Medical researchers have been examining the link between excess calcium in heart cells and the death of those cells during heart attacks. But a new study at the Johns Hopkins University School of Medicine appears to throw a monkey wrench into this line of work.

A previous study in 2012 at the University of Iowa Carver College of Medicine demonstrated how the enzyme CaM kinase II triggers heart cell death following heart damage, showing the action takes place in the cells' energy-producing mitochondria. In animal tests, the team reported that blocking the enzyme could prevent heart cells from dying and protect the animals from heart failure.

The study demonstrated that activated CaM kinase II promotes leakiness of mitochondria and increases heart muscle damage by allowing too much calcium to enter mitochondria. Specifically, the research team found that CaM kinase II regulates calcium entry into mitochondria by modifying a special mitochondrial calcium channel. Simply put, too much enzyme activity increased the amount of calcium flowing into mitochondria, and this calcium overload triggers cell death.

But in a recent study of mice engineered to lack a key calcium channel in their heart cells, researchers appear to have now cast a shadow of doubt on that theory. Although this calcium channel is important for heart function, recent study results also showed this is almost certainly not going to be a good pathway to exploit in a long-term therapy, at least for heart attacks.

Through the years, the researchers, led by senior investigator Mark Anderson, M.D., Ph.D., director of the Department of Medicine at the Johns Hopkins University School of Medicine, began to understand the role of calcium in heart function. With each beat of the organ, molecules of calcium rush in and out of mitochondria powerhouses of heart and other cells.

Inside the mitochondria, calcium is generally a good thing because it helps generate energy the cells use to stay alive. But for almost half a century, researchers have also known that too much mitochondrial calcium can overwhelm and cause cells to die. And after a heart attack or stroke, a sudden rush of calcium into the organelles sets off this cell death pathway, leading to long-term damage.

But Anderson and colleagues decided to test the effects of blocking calcium from mitochondria by generating genetically-altered mice with a mutation that disabled heart mitochondrial calcium uniporter (MCE) function over the entire lifetime of the mice and blocked calcium flow to mitochondria in heart muscle cells.

Here's what happened. Although almost no calcium passed into the mitochondria of mice cardiomyocytes, their hearts still beat and developed normally. But when the team stressed the mice in a way that would normally cause an increase in heart rate, the mice heart rates only barely rose, and their heart muscles lost efficiency, requiring extra oxygen to function.

In further experiments, when the scientists cut off oxygen to the cardiomyocytes and then restarted it — which is what happens during some heart attacks — the cells still died, even though calcium in the mitochondria clearly wasn't causing the cell death.

The researchers discovered the cardiomyocytes were compensating for the lack of calcium by activating other cell death pathways and turning on a host of new genes to get that job done. Blocking calcium from the mitochondria, it turned out, just changed the way the cells died after a heart attack.

All in all, the predictions that blocking this calcium channel would protect against calcium overload didn't, in fact, protect against cell death. Future studies are needed to confirm whether the same is true in brain cells. However, these new results may dispute the idea of creating drugs to block MCUs in humans requiring long-term treatments to prevent heart attacks.