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Scientists have uncovered how a potential drug for hypertrophic cardiomyopathy might work to treat the root cause of the disease in heart’s muscles. Hypertrophic cardiomyopathy is a leading cause of sudden cardiac death in young people (such as the near-fatal cardiac arrest suffered by the then 23 year old footballer Fabrice Muamba, and the death of Sir David Frost’s son Miles Frost), but no current therapies treat the cause of the disease, many of which lie in the molecular motors that make the heart contract to pump blood around the body.

Now a study published in the journal Circulation has identified how the molecular motor (a protein called myosin) is altered in hypertrophic cardiomyopathy, and how a potential drug treatment reverses these changes in heart tissue from patients.

In people with hypertrophic cardiomyopathy, the heart walls are abnormally thick, with heart muscles contracting too much, and not relaxing enough between heart beats. These changes are ultimately caused by genetic changes in a gene for a protein called myosin, which makes heart muscles contract. New results from the study now suggest that the disease might be caused by damage to a mechanism that hibernating animals evolved to conserve energy.

Scientists already know that myosin can be folded into two different shapes, with one shape conserving energy by switching myosin ‘off’, and another state that contracts more, but uses up more energy. But the new study found that heart muscles from hibernating squirrels had more of the energy conserving ‘off’ myosin.

‘A hibernating animal might find it useful to switch to a less active form of myosin, to conserve energy while it is asleep, as the heart is a very energy-hungry organ’, said Oxford University’s Dr Christopher Toepfer. ‘But we wondered if humans also have the same energy-conserving ‘off’ state in their heart muscles too’.

So a team of researchers from Oxford University, Harvard Medical School, Boston University and other academic institutions in the US and Brazil studied heart muscles from people with hypertrophic cardiomyopathy.

The researchers found that hypertrophic cardiomyopathy patients had an abnormally high level of myosin in the high energy state, which made their heart cells contract more. Patients that had more energy-hungry myosin were more likely to suffer from irregular heartbeats and heart failure.

What seems to be happening is that a useful switch to toggle between energy-hungry and energy-conserving states is permanently stuck in the energy-hungry state in people with hypertrophic cardiomyopathy.
- Dr Christopher Toepfer

 ‘This explains why their heart muscles contract too much, and don’t relax properly,” said Dr Toepfer

“The good news is that this switch is reversible – when we applied a potential drug treatment to the patients’ heart muscles in a petri-dish, the myosin molecules change their shape, so that the normal myosin energy-conserving shape is restored.’

The drug, known as MYK-461 (Mavacamten), was developed specifically to treat hypertrophic cardiomyopathy, and it is now being tested in patients..

“By finding out what is happening in hypertrophic cardiomyopathy at the molecular level, we’re really hoping that we’ll finally be able to come up with a treatment that addresses the root cause of the disease, and help save lives’, said Dr. Toepfer.

The study was funded by the Wellcome Trust and the British Heart Foundation.

Read the paper.