A multi-center preclinical research team involving Harvard Medical School, Brigham and Women’s Hospital, University of Oxford, and other prestigious research centers reveal that when too many of the heart’s molecular motor units get switched on and too few remain off, the heart muscle begins to contract excessively and fails to relax normally, leading to its gradual overexertion, thickening and failure. Treatment with an experimental small-molecule drug—produced by Third Rock Ventures-backed MyoKardia (founders include authors Jonathan & Christine Siedman)—restores proper contraction and energy consumption as the team has found in human and rodent heart cells. If subsequent studies can affirm these findings, new therapies could potentially help prevent common complications, including arrhythmias and heart failure.
The results of this research, published Jan. 27 in Circulation, reveal that a balancing act is an evolutionary mechanism conserved across species to regulate heart contraction by controlling the activity of a protein called myosin, the main contractile protein of the heart muscle. TrialSite News breaks this down below.
A condition in which a portion of the heart becomes thickened without an obvious cause. This results in the heart being less able to pump blood effectively. Symptoms vary from none to feeling tired, leg swelling and shortness of breath. It may also result in chest pain and fainting. Complications include heart failure, irregular heartbeat and sudden cardiac death. It is most commonly inherited from a person’s parents. It is often due to mutations in certain genes involved with making heart muscle proteins. There are other causes as well. Treatments include beta blockers, diuretics, or disopyramide. An implantable cardiac defibrillator could be recommended in those with certain types of irregular heartbeat. Surgery in the form of a septal myectomy or heart transplant, may be done in those who do not improve with other measures. No treatments address the underlying cause of the disease.
What Centers were involved in this Research?
- Harvard Medical School
- Brigham and Women’s Hospital
- University of Oxford
What is the basis of this Research?
The researchers, using heart cells from squirrels, mice and people identified an evolutionary mechanism critical for heart muscle function. They uncovered a gene defect that affects a protein found in the heart muscle that interferes with this mechanism to cause hypertrophic cardiomyopathy, a potentially fatal heart condition. Hypertrophic cardiomyopathy is the most common genetic disease of the heart and a leading cause of sudden cardiac death in young people and athletes.
What is the Core Finding?
Like a fleet of molecular motors that get turned on and off, these proteins cause the heart cells to contract, then form them to relax, beat after life-sustaining beat. Christine Seidman, professor of genetics in the Blavatnik Institute at Harvard Medical School (and a cardiologist at Brigham and Women’s Hospital and a Howard Hughes Medical Institute Investigator), reports, “Our findings offer a unifying explanation for the heart muscle pathology seen in the hypertrophic cardiomyopathy that leads to the heart muscle dysfunction and, eventually, causes the most common clinical manifestations of the condition”
Seidman noted, “Taken together, our findings map out the molecular mechanisms that give rise to the cardinal features of the disease,” Seidman said. “They can help explain how chronically overexerted heart cells with high energy consumption 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.”
A Future Treatment?
Importantly, the research experiments revealed that a treatment with an experimental small-molecule drug restored the balance of myosin arrangements and normalized the contraction and relaxation of both human and mouse cardiac cells that carried the two most common gene mutations responsible for nearly half of all hypertrophic cardiomyopathy worldwide. If this is confirmed in further research experiments, the results could inform the design of therapies that halt disease progression and prevent complications.
According to the study first author, Christopher Toepfer who performed the work as a postdoctoral researcher in Seidman’s lab and is now a joint fellow in Radcliffe Department of Medicine at the University of Oxford, “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.”
When studying ‘Imbalances in the motor fleet” the researchers noted that myosin initiates contraction by cross-linking with other proteins to propel the cell into motion. In the current study, the researchers traced the epicenter of mischief down to an imbalance in the ratio of myosin molecule arrangements inside heart cells. They note that cells containing hypertrophic cardiomyopathymutations had too many molecules ready to spring into action and too few myosin molecules idling standby which resulted in stronger contractions and poor relaxation of the cells. The team found that the ratio between “on” and “off” myosin molecules is off balance in heart cells that harbor hypertrophic cardiomyopathymutations, with disproportionately more molecules in active versus in active states. The team conducted a series of initial experiments analyzing heart cells obtained from a breed of hibernating squirrel as a model to reflect extremes in physiologic demands during normal activity and hibernation.
Pursuing the “on” and “off” Premise
Thereafter the team analyzed cardiac muscle cells from mice harboring the two most common gene defects in hypertrophic cardiomyopathy. As expected, these cells had altered ratios of “on” and “off” myosin reserves. The researchers also looked at myosin ratios in two types of human heart cells: Stem cell-derived human heart cells engineered in the lab to carry hypertrophic cardiomyopathy mutations and cells obtained from the excised cardiac muscle tissues of patients with hypertrophic cardiomyopathy. They reported both had out-of-balance ratios in their active and inactive myosin molecules.
Intense Fuel Consumption/Altered Metabolism
Additional experiments revealed that this imbalance perturbed the cells’ normal contraction and relaxation cycle. Again, cells harboring hypertrophic cardiomyopathy mutations contained too many “on” myosin molecules and contracted more forcefully but relaxed poorly. The study revealed that these cells consumed enormous amounts of ATP, the cellular fuel that sustains the work of each cell in the human body. As oxygen is necessary for ATP production, the mutated cells consumed far more oxygen than normal cells. To keep up with energy demands, the cells turned to breaking down sugar molecules and fatty acids—a sign of altered metabolism.
How to Restore Balance?
The research team found that they could restore the myosin ratios to levels comparable to those in heart cells free of hypertrophic cardiomyopathy mutations. This experimental treatment also normalized contraction and relaxation of the cells and lowered oxygen consumption to normal levels. The drug in use is produced by MyoKardia.
The Experimental Drug from MyoKardia
The experimental drug of interest discussed in this preclinical early-stage research is currently in human clinical trials. The compound is being developed MyoKarida, a biotech company founded in 2012 by two of the research authors—Christine Siedman and Jonathan Siedman and financed by Third Rock Ventures. See the company’s pipeline.
- Wellcome Trust
- Sarnoff Cardiovascular Research Foundation
- National Science Foundation
- MyoKardia (Third Rock Ventures—Seidmans—authors of study shareholders)
- Italian Ministry of Health
- American Heart Association
- A Alfred Taubman Medical Research Institute
- British Heart Foundation
- British Heart Foundation Centre of Research Excellence
- Leducq Foundation
- National Institutes of Health
- Sao Paulo Research Foundation
- Howard Hughes Medical Institute
Christine Seidman and Jonathan Seidman are lead authors of this study and they are founders and own shares in MyoKardia, a company developing therapies that target the heart muscle, including the chemical compound used in the experiments covered in this study.
Other investigators include: Christopher Toepfer, Amanda Garfinkel, Gabriela Venturini, Hiroko Wakimoto, Giuliana Repetti, Lorenzo Alamo, Arun Sharma, Radhika Agarwal, Jourdan Ewoldt, Paige Cloonan, Justin Letendre, Mingyue Lun, Iacopo Olivotto, Steven Colan, Euan Ashley, Daniel Jacoby, Michelle Michels, Charles Redwood, Hugh Watkins, Sharlene Day, James Staples, Raúl Padrón, Anant Chopra, Christopher Chen, Carolyn Ho, Alexandre Pereira.