Study identifies a faulty molecular brake in the most common form of hypertrophic cardiomyopathy
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A study in human and mouse heart cells identifies a faulty molecular brake in the most common form of hypertrophic cardiomyopathy, a leading cause of sudden cardiac death in young people and athletes and the most common genetic disease of the heart.
The faulty brake, found about a quarter of all genetic mutations in hypertrophic cardiomyopathy, interferes with the heart muscle’s ability to contract and relax,. Treatment with a chemical compound successfully restores normal contractility and relaxation in human heart cells.
Yet, the sparkplug that ignites such disordered muscle movement has thus far remained unknown.
Such approaches include medications to relieve symptoms, surgery to shave the enlarged heart muscle or implanting tiny cardioverter defibrillators that shock the heart back into rhythm if its electrical activity ceases or goes haywire.
“Our results reveal the presence of a unifying molecular mechanism the presence of an overactive motor that propels heart muscle dysfunction in HCM,”
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said study first author Christopher Toepfer, a postdoctoral researcher in genetics at the Blavatnik Institute at Harvard Medical School.
Toepfer said.
The glitch arises from a mutation in a gene that makes a protein called myosin-binding protein C3 (MyBPC3), the study showed.
But a series of experiments in human and mouse heart cells revealed that the mutated gene lacks this molecular brake.
Its absence, the work showed, put the cells of the heart muscle into overdrive, causing them to contract too much and relax poorly.
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When scientists compared sarcomeres in the beating heart cells of mice with and without the missing molecular brake, they noticed dramatically shorter and therefor more potently contracting and poorly relaxing sarcomeres in cells carrying the genetic mutation seen in HCM.
Indeed, these sarcomeres showed 100 percent increase in contraction compared with normal cells.
Mouse cells that lacked the molecular brake had abnormally prolonged relaxation between beats, a sign of disordered muscle relaxation, a feature present in people with the disease.
Toepfer said.
To initiate contraction, the heads of these myosin motors latch onto another protein called actin and pull it, then release it the essence of contraction that fuels the blood-pumping, life-sustaining movements of the heart muscle.
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This cycle of coupling and detachment repeats itself over and over again, heartbeat after heartbeat.
To achieve that, they turned to ATP, the universal fuel that propels all cellular activities, including myosin movement and muscle contraction.
Use of the compound currently tested in human trials successfully restored normal contractility of cardiac cells.
The compound is being developed by a biotech company, two of whose co-founders are authors on the study.
Treated mouse cells carrying the mutation showed dramatic reduction in overactive myosin heads compared with untreated cells.
The treatment normalized myosin function and reduced muscle hypercontractility in those cells.
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said study senior author Christine Seidman, cardiovascular geneticist in the Department of Genetics at HMS and in the Cardiovascular Division at Brigham and Women’s Hospital.
“We hope that our findings can be translated into medicines that directly treat the fundamental malfunction in HCM.”
Story source
Harvard Medical School