1. Hypertrophic Cardiomyopathy

1.1 Overview and Definition

• Cardiomyopathies are diseases of the heart muscle (myocardium) not explained by coronary artery disease, hypertension, valvular disease, or congenital heart disease.
• Hypertrophic Cardiomyopathy (HCM) is characterised by abnormal hypertrophy of the ventricular myocardium, typically the left ventricle (LV), with no apparent systemic or haemodynamic cause (e.g., longstanding hypertension, valvular stenosis).

1.2 Epidemiology and Aetiology

• Prevalence: ~1 in 500 adults; often presents in adolescence or early adulthood.
• Autosomal dominant inheritance with incomplete penetrance (some gene carriers are phenotypically unaffected) and variable expression (clinical manifestations differ despite the same genetic mutation).
• Genetic mutations (hundreds identified) most commonly affect sarcomeric proteins (e.g., myosin, actin, troponin).

1.3 Pathogenesis

1. Microscopic Changes
   • Myocyte disarray (chaotic arrangement of cardiac fibres)
   • Fibrosis of intramural coronary arteries (narrowing)
   • Extracellular fibrosis replacing normal structure
2. Macroscopic (Gross) Changes
   • Asymmetric septal hypertrophy is most common (septum > free LV wall), though concentric patterns occur occasionally.
   • Right ventricular (RV) involvement is possible but less common and usually does not occur in isolation.
3. Functional Consequences
   • Diastolic dysfunction (stiff, hypertrophied ventricle impairs filling)
   • Possible left ventricular outflow tract (LVOT) obstruction, especially if the septum is significantly hypertrophied and the mitral valve is pulled or “sucked” into the outflow tract (systolic anterior motion of the mitral valve).

1.4 Clinical Features

1. Symptomatology
   • Chest pain due to increased oxygen demand of hypertrophied myocardium and narrowed intramural arteries.
   • Exertional dyspnoea, palpitations (arrhythmias), syncope (often linked to arrhythmias or obstructive physiology).
   • Sudden cardiac death in severe cases, often in young athletes, due to lethal ventricular arrhythmias.
2. Physical Examination
   • May be asymptomatic (found incidentally on ECG or echocardiography).
   • An ejection systolic murmur if LVOT obstruction is present, often best heard at the left sternal edge.
   • A jerky or rapidly rising carotid pulse (in obstructive forms).
   • S4 heart sound (atrial contraction into a stiff ventricle) is sometimes noted.
3. Other Key Points
   • Diastolic dysfunction is frequent; about 10% progress to LV systolic impairment over time.
   • Syncope with exercise may also reflect subaortic hypertrophy, producing a functional obstruction similar to aortic stenosis.

1.5 Diagnostic Approach

1. Electrocardiogram (ECG)
   • Often shows LV hypertrophy, possible left axis deviation, and repolarisation abnormalities (e.g., T-wave inversions).
   • Can precede echocardiographic changes in some individuals.
2. Echocardiography (Key Investigation)
   • Confirms ventricular hypertrophy (wall thickness >15 mm is diagnostic for HCM in the absence of other causes).
   • Identifies asymmetric septal thickening and potential systolic anterior motion of the mitral valve.
   • Doppler assessment of LVOT gradient (if present).
3. Cardiac Magnetic Resonance Imaging (MRI)
   • Useful for detecting early disease, clarifying ventricular anatomy, and assessing fibrosis.
4. Family Screening
   • First-degree relatives should undergo clinical evaluation, ECG, echocardiogram, and, if available, genetic testing for known mutations.
   • Periodic screening is advised, especially for children who may manifest the condition later.

1.6 Risk of Sudden Cardiac Death

• HCM is a well-known cause of sudden cardiac death in adolescents and young adults, often triggered by ventricular arrhythmias.
• Major risk factors (assessed regularly) include (see also table below):
  1. Family history of sudden cardiac death
  2. Unexplained syncope
  3. Non-sustained ventricular tachycardia on 24-hour ECG
  4. Severe septal hypertrophy (wall thickness >30 mm)
  5. Abnormal blood pressure response to exercise

Note: Patients with multiple risk factors are more likely to benefit from implantable cardioverter defibrillator (ICD)placement.

1.7 Management

1. Lifestyle and Activity
   • Avoid competitive or high-intensity sports that can trigger arrhythmias or exacerbate outflow obstruction.
2. Pharmacological Therapy
   • Beta-blockers (e.g., bisoprolol, propranolol)
     • Reduce heart rate, improve diastolic filling, suppress supraventricular arrhythmias, and reduce outflow tract gradient.
   • Verapamil (if beta-blockers are contraindicated or insufficient).
   • Disopyramide may be added for persistent outflow obstruction and symptoms.
   • Anticoagulation (e.g., warfarin) if atrial fibrillation develops.
3. Invasive Procedures
   • Septal myomectomy: Surgical removal of hypertrophied septal myocardium if outflow obstruction persists despite medical therapy.
   • Alcohol septal ablation: A less invasive alternative to myomectomy using targeted infarction of the septum via a coronary branch.
4. Implantable Cardioverter Defibrillator (ICD)
   • No intervention except ICD placement has been shown to prolong life.
   • ICD is recommended in patients with high-risk features (multiple risk factors for sudden death).

1.8 Prognosis

• ICD placement can be life-saving in selected high-risk individuals.
• Overall prognosis is relatively good if diagnosed early and risk-stratified properly.
• Sudden cardiac death risk peaks in adolescents and young adults; careful monitoring of risk factors is crucial.
• With appropriate lifestyle modifications, medical therapy, and occasional surgical intervention, most patients lead active lives.

2. Dilated Cardiomyopathy (DCM)

2.1 Overview and Definition

• Dilated cardiomyopathy is characterised by:
  • Impaired ventricular function (systolic dysfunction)
  • Ventricular chamber dilatation
  • Normal or reduced ventricular wall thickness
  • Absence of a secondary cause (i.e., no significant coronary artery disease, hypertension, valvular disease, or congenital anomaly to explain the dysfunction)

2.2 Types and Aetiology

• Idiopathic DCM is common, with about one-third having a familial (genetic) basis.
• Familial DCM:
  • ~90% inherited in an autosomal dominant manner (e.g., lamin A/C, SCN5A mutations).
  • ~5% are X-linked (e.g., Duchenne’s and Becker’s muscular dystrophy).
• Other causes (see table below) include alcohol excess, drug toxicity (e.g., anthracyclines), endocrine disorders, infection, and post-partum cardiomyopathy.

2.3 Epidemiology

• True incidence of familial DCM is not well defined but estimated at ~0.05% in the general population.
• Most commonly presents in middle age, although it is the leading cause of heart failure in younger adults.
• Alcohol-related DCM is increasingly observed in younger adults; complete abstinence can lead to potential functional recovery.

2.4 Pathophysiology and Pathology

• Ventricular dilatation and global systolic dysfunction (ventricles cannot pump effectively).
• This leads to biventricular heart failure with resultant reduced ejection fraction.
• Secondary effects include mitral and tricuspid regurgitation (due to annular dilation) and arrhythmias.

2.5 Clinical Features

1. Symptoms
   • Heart failure symptoms: breathlessness, reduced exercise tolerance, orthopnoea, paroxysmal nocturnal dyspnoea.
   • Fatigue, chest pain (non-specific).
   • Peripheral oedema, ascites, or congestion if right-sided function is severely affected.
2. Signs
   • Laterally displaced apex beat (due to enlarged heart).
   • Third or fourth heart sounds (S3, S4) from volume/pressure overload.
   • Pansystolic murmur if there is functional mitral or tricuspid regurgitation.

2.6 Diagnostic Approach

1. Chest X-Ray
   • Enlarged cardiac silhouette, consistent with dilatation.
2. Echocardiography
   • Confirm and quantify ventricular dilation and systolic impairment.
   • Assess severity of any valvular regurgitation (particularly mitral/tricuspid).
3. ECG
   • May be normal or show bundle branch blocks, conduction delays, or arrhythmias.
   • Ambulatory ECG helps detect ventricular or supraventricular arrhythmias.
4. Cardiac MRI
   • Useful in differential diagnosis (e.g., distinguishing DCM from other forms of cardiomyopathy or myocarditis).
5. Genetic/Familial Evaluation
   • If idiopathic and suspicion of familial disease, evaluate first-degree relatives (ECG, echo, possibly genetic testing).

2.7 Management

1. Pharmacological Therapy
   • Standard heart failure treatments:
     • Diuretics (e.g., loop diuretics) for fluid overload.
     • ACE inhibitors (or ARBs) to reduce afterload and slow disease progression.
     • Beta-blockers to improve survival, reduce arrhythmic risk, and slow remodelling.
     • Mineralocorticoid receptor antagonists (e.g., spironolactone) if indicated.
   • Alcohol abstinence if alcohol-induced DCM.
2. Device Therapy
   • Pacemaker implantation in cases of significant conduction disorders.
   • Cardiac Resynchronisation Therapy (CRT) if there is dyssynchrony (typically LBBB) and reduced ejection fraction, following guidelines for systolic heart failure.
   • Implantable Cardioverter Defibrillator (ICD) for primary or secondary prevention of sudden cardiac death (often combined with CRT in a CRT-D device).
3. Other Considerations
   • Arrhythmia management: Specific antiarrhythmics or ablation if indicated.
   • Cardiac transplantation in refractory end-stage disease.

2.8 Prognosis

• Variable; depends on aetiology, degree of LV dysfunction, and response to therapy.
• Natural history often involves progressive heart failure with periods of stability interspersed with decompensations.
• Early and appropriate medical treatment improves quality of life and prolongs survival.

2.9 Family Screening

• Periodic re-evaluation may be needed in younger relatives who could develop clinical features later.
• First-degree relatives of patients with apparently idiopathic DCM should undergo assessment, especially if there is a positive family history of early heart failure or sudden cardiac death.

3.1 Definition

• Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited myocardial disorder primarily affecting the right ventricle (RV).
• Characterised by fibro-fatty replacement of right ventricular myocardium, myocyte loss, and a propensity to ventricular arrhythmias, heart failure, and sudden cardiac death.

3.2 Epidemiology and Aetiology

• Estimated prevalence: ~1 in 5000 people.
• Genetic Basis:
  • Mutations in desmosomal genes such as desmoplakin (DSP), desmoglein-2 (DSG2).
  • Inheritance patterns vary; often autosomal dominant with incomplete penetrance.

3.3 Pathophysiology

• Fibro-fatty infiltration of the RV myocardium → loss of normal myocytes.
• The weakened or thinned RV wall predisposes to ventricular arrhythmias, systolic dysfunction, and heart failure.
• Arrhythmias often originate from the RV and can be life-threatening (ventricular tachycardia or fibrillation).

3.4 Clinical Features

1. Arrhythmias
   • Ventricular tachycardia (often with left bundle branch block morphology on ECG)
   • Palpitations, possible presyncope or syncope
2. Heart Failure
   • Primarily right-sided dysfunction, leading to peripheral oedema, raised jugular venous pressure.
   • Left ventricular involvement can occur in advanced disease.
3. Sudden Cardiac Death
   • Occurs in younger individuals, especially during exercise or physical stress.

3.5 Diagnostic Approach

1. Clinical Assessment and Family History
   • Clues: young patient with syncope, palpitations, family history of sudden cardiac death or known ARVC.
2. Echocardiography
   • May show right ventricular dilation, wall motion abnormalities, or reduced RV function.
3. Cardiac MRI
   • Key investigation: detects fibro-fatty infiltration and detailed structural changes of the RV.
   • More sensitive for RV pathology than echo alone.
4. ECG
   • Ventricular arrhythmias with QRS complexes indicative of RV origin (often LBBB pattern).
   • T-wave inversions in V1–V3 or epsilon waves can be seen.
5. Cardiac Biopsy (Occasionally)
   • Histological confirmation of fibro-fatty replacement of myocytes.
6. International Criteria (e.g., Task Force Criteria)
   • Combine historical, structural, histological, and electrophysiological findings (e.g., family history, imaging findings, tissue changes, arrhythmias).

3.6 Management

1. Pharmacological Therapy
   • Heart failure treatments if RV dysfunction is prominent (diuretics, ACE inhibitors).
   • Antiarrhythmics (e.g., beta-blockers, amiodarone) to suppress atrial and ventricular arrhythmias.
2. Implantable Cardioverter Defibrillator (ICD)
   • Indicated in high-risk patients (e.g., documented ventricular tachycardia, previous cardiac arrest, strong family history of sudden death).
   • Can be life-saving by terminating lethal arrhythmias.
3. Lifestyle Modifications
   • Avoid high-intensity exercise, which can exacerbate arrhythmias or disease progression.
   • Family screening and genetic counselling where applicable.

3.7 Prognosis

• Ongoing surveillance and management of arrhythmias and heart failure are critical for optimal outcomes.
• Variable course: Some remain stable for years, while others experience progressive RV dysfunction, severe arrhythmias, or sudden death.
• ICD placement significantly reduces the risk of sudden cardiac death in high-risk individuals.

4. Other Cardiomyopathies

4.1 Restrictive Cardiomyopathy

4.1.1 Definition and Key Features

• Restrictive cardiomyopathy (RCM) is characterised by increased stiffness of the myocardium and endocardial fibrosis, resulting in impaired diastolic filling despite often normal or reduced ventricular cavity size.

4.1.2 Aetiology

• Idiopathic in some cases.
• Associated conditions include:
  • Storage disorders: e.g., haemochromatosis, Fabry’s disease
  • Infiltrative disease: e.g., amyloidosis, sarcoidosis, scleroderma, carcinoid
  • Endomyocardial fibrosis: e.g., Loeffler syndrome (with eosinophilia)
  • Endocardial fibroelastosis (mainly in children)

4.1.3 Pathophysiology

• Stiff, fibrotic myocardium → small changes in volume cause large increases in ventricular pressure.
• Leads to significant diastolic dysfunction but often preserved systolic function until late in the disease.

4.1.4 Clinical Presentation

• Symptoms predominantly of congestive heart failure: exertional dyspnoea, oedema, raised jugular venous pressure.
• Arrhythmias may occur, exacerbating heart failure.

4.1.5 Investigations

• ECG: Can show low voltage QRS, conduction disturbances.
• Echocardiography: Reveals diastolic dysfunction, normal or thickened myocardium.
• Cardiac catheterisation: Characteristic haemodynamic findings of restrictive physiology (steep diastolic pressure rise).
• MRI: May help identify infiltrates (e.g., amyloid).

4.1.6 Management

• Symptomatic treatment of heart failure (diuretics, etc.).
• Arrhythmia control (e.g., beta-blockers, amiodarone).
• Aetiology-specific therapy:
  • For example, iron chelation in haemochromatosis, immunomodulatory treatment in sarcoidosis (if significant inflammatory activity), etc.

4.1.7 Prognosis

• Often poor unless the underlying cause can be arrested or reversed (e.g., controlling haemochromatosis).
• Progressive diastolic dysfunction commonly leads to intractable heart failure.

4.2 Takotsubo Cardiomyopathy

4.2.1 Definition

• Takotsubo cardiomyopathy (stress-induced cardiomyopathy or broken heart syndrome) involves transientsystolic dysfunction of the left ventricle, typically apical ballooning with normal coronary arteries.

4.2.2 Aetiology and Triggers

• Often triggered by acute physical or emotional stress (e.g., bereavement, severe pain, intense fear).
• Exact pathophysiology is not fully understood, but it is thought to involve catecholamine surges.

4.2.3 Clinical Presentation

• Presents mimicking acute myocardial infarction:
  • Chest pain, shortness of breath.
  • ECG changes (ST elevations/T-wave inversions) suggestive of ischaemia.
  • Elevated cardiac enzymes possible, but less than typically found in full-thickness myocardial infarction.

4.2.4 Diagnosis

• Coronary angiography: Normal coronary arteries with absence of significant obstructive disease.
• Ventriculogram or echocardiogram: Shows apical ballooning (dyskinesis) and often hypercontractile basal segments, giving a characteristic “takotsubo” appearance.

4.2.5 Management

• Supportive treatment:
  • Standard heart failure therapies (e.g., beta-blockers, ACE inhibitors, diuretics) if reduced ejection fraction is present.
  • Monitoring for arrhythmias or complications.
• Recovery typically occurs over days to weeks; up to 10% recurrence reported.

4.2.6 Prognosis

• More common in women and may recur in a minority.
• Generally good; most patients recover fully with appropriate care.

5. Inherited Arrhythmias

5.1 Overview and Definition

• Inherited arrhythmias are a group of genetic disorders affecting the heart’s electrical system, leading to abnormal heart rhythms.
• They are caused by mutations in ion channel genes, which disrupt the normal flow of ions across cardiac cell membranes.
• These arrhythmias can present with symptoms such as syncope (fainting), dizziness, palpitations, and are significant due to their association with sudden cardiac death.

5.2 Types of Inherited Arrhythmias

5.2.1 Brugada’s Syndrome

5.2.1.1 Definition and Key Features

• Brugada’s syndrome is an inherited channelopathy that can lead to sudden cardiac death, particularly in younger individuals.
• It is often asymptomatic and may be discovered incidentally or through family screening.

5.2.1.2 Aetiology

• Autosomal dominant inheritance pattern.
• Genetic mutations: Up to 20% of cases involve mutations in the SCN5A gene, which encodes the sodium channel.

5.2.1.3 Clinical Features

• Asymptomatic in many patients.
• May present with palpitations or syncope.
• Sudden cardiac death is a rare but serious manifestation.
• Family history of Brugada’s syndrome or sudden cardiac death is common.

5.2.1.4 Diagnostic Approach

• Electrocardiogram (ECG): Characteristic findings include ST elevation in leads V1-V3 with a right bundle branch block pattern.
• Confirmation requires the presence of the ECG pattern plus another feature such as:
  • Documented polymorphic ventricular tachycardia or fibrillation.
  • Family history of sudden cardiac death.
  • Inducible ventricular tachycardia during electrophysiological studies.
  • Family members with Brugada’s type ECGs or syncope.
• Referral to a cardiologist for comprehensive assessment is essential.

5.2.1.5 Management

• Implantable Cardioverter Defibrillator (ICD): The only effective treatment to prevent sudden cardiac death, particularly in high-risk individuals (e.g., those with documented ventricular arrhythmias or previous cardiac arrest).
• Lifestyle Modifications:
  • Avoidance of drugs that can induce Brugada’s syndrome (e.g., certain antiarrhythmics, psychotropic, and anaesthetic agents). A comprehensive list of contraindicated drugs should be provided to patients.
• Family Screening:
  • First-degree relatives should undergo screening, including ECG and clinical evaluation.
  • Genetic testing may be considered if a mutation is identified in the proband.

5.2.2 Long QT Syndrome (LQTS)

5.2.2.1 Definition and Key Features

• Long QT syndrome (LQTS) is a disorder of myocardial ion channels leading to prolonged ventricular repolarisation, increasing the risk of torsades de pointes and sudden cardiac death.
• Can be congenital or acquired.

5.2.2.2 Types and Aetiology

• Congenital LQTS has several subtypes, with types 1-3 being the most common:
  • Type 1:
    • Accounts for one third of cases.
    • Mutation in the KCNQ1 gene (slow potassium rectifier channel).
    • Inheritance: Autosomal dominant or recessive.
    • Triggers: Exercise, particularly swimming.
  • Type 2:
    • Accounts for one quarter of cases.
    • Mutation in the KCNH2 gene (rapid delayed potassium rectifier channel).
    • Triggers: Auditory stimuli or emotional stress.
  • Type 3:
    • Mutation in the SCN5A gene (sodium channel).
    • Inheritance: Autosomal dominant.
    • Triggers: Events most commonly occur during sleep (‘dead-in-bed syndrome’).
• Other Types (4-10): Much less common, each associated with specific genetic mutations.
• Acquired LQTS:
  • Caused by medications (e.g., certain antiarrhythmics, antibiotics, antipsychotics).
  • Electrolyte imbalances (e.g., hypokalaemia, hypomagnesaemia).

5.2.2.3 Clinical Features

• Often asymptomatic, but can present with:
  • Syncope
  • Palpitations
  • Sudden cardiac death
• Triggers vary by subtype:
  • Type 1: Exercise, especially swimming.
  • Type 2: Loud noises, emotional stress.
  • Type 3: Occur during sleep.

5.2.2.4 Diagnostic Approach

• Electrocardiogram (ECG): Prolonged corrected QT interval (QTc).
• Additional Tests:
  • Exercise ECG or signal-averaged ECG.
  • Holter monitor for QT interval assessment.
  • Adrenaline challenge in selected cases.
• Family Screening:
  • Immediate family members should be screened using ECG and, if necessary, genetic testing.
• Differential Diagnosis:
  • Conditions like epilepsy may present similarly; Schwartz’s criteria can aid in diagnosis.
• Referral to a specialised cardiologist is often necessary for confirmation and management.

5.2.2.5 Management

• Lifestyle Modifications:
  • Avoid competitive sports, especially in high-risk subtypes.
  • Avoid loud noises (Type 2).
  • Avoid QT-prolonging drugs.
• Pharmacological Therapy:
  • Beta-blockers: First-line treatment to reduce the risk of arrhythmias.
  • Implantable Cardioverter Defibrillator (ICD):
    • Indicated for patients with recurrent syncope, documented ventricular tachycardia, or those who have survived a cardiac arrest.
• Genetic Counselling:
  • Essential for affected families to understand inheritance patterns and risks.

5.2.2.6 Prognosis

• Variable depending on subtype and adherence to management strategies.
• Good prognosis with appropriate treatment and lifestyle modifications.
• Risk of sudden cardiac death can be significantly reduced with ICD placement in high-risk individuals.

5.3 Summary of Inherited Arrhythmias

5.4 Clinical Importance

• Early Diagnosis: Critical to prevent sudden cardiac death.
• Family Screening: Identifies at-risk relatives who may benefit from preventive measures.
• Genetic Testing: Facilitates accurate diagnosis and family counselling.
• Lifestyle Modifications: Essential to reduce exposure to triggers that may precipitate arrhythmias.

5.5 Prognosis

• ICD significantly reduces mortality in high-risk patients.
• Brugada’s Syndrome:
• Generally favourable with appropriate management.
• ICD can prevent sudden cardiac death in high-risk individuals.
• Long QT Syndrome:
• Good prognosis with adherence to treatment and lifestyle changes.

6. Other Inherited Cardiac Conditions

6.1 Marfan’s Syndrome

6.1.1 Definition and Overview

• Marfan’s syndrome is a multisystem connective tissue disorder that predominantly affects the eyes, the cardiovascular system, and the musculoskeletal system.
• It is an inherited condition with significant implications for multiple organ systems.

6.1.2 Epidemiology and Aetiology

• Prevalence: Estimated to affect 2-3 in 10,000 individuals.
• Inheritance Pattern:
  • Autosomal dominant.
  • Approximately 25% of cases arise spontaneously from a new mutation, with no family history.
• Genetic Basis:
  • Most patients have mutations in the FBN1 gene, which encodes fibrillin-1, a critical component of connective tissue.

6.1.3 Clinical Features

6.1.3.1 Musculoskeletal Features

• Tall and thin physique.
• Long arms and fingers (arachnodactyly).
• High arched palate with overcrowded dentition.
• Skin striae (stretch marks).

6.1.3.2 Cardiovascular Features

• Aortic dilation, dissection, or rupture.
• Valvular involvement:
  • Aortic regurgitation.
  • Mitral valve prolapse.

6.1.3.4 Ophthalmic Features

• Lens subluxation (ectopia lentis).
• Myopia (nearsightedness).

6.1.4 Diagnostic Approach

6.1.4.1 Diagnostic Criteria

• Ghent Nosology: Internationally accepted criteria for diagnosing Marfan’s syndrome.
  • Major Criteria: Involves features in different organ systems (cardiovascular, skeletal, ocular).
  • Minor Criteria: Additional supporting features that enhance diagnostic confidence.
  • Family History: Affected family members increase diagnostic likelihood.

6.1.4.2 Investigations

• Annual Assessments: Due to the progressive nature of the disease, regular monitoring is essential.
• Cardiovascular Evaluation:
  • Echocardiography: Primary tool for assessing aortic dimensions and valvular function.
  • Cardiac MRI: Provides detailed imaging for better characterisation of aortic pathology.
• Ophthalmic Examination: To identify lens subluxation and other ocular manifestations.
• Musculoskeletal Assessment: Clinical evaluation of skeletal abnormalities.

6.1.5 Management

6.1.5.1 Cardiovascular Management

• Beta-blockers: Initiated if aortic dilation is detected to reduce the stress on the aortic wall.
• Angiotensin II Receptor Blockers (ARBs):
  • Used even in normotensive patients due to evidence suggesting they reduce aortic dilatation.
• Surgical Intervention:
  • Aortic Root Surgery: Considered when the aortic root diameter exceeds 4.5 cm at the level of the sinus of Valsalva to prevent dissection or rupture.

6.1.5.2 Multidisciplinary Care

• Specialist Referrals:
  • Ophthalmologist: For regular eye examinations.
  • Orthopaedic Specialist: To manage musculoskeletal complications.
• Genetic Counselling and Family Screening:
  • First-Degree Relatives: Should undergo genetic testing and clinical evaluation.
  • Family Pedigree Documentation: Essential for identifying at-risk family members.
• Post-Mortem Studies: May be necessary to confirm the diagnosis and understand inheritance patterns in cases of sudden death.

6.1.6 Prognosis

• Good Prognosis with appropriate management and regular monitoring.
• Aortic Complications remain the leading cause of mortality; timely surgical intervention significantly improves outcomes.
• Early Detection and Treatment are crucial in preventing severe cardiovascular events.

6.2 Familial Hypercholesterolaemia (FH)

6.2.1 Definition and Overview

• Familial hypercholesterolaemia (FH) is an inherited disorder leading to the accumulation of low-density lipoprotein (LDL) cholesterol.
• It significantly increases the risk of premature atherosclerosis, particularly coronary heart disease.

6.2.2 Epidemiology and Aetiology

• Prevalence:
  • Heterozygous FH: ~1 in 500 individuals in the general population.
  • Homozygous FH: ~1 in a million individuals; much rarer and more severe.
• Inheritance Pattern:
  • Autosomal dominant.
• Genetic Basis:
  • Mutations primarily in the LDLR gene, which encodes the LDL receptor.
  • Other Genes: APOB and PCSK9 may also be involved.

6.2.2.1 Heterozygous FH

• Genotype: Mutation in one copy of the LDLR gene.
• Clinical Implications:
  • Increased LDL levels lead to early onset of atherosclerosis.
  • 50% of men and 30% of women develop coronary heart disease by age 50 if untreated.

6.2.2.2 Homozygous FH

• Genotype: Mutations in both copies of the LDLR gene.
• Clinical Implications:
  • Severe hypercholesterolaemia.
  • Early onset atherosclerosis, often presenting in childhood with severe cardiovascular complications.

6.2.3 Clinical Features

6.2.3.1 Heterozygous FH

• Premature Coronary Heart Disease:
  • Myocardial Infarction or angina in early adulthood.
• Other Atherosclerotic Manifestations:
  • Stroke.
  • Peripheral Vascular Disease.

6.2.3.2 Homozygous FH

• Severe Atherosclerosis:
  • Early myocardial infarction in childhood or adolescence.
• Physical Signs:
  • Tendon xanthomas: Cholesterol deposits in tendons, particularly the Achilles tendon and extensor tendons of the hands.
  • Corneal arcus: Cholesterol deposits in the cornea, appearing as a grey-white ring around the iris.

6.2.4 Diagnostic Approach

6.2.4.1 Diagnostic Criteria (Simon Broome Criteria)

Definite Familial Hypercholesterolaemia

• For Adults:
  • Cholesterol > 7.5 mmol/L or LDL cholesterol > 4.9 mmol/L.
  • Plus:
    • Tendon xanthomas in the patient or a first- or second-degree relative.
    • Family history of premature myocardial infarction (<60 years in a first-degree relative; <50 years in a second-degree relative).
• For Children (<16 years):
  • Cholesterol > 6.7 mmol/L or LDL cholesterol > 4 mmol/L.
  • Plus:
    • Tendon xanthomas in the patient or a first- or second-degree relative.
    • DNA evidence of a known mutation.

Possible Familial Hypercholesterolaemia

• For Adults:
  • Cholesterol > 7.5 mmol/L or LDL cholesterol > 4.9 mmol/L.
  • Plus:
    • Family history of premature myocardial infarction or increased cholesterol levels in relatives.
• For Children (<16 years):
  • Cholesterol > 6.7 mmol/L or LDL cholesterol > 4 mmol/L.
  • Plus:
    • Family history of increased cholesterol levels.

6.2.4.2 Investigations

• Blood Tests:
  • Serum Cholesterol and LDL Levels: Elevated as per diagnostic criteria.
• Physical Examination:
  • Identification of tendon xanthomas and corneal arcus.
• Family History:
  • Detailed pedigree analysis to identify affected relatives.
• Genetic Testing:
  • Confirmation of known mutations in the LDLR gene or other associated genes.

6.2.5 Management

6.2.5.1 Pharmacological Therapy

• Statins: First-line therapy to lower LDL cholesterol.
  • Intense Lipid-Lowering: Target reduction of 50% from baseline levels.
• Ezetimibe: Second agent if LDL targets are not met with statins alone.
• Other Lipid-Lowering Agents:
  • Bile Acid Sequestrants (e.g., cholestyramine).
  • PCSK9 Inhibitors for refractory cases.

6.2.5.2 Lifestyle Modifications

• Dietary Changes:
  • Low-Fat Diet: Reduces cholesterol intake.
  • Smoking Cessation: Reduces cardiovascular risk.
  • Weight Loss: Improves lipid profile and overall health.
• Exercise: Regular physical activity within recommended limits.

6.2.5.3 Special Considerations

• Hypothyroidism:
  • Thyroid Function Correction: Essential before initiating lipid-lowering therapy as it may normalise lipid levels.
• Severe Cases:
  • Lipoprotein Apheresis: For patients with homozygous FH or those who do not respond to medication.

6.2.5.4 Surgical Intervention

• Coronary Artery Bypass Grafting (CABG): For patients with significant atherosclerosis.
• Heart Transplantation: In cases of severe atherosclerosis leading to end-stage coronary artery disease.

6.2.5.5 Family Screening and Genetic Counselling

• First-Degree Relatives:
  • Screening: ECG, lipid profile, and genetic testing if a mutation is identified.
  • Genetic Counselling: To inform family members of their risk and the importance of early detection and treatment.

6.2.6 Prognosis

• Heterozygous FH:
  • Early Intervention: Significantly reduces the risk of premature atherosclerosis and associated complications.
  • Life Expectancy: Approaches normal with effective management.
• Homozygous FH:
  • Severe Prognosis: High mortality rate if untreated.
  • Early and Aggressive Treatment: Essential for improving survival and quality of life.

6.3 Summary of Other Inherited Cardiac Conditions

6.4 Clinical Importance

• Early Diagnosis and Intervention: Crucial in preventing severe complications such as aortic dissection in Marfan’s syndrome and premature coronary artery disease in FH.
• Multidisciplinary Approach: Involves various specialists (cardiologists, geneticists, ophthalmologists, orthopaedic surgeons) to manage the diverse manifestations of these conditions.
• Family Screening and Genetic Counselling: Essential for identifying at-risk relatives and implementing preventive measures early.
• Lifestyle Modifications: Integral part of management to reduce disease progression and associated risks.

6.5 Prognosis

• Homozygous FH: High mortality without aggressive treatment; improved outcomes with early and intensive management.
• Marfan’s Syndrome:
• Good Prognosis with timely medical and surgical interventions.
• Regular Monitoring is essential to manage aortic and valvular complications.
• Familial Hypercholesterolaemia:
• Heterozygous FH: Near-normal life expectancy with appropriate lipid-lowering therapy.