GC069 Inherited Cardiac Conditions
Inherited cardiac conditions are a group of genetically determined disorders affecting the heart's structure, rhythm, or function—including cardiomyopathies, channelopathies, and familial aortopathies—that predispose affected individuals to arrhythmias, heart failure, and sudden cardiac death.
Inherited Cardiac Conditions
This lecture by Dr. Jo Jo Hai (Department of Medicine, HKU) covers hereditary cardiac diseases — a group of genetically-determined conditions that affect the heart's structure (cardiomyopathies), electrical system (channelopathies), lipid metabolism (familial hypercholesterolemia), and connective tissue (aortic/valvular disorders). The lecture is clinically vital because these conditions are a major cause of sudden cardiac death (SCD) in young, apparently healthy individuals, and many are treatable or at least modifiable if recognized early.
How this fits into exams and clinical practice:
- Summative exams love inherited cardiac conditions because they cross-cut cardiology, genetics, pharmacology, paediatrics, and preventive medicine.
- Common question formats: ECG interpretation (LQTS, Brugada, ARVC), vignettes of young sudden death, management algorithms (ICD indications), drug lists (QT-prolonging drugs), and FH diagnosis/management.
- Clinically, you will encounter FH frequently; cardiomyopathies and channelopathies are rarer but carry life-threatening consequences — the exam tests whether you can recognize them and initiate appropriate workup.
The lecture explicitly notes that congenital ≠ inherited: inherited diseases can present later in life, and congenital diseases need not be heritable. [1][2]
Four major categories: [1]
- Inherited cardiomyopathies — HCM, DCM, ARVC, RCM
- Inherited disorders of rhythm and conduction — LQTS, BrS, CPVT, PCCD
- Familial hypercholesterolemia (FH)
- Connective tissue diseases — Marfan, Ehlers-Danlos, Loeys-Dietz, familial thoracic aortic aneurysm/dissection, bicuspid valve aortopathy
Congenital ≠ Inherited
A congenital heart defect (e.g. VSD, ASD, WPW) is NOT necessarily inherited, and inherited cardiac diseases need NOT present at birth. Many inherited cardiomyopathies and channelopathies manifest in adolescence or adulthood due to variable age-related penetrance. The lecture explicitly separates these concepts. [1][2]
2. Cardiomyopathies — General Framework
Definition: A heterogeneous group of diseases of the myocardium exhibiting inappropriate ventricular hypertrophy, dilatation, or stiffness, associated with mechanical and/or electrical dysfunction. [1]
| Heart Failure (HF) | Cardiomyopathy (CM) | |
|---|---|---|
| Nature | Clinical syndrome (symptoms + signs) | Anatomic/pathologic diagnosis |
| Relationship | Can be caused by CM, but also by VHD, IHD, arrhythmias | Can cause HF, but does NOT always cause HF |
| Key point | HF is the consequence | CM is the substrate |
This distinction is exam-favourite: a patient with HCM may never develop HF; a patient with HF may have no cardiomyopathy (e.g., pure valvular disease). [1]
| Type | LV Change | Key Functional Problem | Characteristic Feature |
|---|---|---|---|
| DCM | LV dilatation | Systolic dysfunction (↓LVEF) | Dilated, thin-walled ventricle |
| HCM | ↑LV wall thickness | ± LVOT obstruction, diastolic dysfunction | Asymmetric septal hypertrophy, SAM of AMVL |
| ARVC | Predominantly RV | Fibro-adipose infiltration of RV | VT with LBBB morphology |
| RCM | Normal or near-normal size | ↑Myocardial stiffness, diastolic dysfunction | Restrictive filling pattern |
3. Dilated Cardiomyopathy (DCM)
Prevalence: 1:250 to 1:500 individuals; ~60% of all cardiomyopathies. [1]
| Category | Examples |
|---|---|
| Genetic/Familial | Titin (TTN), Lamin A/C (LMNA), neuromuscular disorders |
| Infection | Enteroviruses (Coxsackie A/B), herpesviruses, adenoviruses, parvoviruses |
| Drugs/Alcohol/Toxins | Alcohol, anthracyclines, cocaine |
| Metabolic/Endocrine | Thyrotoxicosis, hypothyroidism, pheochromocytoma |
| Pregnancy | Peripartum cardiomyopathy |
| Infiltrative | Sarcoidosis, amyloidosis, haemochromatosis |
| Autoimmune | SLE, scleroderma |
| Neuromuscular | Duchenne, Becker, myotonic dystrophy |
The lecture specifically highlights the viral myocarditis → immune-mediated injury → DCM pathway:
- Viral entry (Coxsackie B most classic) → direct cardiomyocyte damage
- Immune activation → inflammatory infiltrate, cytokine release
- Ongoing autoimmune injury → even after virus cleared
- Myocyte death and fibrosis → LV dilatation → systolic dysfunction → HF / SCD
This is why myocarditis can be a precursor to idiopathic DCM, and why no exercise for 3–6 months after myocarditis is recommended. [1][3]
15–30% of all DCM is familial. [1]
- Onset: 20–50 years old
- Criteria: ≥2 first/second degree relatives with DCM, OR 1 first-degree relative with autopsy-proven DCM and SCD < 50 y/o
- Inheritance: >90% autosomal dominant
- Most common genes: Titin (TTN, 20–25%) and Lamin A/C (LMNA, ~6%)
Challenges in diagnosing familial DCM: [1]
- Incomplete family history (autopsy often waived)
- Variable age-related penetrance (some present young, some old, some never)
- Concomitant cardiac conditions (e.g., hypertension may mask underlying CM)
Key investigations: [1]
- Echo: LV end-diastolic volume/diameter > 2SD from normal (corrected for age and BSA); LVEF < 50%
- ECG: No specific features but usually abnormal — AF, AV block, LBBB common
- Cardiac MRI: Late gadolinium enhancement (LGE) pattern; myocardial oedema
- CT coronary angiogram: Exclude CAD as cause
- FDG-PET scan: For sarcoidosis
- Endomyocardial biopsy: If inflammatory/infiltrative CM suspected
- Blood tests: BNP/NT-proBNP, TFT, iron studies, autoimmune screen
- Idiopathic DCM → genetic counselling (3-generation family tree; genetic screening)
Follows standard HF guidelines (2020 ESC): [1]
- Pharmacological: ARNI (or ACEI/ARB), beta-blocker, MRA, SGLT2 inhibitor, diuretics
- Device therapy: ICD if LVEF ≤35% or history of sustained VT/SCA; CRT if indicated
- Specific therapies: Immunosuppressants for autoimmune disease
- No exercise for 3–6 months after myocarditis
- Leisure-time activities only if high risk for life-threatening arrhythmias
- End-stage: LVAD / heart transplant for intractable ventricular arrhythmias or HF
4. Hypertrophic Cardiomyopathy (HCM)
Definition: Increased LV wall thickness at end-diastole that cannot be explained by abnormal loading conditions. [1]
- Prevalence: 1:500 to 1:1000
- Major cause of premature sudden cardiac death in young, apparently healthy athletes
- Autosomal dominant inheritance with variable penetrance
High Yield
HCM is the most common cause of SCD in young athletes. This is a classic exam fact. The mechanism involves LVOT obstruction during exertion and/or malignant ventricular arrhythmias triggered by the disorganized myocardial architecture. [1]
| Pattern | Location | ECG Clue |
|---|---|---|
| Asymmetric septal hypertrophy | Most common; interventricular septum | LVH with strain pattern |
| Symmetric hypertrophy | Concentric | LVH criteria |
| Apical hypertrophy | LV apex | Deep precordial T-wave inversions (giant TWI) |
The 2020 AHA/ACC Guidelines state that conditions mimicking HCM morphologically but with different pathophysiology should NOT be called HCM. [1]
These include: Fabry disease, cardiac amyloidosis (especially ATTR), glycogen storage diseases, Noonan syndrome, and athlete's heart. Their pathophysiology, natural history, and treatment are fundamentally different. This is a common exam trap. [1]
Variable ages at onset and clinical presentations even with the same disease-causing mutation. [1]
| Symptom | Frequency | Mechanism |
|---|---|---|
| Dyspnoea on exertion | 90% | LVOT obstruction during exertion, systolic HF, or diastolic HF |
| Angina | 70–80% | LVH + LVOTO → supply-demand mismatch |
| Syncope | 20% | LVOTO on exertion or arrhythmias (AT, AF, VT, VF) |
| Pre-syncope | 50% | Same mechanisms as syncope |
| Stroke/thromboembolism | Variable | Due to AF |
| Sudden cardiac death | — | Ventricular arrhythmias from myocardial disarray |
Four interrelated processes: [1]
- LVOT obstruction — Asymmetric septal hypertrophy + systolic anterior motion (SAM) of the anterior mitral valve leaflet (AMVL) → dynamic obstruction that worsens with ↑contractility, ↓preload, ↓afterload
- Diastolic dysfunction — Stiff, hypertrophied ventricle impairs relaxation and filling
- Myocardial ischaemia — ↑O₂ demand from hypertrophy, ↓supply from compressed intramyocardial coronaries, and ↓diastolic filling time
- Mitral regurgitation — SAM distorts the MV → posteriorly directed MR jet
Patients with LVOT obstruction have worse survival than those without. [1]
Understanding Dynamic LVOT Obstruction
Think of LVOT obstruction in HCM as a dynamic process — it gets WORSE with anything that:
- ↑Contractility (exercise, digoxin, catecholamines)
- ↓Preload (dehydration, Valsalva, standing up, diuretics)
- ↓Afterload (vasodilators)
This is why vasodilators are contraindicated in obstructive HCM — they worsen the gradient. Conversely, squatting ↑preload and ↑afterload, reducing obstruction.
Key investigations: [1]
- 3-generation family history / genetic testing
- Echo: Measure LVOT gradient (resting / provocated / exercise)
- ≥30 mmHg = obstructive; ≥50 mmHg = requires treatment
- ECG: LVH with strain (asymmetric/symmetric); precordial TWI (apical HCM); low voltage (think amyloidosis)
- Holter: Non-sustained ventricular tachycardia (NSVT) — key SCD risk factor
- Cardiac MRI: Extensive late gadolinium enhancement (LGE) → ↑SCD risk
Major risk factors to know: [1]
- History of cardiac arrest / sustained VT
- Family history of SCD from HCM
- Unexplained syncope
- LV wall thickness ≥30 mm
- NSVT on Holter
- Abnormal BP response to exercise (failure to rise or frank drop)
- Extensive LGE on MRI
- LV apical aneurysm
- LVEF < 50% (end-stage HCM)
The ICD implantation flowchart from the lecture follows the 2020 AHA/ACC guideline: patients with prior cardiac arrest or sustained VT get an ICD (Class I). Others undergo individualized risk assessment using the above factors. [1]
Comprehensive management algorithm: [1]
| Aspect | Approach |
|---|---|
| Baseline | SCD risk assessment + stress testing |
| Follow-up | Clinical, echo, Holter ± stress testing every 1–2 years or when symptoms change |
| Genetic counselling | 3-generation pedigree; cascade screening |
| Exercise | Mild-to-moderate intensity recreational exercise acceptable for most |
| Obstructive + Symptomatic | Avoid vasodilators. Use: Beta-blocker → Non-DHP CCB (verapamil/diltiazem) → Disopyramide → Septal ablation / Myectomy |
| Systolic dysfunction (end-stage) | Avoid negative inotropes. ARNI/ACEI/ARB, BB, MRA, CRT as per HF guidelines |
| High SCD risk | ICD implantation |
| Recurrent VA | Antiarrhythmics |
| Intractable VA or HF | LVAD / Heart transplant |
Pharmacology Trap — HCM
Obstructive HCM: Avoid vasodilators (ACEi, ARBs, nitrates, DHP-CCBs), positive inotropes (digoxin), and high-dose diuretics. These all worsen LVOT obstruction.
End-stage HCM with systolic dysfunction: Now the LVEF is low, so you MUST avoid negative inotropes (beta-blockers used cautiously, stop disopyramide, stop non-DHP CCB) and treat as HFrEF.
The management literally flips depending on which phase the patient is in.
5. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
ARVC: Arrhythmogenic cardiomyopathy not explained by CAD, VHD, CHD, or HT, with predominant RV involvement and fibrous/fibrofatty replacement of RV myocardium. [1]
- Most commonly autosomal dominant, variable penetrance, 1/3 familial
- Genes: mostly encode desmosome, intercalated disc, and ion channel proteins
- High prevalence in certain Italian regions
- Presents with ventricular arrhythmias of LBBB morphology (origin from RV) / SCD in the young
- Disease progression related to exercise — exercise accelerates fibrofatty infiltration
Diagnosis requires a combination of criteria from multiple categories: [1]
| Category | Finding |
|---|---|
| Structural | Echo/MRI/RV angiography: RV akinesia, dyskinesia, aneurysms, significant dilatation, ↓RV systolic function |
| Depolarization | Epsilon wave on ECG |
| Repolarization | T-wave inversion V1–V3 or beyond in patients > 14 y/o without complete RBBB |
| Arrhythmias | VT/NSVT of LBBB morphology with superior axis |
| Family history | ≥1 first-degree relative with ARVC diagnosed pathologically or by Task Force Criteria |
| Tissue | Endomyocardial biopsy showing significant fibrous replacement of RV free wall myocardium |
ECG Pearl: Epsilon Wave
The epsilon wave is a small positive deflection buried at the end of the QRS complex in V1–V3, representing delayed RV activation through the fibrofatty tissue. It is pathognomonic but rare — more commonly you'll see T-wave inversions in the right precordial leads. [1]
Risk stratification: [1]
- History of VT/SCA
- LVEF ≤35%
- Major risk factors: NSVT, inducible VT at EPS, LVEF ≤49%
- Minor risk factors: Male sex, >1000 PVCs/24h, RV dysfunction, proband status, ≥2 desmosomal variants
- ICD consideration: 3 major, or 2 major + 2 minor, or 1 major + 4 minor risk factors
- If NSVT is present, PVC criteria is NOT counted
Key management principles: [1]
- Genetic counselling
- Arrhythmia management: ICD consideration; beta-blockers if no ICD; antiarrhythmics + BB if recurrent VA
- RV dysfunction: Symptomatic → nitrate to ↓preload; may try ACEI/ARB/BB/MRA/diuretics
- Thromboembolic risk: Antithrombotic therapy if AF, intracavitary thrombosis, or prior thromboembolism
- Exercise: NO competitive or frequent high-intensity endurance exercise — associated with ↑VA and disease progression
- Intractable VA/HF: LVAD / heart transplant
6. Restrictive Cardiomyopathy (RCM)
↑Myocardial stiffness → extremely impaired ventricular filling and diastolic dysfunction = "restrictive physiology." [1]
- The least common form of cardiomyopathy
- Mostly acquired; idiopathic RCM carries relentless symptomatic progression and high mortality
- Autosomal dominant forms exist (sarcomere subunit mutations)
- Presents as HFpEF but arrhythmias are possible
Functional resemblance to constrictive pericarditis — differentiating the two is mandatory because constriction is surgically treatable. [1]
| Feature | RCM | Constrictive Pericarditis |
|---|---|---|
| Pericardium | Normal | Thickened/calcified |
| Septal bounce | Absent | Present |
| Respiratory variation in flow | Absent | Present (discordant) |
| MRI | Myocardial LGE/infiltration | Pericardial thickening |
| Right heart cath | ↑LVEDP > RVEDP | Equalization of diastolic pressures |
| Treatment | Medical (± specific) | Pericardiectomy |
The lecture devotes several slides to causes, which include:
- Infiltrative: Amyloidosis (AL and ATTR), sarcoidosis, haemochromatosis
- Storage: Fabry disease, glycogen storage diseases
- Endomyocardial: Endomyocardial fibrosis, hypereosinophilic syndrome (Löffler endocarditis), carcinoid, radiation
- Idiopathic
- Genetic/Familial: Sarcomere mutations (overlap with HCM)
Multimodality imaging is essential: [1]
- Echo, right heart catheterization, cardiac MRI
- Nuclear imaging: Technetium-labelled bisphosphonates for ATTR-cardiac amyloidosis; Gallium-67 for sarcoidosis
- FDG-PET for sarcoidosis
- Endomyocardial biopsy — definitive for many causes
- Blood tests (serum free light chains, troponin, BNP); other biopsies (fat pad, rectal)
Treatment may be available for specific conditions: [1]
- Fabry disease: Enzyme replacement therapy
- ATTR-cardiac amyloidosis: Tafamidis
- Sarcoidosis: Immunosuppression
- AL amyloidosis: Chemotherapy directed at plasma cell clone
- Haemochromatosis: Phlebotomy/chelation
7. Long QT Syndrome (LQTS)
LQTS is a disorder characterized by: (1) QT prolongation on ECG and (2) a propensity to ventricular tachyarrhythmias. [1]
- Usual presentations: syncope, seizures, or SCD; can remain asymptomatic
- Ion channelopathy
- Congenital: Autosomal dominant (Romano-Ward) or autosomal recessive (Jervell & Lange-Nielsen — with sensorineural deafness)
- Acquired: Much more common — drugs, electrolytes, medical conditions
- The QT interval = beginning of QRS complex to end of T wave → represents the total ventricular electrical cycle (depolarization + repolarization)
- Since repolarization dominates, QT prolongation ≈ prolonged repolarization
- QT varies with heart rate — must correct: QTc = QT / √RR (Bazett equation) [1]
- Normal QTc: Male ≤ 440 ms; Female ≤ 460 ms [4]
Prolonged repolarization occurs due to: [1]
- Reduced repolarizing (outward) K⁺ currents: IKs, IKr → delays phase 3 repolarization
- Enhanced depolarizing (inward) Na⁺ current: INa → persistent late sodium current keeps the cell depolarized longer
This prolonged repolarization creates heterogeneity of refractoriness across the myocardial wall (transmural dispersion of repolarization). Early afterdepolarizations (EADs) can trigger polymorphic VT = Torsade de Pointes (TdP).
TdP is the classic arrhythmia of LQTS — the QRS axis appears to twist around the baseline. It is usually self-terminating (~95% of events), but can degenerate into VF → SCD. [1]
Pause-dependent TdP is characteristic of acquired LQTS: a long pause (e.g., after a PVC) → exaggerated repolarization → EAD → "short-long-short" sequence → TdP. [1]
| Type | Gene | Channel | Trigger | ECG Pattern | Treatment Note |
|---|---|---|---|---|---|
| LQT1 | KCNQ1 | IKs (↓) | Exercise (especially swimming) | Broad-based T wave | BB very effective |
| LQT2 | KCNH2 (HERG) | IKr (↓) | Auditory stimuli, emotional stress, postpartum | Low-amplitude notched/bifid T | BB effective; avoid K⁺ wasting |
| LQT3 | SCN5A | INa (↑, gain-of-function) | Rest/sleep | Late-onset peaked T, long ST | BB less effective; mexiletine may help |
| LQT7 (Andersen) | KCNJ2 | IK1 (↓) | — | Prominent U wave | Triad: VA, periodic paralysis, dysmorphism |
| LQT8 (Timothy) | CACNA1C | ICa (↑) | — | — | Syndactyly, cognitive impairment |
Three categories of acquired causes: [1]
Electrolyte imbalance:
- Hypokalaemia, hypocalcaemia, hypomagnesaemia
Medical conditions:
- AV block, severe sinus bradycardia, DM, hypothyroidism, CVA, subarachnoid haemorrhage, starvation, obesity, alcoholism
Drugs (HIGH YIELD — frequently tested):
| Category | Examples |
|---|---|
| Antiarrhythmics | Class IA (quinidine, procainamide, disopyramide), Class III (sotalol, dronedarone, ibutilide, dofetilide) |
| Antibiotics | Erythromycin, clarithromycin, moxifloxacin, TMP-SMX, pentamidine |
| Antifungals | Ketoconazole, fluconazole, itraconazole |
| Antihistamines | Terfenadine, astemizole, diphenhydramine |
| Psychotropics | Phenothiazines, TCAs (amitriptyline), haloperidol, risperidone, pimozide |
| Immunosuppressives | Tacrolimus |
| GI agents | Cisapride |
| Others | Chloral hydrate, organophosphates |
Drug-Induced QT Prolongation
This is one of the most commonly tested pharmacology topics. The key drug classes to remember are: Class IA and III antiarrhythmics, macrolide antibiotics, azole antifungals, and antipsychotics. Always check QTc before starting these drugs and monitor electrolytes (especially K⁺ and Mg²⁺).
Four-pronged approach: [1]
- Clinical syndrome recognition — symptoms, family history, ECG findings, arrhythmias
- Provocative testing — exercise stress test; epinephrine/isoproterenol challenge → looking for maladaptation of QT to changing heart rate (QTc prolongation ± VT)
- Exclusion of reversible causes — electrolytes, TFT
- Genetic identification — confirms diagnosis if positive, but a negative genetic test has limited diagnostic value as it could be negative in 25–50% of LQTS patients
Scoring system: [1]
| Score | Interpretation |
|---|---|
| ≥4 | Definite LQTS |
| ≥3.5 | High probability |
| 1.5–3 | Intermediate probability |
| ≤1 | Low probability |
Components include: QTc value, T-wave morphology, Torsade de Pointes, syncope (with/without stress), congenital deafness, family history of definite LQTS, unexplained SCD in family member < 30 y/o.
Important caveats:
- (a) No medications/disorders accountable for changes
- (b) Bazett's formula used
- (c) Mutually exclusive criteria
- (d) Resting HR below 2nd centile for age
- (e) Same family member cannot be counted in both categories A & B
Stepwise approach (2017 AHA/ACC/HRS Guideline): [1]
| Measure | Detail |
|---|---|
| Genetic counselling | All patients |
| Beta-blockers | Effective in preventing cardiac events in ~70% of patients; nadolol or propranolol preferred |
| Lifestyle advice | Specific exercise advice based on genotype (e.g., LQT1 — avoid swimming; LQT2 — avoid alarm clocks, sudden loud noises); avoid electrolyte imbalance, heatstroke; avoid QT-prolonging drugs; use AED if available |
| ICD | If SCA or symptomatic despite beta-blockers |
| Cardiac pacemaker | Eliminates arrhythmogenic bradycardia, eliminates short-long-short sequences → ↓TdP risk |
| Left cervicothoracic stellectomy | Anti-adrenergic measure for high-risk patients with recurrences despite beta-blockers |
| Combination therapy | Beta-blockers + stellectomy + ICD with pacing in highest-risk patients |
Key prognostic points: [1]
- TdP episodes usually self-terminating; only ~4–5% of cardiac events are fatal
- Prognosis with beta-blockers is good overall
- Prognosis after ICD implantation is very good
- Genotype +ve / phenotype –ve patients have a 10% risk of major cardiac events by age 40 if untreated
8. Brugada Syndrome (BrS)
Brugada Syndrome is characterized by: [1]
- ST-segment elevation in right-sided precordial leads
- A grossly structurally normal heart
- Conduction block at the right ventricle
- Propensity for life-threatening ventricular tachyarrhythmias
- Mean age: mid-late 30s (range 4–70 years)
- M:F ratio 8–10:1
- Associated with SCN5A mutation → loss of function → ↓inward sodium current
- Autosomal dominant with variable penetrance
- Patients often show periodic normalization of ECG
- Manifests during fever / use of Na channel blockers
The sodium channel is responsible for the rapid upstroke (phase 0) of the action potential, particularly in the RV epicardium. Loss of function → reduced inward Na⁺ current → heterogeneous shortening of the epicardial action potential → voltage gradient between epicardium and endocardium → ST elevation. The dispersion of repolarization creates a substrate for re-entrant VT/VF. [1]
| Type | Description | Diagnostic? |
|---|---|---|
| Type 1 (Coved) | J-wave amplitude / ST elevation ≥2 mm at peak; negative T-wave with little/no isoelectric separation | YES — the only diagnostic ECG |
| Type 2 (Saddle-back) | J-wave ≥2 mm; gradually descending ST ≥1 mm above baseline; positive/biphasic T-wave → saddle-back shape | No — suggestive only |
| Type 3 | Right precordial ST elevation not meeting Type 1 or 2 criteria | No |
Key clinical points: [1]
- Malignant tachyarrhythmias usually occur at rest and at night (vagal influence → ↓Na⁺ current further compromised)
- SCD from VF can be the first and only event
- Arrhythmia recurrence rate is 40% over 2–3 year follow-up
- LQT/Brugada overlap syndrome exists
- Possible overlap with ARVC
Diagnostic approach: [1]
- Type I ECG pattern (spontaneous or provoked)
- Latent/intermittent Brugada: Repeat ECG periodically; repeat at 2nd/3rd intercostal space; administration of ajmaline, procainamide, or flecainide (Na channel blockers unmask the pattern)
- Brugada-like ECG: Must exclude RBBB, septal hypertrophy, ARVC
- Brugada ECG phenocopies: Myocardial ischaemia, PE, pericardial disease, metabolic disorders, mechanical compression of RVOT
Management algorithm (2017 AHA/ACC/HRS Guideline): [1]
| Situation | Management |
|---|---|
| Genetic counselling | All patients |
| Symptomatic individuals | ICD (syncope, seizure, nocturnal agonal respiration) |
| Asymptomatic | Follow-up (annual arrhythmic event rate = 0.5–1.2%/year) |
| Recurrent VA | Isoproterenol / epinephrine / quinidine |
| Lifestyle | Avoid Brugada-aggravating drugs; treat fever promptly; avoid excess alcohol; avoid cocaine |
| Refractory VA | Catheter ablation |
Catheter ablation is the treatment of choice for refractory ventricular arrhythmias in many cardiomyopathies/channelopathies. [1]
Brugada and Fever
Fever unmasks Brugada ECG patterns and can trigger arrhythmias. In a known Brugada patient, fever should be treated aggressively with antipyretics. This is a very testable clinical scenario — e.g., a young man with syncope during a febrile illness. [1]
The lecture mentions Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and Progressive Cardiac Conduction Defect (PCCD) as inherited rhythm disorders but defers detailed teaching to Block C (Paediatric Cardiology). [1][2]
Key facts for completeness:
- CPVT: Presents in children with exercise/emotion-induced bidirectional VT; structurally normal heart; ryanodine receptor (RyR2) mutations; treatment = beta-blockers, ICD, flecainide
- PCCD (Lenègre-Lev disease): Progressive fibrosis of the cardiac conduction system → progressive AV block; can be SCN5A-related
10. Familial Hypercholesterolaemia (FH)
FH is an autosomal dominant genetic disease characterized by elevated LDL-C. [1]
- Heterozygous FH (HeFH): ~1:200 to 1:500
- Homozygous FH (HoFH): ~1:160,000 to 1:1,000,000
- Caused by mutations in LDLR, APOB, PCSK9, LDLRAP1
- Increased risk of premature atherosclerotic coronary heart disease
The lecture presents a powerful graph showing cumulative LDL-year burden:
| Group | Age of CVD Threshold (~160 mmol-years) |
|---|---|
| HoFH | ~12.5 years |
| HeFH (no treatment) | ~35 years |
| HeFH + low-dose statin | ~48 years |
| HeFH + high-dose statin | ~53 years |
| No FH | ~55 years |
This illustrates why early diagnosis and treatment are critical — every year of delay adds to the cumulative LDL burden. Additional risk factors (female sex, smoking, HT, DM, high TG, low HDL, high Lp(a)) lower the threshold further. [1]
Dutch Lipid Clinic Network Criteria — a scoring system incorporating: [1][5]
- Family history (premature CAD, elevated LDL in relatives)
- Clinical history (premature CAD in proband)
- Physical examination — tendon xanthomata, corneal arcus (in young patients — in elderly, arcus senilis is normal)
- LDL-C level
- Genetic testing (definitive)
Children diagnostic thresholds: [1]
| Scenario | LDL-C threshold |
|---|---|
| No FHx of premature CAD | ≥5 mmol/L |
| FHx of premature CAD | ≥4 mmol/L |
| FHx of known mutation | ≥3.6 mmol/L |
Hong Kong data: [1]
- PWH study (1990–2000): 252 subjects clinically diagnosed as HeFH → estimated prevalence 1:4000 (likely underdiagnosed)
- HK West Cluster: In 143,400 statin-naïve subjects, 1/10 had LDL ≥4.0; 1/50 had LDL ≥5.0; 1/390 had LDL ≥6.5
Pharmacological treatment: [1]
- First-line: High-intensity statins (atorvastatin 40–80 mg or rosuvastatin 20–40 mg)
- Add-on: Ezetimibe (inhibits intestinal cholesterol absorption via NPC1L1)
- Additional: Bile acid sequestrants, niacin
- Current oral treatments reduce LDL-C by 50–65%, but many patients are unable to reach LDL targets
- PCSK9 inhibitors (alirocumab, evolocumab): Monoclonal antibodies that ↓LDL receptor degradation → ↑LDL clearance → dramatic LDL reduction
- Case example from lecture: 50-year-old HeFH man — LDL dropped from 4.24 to 0.59 mmol/L with alirocumab added to atorvastatin + ezetimibe, with resolution of xanthelasmata
Normally, the LDL receptor on hepatocyte surfaces binds LDL, internalizes it (endocytosis), delivers LDL for lysosomal degradation, and the receptor is recycled back to the cell surface. PCSK9 binds the LDL receptor and targets it for lysosomal degradation (instead of recycling) → fewer LDL receptors on the surface → less LDL clearance → higher LDL levels.
PCSK9 inhibitors block this interaction → LDL receptors are recycled → more receptors on the surface → more LDL cleared from blood. This is why they are so effective, especially in FH patients who already have fewer functional LDL receptors. [1]
The lecture assigns this as homework. Key conditions and their cardiac manifestations: [1][2]
| Condition | Inheritance | Cardiac Manifestation |
|---|---|---|
| Marfan syndrome | AD (FBN1) | Aortic root dilatation → AR, MVP, aortic dissection |
| Ehlers-Danlos (vascular type) | AD (COL3A1) | Arterial rupture, valve prolapse |
| Loeys-Dietz syndrome | AD (TGFBR1/2) | Aortic aneurysm/dissection, tortuosity |
| Familial thoracic aortic aneurysm/dissection | AD | Thoracic aortic aneurysm and dissection |
| Bicuspid aortic valvulopathy | AD (variable) | Aortic stenosis, aortic dilatation |
12. Integration Points
| ECG Finding | Condition |
|---|---|
| LVH, low voltage, poor R progression, LBBB, Q waves, ST depression, TWI, epsilon wave, AF, PVCs/NSVT | Cardiomyopathies |
| Epsilon wave specifically | ARVC |
| Low voltage with LVH pattern (pseudo-infarct) | Cardiac amyloidosis (think RCM) |
| Giant TWI in precordial leads | Apical HCM |
| Coved ST elevation V1–V3 | Brugada syndrome |
From GC 115: Heart failure can occur during pregnancy in a woman with well-compensated cardiac disease due to: [7]
- Physiological ↑cardiac output
- Antenatal anaemia
- Beta-adrenergic tocolytics
- Stress during labour/delivery
- Excessive IV fluids
This is relevant for HCM and DCM patients who may decompensate during pregnancy.
From Ryan Ho Critical Care: Causes of cardiac arrest include structural heart disease (HCM, DCM, ARVC) and channelopathies (LQTS, BrS, WPW). These account for ~15% of all cardiac arrests, but are the dominant cause in young patients. [8]
Past Paper Style Stems & Markscheme Points
1. A 25-year-old male athlete collapses and dies during a football match. Post-mortem shows asymmetric septal hypertrophy with myocardial disarray. What is the diagnosis? Describe the pathophysiology.
- Diagnosis: HCM
- Pathophysiology: Asymmetric septal hypertrophy → LVOT obstruction (dynamic, worsened by exercise) + diastolic dysfunction + myocardial ischaemia + mitral regurgitation → substrate for ventricular arrhythmias → VF → SCD
2. List 5 risk factors for SCD in HCM.
- Prior cardiac arrest/sustained VT, FHx of SCD from HCM, unexplained syncope, LV wall thickness ≥30 mm, NSVT on Holter, extensive LGE on MRI, LV apical aneurysm, abnormal BP response to exercise, LVEF < 50%
3. A 35-year-old man presents with palpitations and syncope. ECG shows coved ST elevation in V1–V3 with negative T wave. What is the diagnosis? What is the management?
- Diagnosis: Brugada syndrome (Type 1 ECG)
- Management: ICD (symptomatic); genetic counselling; avoid Na channel blockers, fever, alcohol, cocaine; annual follow-up
4. Name 4 classes of drugs that can cause acquired LQTS.
- Class IA and III antiarrhythmics, macrolide antibiotics, azole antifungals, antipsychotics (phenothiazines, haloperidol), TCAs
5. A 40-year-old woman with DCM (LVEF 30%) is being considered for ICD. What is the indication?
- LVEF ≤35% or history of sustained VT/SCA → ICD indicated per ESC guidelines
6. How do you differentiate RCM from constrictive pericarditis? Why is it important?
- Important because constriction is surgically treatable (pericardiectomy) while RCM is not
- Differentiation: Echo (septal bounce, respiratory variation), MRI (pericardial thickness), right heart catheterization (equalization of pressures in constriction)
7. A child with FH has a family history of premature CAD. What LDL level would prompt further investigation?
- LDL ≥4 mmol/L (with FHx of premature CAD) [1]
8. Describe the mechanism of action of PCSK9 inhibitors.
- PCSK9 normally binds LDL receptor → targets it for degradation → fewer receptors → ↑LDL. PCSK9 inhibitors block this → LDL receptors recycled → more LDL cleared from blood
| Condition | Inheritance | Key Pathology | Classic Presentation | Key Investigation | Key Treatment |
|---|---|---|---|---|---|
| HCM | AD | LV hypertrophy, myocardial disarray | Exertional syncope/SCD in young athlete | Echo (wall ≥15mm, LVOTO), MRI (LGE) | BB, avoid vasodilators, ICD if high risk |
| DCM | AD (mostly) | LV dilatation, ↓LVEF | HF symptoms, age 20–50 | Echo (LVEF < 50%), MRI | HF therapy, ICD if LVEF ≤35% |
| ARVC | AD | RV fibrofatty infiltration | VT with LBBB morphology, young | Echo/MRI (RV changes), ECG (epsilon wave, TWI V1-3) | Exercise restriction, ICD, BB |
| RCM | Variable | ↑Myocardial stiffness | HFpEF, restrictive physiology | Echo, MRI, biopsy, nuclear imaging | Treat specific cause (tafamidis, ERT) |
| LQTS | AD/AR | Ion channelopathy → prolonged repolarization | Syncope, seizures, SCD | ECG (↑QTc), genetic testing | BB, lifestyle, ICD if refractory |
| BrS | AD | SCN5A loss-of-function | Nocturnal SCD, rest arrhythmias | ECG (Type 1 coved ST), Na blocker challenge | ICD if symptomatic, avoid triggers |
| FH | AD | ↑LDL, premature atherosclerosis | Premature CAD, xanthomata | LDL-C, genetic testing | Statins, ezetimibe, PCSK9i |
High Yield Summary
Inherited cardiac conditions encompass cardiomyopathies (HCM, DCM, ARVC, RCM), channelopathies (LQTS, BrS, CPVT, PCCD), familial hypercholesterolaemia, and connective tissue diseases. Key exam themes: (1) HCM = most common cause of SCD in young athletes; avoid vasodilators in obstructive form. (2) DCM = most common cardiomyopathy; ICD if LVEF ≤35%. (3) ARVC = exercise worsens disease; epsilon wave and LBBB-morphology VT. (4) LQTS = know the QT-prolonging drug classes; beta-blockers effective in 70%; ICD if refractory. (5) Brugada = Type 1 coved ECG is diagnostic; fever and Na blockers unmask it; ICD for symptomatic patients. (6) FH = cumulative LDL burden concept; PCSK9 inhibitors for refractory cases. (7) ALL conditions require genetic counselling and 3-generation family tree. (8) Congenital ≠ inherited.
Active Recall - Inherited Cardiac Conditions
[1] Lecture slides: GC 069. Inherited Cardiac conditions.pdf (all pages) [2] Senior notes: Block A - Inherited Cardiac conditions.pdf [3] Senior notes: Block A - Three Cases of Dyspnea.pdf [4] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.517) [5] Senior notes: Introduction to Clinical pharmacology (I) (Pharmaco- Genomics, Precision Medicine).pdf (p.2) [6] Lecture slides: General Clerkship_Introduction to CVS Investigations_2026 Yiu (2 Feb 2026).pdf (p.7) [7] Lecture slides: GC 115. I am pregnant medical problems complicating pregnancy.pdf (p.30) [8] Senior notes: Ryan Ho Critical Care.pdf (p.28)
GC068 Indigestion And ‘heartburn’
Indigestion (dyspepsia) and heartburn are upper gastrointestinal symptoms characterized by epigastric discomfort, bloating, and a retrosternal burning sensation typically caused by gastric acid reflux or impaired digestion.
GC070 Is This The Best Drug For Me
Pharmacogenomics is the study of how an individual's genetic makeup influences their response to drugs, enabling personalized medication selection to optimize efficacy and minimize adverse effects.