Cardiomyopathy and Arrhythmia Flashcards
(10 cards)
What is HCM?
o Genetically heterogeneous disorder (4 core genes)
o Can be autosomal dominant, but there are also recessive forms
o Referrals due to history of cardiac death in family / palpitations / ECG findings
o Hypertrophic (thickening of right ventricle)
o Heart less effective at pumping blood
o Leading cause of sudden cardiac death
o Prevalence : 1/500
o Associated with pathogenic variants in 4 core genes (sarcomere proteins)
o Echocardiogram + Electrocardiogram (ECG) screening
What is DCM?
o Dilated (Left ventricular enlargement (floppy left ventricle) o Incomplete penetrance
What is ARVC
o o AD
o Often associated with pathogenic variants in Desmin-related genes (DES)
o Desmin is an intermediate filament protein (linked to desmosomes)
o RYR2, DSP, PKP2, JUP, DSG2
o Arrhythmogenic right ventricular cardiomyopathy (diseased right ventricle subject to arrhythmias)
What are the Cardiomyopathy core genes and what do they do? What is involved in a cardiac contraction?
o Myosin binding proteins
o Found in striated muscle
o MYBPC3: Cardiac isoform exclusively found in cardiac cells
• Responsible for stability of sarcomere
o MYH7: subunit of cardiac myosin
• Expressed predominantly in ventricles
o TNNI3 & TNNT2
• Troponin proteins, located on thin filament of striated muscles and regulate muscle contraction in response to intracellular calcium ion concentration alterations
o Cardiac contraction:
o Calcium binds troponin complex
o Troponin releases inhibition of myosin-actin interctions
o ATPase activity and binding of actin by myosin head results in conformational change: generates power stroke
What is Long QT
• Prolonged QT interval on basal ECG
• Disorder of ventricular repolarization predisposing to cardiac arrhythmias, syncope and sudden death
• Prolonged QT can occur due to:
o Decrease in repolarizing current (potassium channel current essential for QT interval shortening during increased heard rate)
o Increase in excitatory membrane current (sodium or calcium channel currents)during action potentials plateau phase.
- Cardiac events usually in young healthy individuals – emotional stress or physical activity, can occur at rest
- Up to 30% carriers of path LQT variant without LongQT are still at risk of cardiac events by 40y.
- Variable penetrance and pleiotropic expression of phenotype complicate genotype-phenotype
What does pathogenic Homozygous KCNQ1 variant mean?
• Jervell and Lange- Nielsen syndrome:
o Jervell and Lange-Nielsen syndrome is a condition that causes profound hearing loss from birth and a disruption of the heart’s normal rhythm (arrhythmia). This disorder is a form of long QT syndrome, which is a heart condition that causes the heart (cardiac) muscle to take longer than usual to recharge between beats. Beginning in early childhood, the irregular heartbeats increase the risk of fainting (syncope) and sudden death.
o Jervell and Lange-Nielsen syndrome is caused by mutations in the KCNE1 and KCNQ1 genes.
o About 90 percent of cases of Jervell and Lange-Nielsen syndrome are caused by mutations in the KCNQ1 gene; KCNE1 mutations are responsible for the remaining cases. Mutations in these genes alter the usual structure and function of potassium channels or prevent the assembly of normal channels. These changes disrupt the flow of potassium ions in the inner ear and in cardiac muscle, leading to hearing loss and an irregular heart rhythm characteristic of Jervell and Lange-Nielsen syndrome.
What is Brugada?
electrical activity within the heart is abnormal. It increases the risk of abnormal heart rhythms and sudden cardiac death.
Associated with SCN5A variants
CPVT
inherited arrhythmogenic disease characterized by cardiac electrical instability exacerbated by acute activation of the adrenergic nervous system. Episodic syncope in individuals without
structural cardiac abnormalities, occurring during exercise or acute emotion, due to
onset of fast ventricular tachycardia. (Highly lethal- approx. 30% experience cardiac event and 80% experience syncope) 4 Major genes associated.
KCNQ1
LQT & JLN: alpha subunit of V-gated potassium channel required for repolarization phase of cardiac action potential (preferential expression from maternal allele)
Mutations cause reduction to potassium current
SCN5A
Voltage gated sodium channel subunit (Brugada)
Sodium channel folds onto itself to surround the channel pore. Mutations include missense and in-frame insertions or deletions. Associated with ‘Gain of function’ mutations that cause increased late inward sodium current prolonging action potential duration. SCN5A found in cardiac muscle, responsible for initial upstroke of action potential.
