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Revealed: The molecular mechanism underlying hypertrophic cardiomyopathy, or “workaholic heart”

Revealed: The molecular mechanism underlying hypertrophic cardiomyopathy, or “workaholic heart”

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The big throbby thing in the middle of your chest — your heart — is made mostly of muscle, whose rhythmic contractions force some 2,000 gallons a day of blood throughout our bodies. About one in every 500 of us is born with hypertrophic cardiomyopathy, a genetic disease caused by one of numerous mutations that, mysteriously, cause heart muscle to contract with too much force.

A team led by a Stanford scientists has figured out what many of these seemingly disparate mutations have in common — and opened the door to a whole new class of treatment for a disorder that has shortened too many lives short and constrained far more of them.

You’d think that hypertrophic cardiomyology would make you a natural athlete. But instead, it can be lethal. As Lasker Prize-winning Stanford biochemist Jim Spudich, PhD, says, “This is the disease that causes young athletes to keel over from sudden death on the basketball court.”

You can have too much of a good thing, says Spudich. “If you’re carrying one of these mutations, it’s as if you’re out for a jog. The problem is, you’re doing that 24 hours a day for your whole life.” At some point, your heart begins to feel the effects, becoming first swollen, then fibrotic, and eventually giving out.

Spudich has spent decades studying, at the molecular level, how muscles contract — and, in particular, the workings of myosin, a protein that’s a key constituent of every muscle cell, including the ones composing heart muscle.

Of the many mutations known to be able to cause hypertrophic cardiomyopathy, a preponderance — about 40 percent of them — occur in the gene coding for the particular variety of myosin found in heart muscle, leading Spudich to wonder what those mutations have in common.

Each myosin molecule is a hard-working little motor of sorts, whose dynamic action contributes to the overall contraction of a muscle. But it only works part time, spending much of its time in a posture akin to that of a sleeping flamingo, with its head tucked tightly into its torso. That’s just as it should be, from the standpoint of optimal heart function.

But a protein molecule is finicky. How well it works depends on what shape it’s in. (You can relate to that if you’ve ever flown all scrunched up in economy class on a long plane flight.)

Permit me to indulge my geek streak: Every protein molecule (including myosin) is born as a long string of small chemical building blocks called amino acids. There are 20 different types of amino acids, each with its own biochemical quirks and distinctive shape, like a jigsaw puzzle piece. Any genetic mutation that causes one amino acid type to be replaced by another can translate into a detrimental change in that protein’s ultimate 3D configuration, which is critical to how it functions.

In a years-long effort culminating recently in a paper in the Proceedings of the National Academy of Sciences, Spudich and his labmates showed that many hypertrophic cardiomyopathy-associated mutations, although they occur at different points along the myosin gene’s sequence, often wind up affecting amino acids on the same surface of the folded protein’s outer edge, altering the myosin molecule in ways that coax it out of its “sleeping flamingo” posture. The changed postural preference, in turn, keeps a myosin molecule from spending enough time snoozing on the job, collectively causing constant overdrive in heart muscle’s power output.

A company Spudich co-founded is developing a drug that might lull workaholic myosin molecules back into their torpor and calm the hypercontractile heart.

Photo by Alexas_Fotos

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