New Precision Therapy in Development to Combat Cardiomyopathy

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Heart rate with ECG graph in the cyberspace

Researchers at Harvard may have discovered the molecular basis that can lead to cardiomyopathy in patients, as well as a new drug to treat this genetic conditions.

Cardiac cells, also known as cardiomyocytes, are unique muscular cells in the body, in that they will repeatedly contract, without rest, over the lifetime of an individual. By contracting in sync, they are responsible for pumping blood throughout the body.  Pacemaker cells ensure that they remained synced, but in case this pattern is disrupted, they will continue to contract individually, and involuntarily.  The intracellular organelle responsible for this contracting movement is called the myofibril.

A new study led by researchers at Harvard Medical School shows that when the ratio of contracted cardiomyocytes greatly exceeds relaxed cardiomyocytes, the entire heart muscle will contract excessively, leading to its gradual overexertion, thickening, and eventual failure.

Myosin, the main contractile protein of the myofibril, initiates contraction by cross-linking with other proteins to propel the cell into motion. In the current study, the researchers traced the molecular disruption to an imbalance in the ratio of myosin molecule arrangements inside myofibril.

An earlier study by the same team found that under normal conditions, the correct ratio of contracted to relaxed myosin molecules in mouse heart cells is around 2-to-3.  This new study shows that when this ratio is off (particularly in cells that harbor hypertrophic cardiomyopathy (HCM) mutations), a disproportionate number of cells will be in a contracted state, resulting in stronger contractions and poor relaxation of the cells.

The findings—based on experiments with human, mouse and squirrel heart cells—also demonstrate that when this mechanism is disrupted it sets off a molecular cascade that culminates in the development of HCM, the most common genetic disease of the heart and a leading cause of sudden cardiac death in young people and athletes.

“Our findings offer a unifying explanation for the heart muscle pathology seen in hypertrophic cardiomyopathy that leads to heart muscle dysfunction and, eventually, causes the most common clinical manifestations of the condition,” said senior author Christine Seidman, professor of genetics and cardiologist at Harvard Medical School.

When researchers looked at patient outcomes obtained from a database containing the clinical histories of people diagnosed with genetically based HCM, and compared the molecular laboratory findings against patient outcomes, the scientists observed that the presence of genetic variants that distorted myosin ratios also predicted the severity of symptoms and likelihood of poor outcomes, such as arrhythmias and heart failure, among the subset of people with these genetic mutations.

This study also showed cells carrying this genetic mutation consumed excessive amounts of ATP and oxygen. To sustain the cellular energy demands, these cells would break down sugar molecules and fatty acids, a sign of altered metabolism.

Seidman said, “[these experiments] can help explain how chronically overexerted heart cells with high energy consumption [and] in a state of metabolic stress can, over time, lead to a thickened heart muscle that contracts and relaxes abnormally and eventually becomes prone to arrhythmias, dysfunction and failure.”

The researchers on this study were simultaneously developing a compound to treat this condition in a biotech company two of the researchers on this study co-founded. The company provided research support for the study.

During the reasearch, the team found that treatment with an experimental, small-molecule drug they developed could restore the balance between the myosin arrangements in the myofibril, and successfully normalize the contraction and relaxation patterns in both human and mouse cardiac cells carrying the two most common genetic mutations – which represents nearly half of all HCM cases worldwide.

Laboratory tests showed that treating both mouse and human heart cells with this experimental drug restored the myosin ratios to levels comparable to those in heart cells free of HCM mutations, normalized contraction and relaxation of the cells, and lowered oxygen consumption to normal levels.

“Correcting the underlying molecular defect and normalizing the function of heart muscle cells could transform treatment options, which are currently limited to alleviating symptoms and preventing worst-case scenarios such as life-threatening rhythm disturbances and heart failure,” said study first author Christopher Toepfer, who performed the work as a postdoctoral researcher at the University of Oxford.

The drug is currently in human trials, and so far it has successfully restored myosin ratios, including in tissue obtained from the hearts of patients with HCM.

If these results can be confirmed in further experiments, they can inform the design of additional therapies, which could potentially halt heart disease progression and prevent complications.

“This information can help physicians stratify risk and tailor follow-ups and treatment accordingly,” Seidman added.

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