Hypertrophic cardiomyopathy Flashcards
What is hypertrophic cardiomyopathy?
A disease in which the heart muscle becomes abnormally thick (hypertrophied)
Background about hypertrophic cardiomyopathy
- Hypertrophic cardiomyopathy (HCM) is characterised by abnormal thickening of the LEFT ventricle
- Around 12,000 people in the UK and 20 million people worldwide affected
- Annual mortality rate of 0.5%
What causes hypertrophic cardiomyopathy?
- An inherited abnormal gene which causes the heart muscle in left ventricle to grow abnormally thick – causes muscle dysfunction
- Reduces amount of blood pumped out of the heart to the body
Explain what myofibrils and sarcomeres are?
- Heart is made of muscle fibre
- Muscle fibre made of myofibrils
- Myofibrils made of chain of sarcomeres
- Sarcomeres contain actin and myosin
- Dysfunction in chain of sarcomeres can cause HCM
How does muscle contraction happen?
- Action potential generated which stimulates muscle
- Ca2+ released
- Ca2+ binds to troponin shifting the actin filaments exposing binding sites
- Myosin cross bridges attach and detach pulling actin filaments towards centre (requires ATP)
- Muscle contracts
What causes HCM?
- Mutations in sarcomere proteins result in increased contractility – reduces relaxation of muscles causing muscle stiffness
- Too many myosin-actin cross bridges – hypercontractility
- Increased Ca2+ results in muscle contraction due to an increase in actin-myosin contracting movement which causes ENLARGEMENT of heart
What does hypertrophic cardiomyopathy cause?
• It causes left ventricular outflow tract obstruction (LVOT)
Compare a normal heart to a heart with left ventricular hypertrophy
- The cavity size has decreased in heart with Left ventricular hypertrophy which means decrease in blood uptake
- Less blood to pump
- The cavity size decrease can mean the heart is trying extra hard to meet the demands of the body
How likely is it to get HCM?
- It is a genetic condition – 50/50 chance of getting it due to pathogenic variant being inherited from one generation to another
- Can be detected during screening
What is a pathogenic variant?
• A genetic alteration which increases an individual’s susceptibility to a certain disease
What are the symptoms of HCM?
- Shortness of breath - dyspnoea
- Excess fluid in body
- Arrythmia symptom – palpitation
- Angina like symptom
- Dizzy spells
- Fainting episodes – syncope
How to diagnose HCM?
- An ECG will come up abnormal
- Shows repolarisation of heart (diastolic part)
- Echocardiogram can be done - thickening of wall can be seen
- Cardiac MRI – creates images which show how the heart and valves work
How does LVOT impact us?
Symptoms
- Shortness of breath
- Chest pain
- Presyncope
- Syncope
How is obstruction measured
Measured by blood pressure which is measured by mercury mmHg
Which mercury level means there is abnormal obstruction?
> 30mHg
What are the current treatment options for HCM?
- Beta blockers – metoprolol and propranolol
* Calcium channel blockers = verampil
What are the limitations for the current HCM treatment
• Helps with function but does not target source of the problem
How do calcium channel blockers manage LVOT obstruction
- Calcium channel blockers inhibit entry of Ca2+ ions
- Slow calcium channels in the myocardium during depolarisation
- This inhibition produces relaxation in muscles
- Reduces contraction
List NEW drug treatments for HCM
Blebbistatin - Ca2+ sensitivity - A myosin inhibitor mostly specific for myosin 2
Mavacamten - Reduces contractility by decreasing ATPase activity of sacromeric myosin
Disopyramide - Enhanced cardiomyocyte contraction
Cells responsible for generating contractile force in the intact heart
How do beta blockers manage LVOT obstruction
- Prevents adrenergic signalling
- Reduces heart rate
- Improved ventricular relaxation
What is Mavacamten?
NEW drug developed for HCM through targeted molecular approach
How does Mavacamten work?
- Selective allosteric modulator of cardiac myosin
- Reversibly binds to cardiac myosin to restore population of myosin heads in the ‘off state’
- Reduces cross-bridges and normalises ATP consumption
- Mavacamten can repopulate SUPER RELAXED STATE of myosin restoring cardiac reserve
- Reduces contractility and improving function
clinical trial - Pioneer HCM
- Open label nonrandomised phase 2 trial
- 21 patients with HCM
- Group A received Mavacamten without background medication
- Group B received Mavacamten with B-blockers
- Primary end point – change is LVOT (left ventricular outflow obstruction) gradient at 12 weeks
Explorer HCM
- Phase 3 double blind placebo controlled parallel group trial
- Randomisation either Mavacamten or placebo
- Individual doses given orally
- Patients assessed every 2-4 weeks
- Primary end point = greater increase in pVO2 (oxygen) AND one NYHA (heart failure stages) reduction
- Secondary endpoint: LVOT gradient decreased
