Cardiology JC008: Inherited Cardiac Conditions

Question 1

Types of Hereditary Cardiac Diseases

Answer 1

1. Inherited Cardiomyopathies (CMP)
   - Hypertrophic (HCMP)
   - Dilated (DCMP)
   - Restricted (RCMP)
   - Arrhythmogenic Right Ventricular Dysplasia (ARVD)
2. Inherited Disorders of Rhythm and Conduction
   - Long QT syndrome (LQTS)
   - Brugada syndrome (BRS)
   - Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
   - Progressive Cardiac Conduction Disorder (PCCD)
3. Connective Tissue Diseases
   - Marfan
   - Ehlers-Danlos
   - Loeys-Dietz syndrome
   - Familial thoracic aortic aneurysm and dissection
   - Bicuspid valve aortopathy
4. Familial Hypercholesterolaemia

Congenital (abnormal differentiation, maybe genetic unrelated) =/= Inherited
- VSD, ASD, WPW (Wolff-Parkinson-White syndrome)

Question 2

Cardiomyopathies

Answer 2

• Heterogeneous group of diseases of ***myocardium
• Usually inappropriate Ventricular **Hypertrophy / **Dilatation —> ***Mechanical / Electrical dysfunction —> Heart failure, Syncope, Arrhythmia
• Confined to heart / Part of generalised systemic disorders

Question 3

***Classification of Cardiomyoapthies

Answer 3

1. Hypertrophic
   - Inappropriate **LVH +/- **LVOTO
   —> can develop LV dilatation, Systolic dysfunction in late stage (i.e. Burnout HCMP)
   - ***Obstructive / Non-obstructive
2. Dilated
   - LV dilation
   - ***Systolic dysfunction
3. Arrhythmogenic Right Ventricular Dysplasia (ARVD)
   - ***Fibro-adipose infiltrate —> Dilatation, Dysfunction, Arrhythmia of RV
   - LV involvement not uncommon
4. Restrictive
   - Abnormal LV filling
   - ***Diastolic dysfunction

Question 4

Hypertrophic Cardiomyopathy (HCMP)

Answer 4

• 1:500 - 1:1000 individuals
• ***major cause of premature sudden cardiac death in young / apparently healthy athletes
• Autosomal Dominant
• Genetically heterogeneous disease (wide range of mutations in genes encoding ***sarcomeric proteins)
  —> variable penetrance (not everyone with mutation will develop disease in same way)
  —> variable clinical presentation (can be asymptomatic)
  —> variable prognosis

***3 types of hypertrophy:
1. Asymmetrical septal
2. Symmetrical
3. Apical

Question 5

HCMP etiologies

Answer 5

1. ***Sarcomeric protein gene mutation (40-60%)
2. Others (5-10%)
   - **Inborn errors of metabolism (e.g. Glycogen storage diseases)
   - Malformation syndromes
   - **Amyloidosis
   - Neuromuscular diseases (e.g. ***Friedreich’s ataxia)
   - Drug-induced (Tacrolimus, Hydroxychloroquine, Steroids)
3. Unknown (25-30%)

Question 6

HCMP Clinical presentation

Answer 6

Variable
- Age of onset
- Degree / Location of hypertrophy

1. ***Incidental ECG / ECHO findings
2. ***Dyspnea on exertion (90%) (∵ Diastolic dysfunction —> ↑ LA pressure —> Fluid congestion in lungs)
3. ***Angina (80%)
4. Syncope (20%), Pre-syncope (50%)
   - ∵ **LVOT obstruction (worsens with ↑ contractility during exertion)
   - ∵ **Cardiac arrhythmia (AF, VT/VF)
5. Sudden cardiac death

Question 7

HCMP diagnosis

Answer 7

Presence of ↑ LV wall thickness + Not solely explained by abnormal loading condition

Adults: >=15 mm / >=13 mm (if +ve family history)
Children: > 2 SD above mean

***3 types of hypertrophy:
1. Asymmetrical septal
2. Symmetrical
3. Apical

**ECG findings:
1. **LVH with strain pattern (Symmetrical / Asymmetrical HCMP)
2. Precordium **T wave inversion (Apical HCMP)
3. **Low voltage (Amyloidosis: pathognomonic)
(4. ***Dagger Q waves in lateral + inferior leads (fast lane))

**Echo:
Obstructive HCMP:
- **LVOTO: >=30 mmHg (>=50 mmHg require treatment)

Abnormal BP response during exercise:
- Fail to ↑ SBP >=20 mmHg
or
- ↓ >20 mmHg from peak pressure

Question 8

Pathophysiology of Obstructive HCMP

Answer 8

4 interrelated processes:
1. LVOT obstruction (Asymmetrical septal hypertrophy + Systolic anterior motion of AMVL)
2. Diastolic dysfunction
3. Myocardial ischaemia
4. Mitral regurgitation

Overall effect: ↓ CO + Syncope

Much worse survival than without obstruction

Question 9

Risk factors for Sudden Cardiac Death in HCMP

Answer 9

1. ***Cardiac arrest (Ventricular fibrillation)
2. Sustained ventricular tachycardia
3. ***Unexplained syncope
4. Non-sustained ventricular tachycardia
5. ***Extreme LV thickness >= 30mm
6. Abnormal exercise BP
7. ***Family history of premature sudden cardiac death

Question 10

***Treatment Algorithm for HCMP

Answer 10

1. Exclude secondary causes
   - Amyloidosis
   - Metabolic diseases
   - Phaemochromocytoma
2. Assess symptoms
   No Syncope
   —> LVOTO —> **β blockers, Disopyramide —> **Myotomy-myectomy / Septal alcohol ablation / Dual chamber pacing
   —> Non-obstructive —> ***β blockers, Ca blockers
3. Assess complications / risks
   - History of sustained VT / VF / aborted SCD
   - High HCM Risk / SCD score
   —> ***ICD (implantable cardioverter defibrillator) + Amiodarone

• Atrial fibrillation —> ***Rate control (Amiodarone) + Anticoagulation + Direct current cardioversion
• Progressive heart failure —> ***ACE inhibitor + Diuretic + β blockers —> Heart transplant

4. Counselling / Genotyping / Family screening
   - patient information
   - insurance
   - employment
   - pregnancy
   - ***avoid competitive sports
   - recreational activities tailored to symptoms / SCD risk

Question 11

HCM-Risk SCD

Answer 11

Variable:
- Age
- **Family history of SCD
- **Unexplained syncope
- LVO gradient
- ***Maximum LV wall thickness
- Non-sustained VT
- LA diameter

**Score
- High risk: 5-year risk >=6% —> ICD for **Primary prevention
- Low risk: 5-year risk <4% —> ICD not indicated
- Intermediate: 5-year risk 4-6% —> ICD may be considered

Question 12

Restrictive Cardiomyopathy (RCMP)

Answer 12

Least common CMP

Hallmark:
- Normal systolic but **Abnormal diastolic function
- ∵ **Rigid ventricular wall with impeded ventricular filling

Secondary form:
- Systemic diseases (endocardial involvement)
—> tropical endomyocardial fibrosis
—> endocardial fibroelastosis
—> eosinophilic endomyocardial disease
—> haemochromatosis
—> amyloidosis

Functionally ~ ***Constrictive pericarditis (normal systolic function but abnormal ventricular filling) —> CP can be surgically released

Symptoms:
- Arrhythmia
- Chest pain / Syncope (less likely than HCMP, ∵ less muscle mass / LVOTO than HCMP)

Prognosis:
- Variable
- Idiopathic form: No specific treatment —> Relentless symptomatic progression + High mortality

Question 13

Dilated Cardiomyopathy (DCMP)

Answer 13

• 60% of all CMP
• Clinically heterogeneous

Etiologies:
- Viral infection
- Toxin exposure
- Infiltration
- **Valvular dysfunction
- **Myocardial Ischaemia
- ***Idiopathic (35% (Positive family history in ~50% of patients))

Question 14

Familial DCMP

Answer 14

• Uncommon (2-8 per 100,000)
• Spectrum of genetic disorders
• Multiple genetic etiologies
  —> Autosomal Dominant (>90%)
  —> ***Laminopathies (most common) —> Heart block / AF
  —> X-linked recessive (e.g. Dystrophin)
  —> Mitochondrial DNA defects
• Overlapping phenotypes

Challenges in diagnosis:
- Insufficient Family Hx
- Variable + Age-related penetrance
- Concomitant cardiac conditions

Question 15

Pathogenesis of DCMP

Answer 15

Unknown

Genetic predisposition + Environmental trigger (e.g. Myocarditis by viral infection)
—> Dysregulated immune response
—> ***Myocardial damage
—> DCMP

DNA mutation
—> Altered gene products
—> ***Altered myocardial function
—> LV dilatation / failure
—> DCMP

Question 16

Arrhythmogenic Right Ventricular Dysplasia (ARVD)

Answer 16

• Ventricular arrhythmia / SCD in young
• Disease progression / onset related to exercise

Pathogenesis:
- Focal fibrofatty infiltration of RV (sometimes LV)
—> ***RV dyskinesia, dilatation, dysfunction

Etiologies:
- Autosomal dominant inheritance with variable penetrance / expressivity (1/3 familial)
—> 9 chromosomal loci identified
—> RyR2 gene, Desmoplakin, Plakoglobin
—> Naxos disease / ARVD loci on chromosome 17q: Palmar-plantar keratoderma, wooly hair, + ARVD

Question 17

ARVD Diagnosis

Answer 17

Criteria:
1. Imaging
- ***Echo / MRI / RV angiography —> imaging evidence of RV dyskinesia, dilatation, dysfunction

2. ***ECG
   - Depolarisation / Repolarisation abnormalities
3. Arrhythmia
   - ***VT of LBBB + Superior axis (major diagnostic criteria)
4. Family history of confirmed ARVD
5. ***Endomyocardial biopsy
   - fibrofatty infiltration of RV
   - in selected cases

Question 18

ARVD Management

Answer 18

1. ***ICD
   - Cardiac arrest / Sustained VT/VF
   - LV impairment
   - NSVT / VT inducible (at electrophysiology study)
   - High risk mutations: Phospholamban, Lamin A/C, FLNC
2. Treatment of HFrEF (Heart failure with reduced Ejection Fraction)
3. Symptomatic ***RV dysfunction
   - ACE-1, ARB, BB, AA, Diuretics, Nitrates
4. ***Arrhythmia management (AF / VT)
   - Rate / Rhythm control + Anticoagulants
5. Exercise restriction
   - refrain from competitive / frequent high-intensity endurance exercise

Question 19

Primary disorders of Rhythm and Conduction

Answer 19

1. Long QT syndrome
2. Brugada syndrome

Question 20

Definition of QT prolongation

Answer 20

QT interval:
- beginning of QRS complex —> end of T wave
- QTc: corrected for HR > / < 60 bpm (by Bazett equation): ***0.44-0.45 secs
- Normal QTc: slightly prolonged in female (0.46 sec)

Criteria of Prolonged:
- Male: >0.45s
- Female: >0.46s
- Children: >0.46s

Question 21

Polymorphic Ventricular Tachycardia and TdP

Answer 21

PVT:
- multiple ventricular foci with the resultant QRS complexes varying in amplitude, axis and duration

TdP:
- specific form of PVT occurring in the context of QT prolongation

Question 22

1. Long QT syndrome (LQTS)

Answer 22

Characterised by:
1. QT prolongation
2. Propensity to Ventricular tachyarrhythmias

Clinical presentation:
- Syncope
- Seizures
- SCD
- can remain Asymptomatic

Etiologies:
- Congenital: Ion channelopathy
—> Autosomal Dominant: Romano-Ward syndrome
—> Autosomal Recessive: Jervell syndrome, Lange-Nielson syndrome —> congenital deafness

• Acquired: Drug-induced (may be genetically related), Bradycardia, Metabolic disorders, Malnutrition, Myocardial injuries, CNS disorders
  —> Pause-dependent TdP (onset of TdP is often preceded by a sequence of short-long-short R-R intervals, so called “pause dependent” TDP, with longer pauses associated with faster runs of TdP)

Question 23

Pathophysiology of Long QT syndrome

Answer 23

1. QT interval (i.e. Ventricular repolarisation)
   —> determined by K efflux, Ca + Na influx
   —> if Channelopathy
   —> LQTS
2. Prolonged repolarisation secondary to:
   —> **Reduced repolarisation current (Low K)
   —> **Enhanced depolarisation current (High Ca, Na)

Overall effect:
—> Functional substrate for **Transmural re-entry + **Polymorphic ventricular tachycardia (Torsade de pointes TdP)

Question 24

Congenital LQTS

Answer 24

Type 1-3 (2/3 of all LQTS):

LQTS1:
- KCNQ1 loss of function (K channel)
- ***tall, broad T wave
- exercise-induced TdP (esp. swimming)

LQTS2:
- KCNH2 loss of function (K channel)
- ***notch T wave
- arousal-induced TdP

LQTS3:
- SCN5A gain of function (Na channel)
- ***late peaking of T wave
- SCD during sleep

Question 25

Medical conditions associated with LQTS / TdP

Answer 25

***Electrolyte imbalance:
- HypoK
- HypoCa
- HypoMg

Medical conditions:
- Arrhythmia: AV block, severe bradycardia, sick sinus syndrome
- Endocrine: DM, hyperparathyroidism, hypothyroidism, phaeochromocytoma
- Neurologic: CVA, trauma, subarachnoid haemorrhage, encephalitis
- Nutritional: acute weight loss, alcoholism, liquid protein diet, starvation, obesity

ALL need to be excluded in LQTS

Question 26

Drugs associated with LQTS, TdP

Answer 26

1. ***Epinephrine
2. Anti-anginal
3. ***Anti-arrhythmic (Class 1A (Disopyramide), Class 3 (Sotalol))
4. ***Antibiotics (erythromycin, co-trimoxazole, clarithromycin, moxifloxacin)
5. ***Antihistamine (diphenhydramine)
6. ***Antifungal (flucoconazole, ketoconazole)
7. Diuretics (indapamide)
8. GI (cisapride)
9. Psychotropics (phenothiazine, amitriptyline, haloperidol, risperidone)
10. Tacrolimus
11. Chloral hydrate
12. Muscle relaxant

Question 27

Discrimination of LQT and LQTS

Answer 27

1. Clinical syndrome
   - symptoms
   - family history
   - other ECG findings
   - arrhythmia (presence of TdP)
2. **Exercise testing
   - maladaptation of QT interval duration to the changing HR, with evident QTc prolongation at a **faster HR +/- VT
3. **Genetic identification
   - known mutations in DNA samples
   - identification of LQTS gene mutation confirms diagnosis
   - **limited diagnostic value as +ve in 50%

Question 28

Diagnosis of LQTS

Answer 28

***Schwartz score

Definite: >=4
High probability: >=3.5
Intermediate: 1.5-3
Low: <=1

Criteria:
- **QTc
- HR
- T wave alternans
- T wave notching
- **TdP
- **syncope
- congenital deafness
- **family history

Question 29

Treatment of LQTS

Answer 29

1. Lifestyle advices
   - avoid strenuous / competitive exercise
   - avoid QT prolonging drugs
2. ***β-blockers
   - all patients unless CI
3. ***Left cervicothoracic stellectomy (remove Stellate ganglion)
   - anti-adrenergic measure in high-risk patients with LQTS
   - recurrence of cardiac events despite β-blocker
4. ***ICD
   - symptoms despite β-blockers
   - most effective for high-risk patients
   - deliver shock during TdP
5. ***Cardiac pacemakers
   - Eliminate Arrhythmogenic bradycardia
   - ↓ HR irregularities (eliminate short-long-short series)
   - ↓ Repolarisation heterogeneity
   —> ↓ risk of TdP ventricular tachycardia

Some high risk patients:
- β-blockers + Stellectomy + Cardioverter-defibrillator with Cardiac pacing function

Question 30

Prognosis of LQTS

Answer 30

• Good with β-blockers
• Very good after ICD
• TdP episodes are usually self-terminating
• 4-5% fatal

Question 31

2. Brugada syndrome

Answer 31

Pathophysiology:
- SCN5A loss of function —> ***↓ inward Na current —> abnormal electrophysiologic activity in RV

• Mean age: Mid-late 30
• M:F = 10:1
• Autosomal dominant with variable penetrance
• Periodic normalisation of ECG
• ***Na blockers used to unmask syndrome
• ***Malignant tachyarrhythmia at rest / night
• SCD due to VF: first event in some patients, high recurrence rate
• ***LQT/Brugada overlap syndrome
• possible overlap with ***ARVD suggested

Characterised by:
1. **ST elevation in right-sided precordial leads
2. **Conduction block at RV
3. Structurally normal heart
4. Propensity for life-threatening ***polymorphic ventricular tachyarrhythmia

Epidemiology:
- Asia: Type 1, 2

Question 32

Type 1, 2, 3 Brugada ECG

Answer 32

Type 1 (**Coved-type ST elevation):
- only diagnostic ECG in Brugada syndrome
- J-wave / ST elevation of >=2mm / 0.2 mV at its peak
- **Negative T wave with little / no isoelectric separation

Type 2 (**Saddle-back-type ST elevation):
- J-wave >=2mm
- gradually descending ST elevation (remaining >=1mm above baseline)
- **Positive / Biphasic T wave —> saddle-back

Type 3:
- Right precordial ST elevation (Saddle-back type / Coved type) without meeting aforementioned criteria

Question 33

Diagnosis of Brugada syndrome

Answer 33

1. Type 1 Brugada ECG pattern
2. Other Brugada ECG pattern
   - Type 2-3
3. Latent / Intermittent Brugada
   - Repeat ECG periodically
   - Repeat ECG at 2nd / 3rd ICS
   - ***administration of Na blockers: Ajmaline, Procainamide, Flecainide
4. Exclude ECG mimicking Type 1 Brugada syndrome (i.e. Brugada ECG phenocopy)
   - **MI
   - **PE
   - Myocardial / Pericardial diseases
   - Metabolic disorders
   - ***Mechanical compression of RVOT
   —> Brugada ECG pattern should resolve if above resolved
   —> Evidence supporting phenocopy: Absence of symptoms, Absence of family history, Negative Na channeling test

Question 34

Treatment of Brugada syndrome

Answer 34

Difficult (∵ lack of good stratification)

1. ICD
   - for symptomatic (e.g. syncope, seizure, nocturnal agonal respiration)
2. Follow-up for symptoms / ICD
   - for asymptomatic patients with spontaneous abnormal (type 1) ECG + inducible PVT
3. Follow-up (very low event rate)
   - avoid Brugada-aggravating drugs
   - treat fever early
   - avoid excess alcohol
   - avoid cocaine

Question 35

Familial hypercholesterolaemia (FH)

Answer 35

• Autosomal Dominant
• ***Elevated LDL
• Heterozygous: 1 in 200-500
• Mutations of ***LDL-R, ApoB, PCSK9, LDL-RAP
• ↑ risk of premature atherosclerotic coronary heart disease

Current treatments:
1. Statins
- ↓ Cholesterol synthesis
- ↑ SREBP-2 activity —> ↑ synthesis of LDL-R in liver
(but SREBP-2 also ↑ PCSK9 secretion)

2. Ezetimibe
3. Bile acid sequestrants
4. Niacin
   —> many still fail to achieve LDL target

Newer treatment:
5. PCSK9 inhibitor (Human mAb against PCSK9)
- ***Alirocumab
- PCSK9: enzyme mediating degradation of LDL-R
- significant no. of patient have gain-of-function mutation of PCSK9 —> Statin not effective

Question 36

Diagnosis of FH

Answer 36

1. Dutch lipid clinic criteria (not used in children)
   - Family history
   - Clinical history
   - Physical examination
   - Cholesterol level
   - DNA analysis
2. LDL-C level **>8 mmol/L —> FH for sure
   - **>=6.5 —> highly probable
3. Tendon xanthomata
4. ***Genetic testing
   - useful for family screening

Question 37

Management of FH

Answer 37

1. Lifestyle modification (Mandatory)
   - minimise CVS risk
2. Lipid-lowering drugs
   - target LDL-C (Adults: ***<2.5 mmol / L, Children: <3.5 mmol/L)