Cardiac - Hereditary Cardiac Diseases Flashcards by Max Kam

Types of hereditary cardiac diseases

Inherited cardiomyopathies

Inherited rhythm and conduction disorders

Familial hypercholesterolemia - CAD

Connective tissue diseases - Valvular heart diseases

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List 4 major inherited cardiomyopathies**

Hypertrophic cardiomyopathy - HCM

Dilated cardiomyopathy - DCM

Arrhythmogenic Right Ventricular Cardiomyopathy - ARVC

Restrictive cardiomyopathy - RCM

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List 4 major types of inherited cardiac rhythm/ conduction disorders **

Long QT syndrome - LQTS ***

Brugada Syndrome - BrS ***

Catecholaminergic polymorphic VT - CPVT

Primary ciliary dyskinesia - PCCD

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Define cardiomyopathy

heterogeneous group of diseases of myocardium:
 Usually exhibit inappropriate ventricular hypertrophy/ dilatation
 Associated with mechanical and/or electrical dysfunction
 confined to the heart vs. part of generalized systemic disorders

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Long QT syndrome

- Pathogenesis

Pathogenesis: Ion balance/ Ion channel dysfunction

Prolonged ventricular repolarization due to Decreased repolarized current (Blocked K channels) and Increased depolarization current (High Na)
Causing transmural re-entry and risk of torsade de pointes, polymorphic ventricular tachycardia

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Long QT syndrome

Cut-off for Prolonged QT
Formula for corrected QT

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Long QT syndrome

Presentation and symptoms
Triggers

 Syncope (usual)
 Sudden cardiac death (usual)
 Seizures

Triggers (like ACS): exercise, emotional stress, sleep (circadian), repose, etc.

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Long QT Syndrome

Causes - Congenital and Acquired

Congenital:
- Ion Channelopathy (LQT1-10, JLN1, JLN2 mutations) due to Andersen syndrome, Timothy syndrome, Jervell and Lange-Nielson syndrome (AR) , Romano-Ward syndrome (AD)..etc

Acquired:

Drug-induced
Electrolyte imbalance: HypoK, HypoCa, HypoMg
** Myocardium ischemia, myocarditis **
Metabolic/ endocrine: DM, Hypothyroidism, Pheochromocytoma…
Nutritional: Anorexia/ starvation, Bulimia, Alcoholism…
CNS: Trauma, SAH, CVA, Encephalitis
Cardiac: AV block, severe bradycardia, sick sinus syndrome

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List classes of drugs that can cause LQTS

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First-line investigations for LQTS

Relevant clinical history for Dx

ECG: Long QT interval, Notched T wave/ T wave alternans, TdP
Stress testing:
a) Exercise testing (paradoxical QTc prolongation at faster HR)
b) Adrenergic stimulation (Trigger polymorphic VT/ TdP)
Exclude acuqired causes:
- Electrolytes
- Hormone tests
- Head CT (for CNS causes)
Genetic testing for ion channelopathies
- LQTS gene mutation, JLN gene mutation (50% positive only due to limited penetrance)

___________________________________________________
Clinical History:
- Syncope with/without stress
- Arrhythmias
- Congenital deafness

Family History:
- Family members with confirmed LQTS
- Unexplained Sudden Cardiac Death in young

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Name of clinical diagnostic criteria for LQTS

Schwartz score

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Long QT syndrome

Treatment

Resuscitate cardiac arrest
Lifestyle advices: Low-intensity exercise only, Reduce startles/ emotional stresses, avoid heat stroke, avoid AED usage
Beta-blockers (adrenergic blockade)***
Cardiac implants and surgery:
- Cardioverter-defibrillator (ICD)***,
- Left cervicothoracic stellectomy (anti-adrenergic),
- cardiac pacemakers (vs arrhythmogenic bradycardia),
- Left cardiac sympathetic denervation

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Brugada syndrome

- Pathogenesis

Defect in an ion channel gene - Mutation in SCN5A (cardiac Na+ channel gene) - Autosomal Dominant inheritance

> > Depolarization disorder in the RIGHT ventricle

> > ventricular tachyarrhythmias occurring at night/ at rest, causing sudden and unexpected death syndrome (SUDS) in males/ infants

SCN5A can also cause LQT3 - LQT/Brugada overlap syndrome
SCN5A also causes Arrhythmogenic right ventricular dysplasia (ARVD)

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First-line investigations for Brugada syndrome

ECG
- ST elevation in right precordial leads (V1-V3), Inverted T wave
- RV conduction block
- Na channel blockers (ajmaline/ procainamide/flecainide) trigger/ unmask polymorphic VT
ECHO
- Usually normal
- Septal hypertrophy, ARVC

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Subtypes of Brugada syndrome

Type 1 ECG pattern (Diagnostic)

Latent/ Intermittent Brugada syndrome (need repeat ECG with Na channel blocker)

Brugada-like ECG (RBBB, Septal hypertrophy, ARVC)

Brugada ECG phenocopies (MI, PE, myocardial/ pericardial diseases)

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Brugada syndrome

Presentation

Malignant tachyarrhythmias at rest/ night (vagal influence) 
Sudden Cardiac death 
Persistent/ recurrent arrhythmias
Syncope, Seizures
Nocturnal agonal respiration

Brugada syndrome

Treatment

Genetic counseling

Surgery: ICD, Catheter ablation

Recurrent ventricular arrhythmia: Adrenaline/ Isoproterenol (B-adrenergic agonist, analog of adrenaline)/ Quinidine (Class IA antiarrhythmic)

Life-style modification: Reduce fever, No alcohol, No cocaine

Familial hypercholesterolemia

Pathogenesis
Demographics

Mutation in LDLR, APOB, PCSK9, LDLPAR (Autosomal Dominant)

> > Reduce LDL uptake from blood
Increase LDL deposition on vessel walls
Increase risk of premature, atherosclerotic Coronary heart disease

Homozygous mutation: Sudden cardiac death at 12.5 years
Heterozygous mutation: SCD at 35 years

Familial hypercholesterolemia (FH)

Risk factors for SCD
Presentation

Same RFs as atherosclerotic CAD

Smoking, HTN, DM, Dyslipidemia…etc
Male sex

S/S:
 Xanthelasma
 Tendon xanthoma
 Sudden cardiac death

Familial hypercholesterolemia

Diagnostic criteria name
Classification name
Treatment options

Diagnosis: Dutch Lipid Clinic Network criteria
Classification: Frederickson Classification

Treatment:
1. Lifestyle modification: smoking cessation, dietary advice

Drugs:
Statins (HMG-CoA reductase inhibitors, e.g. atorvastatin)*** +/- Bile acid- binding resin, Fibrates, Niacins, PCSK9 inhibitors
Lipoprotein apheresis (refractory)
Family member screening: FH, SCD, LDL cholesterol levels, Genetic tests for mutations…etc

Hypertrophic cardiomyopathy (HCM)

Structural features
Epidemiology

Structural: Inappropriate LVH +/- LVOT obstruction

1) LVOT obstruction
2) Diastolic dysfunction
3) Myocardial ischemia
4) Mitral regurgitation

Epidemiology:
 1:500-1000 individuals
 Major cause of premature sudden cardiac death in young and apparently healthy athletes

Hypertrophic cardiomyopathy (HCM)

Causes (genetic and non-genetic)

Genetic: Autosomal dominant genetic defects

Sarcomeric protein gene mutation: MYBPC3, MYH7, TNNT3, TNN13, TPM1, MYL3…etc
IEMs: Glycogen storage diseases
Lysosomal storage diseases, Neuromuscular diseases…etc
Mitochondrial diseases

Acquired:

Amyloidosis
Drug-induced (tacrolimus, hydroxychloroquine, steroids)
Diabetic mother

Hypertrophic cardiomyopathy (HCM)

Clinical presentation

Variable presentations:

Incidental ECG/ ECHO
Dyspnea on exertion, orthopnea, PND
Angina
Pre-syncope/ syncope
Arrhythmias
Sudden Cardiac death

Hypertrophic cardiomyopathy (HCM)

Risk factors for sudden cardiac death

Clinical risk factors:
Cardiac arrest by V-Fib, sustained V-tach
Family history of premature SCD
Unexplained syncope

Risk factors on investigations:
Massive LVH on ECHO
LV systolic dysfunction on Cardiac MRI (CMR)
LV apical aneurysm on cardiac imaging

Hypertrophic cardiomyopathy (HCM) Treatment options

1. Exclude secondary causes (amyloidosis, metabolic disease, phaeochromocytoma) 2. Genetic Counselling (genotyping, family screening) 3. Symptomatic: *** - LVOTO: β blockers, disopyramide (verapamil), Myotomy-myectomy, septal alcohol ablation, dual chamber pacing - No LVOTO: β blockers, calcium antagonists 4. High risk of SCD: implantable cardioverter defibrillator (ICD) *** 5. High risk HF: ACE inhibitors, diuretics, β blockers 6. High risk arrhythmia: antiarrhythmics

Dilated cardiomyopathy (DCMP) Causes Presentation

Genetic: Familial DCMP - 90% AD Titin (TTN) and Lamin A/C (LMNA) gene mutations ** - Neuromuscular disorders: DMD, BMD, Myotonic dystrophy - Mitochondrial diseases Acquired: - Valvular heart disease - Viral myocarditis * - Myocardial ischemia - Toxins induced - Idiopathic Presentation: HF, SCD

Dilated cardiomyopathy (DCMP) Pathogenesis

Genetic mutations: - DNA mutation altering gene product or MHC mutation altering immune system >> T cell dysfunction >> Generate autoantibodies against myocardium Viral infection trigger: - Enteroviruses (esp. Coxsackie A/B), Herpesviruses, Adenovirus, Parcovirus..etc - Exacerbates immune response against myocardium - Myocardium damage

Dilate Cardiomyopathy Treatment options

Treat as Heart failure HFrEF: 1. Drugs: - ACE-I/ ARNI - BB - MRA - Loop Diuretics - Dapagliflozin 2. ICD, CRT 3. Lifestyle modification: - Low-intensity exercise only - No exercise for 6 months after myocarditis 4. Immunosuppressant vs autoantibodies 5. Intractable ventricular arrhythmia: LVAD, Heart transplant

Arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD) Pathogenesis Inheritance

Fibro-adipose infiltration into myocardium due to mutations: RyR2 gene, Desmoplakin, Plakoglobin...etc Inheritance:  Primarily autosomal dominant  Variable penetrance and expressivity (1/3 familial)

Arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD) Presentation

 Ventricular arrhythmias/ SCD in young □ Cardiac symptoms: palpitations, syncope, atypical chest pain □ Right heart failure  Naxos disease - Palmar-plantar keratoderma - Wooly hair - ARVD (May overlap with Brugada syndrome)

Arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD) First-line investigations

ECHO, MRI, RV angiography - RV akinesia/ dyskinesia, RV dilatation, Poor RV function ECG: Depolarization (Epsilon wave) or repolarization wave inversion in V1-V3 Arrhythmia: VT/ LBBB morphology Family history: family members with ARVC Tissue characterization (rarely done): Endomyocardial biopsy

Arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD) Risk factors for SCD

``` History of VT Poor LVEF (<35%) NSVT/ Inducible VT in electrophysiology stufy Male sex Desmosomal variants RV dysfunction ...etc ```

Treatment of ARVC

Genetic counseling Arrhythmia: ICD, BB, Antiarrhythmics RV dysfunction: Nitrates, ACEi/ ARB, BB, Diuretics Thromboembolism: Antithrombotic therapy HF: LVAD/ Heart transplant Lifestyle: No competitive/ high intensity exercises

Restrictive cardiomyopathy (RCM) Pathogenesis, presentation

Stiff myocardial wall due to inherited or acquired causes >> Normal systolic but abnormal diastolic dysfunction - rigid ventricular walls impeding LV filling (functionally resembles constrictive pericarditis) S/S: Symptoms: □ Venous congestion → dyspnoea, systemic congestion □ ↓CO → fatigue, weakness Signs: □ Congestive HF: pulmonary rales, distended veins, ascites, peripheral oedema □ Kussmaul sign/hepatojugular reflux: positive (due to poor RV compliance)

Restrictive cardiomyopathy (RCM) Causes- genetic and acquired

Genetic: AD mutation in sarcomere subunits, Myofibrillar myopathies...etc Endocardial fibroelastosis Acquired: - Idiopathic - Infiltrative diseases: Amyloidosis, Sarcoidosis - Storage diseases: Fabry disease, Gaucher disease, Hemochromatosis, MPS Type 1 and 2 - Diabetic cardiomyopathy - Scleroderma - Carcinoid heart diseases - Endomyocardial fibrosis - chemo drugs, radiation induced

Restrictive cardiomyopathy (RCM) First-line investigations

1. ECG 2. Right heart catherization 3. Cardiac MRI 4. Nuclear scans for amyloidosis, sarcoidosis 5. FDG- PET for sarcoidosis 6. Endomyocardial biopsy

Restrictive cardiomyopathy (RCM) Treatment

no specific Tx (other than symptomatic) available □ Treat underlying disease, eg. infiltrative disorders □ Idiopathic RCMP: usually with relentless symptomatic progression and high mortality