Researchers identify a defective "brake" that interferes with the heart muscle's ability to contract and relax

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease and one of the leading causes of sudden heart death in youth and athletes.

Scientists have long known that the cardinal element of the disease, namely an unusually thick heart muscle that contracts and relaxes abnormally, is fueled by glitches in the molecular mechanisms of the heart. Yet, the ignition candle that ignites such disordered muscle movement is so far unknown.

A new study conducted by researchers at Harvard Medical School and Brigham and Women's Hospital has highlighted a defective molecular brake present in the most common form of the disease and identified a candidate compound that would restore function cardiac muscle in human and mouse cells.

The results of the work are reported on January 23 at Translational medicine science.

If they are replicated in other studies, the team's findings can lead to the development of precision-targeted, essential therapies, which correct the dysfunction of the underlying muscle proteins in the body. HCM – a significant improvement over current treatments that attack the disease symptomatically, but not at its root cause. These approaches include medications to relieve symptoms, surgery to shave the enlarged heart muscle or implantation of tiny cardioverter defibrillators that shock the heart rhythmically if its electrical activity stops or runs out of steam.

"Our results reveal the presence of a unifying molecular mechanism, namely the presence of a hyperactive motor that promotes dysfunction of the heart muscle in the HCM," said the first author of the study. study, Christopher Toepfer, postdoctoral researcher in genetics at the Blavatnik Institute of Harvard Medical School.

"In addition, our results offer an interesting avenue for pharmacological treatment that can correct the defect and normalize the function of the heart muscle," said Toepfer.

Mischief in the engine

In this study, researchers have identified an aberration in the braking mechanisms of motors that propel the movement of the heart muscle. The glitch stems from a mutation in a gene that makes a protein called myosin binding protein C3 (MyBPC3), the study showed.

Cells carrying the mutated gene have too little of this molecular drag. Protein deficiency is the most prevalent genetic mutation in HCM. It is particularly common among people of South Asian descent, which is found in about 4% of people in this group.

Normally, MyBP-C acts like a shackle on another protein called myosin, the motor that forces cardiac muscle cells to contract and relax, beat after beat. But a series of experiments on human and mouse heart cells revealed that the mutated gene did not have this molecular brake. The work showed that his absence caused an overdrive of the heart muscle cells, forcing them to contract too much and relax badly.

To measure the effect of this anomaly, scientists have focused on a muscle component called sarcomere, the basic contractile unit of the muscle cell that regulates muscle contraction and relaxation. When scientists compared sarcomeres in the beating heart cells of mice with and without the missing molecular drag, they found a dramatic reduction – and thus a stronger contraction and relaxation – of sarcomeres in cells carrying the observed genetic mutation in HCM. Indeed, these sarcomeres showed a contraction of 100% greater than that of normal cells.

The researchers compared the duration of relaxation between heart beats in mice with and without mutation. Mouse cells lacking the molecular brake exhibited abnormally prolonged relaxation between beats, a sign of disordered muscle relaxation, characteristic of people with the disease.

"What we saw in our experiments reflected the characteristics of the disease – increased heart contractility and low relaxation," said Toepfer.

Muscle cells have a fleet of molecular motors (myosin proteins) that propels the heart muscle in motion. To initiate the contraction, the heads of these myosin motors attach to another protein called actin and pull it out and release it – the essence of the contraction that feeds the cardiac muscle life-sustaining movements essential to blood survival. This cycle of coupling and detachment is repeated again and again, heartbeat after heartbeat.

Under normal conditions, a subset of these driving heads should remain inactive, but the team's experiments revealed that the absence of the normal braking mechanism put the inactive pool in motion, forcing them to engulf excess cellular energy and to feed excessive muscular contractions – hypercontractility. seen in the disease.

Starve the engine

How could these primed molecular motors be stopped, the researchers wondered. To achieve this, they turned to ATP, the universal fuel that propels all cellular activities, including the movement of myosin and muscle contraction.

The team used a chemical known to block the action of myosin ATPase, the enzyme that releases cellular fuel and propels motor movement. The use of the compound – currently tested in human trials – successfully restores the normal contractility of heart cells. The compound is developed by a biotechnology company, whose two co-founders are the authors of the study.

When applied to human and mouse heart cells, the compound blocking ATPase slows the fuel consumption of the engines by extinguishing them. Mice treated with the mutation showed a dramatic reduction in the number of overactive myosin heads compared to untreated cells. The treatment normalized the function of myosin and reduced muscle hypercontractility in these cells.

The discovery paves the way for drug therapy to correct the underlying protein defect and restore cardiac muscle contractility in the hope of avoiding common and serious complications of the disease, including the dangerous heart rhythm disorder, atrial fibrillation and heart failure.

"Today, our treatment regimen for HCM remains limited to symptom relief," said lead author of the study, Christine Seidman, a cardiovascular geneticist at the Department of Genetics. HMS and the Cardiovascular Division of Brigham and Women's Hospital. "We hope that our results can be translated into drugs that directly address the fundamental dysfunction of HCM."

Provided by
Harvard Medical School