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Cardiovascular > Hypertrophic cardiomyopathy > Flashcards

Hypertrophic cardiomyopathy Flashcards

1
Q

What is hypertrophic cardiomyopathy?

A

A disease in which the heart muscle becomes abnormally thick (hypertrophied)

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2
Q

Background about hypertrophic cardiomyopathy

A
  • 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%
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3
Q

What causes hypertrophic cardiomyopathy?

A
  • 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
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4
Q

Explain what myofibrils and sarcomeres are?

A
  • 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
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5
Q

How does muscle contraction happen?

A
  1. Action potential generated which stimulates muscle
  2. Ca2+ released
  3. Ca2+ binds to troponin shifting the actin filaments exposing binding sites
  4. Myosin cross bridges attach and detach pulling actin filaments towards centre (requires ATP)
  5. Muscle contracts
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6
Q

What causes HCM?

A
  • 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
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7
Q

What does hypertrophic cardiomyopathy cause?

A

• It causes left ventricular outflow tract obstruction (LVOT)

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8
Q

Compare a normal heart to a heart with left ventricular hypertrophy

A
  • 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
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9
Q

How likely is it to get HCM?

A
  • 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
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10
Q

What is a pathogenic variant?

A

• A genetic alteration which increases an individual’s susceptibility to a certain disease

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11
Q

What are the symptoms of HCM?

A
  • Shortness of breath - dyspnoea
  • Excess fluid in body
  • Arrythmia symptom – palpitation
  • Angina like symptom
  • Dizzy spells
  • Fainting episodes – syncope
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12
Q

How to diagnose HCM?

A
  • 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
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13
Q

How does LVOT impact us?

Symptoms

A
  • Shortness of breath
  • Chest pain
  • Presyncope
  • Syncope
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14
Q

How is obstruction measured

A

Measured by blood pressure which is measured by mercury mmHg

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15
Q

Which mercury level means there is abnormal obstruction?

A

> 30mHg

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16
Q

What are the current treatment options for HCM?

A
  • Beta blockers – metoprolol and propranolol

* Calcium channel blockers = verampil

17
Q

What are the limitations for the current HCM treatment

A

• Helps with function but does not target source of the problem

18
Q

How do calcium channel blockers manage LVOT obstruction

A
  • Calcium channel blockers inhibit entry of Ca2+ ions
  • Slow calcium channels in the myocardium during depolarisation
  • This inhibition produces relaxation in muscles
  • Reduces contraction
19
Q

List NEW drug treatments for HCM

A

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

20
Q

How do beta blockers manage LVOT obstruction

A
  • Prevents adrenergic signalling
  • Reduces heart rate
  • Improved ventricular relaxation
21
Q

What is Mavacamten?

A

NEW drug developed for HCM through targeted molecular approach

22
Q

How does Mavacamten work?

A
  • 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
23
Q

clinical trial - Pioneer HCM

A
  • 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
24
Q

Explorer HCM

A
  • 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

Cardiovascular (4 decks)

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