Cardiac - Hereditary Cardiac Diseases Flashcards
Types of hereditary cardiac diseases
Inherited cardiomyopathies
Inherited rhythm and conduction disorders
Familial hypercholesterolemia - CAD
Connective tissue diseases - Valvular heart diseases
List 4 major inherited cardiomyopathies**
Hypertrophic cardiomyopathy - HCM
Dilated cardiomyopathy - DCM
Arrhythmogenic Right Ventricular Cardiomyopathy - ARVC
Restrictive cardiomyopathy - RCM
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
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
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
Long QT syndrome
- Cut-off for Prolonged QT
- Formula for corrected QT
Long QT syndrome
- Presentation and symptoms
- Triggers
Syncope (usual)
Sudden cardiac death (usual)
Seizures
Triggers (like ACS): exercise, emotional stress, sleep (circadian), repose, etc.
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
List classes of drugs that can cause LQTS
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
Name of clinical diagnostic criteria for LQTS
Schwartz score
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
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)
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
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)
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
- Exclude secondary causes (amyloidosis, metabolic disease, phaeochromocytoma)
- Genetic Counselling (genotyping, family screening)
- Symptomatic: ***
- LVOTO: β blockers, disopyramide (verapamil), Myotomy-myectomy, septal alcohol ablation, dual chamber pacing
- No LVOTO: β blockers, calcium antagonists - High risk of SCD: implantable cardioverter defibrillator (ICD) ***
- High risk HF: ACE inhibitors, diuretics, β blockers
- 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»_space; T cell dysfunction»_space; 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:
- Drugs:
- ACE-I/ ARNI
- BB
- MRA
- Loop Diuretics
- Dapagliflozin - ICD, CRT
- Lifestyle modification:
- Low-intensity exercise only
- No exercise for 6 months after myocarditis - Immunosuppressant vs autoantibodies
- 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
- ECG
- Right heart catherization
- Cardiac MRI
- Nuclear scans for amyloidosis, sarcoidosis
- FDG- PET for sarcoidosis
- 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
