5th July 2026

Cardiomyopathy

Background

Cardiomyopathy describes distinct structural abnormalities in the heart muscle, causing various degrees of functional abnormalities where effective circulation is diminished. Cardiomyopathy is a broad term and can be divided into dilated (DCM), hypertrophic (HCM) – further divided into obstructive (⅔) and non-obstructive (⅓) – restrictive (RCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). It can be primary in nature and or secondary to pre-existing disease. Genetic cardiomyopathies tend to be autosomal dominant in nature.  Eventually, cardiomyopathy can result in heart failure. The varying subtypes of cardiomyopathy influence specific management, potential complications, and long-term prognosis. 

• ARVC is when the replacement of myocardial tissue with fibrofatty tissue in the right ventricle results in arrhythmias. 
• DCM is ​​left ventricular or biventricular dilation and impaired contraction, unexplained by abnormal loading conditions or coronary artery disease.
• HCM is when there is hypertrophy of the ventricles. When it becomes obstructive, it is known as HOCM.
• RCM is a functional classification where the occurrence of left ventricular myocardial stiffness results in adverse filling of the left ventricle.

Risk factors

• infections (including viral hepatitis and HIV)
• metabolic and endocrine conditions (including thyroid disease, diabetes and obesity)
• infiltrative diseases (including sarcoidosis and amyloidosis)
• myopathies (including Duchenne muscular dystrophy)
• cocaine use/amphetamines
• stress
• excess alcohol consumption
• radiation exposure
• chemotherapy
• family history of cardiomyopathy or heart conditions 

Arrhythmogenic cardiomyopathy

• Prevalence: 1 in 1,000 to 1 in 5,000 people.
• Age: It is most commonly diagnosed in adolescents and young adults, often presenting with arrhythmias or sudden cardiac death in athletes.
• Gender: male-to-female ratio of approximately 2:1.

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disease characterised by replacement of myocardial tissue with fatty or fibrofatty scar tissue. It predisposes affected individuals, typically young adults and athletes, to malignant ventricular arrhythmias and sudden cardiac death. Disease prevalence is estimated at 1 in 5000, and pattern of inheritance in the majority of ACM-affected families is autosomal dominant. Penetrance of the disease in genetic carriers is variable depending on age, sex and physical activity. Mutations to genes encoding proteins such as desmoplakin (DSP), plakophilin-2 (PKP2) and desmoglein-2 (DSG2) are implicated in ACM. This is usually inherited in an autosomal dominant pattern with variable penetrance. Rare cases can be autosomal recessive. ARVC most commonly affects genes encoding desmosomal proteins, crucial for cell adhesion and structural integrity of cardiac muscle cells. Without effective cell-cell-adhesion, the myocardium becomes susceptible to mechanical stress, leading to cell death and fibrofatty replacement. This fibrofatty replacement is characterised by the infiltration of fibrous tissue, which disrupts normal myocardial architecture and contributes to electrical instability. The structural irregularities result ultimately in re-entrant circuits and ventricular arrhythmias. 

ACM was originally described as a disease that favours the right ventricular (RV) myocardium, with only mild or no involvement of the left ventricle (LV). LV disease was once regarded as a result of disease progression associated with advanced RV disease. This led to the designation of the term ‘arrhythmogenic right ventricular cardiomyopathy (ARVC)’. In recent years, however, there has been increased recognition of biventricular and left dominant phenotyping variants owing to autopsy findings and emergence of tissue characterisation using contrast-enhanced cardiac magnetic resonance (CMR). As such, the generic term ACM is now preferred. 

Diagnosis and Diagnostic Criteria

Diagnostic Criteria

One of the most common underdiagnosed causes of sudden cardiac death in young people, ARVC is diagnosed with either two major criteria, one major and two minor criteria, or four minor criteria, summarised in Table 1 below.

Table 1. Diagnostic Criteria of AVRC, adapted from Escardio.org/Journals/E-journal-of-cardiology-practice/Volume-1/Arrhythmogenic-right-ventricualr-cardiomyopathy-Title-Arrhythmogenic-right-ve

The standard of reference for diagnosis of ARVC is the histologic demonstration of transmural fibrofatty replacement of the right ventricular myocardium at autopsy or surgery, with criteria of greater than 3% fat and less than 40% fibrous tissue replacing the myocardial muscle.

Signs and symptoms

• Palpitations and syncope: most frequently experienced symptoms in patients with ACM. These are often triggered by exercise, and related to ventricular arrhythmias which include premature ventricular complexes, sustained or non-sustained ventricular tachycardia (NSVT) and ventricular fibrillation.

• Sudden cardiac death (SCD) can be the first presenting feature in patients subsequently diagnosed with ACM. Over half of affected individuals (estimated at 60%) may be asymptomatic prior to mortality. 
• Progressive heart failure affecting the right, left or both ventricles, is also observed in some patients and is a common indication for heart transplant. 
• Angina, fatigue, and dyspnoea may also be reported.

Clinical examination may be normal, or signs that may be elicited include: 

• split S2
• S3 gallop during rapid ventricular phase of diastole, indicating ventricular dilatation
• S4

Investigations

Primary investigations for patients with ARVC include:

• Bloods: BNP elevation, FBC, U+Es, thyroid function, LFTs and troponin
• ECG: 
  • May have T wave inversion in leads V1-V3 suggests abnormal repolarisation in the right ventricle. 
  • Epsilon waves represent delayed depolarisation in the right ventricular outflow tract. They are characterised by small positive deflections at the end of QRS complexes in leads V1-V4 (figure 1). 
  • Ventricular ectopy and recurrent monomorphic VT with an LBBB pattern indicate abnormal ventricular electrical activity. 
  • Late potentials on a signal-averaged ECG reflect delayed conduction, all pointing to electrical instability in ARVC.
• Echocardiogram: may show a right ventricular dilatation or demonstrate aneurysmal projections from the right ventricular wall.

Other investigations to consider include:

• Ambulatory monitoring
  • Represents a major criterion in detecting frequent ventricular extrasystoles (>500) across 24 hours, non-sustained or sustained ventricular tachycardia of left bundle branch block morphology. 
• Cardiac MRI: 
  • On T1-weighted images, the right ventricular free wall often shows increased signal intensity due to the replacement of normal heart muscle with fatty or fibrous tissue. Thinning refers to the reduction in thickness of the right ventricular free wall, which can be a result of structural damage or atrophy. Akinesis may also be a result of this due to poor movement, and over time, this can be the predisposing cause of aneurysms, which can also be detected on MRI. In particular, ARVC may affect the triangle of dysplasia particularly, including the right ventricular outflow tract, the apex, and the inflow tract.
• Cardiac catheterisation
  • May show right ventricular enlargement or right ventricular wall motion abnormalities.
• Exercise stress testing
  • Might demonstrate any exercise-related ventricular tachyarrhythmias
• Endomyocardial biopsy
  • Used to detect fibro-fatty replacement of myocardium.

Management

General Management 

Patients diagnosed with ACM are advised against intense exercise or competitive sports to avoid triggering fatal arrhythmias and decelerate disease progression. Genetic counselling and testing may be offered to patients and their families to identify genetic mutations associated with ARVC and assess the risk of transmission to offspring. Annual ECG monitoring may aid in diagnosis, management and risk stratification.

Medical Management

• Beta-blockers are the recommended first-line pharmacological therapy in patients with ACM to reduce arrhythmia burden. 
• Antiarrhythmics such as sotalol (non-selective beta-blocker with class III antiarrhythmic properties) and mexiletine (class Ib antiarrhythmic) can be used to manage arrhythmia-related symptoms not controlled by conventional beta-blocker therapy alone. 
• Caution should be exercised when prescribing amiodarone to young patients with ACM due to its long-term adverse effects.
• For patients with ARVC with phenotypic LV dysfunction, HFrEF RCTs have suggested inclusion of ACEi/angiotensin receptor neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists (MRA), and sodium–glucose co-transporter 2 inhibitors (SGLT2i).

Surgical Management

• Catheter ablation can be considered in refractory cases or when appropriate ICD interventions for ventricular arrhythmia is recurrent despite pharmacological therapy.
• Implantable cardiac defibrillator (ICD) is implicated in the secondary prevention of sudden cardiac death in patients with ACM who have survived a cardiac arrest or recovered from a ventricular arrhythmia resulting in haemodynamic instability. High-risk features, including unexplained syncope, ventricular dysfunction and non-sustained VT, should be considered to inform individualised decision-making for primary prevention ICD implantation. 
• Left Ventricular Assist Devices (LVADs) may be considered in advanced cases of ARVC with biventricular dysfunction, advanced heart failure, or life-threatening arrhythmias, while awaiting heart transplantation or as destination therapy.
• Heart Transplantation is considered in end-stage ARVC patients with refractory heart failure, recurrent ventricular arrhythmias, or poor prognosis despite optimal medical and surgical management.

Complications

• Ventricular arrhythmias
  • ARVC is characterised by an increased risk of ventricular arrhythmias, including VT and VF, which may lead to syncope, cardiac arrest, or sudden cardiac death
• Heart failure
  • Progressive fibrofatty replacement of the right ventricular myocardium leads to right ventricular dysfunction and heart failure.
• Thromboembolism 
  • Right ventricular dysfunction and blood stasis may predispose individuals with ARVC to thrombus formation and subsequent thromboembolic events such as pulmonary embolism.
• Risk of sudden cardiac death
  • ARVC carries a significant risk of sudden cardiac death, often attributed to ventricular arrhythmias occurring in the setting of structural abnormalities and fibrofatty infiltration of the myocardium.

Dilated cardiomyopathy

• Prevalence: DCM affects approximately 1 in 250 to 1 in 500 adults globally. 
• Most common form of cardiomyopathy.
• Age: It can occur at any age, but is most commonly diagnosed in people between the ages of 20 and 60.
• Gender: It is more prevalent in men than in women.

Dilated cardiomyopathy (DCM) is characterised by the presence of left ventricular (LV) or biventricular dilatation and global systolic dysfunction (LVEF <50%) that cannot be solely determined by coronary artery disease or abnormal loading conditions. The prevalence of DCM is estimated to range from 1 in 2500 to 1 in 250 people, and disease onset is typically observed in the third or fourth decade of life. There is a predilection towards the male population, with a 3:1 ratio compared to females, and it is a leading cause for heart transplantation. 

Patients with DCM can present with signs of heart failure (shortness of breath, orthopnoea, paroxysmal nocturnal dyspnoea), arrhythmias (both atrial and ventricular), conduction blocks, or sudden cardiac death (SCD). These presentations are a late consequence of severe contractile dysfunction and biventricular remodelling that occur following a period of silent disease progression, where patients have been asymptomatic. To note, DCM patients with a genetic mutation to the lamin A/C protein, in particular, are predisposed to developing SCD from life-threatening ventricular arrhythmias regardless of the severity of LV dysfunction. This phenomenon highlights the importance of early disease detection through systematic genetic screening of a proband and their family members.

Aetiology

DCM encompasses a heterogeneous variety of genetic or acquired disorders that result in the same phenotype. They are not, however, mutually exclusive. The presence of environmental risk factors such as pregnancy, viral myocarditis or reported excessive alcohol intake can aggravate the expression of DCM in patients who carry a pathogenic gene variant. It is imperative to mention that the diagnosis of “idiopathic DCM” should only be established after ruling out acquired causes, as some causes may be reversible. A detailed list of acquired, non-genetic causes of DCM are described in Table 2.

Inherited causes 

Idiopathic or familial DCM account for approximately 30-40% of cases of DCM, with the most common pattern of inheritance being autosomal dominant. Nevertheless, the true prevalence of familial DCM may be underestimated due to variable clinical presentation and incomplete penetrance. A negative family history does not exclude a genetic form of DCM due to the presence of de novo mutations. The most commonly described genetic mutations involve genes that encode proteins of the cardiac myocyte, including titin, lamin A, filamin C, dystrophin and phospholamban.

Acquired causes

• Cardiovascular 
  • Chronic hypertension increases afterload, which can lead to left ventricular hypertrophy and subsequent dilation, impairing cardiac output. 
  • MI results in scar formation and remodelling, which can weaken the heart muscle and lead to dilation. 
  • Chronic ischaemia from CHD can cause myocardial damage and remodelling, leading to heart muscle weakening. This can also be the result of vasculitis.

• Infective
  • Viral causes include HIV, which can cause direct viral infection of the myocardium, result in opportunistic infections, or side effects of antiretroviral therapy. Myocarditis may also be a complication following coxsackievirus infection, leading to dilation. 
  • Common viral causes: HIV, adenovirus, parvovirus B19, herpes viruses, echovirus, enterovirus, SARS-CoV-2
  • Bacterial: Lyme disease
  • Mycobacterial
  • Parasitic: Chagas disease
  • Fungal
• Drug-related
  • Recreational drugs such as cocaine and methamphetamines, or toxins including cobalt, moreover, have direct toxic effects on the myocardium and can induce severe hypertension and vasospasm. 
  • Alcohol excess is toxic to the myocardium, leading to oxidative stress and cellular apoptosis and may result in deficiencies in essential nutrients like thiamine; these metabolic disturbances can lead to impaired myocardial energy production.
  • Anabolic steroids
  • Systemic anti-cancer treatment: doxorubicin, trastuzumab, and immune checkpoint inhibitors. Anthracyclines, CAR-T therapy
• Pregnancy
  • May occur during pregnancy or postpartum. 
• Endocrine
  • Hypo- and hyperthyroidism – high output cardiac failure, bradycardia, decreased cardiac contractility
  • Cushing/Addison disease
  • Phaeochromocytoma
  • Acromegaly
  • Diabetes Mellitus
• Systemic conditions
  • Giant cell myocarditis
  • Inflammatory (biopsy-proven, non-infectious myocarditis)
  • Eosinophilic granulomatosis with polyangiitis
  • Sarcoidosis
  • Systemic lupus erythematosus
  • Rheumatoid arthritis
  • Haemochromatosis
  • Sarcoidosis  
• Nutritional deficiencies
  • Thiamine deficiency (Beri-beri)
  • Zinc, copper and selenium deficiency 
  • Carnitine deficiency
• Electrolyte disturbances
  • Hypocalcaemia
  • Hypophosphatemia

Diagnosis

Signs and symptoms

Patients with DCM may present with symptoms of:

• cardiac failure: shortness of breath on exertion, orthopnoea, fatigue, paroxysmal nocturnal dyspnoea, abdominal discomfort, or leg swelling

Clinical signs that may be elicited on examination include: 

• bilateral basal crackles on lung auscultation
• hepatomegaly
• jugular venous distension
• peripheral oedema
• S3 gallop during rapid ventricular phase of diastole, indicating ventricular dilatation

Investigations

All patients with suspected DCM require a comprehensive diagnostic work-up to identify the aetiology and provide morphological and prognostic information. They include a detailed series of serological and genetic testing in addition to imaging modalities as described in Table 2. 

Table 2: List of investigations involved in the diagnostic workup of DCM. 

Management

General Management 

Generally speaking, patients with diagnosed DCM should restrict dietary intake of fluid (<1.5-2L fluid/day) and sodium (<5g/day). This is in addition to avoiding obvious precipitants such as alcohol and recreational drugs. Those with acquired causes of DCM require prompt treatment of the underlying metabolic, infective, endocrinological or electrolyte abnormality. 

High-intensity exercise, including competitive sport, is not recommended in symptomatic individuals, those with a left ventricular ejection fraction ≤40%, exercise-induced arrhythmias, or pathogenic variants in LMNA or TMEM43. 

Medical Management 

All patients with DCM should be treated according to established guidelines for the treatment of chronic heart failure. ACE inhibitors/angiotensin receptor blocker (ARB), angiotensin receptor-neprilysin inhibitor (ARNi), beta-blocker, mineralocorticoid receptor antagonist (MRA) and sodium-glucose co-transporter-2 (SGLT2) inhibitors are recommended to reduce hospitalisation and mortality. Moreover, loop diuretics provide symptomatic relief from fluid overload. 

Anticoagulation is advised in DCM patients with coexistent atrial fibrillation according to CHA2DS2-VA score to reduce thromboembolic risk. 

Patients with peripartum cardiomyopathy have a 50% chance of spontaneous recovery after delivery. However, they should be counselled regarding risk of potential recurrence even with recovery of LV function. Pregnancy is not advised in women with peripartum cardiomyopathy or DCM if LV function does not normalise. Beta-blockers and loop diuretics should be initiated carefully to the maximum tolerated dose while avoiding teratogenic agents (ACE inhibitors, ARB, ARNi, MRA) in this cohort of patients.

Surgical Management

• ICDs
  • Patients with DCM and a high risk of sudden cardiac death, as determined by clinical risk stratification including cardiac risk factors, high-risk genotypes (especially so in those with LVEF=<35%), LVEF =<35% or in cardiac arrest or VT with haemodynamic compromise, may undergo implantation of an ICD for primary or secondary prevention of ventricular arrhythmias. However, particularly in young patients, ICDs can have several complications and may require multiple replacements.
• Cardiac Resynchronisation Therapy (CRT)/Biventricular pacing
  • CRT/biventricular pacing may be indicated in DCM patients with evidence of electrical dys-synchrony (e.g., widened QRS complex) and symptomatic heart failure despite optimal medical therapy.
• Heart Transplantation
  • Heart transplantation is considered in end-stage DCM patients with refractory heart failure and poor prognosis despite optimal medical and surgical management. It offers the potential for long-term survival and improvement in quality of life.
• LVADs
  • LVADs may be used while awaiting heart transplantation in patients with advanced heart failure or used in patients unsuitable for heart transplantation.
• Surgical Ventricular Reconstruction (SVR)
  • In select patients with severe left ventricular dilation and dysfunction, SVR involves surgical removal of scarred or non-contractile myocardium, reshaping the left ventricle, and restoring ventricular geometry to improve cardiac function.

Complications

• Heart Failure
  • DCM is characterised by progressive dilation and systolic dysfunction of the ventricles, leading to heart failure symptoms.
• Ventricular Arrhythmias
  • DCM is associated with an increased risk of ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, which can lead to syncope, cardiac arrest, or sudden cardiac death.
• Thromboembolism
  • Stasis of blood within dilated ventricles can increase the risk of thrombus formation and subsequent thromboembolic events.

Restrictive cardiomyopathy

• Least common form of cardiomyopathy.
• Age: It can affect individuals of all ages, but is more commonly diagnosed in older adults.
• Gender: There is no significant gender predilection.

Restrictive cardiomyopathy (RCM) is a heterogeneous group of diseases typified by the presence of myocardial stiffness with diastolic dysfunction and raised filling pressures. This is often accompanied by atrial dilatation and non-dilated ventricles, irrespective of ventricular wall thickness and systolic function. These pathophysiological processes result in pulmonary hypertension, which can potentiate right heart failure. LV ejection fraction (LVEF) is typically preserved in RCM, but can deteriorate over time in the late stages of the disease. Compliance is reduced in RCM, which affects LV filling and stroke volume. Patients with autonomic dysfunction may experience hypotension during exercise as the ability to raise heart rate to improve cardiac output is impaired. Chronic diastolic dysfunction contributes to atrial remodelling and dilatation, resulting in atrial fibrillation (AF). 

Aetiology

RCM can be idiopathic or caused by mutations in genes related to sarcomeric proteins, but also infiltrative diseases, storage diseases, connective tissue disorders, hypereosinophilic syndrome and endomyocardial fibrosis. 

• Genetic
  • Primary RCM
• Drugs
  • Hydroxychloroquine
  • Ergotamine
  • Methysergide
• Systemic disease
  • Amyloidosis
  • Sarcoidosis
  • Friedrich’s ataxia
  • Haemochromatosis
  • Fabry’s disease
• Fibrosis
  • Radiation
  • Chemotherapy (e.g. anthracyclines)
  • Malignancy
  • Systemic sclerosis
  • Diabetes mellitus
  • Inflammatory/granulomatous
• Endomyocardial disease
  • Endomyocardial fibrosis
  • Carcinoid
  • Hypereosinophillia
  • Endocardial fibroelastosis
  • Endocardial neoplasms

Diagnosis

Signs and symptoms

Patients with RCM may be asymptomatic or present with symptoms of:

• angina
• cardiac failure: shortness of breath on exertion, orthopnoea, fatigue, paroxysmal nocturnal dyspnoea, abdominal discomfort, or leg swelling

Clinical signs that may be elicited on examination include: 

• bilateral basal crackles on lung auscultation
• hepatomegaly
• jugular venous distension
• peripheral oedema
• S3 gallop during rapid ventricular phase of diastole, indicating ventricular dilatation
• low pulse volume and faster pulse: in advanced phases

Other factors to consider in the history and examination include:

• Patients typically display signs and symptoms of heart failure with preserved ejection fraction (HFpEF)

• Carpal tunnel syndrome, lumbar spinal stenosis, aortic stenosis, skin bruising, proteinuria (cardiac amyloidosis)
• Erythema nodosum, lupus pernio (sarcoidosis)
• Bronze skin pigmentation, diabetes mellitus, arthralgia, chronic liver disease (haemochromatosis)
• Gait disturbance (Friedrich’s ataxia)
• Learning difficulties, visual impairment (Danon disease)
• Proteinuria, angiokeratoma, peripheral neuropathy (Anderson-Fabry disease)
• Three-generation family history 

Investigations

Table 3: Investigations for RCM

Management

Medical management 

• Broadly speaking, patients with symptomatic heart failure should be managed with loop diuretics for symptomatic relief and guideline-directed medical therapies (beta-blockers, ACEi/ARB/ARNi, MRA, SGLT2i). 
• However, caution should be exercised when using beta-blockers and ACEi/ARB/ARNi in patients with cardiac amyloidosis, as these drugs are poorly tolerated due to hypotension and autonomic dysfunction. Withdrawal of these drugs may help to improve symptoms. 
• All RCM patients with atrial fibrillation, in particular those with cardiac amyloidosis, should be started on oral anticoagulation irrespective of CHA2DS2-VA score due to a high risk of thromboembolism. 
• Disease-modifying treatment for specific RCM phenotypes are listed in Table 4. Patients with bradyarrhythmias may benefit from pacemaker implantation as per guidance from the European Society of Cardiology (ESC).

Table 4: Selected RCM phenotypes and their respective disease-modifying therapies.

Surgical management

• Heart Transplantation
  • Heart transplantation may be considered in end-stage RCM patients with refractory heart failure and poor prognosis despite optimal medical therapy. 
  • Pulmonary vascular resistance study can be used to guide the timing of transplantation.
• ICDs
  • In select cases of RCM associated with severe ventricular arrhythmias or high risk of sudden cardiac death, ICDs may be considered for primary or secondary prevention.
  • Indicated in patients with sarcoidosis when a ventricular arrhythmia is detected

Complications

• Heart Failure
  • RCM is characterised by impaired ventricular filling due to restrictive physiology, leading to heart failure symptoms.
• Atrial Arrhythmias
  • RCM is associated with an increased risk of atrial arrhythmias, including atrial fibrillation, which can further impair cardiac function and increase the risk of thromboembolic events.
• Thromboembolism
  • Atrial arrhythmias and impaired ventricular function increase the risk of thrombus formation within the atria or ventricles, leading to thromboembolic events.
• Conduction Abnormalities
  • Fibrosis and infiltration of the myocardium can disrupt normal conduction pathways, leading to conduction abnormalities such as atrioventricular block or bundle branch block.

Hypertrophic cardiomyopathy

• Genetic, autosomal dominant 
• Prevalence: HCM is estimated to affect about 1 in 500 people worldwide. It is the most genetically inherited cardiac disease and the most common cardiomyopathy.
• Age: It can occur at any age, but is most commonly diagnosed in people in adulthood.
• Gender: HCM affects men and women equally, although some studies suggest a slightly higher prevalence in men.

Hypertrophic cardiomyopathy (HCM) is defined by the presence of left ventricular hypertrophy (maximum left ventricular end diastolic wall thickness ≥15 mm on echocardiography) not explained exclusively by other cardiac, systemic or metabolic conditions that may mimic the degree of hypertrophy observed in a given patient. 

HCM is the most common inherited cardiac disease. It is primarily inherited in an autosomal dominant pattern. Mutations in genes encoding proteins of the cardiac sarcomere are the most common causes. The most common gene includes MYH7 (encoding the beta-myosin heavy chain), and other common genes include MYBPC3 (encoding cardiac myosin-binding protein C), TNNT2 (encoding cardiac troponin T), TNNI3 (encoding cardiac troponin I) and TPM1 (encoding alpha-tropomyosin). Non-sarcomeric genes are less common in causing HCM. The impaired sarcomeric function is responsible for inefficient contraction. In response, the myocardium hypertrophies to compensate. 

It is estimated that the prevalence of HCM in the general adult population worldwide is 1:500. Although the most common mode of genetic inheritance is autosomal dominant, it does not follow sex predilection. Furthermore, penetrance is incomplete and age-related. This implies that not every individual carrying a pathogenic variant will exhibit the disease; meanwhile, there is a great variability in age of onset and disease severity amongst symptomatic individuals.

Pathophysiology

The following mechanisms make up the pathophysiology of HCM: left ventricular outflow tract obstruction (LVOTO), mitral regurgitation, diastolic dysfunction, myocardial ischaemia and arrhythmia. 

Left ventricular outflow tract obstruction 

Left ventricular outflow tract obstruction (LVOTO), either present at rest or provoked during exertion, is demonstrated in approximately two-thirds of individuals with HCM. It is sensitive to ventricular preload, afterload and contractility; and can vary with volume status, level of activity, heart rate, blood pressure and medications. A peak LVOT gradient of greater than 30 mmHg is associated with an increased risk of death and progression to congestive heart failure. 

The pattern of hypertrophy in the left ventricle influences the likelihood of obstruction, the commonest being asymmetric left ventricular hypertrophy, where the basal interventricular septum is typically affected. Increase in septal wall thickness reduces the LVOT diameter and results in abnormal movement of the mitral valve leaflets. Systolic anterior motion (SAM) of the anterior mitral valve leaflets is frequently seen in HCM, the mechanism of which can be explained by the Venturi effect of the rapid flow within the narrowed LVOT, leading to the displacement of the distal anterior mitral valve leaflet towards the septum, resulting in subaortic obstruction. Premature aortic valve closure is also implicated in LVOTO due to abnormal valve apparatus with leaflet slack.

Mitral regurgitation

Mitral regurgitation (MR) occurs secondarily due to SAM or primarily from structural abnormalities of the mitral valve, which can enhance symptom burden. MR caused by SAM is a consequence of compromised leaflet coaptation, and the resulting jet is mid-to-late systolic in timing and posterior or lateral in orientation. Common structural abnormalities of the mitral valve can include excessive leaflet length, anomalous papillary muscle insertion, and anteriorly displaced papillary muscles.

Diastolic dysfunction and autonomic dysfunction

This occurs due to delayed inactivation from abnormal intracellular calcium reuptake, reduced LV compliance due to hypertrophy and fibrosis, and altered ventricular load. LV hypertrophy and stiffness impair compliance, which leads to restricted diastolic filling and decreased stroke volume. Exercise capacity is limited as a result. 

Patients with HCM may also experience autonomic dysfunction, with blunted heart rate recovery and inappropriate vasodilatation. Approximately 25% of patients have an abnormal blood pressure (BP) response to exercise, i.e. systolic BP fails to increase by ≥20 mmHg or demonstrates a paradoxical reduction of >20 mmHg from the peak value. 

Myocardial ischaemia

Several factors contribute to the development of myocardial ischaemia in patients with HCM. Myocardial hypertrophy, microvascular dysfunction with impaired coronary flow reserve, and medial hypertrophy and reduced density of the intramural arterioles are frequently observed in patients with HCM. These are potentiated by LVOTO and hyperdynamic systolic function. LV aneurysm is a negative consequence of apical myocardial ischaemia, which leads to an increased risk of heart failure and ventricular arrhythmias.  

Arrhythmia

Ventricular arrhythmias can be exacerbated by myocardial ischaemia resulting from compromised coronary flow reserve and LVOTO. Non-sustained ventricular tachycardia (NSVT) in particular occurs in approximately 23% of patients. Patients with HCM are also susceptible to developing atrial fibrillation (AF) owing to diastolic dysfunction and LV flow obstruction. Raised filling pressures, MR and LVOTO are features of HCM which result in adverse LA remodelling and dilatation, thus increasing the likelihood of developing AF. Atrial fibrosis caused by microvascular dysfunction and atrial ischaemia is also a substrate for AF.  AF not only increases the risk of thromboembolism, but it also has deleterious effects on cardiac function and overall mortality.

Diagnosis

• History and physical examination Patients may describe chest pain, dyspnoea, palpitations, and/or syncope, in relation to exercise or dehydration. 
• A three-generation family history is important to identify family members with HCM or who have experienced a sudden, unexpected death.
• Physical examination may reveal a jerky carotid pulse, and a harsh ejection systolic murmur is heard loudest at the left sternal edge in patients with associated LVOTO. The intensity of the murmur increases with manoeuvres that reduce preload, such as the Valsalva manoeuvre and standing from the squatting position. By contrast, those without LVOTO may have a normal physical examination. 
• Clinical signs: 
  • systolic ejection murmur may be noted with a crescendo-decrescendo pattern at the apex, during the Valsalva manoeuvre or when standing from a squatting position
  • left sternal border pansystolic murmur of mitral regurgitation at the apex
  • S4 gallop may be noted or a jugular venous pulse with a prominent ‘a’ wave

Investigations

Genetic Testing

• Genetic testing: where wall thickness of ≥15mm in one or more left ventricular myocardial segments is present, unexplained by loading conditions, in a patient whose age of onset is less than 60. Otherwise, unexplained increased LV wall thickness of ≥13mm in one or more LV myocardial segments in those patients with a first-degree relative with unequivocal disease (ideally with LV hypertrophy of ≥15 mm).

• Genetic testing may not be appropriate for adults with wall thickness ≥15 mm not solely explained by loading conditions, especially if clinical and imaging features (e.g., asymmetric hypertrophy, specific wall thickness ratios) provide a clear diagnosis. It also may not be appropriate in cases with characteristic apical hypertrophy that does not meet the full criteria for apical HCM (apical hypertrophic cardiomyopathy diagnostic wall thickness cut-off of ≥15mm, with spade‐like configuration and apical obliteration).

Management

General Management 

• Avoid dehydration, excessive alcohol consumption and exposure to drastic weather conditions (humidity, heat). 
• Weight loss and regular low- to moderate-intensity exercise are advisable in all individuals with cardiomyopathy. 
• High-intensity exercise and competitive sports are not recommended in high-risk individuals and in individuals with LVOTO and exercise-induced ventricular arrhythmia. 
• Cardiopulmonary exercise testing should be performed every 2-3 years in stable patients, or sooner in those with progressive symptoms.

Medical Management 

• Beta-blockers or non-dihydropyridine calcium channel blockers are first-line therapies to improve diastolic filling and reduce outflow tract gradient. 
• Disopyramide, a class Ia antiarrhythmic agent, can be added in HCM patients with refractory LVOTO symptoms. 
• Mavacamten, a novel cardiac myosin ATPase inhibitor, has also demonstrated an improvement in LVOT gradient and exercise performance in patients with LVOTO in a recent phase III, double-blind, placebo-controlled trial. 
• HCM patients with LV systolic dysfunction should be started on guideline-directed medical therapy for HF. 
  • It is recommended that diuretics are started cautiously in patients with LVOTO to avoid exacerbating symptoms. 
• Amiodarone can be used to suppress atrial and ventricular arrhythmias in HCM patients refractory to beta-blockers. 
• All HCM patients with atrial fibrillation must be started on oral anticoagulants irrespective of CHA₂DS₂-VA to reduce thromboembolic risk.

Surgical Management 

• Device therapy
  • Implantable cardiac defibrillator (ICD) is recommended in HCM patients who have survived a cardiac arrest due to a ventricular arrhythmia, or who have sustained VT resulting in haemodynamic compromise. 
  • The HCM Risk-SCD calculator should be utilised as a tool to risk-stratify HCM patients over the age of 16 years for sudden cardiac death (SCD) at 5 years. It encompasses family history of SCD, NSVT, age, history of unexplained syncope, LVOT gradient, LV wall thickness and LA diameter.  
  • Primary prevention ICD is indicated in patients with a risk score ≥6% with life expectancy over one year and should be considered on an individual basis if 4-6%. 
  • Cardiac resynchronisation therapy (CRT) can be assessed in individuals with persistent LV dysfunction with left bundle branch block and QRS interval ≥130ms. 
• Surgery
  • Surgical myomectomy ought to be considered in patients with obstructive symptoms refractory to medical therapy and is performed in combination with mitral valve repair. 
  • Alcohol septal ablation is an alternative to surgical myomectomy to reduce LVOT gradient. 
  • Cardiac transplantation is only considered in eligible patients with NYHA class III-IV symptoms or ventricular arrhythmias refractory to medical and device therapy.

Complications

• Arrhythmias and SCD
  • HCM is associated with an increased risk of ventricular arrhythmias, which can lead to syncope, cardiac arrest, or sudden cardiac death, particularly in young individuals, athletes, or those with a family history of SCD. 
  • Following septal myectomy, likely due to atrial remodelling and changes in haemodynamics following the reduction of LVOT obstruction, atrial fibrillation can be a common complication.
• Heart Failure
  • Severe left ventricular hypertrophy, diastolic dysfunction, and outflow tract obstruction can lead to heart failure symptoms.
• Mitral Valve Abnormalities
  • Mitral valve abnormalities, including mitral regurgitation and systolic anterior motion of the mitral valve, can contribute to heart failure symptoms and increase the risk of arrhythmias.
• Endocarditis
  • HCM is associated with structural abnormalities such as hypertrophied myocardium and altered blood flow dynamics, particularly in the left ventricular outflow tract. These structural changes create areas of turbulence and endothelial injury, which can facilitate bacterial colonisation and increase the risk of endocarditis. 
  • Endocarditis in HCM can lead to severe complications such as worsening heart failure, arrhythmias, systemic embolisation (e.g., stroke), and even death.

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