Athletes, are often looked upon by the general public as some sort of invincible warriors. Thus it is quite unsettling to hear news about an athlete collapsing due to a sudden cardiac arrest. Hypertrophic cardiomyopathy (HCM), is one such genetic condition that predisposes young adults to sudden heart failure. Physical fitness which generally helps maintain the physique and stamina, may strain the heart muscles even more for individuals with HCM, resulting in death.
Big heart is not always a blessing…
The heart muscles between the ventricles (septal wall) become abnormally thick (hypertrophied), and bulges, restricting or even blocking blood flow in severe cases. This may disrupt the electrical signals, and when coupled with vigorous physical activities, may lead to a cardiac arrest. HCM is one of the common causes for Sudden Cardiac Death (SCD) in young adults.
Myosin: The molecular motor of heart
The rhythmic pumping action of the heart is due to myosin, the in house motor. Myosin hydrolyses ATP and interacts with cytoskeletal actin to power the heart muscles into motion. Mutations in myosin gene causes HCM and was initially thought that these mutations reduce the power generation. A mouse model of HCM created with the same amino acid mutation as observed in humans, died of hypertrophic heart, when physically challenged. When the myosin protein from the model was isolated, it was found via in vitro cardiac contraction model, that the mutant motor protein had twice the motion-generating capacity and enhanced ATPase action compared to the normal myosin protein.
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“By analogy, placing the engine of an Indy race car (i.e., mutant myosin) in a stock car chassis (i.e., the heart’s connective tissue matrix) could lead to internal stress and structural damage,” Warshaw,Warshaw, professor and chair of molecular physiology and biophysics at the University of Vermont (UVM) College of Medicine writes in his “Perspectives” article. “For the heart, this amounts to inducing cardiac fibrosis and muscle cell disarray that are characteristic of HCM patients.”
Conventional medicine provides only two options: surgical thinning of septal wall between left and right ventricle or a heart transplant in severe cases. With 1 in 500 individuals having HCM, it could do a whole lot of good if there was a less invasive approach.
Don’t delay matters of the heart!
The gain of function mutant form of myosin is the culprit behind the hypertrophied heart. Thus the researchers inhibited myosin protein to reduce the high power output in a HCM heart, back to that of a normal heart.
MYK-461, a small molecule inhibitor (developed by Myokardia) was administered to HCM mice at two different time points: at an early age (8-15weeks) and post cardiac remodelling (30-35weeks). Surprisingly, only the early chronic drug administration prevented hypertrophy and the associated gene expression. Such a dramatic effect was not observed in older mice, thus suggesting that it is easier to prevent the pathological changes of HCM, than trying to revert back to normal heart muscle after the onset of the disease.
Because HCM runs in families, an infant who tests positive for the genetic mutation could receive the treatment and stave off the disease, Warshaw says. Development of a human drug, however, would require much more extensive testing and many remaining questions to be answered, he says.
Since this drug inhibits the myosin protein overproduction, this has the potential to cure HCM caused by any of the several mutations in myosin’s motor domain. We still have a long way to go in terms of gene therapy to correct a genetic defect, and thus such precision medicine platforms could be our best bet to keep the disease in check.
Source: University of Vermont
The original article can be accessed here.