Hypertrophic Cardiomyopathy

A 25-year-old man is brought into ED in cardiac arrest. The history from a bystander is that he collapsed suddenly whilst playing football. He has a history of exertional dyspnoea and his father died suddenly at age 30. An ECG shows left ventricular hypertrophy and widespread T-wave inversion.

Pathophysiology

Hypertrophic cardiomyopathy (HCM) is characterised by hypertrophy of the left ventricle, commonly with asymmetric septal hypertrophy greater than 15 mm. The interventricular septum thickens disproportionately, leading to a smaller left ventricular chamber volume. This reduces the heart's ability to fill during diastole, resulting in diastolic dysfunction, which reduces systolic output.

At the cellular level, concentric myocyte hypertrophy takes place (parallel duplication of sarcomeres), with myofibrillar disarray and interstitial fibrosis. Reduced myocardial perfusion results in predisposition to arrhythmias.

Additionally, the thickened septum can obstruct the left ventricular outflow tract (LVOT), particularly during systole - hypertrophic obstructive cardiomyopathy (HOCM). This increases the LV systolic pressure required for ejection, leading to prolonged ventricular relaxation and increased diastolic pressure, further exacerbating the reduction in cardiac output.

Obstruction occurs via multiple mechanisms:

• Systolic anterior motion of the mitral valve due to Venturi effect (accelerated flow through the LVOT creates negative pressure which pulls the valve inwards), or ejection against an elongated and distorted mitral valve.
• Muscular obstruction from the hypertrophied septum.

Obstruction is dynamic - i.e. various factors can impact the degree of obstruction:

• Physiological factors: increased LV contractility, reduced preload or reduced afterload
• Clinical factors: physical exercise, dehydration, Valsalva manoeuvre, pharmacological alteration to pre- or after-load (e.g. ACEi/ARB, diuretics, nitrates)

Aetiology

HCM is primarily a genetic disorder, often inherited in an autosomal dominant pattern. Mutations in genes encoding sarcomeric contractile proteins are the most common cause.  Over 70% of mutations are found in genes for β-myosin heavy chain, troponin T, and myosin-binding protein C. These mutations disrupt the normal structure and function of the heart muscle, leading to hypertrophy and fibrosis.

Epidemiology & Risk Factors

HCM is the most common genetic cardiovascular disease, affecting approximately 1 in 500 people. Because of its genetic nature, the most significant risk factor is a family history of HCM or sudden cardiac death. Other factors that may increase the risk of HCM include:

• Hypertension: Chronic high blood pressure can contribute to left ventricular hypertrophy, which can be a precursor to HCM in some cases.
• Aging: Although HCM can affect individuals of any age, it is more commonly diagnosed in young adults.
• Athletic training: While exercise is generally beneficial for heart health, intense athletic training can lead to physiological left ventricular hypertrophy that can be difficult to distinguish from HCM. Individuals with underlying genetic predispositions for HCM may experience more pronounced hypertrophy with intense training.

Clinical Features

HCM can have a wide range of clinical presentations. Many individuals with HCM remain asymptomatic, while others experience symptoms ranging from mild to severe. Common symptoms include:

• Dyspnoea, especially with exertion: This is often the initial symptom and is caused by diastolic dysfunction and/or LVOT obstruction.
• Angina: due to reduced perfusion to the hypertrophied myocardium.
• Syncope: This can be caused by arrhythmias, LVOT obstruction, or reduced cardiac output.
• Palpitations: These can be caused by atrial fibrillation or ventricular arrhythmias.
• Sudden cardiac death: This is the most feared complication of HCM and is most common in young individuals with a family history of sudden death.

Physical examination findings may include a jerky pulse, a double apical impulse, a fourth heart sound (S4), and a harsh ejection systolic murmur heard at the lower left sternal edge, often accompanied by a systolic thrill.

The murmur has the following defining characteristics:

• Increases with Valsalva, standing and inotropes (reduced preload)
• Decreased with hand grip, squatting or passive leg elevation (increased afterload)

Investigations

Echocardiography is the primary imaging modality for diagnosing and evaluating HCM. It allows for the assessment of:

• Wall thickness: Specifically looking for asymmetric septal hypertrophy (septal: posterior LV wall thickness >1.5:1).
• Systolic anterior motion (SAM) of the mitral valve: This occurs when the anterior leaflet of the mitral valve is pulled towards the thickened septum during systole, contributing to LVOT obstruction.
• LVOT pressure gradient: Measuring the pressure difference across the LVOT helps determine the severity of obstruction. A gradient greater than 30 mmHg at rest is considered significant.

Other investigations include:

• ECG:  abnormal in more than 95% of HCM cases and may show left ventricular hypertrophy by voltage criteria, widespread T-wave inversion of anterolateral leads, and pathological Q waves. The ECG pattern may precede hypertrophy.
• Cardiac MRI: a more detailed assessment of myocardial morphology, including the presence and extent of fibrosis. CMR has a sensitivity approaching 100% for anatomical diagnosis of HCM.
• Holter monitoring: This can be used to detect arrhythmias, particularly non-sustained ventricular tachycardia, which is a risk factor for sudden cardiac death.
• Exercise testing: This can help evaluate exercise tolerance and assess for provokable LVOT obstruction or arrhythmias. Blood pressure not increasing by more than 25 mmHg during exercise is a risk factor for sudden cardiac death.
• Genetic testing: Genetic testing can confirm a diagnosis of HCM in individuals with suspected disease and identify family members at risk.

Management

The management of HCM focuses on symptom relief, preventing complications, and improving quality of life.

Lifestyle Modifications

• Restriction of strenuous activity: Competitive athletes and individuals with significant LVOT obstruction or a high risk of sudden cardiac death should avoid high-intensity exercise.
• Adequate hydration: Maintaining proper hydration is important, especially during physical activity.
• Avoidance of dehydration: Dehydration can worsen LVOT obstruction and increase the risk of arrhythmias.

Medical Management

• Beta-blockers: such as metoprolol or atenolol, are first-line therapy for symptom management in HCM. They slow the heart rate and reduce myocardial contractility, improving diastolic filling and reducing LVOT obstruction.
• Calcium channel blockers: Non-dihydropyridines, such as verapamil, can be used as an alternative or in combination with beta-blockers to control heart rate and reduce LVOT obstruction.
• Antiarrhythmics: Medications like amiodarone may be used to control atrial fibrillation or treat ventricular arrhythmias.

Surgical Management

• Septal myectomy: This surgical procedure involves removing a portion of the thickened septum to reduce LVOT obstruction.
• Alcohol septal ablation: This less invasive procedure uses alcohol injection to destroy a small section of the septum, leading to scar tissue formation and reduced obstruction.
• Implantable cardioverter-defibrillator (ICD): An ICD is recommended for patients with HCM who have two or more risk factors for sudden cardiac death.

Complications & Prognosis

HCM can have various complications, including:

• Heart failure: As HCM progresses, diastolic dysfunction can worsen, leading to heart failure symptoms.
• Atrial fibrillation: The enlarged left atrium associated with HCM increases the risk of developing atrial fibrillation.
• Stroke: Atrial fibrillation can lead to blood clot formation in the left atrium, increasing the risk of stroke.
• Infective endocarditis: The abnormal blood flow within the left ventricle can increase the risk of infective endocarditis.
• Sudden cardiac death: This is the most serious complication and is primarily due to ventricular arrhythmias.

The prognosis for most individuals with HCM is good if detected early. Many people with HCM have a normal lifespan. However, some individuals experience progressive disease, leading to heart failure or life-threatening arrhythmias. The presence of risk factors for sudden cardiac death, such as family history, severe LVH, or NSVT, significantly increases the risk of mortality.