid volume depletion.

Asymptomatic cases:

• Observed with routine follow up and surveillance (including repeat ECG and echocardiography) 
• Avoid strenuous exercise.

In setting of heart failure symptoms without left ventricular outflow tract obstruction:

• Beta-blockers (treatment of choice) or nondihydropyridine calcium-channel blockers (CCBs)
• Diuretics if signs or symptoms of fluid overload
• If severe symptoms persist and in case of reconfirmation of the absence of left ventricular outflow tract obstruction, a heart transplant may be needed.

In setting of heart failure symptoms and left ventricular outflow tract obstruction:

• Monotherapy with beta-blockers: 1st-line treatment
• Monotherapy with nondihydropyridine CCBs (i.e., verapamil) may be used if:
  • Beta-blockers are contraindicated or not tolerated
  • No signs or symptoms of hypotension, volume overload, or severe dyspnea 
• If monotherapy is not sufficient:
  • Addition of disopyramide (should not be used as monotherapy or in a setting of prolonged QT interval on ECG)
  • Combination therapy beta-blocker + nondihydropyridine CCBs
• Avoid
  • Diuretics and vasodilators such as dihydropyridine CCBs (i.e., amlodipine)
  • ACE inhibitors
  • Angiotensin II receptor blockers (ARBs)
• If limiting symptoms persist: 
  • Surgical septal myectomy (partial resection of the thickened septal wall)
  • Septal ablation with alcohol (ethanol) via cardiac catheterization (creates localized myocardial infarct resulting in cardiac remodeling)

Complications

• Concurrent atrial fibrillation: 
  • Beta-blockers, CCBs, or antiarrhythmic drug therapy 
  • Cardioversion as a last resort
  • Atrial fibrillation: thromboembolism prophylaxis with a blood thinner such as warfarin
  • Ventricular arrhythmias: Implantable cardioverter-defibrillator (ICD) should be considered.
• LV apical aneurysm: thromboembolism prophylaxis with a blood thinner such as warfarin

Prognosis

• Mortality between 1% and 4%
• Highest in young people
• Early diagnosis and intervention has decreased mortality.

Differential Diagnosis

• Hypertensive heart disease: long-standing, untreated, and uncontrolled high BP may cause left ventricular cardiac hypertrophy. Hypertensive heart disease is typically seen in adults who have had high BP for > 10 years and have signs of other end-organ damage. Diagnosis is made based on ECG and echocardiography. Left ventricular wall thickness rarely exceeds 15 mm in hypertensive disease. Treatment is with anti-hypertensive medications, weight loss, and sodium restriction. Gradual regression of LVH may occur over time with adequate treatment. 
• Aortic valve stenosis: may occur due to congenital valve abnormalities in younger patients or secondary to atherosclerotic narrowing of the valve later in life. Aortic valve stenosis is the most common cause of left ventricular outflow tract obstruction causing left ventricular wall hypertrophy. Signs and symptoms are similar to those in HCM. Echocardiography confirms the diagnosis, showing thickened and calcified aortic leaflets with a narrowed aortic orifice. Treatment is with medications commonly used in heart failure. In severe cases, valve-replacement surgery is recommended. 
• Fabry disease: an X-linked recessive glycolipid storage disease caused by a deficiency of the lysosomal enzyme, alpha-galactosidase A. Men are affected more than women. Fabry disease causes concentric (most common), eccentric, and asymmetric left ventricular hypertrophy, but left ventricular outflow tract obstruction is rare. Although ECG, echocardiography, and cardiac MRI are useful in evaluation, determination of leukocyte alpha-galactosidase A activity and genetic testing are needed for diagnosis. Treatment involves enzyme-replacement therapy in addition to pharmacological therapy for heart failure. 
• Athlete’s heart: non-pathological cardiac hypertrophy with left ventricular wall thickness up to 13–15 mm may also be seen in highly trained athletes. Intense strength training and endurance training can induce increases in left ventricular mass, symmetrical wall thickness, and cavity size. A thorough history including family history, and differentiating the presenting features using ECG, echocardiography, cardiac MRI, and stress testing help distinguish athlete’s heart from HCM. No treatment is required for athlete’s heart as it is a benign condition. 
• Restrictive cardiomyopathy: a condition that occurs secondary to scarring and/or infiltration of the heart muscle. Restrictive cardiomyopathy is characterized by a stiffening of the ventricles causing impaired relaxation and refilling of the heart, resulting in diastolic dysfunction and eventual heart failure. Patients typically present with signs and symptoms of heart failure. Diagnostic studies similar to those used for HCM help make the diagnosis. Treatment includes drug therapy and the use of implantable devices. A heart transplant may be needed in refractory cases. 
• Dilated cardiomyopathy (DCM): the most common type of non-ischemic cardiomyopathy. Dilated cardiomyopathy causes systolic heart failure. The etiology may be idiopathic, familial, or secondary to several underlying conditions. Dilated cardiomyopathy is characterized by the enlargement of 1 or both ventricles and reduced systolic function. Patients typically present with signs and symptoms of heart failure. Diagnostic studies similar to those used for HCM help make the diagnosis. Treatment includes drug therapy and the use of implantable devices. Dilated cardiomyopathy is the most common cause of cardiac transplantation.