Three years of microscopic experiments on heart cells has led to a discovery by a team of University of Maryland researchers and collaborators of the workings of faint calcium signals in the heart cells, a discovery that may translate into new therapies for heart disease.
The researchers named the heart cell signals "quarky" calcium release or QCR.
Perhaps not yet ready for primetime news, but the discovery's publication has made a deep impact in the field of heart physiology, with over 1,400 downloads from the journal Circulation Research in just one month, one of the highest ever, according to managing editor Jonathan Schultz. The paper is the cover story and is accompanied by a supporting editorial.
The new work builds on prior heart research on what are called "Ca2+ sparks," elemental units of calcium that are naturally released from an internal cellular compartment called the sarcoplasmic reticulum (SR).
In the heart muscle, calcium sparks have a fundamental role in linking the heart's electrical activity to its contraction or heart beats.
"Now, we have found that the Ca2+ spark is not the only form of SR calcium release," explains lead author Didier Brochet, PhD, research associate at the University of Maryland's Center for Biomedical Engineering and Technology (BioMET). "We thought previously there was only one kind of SR calcium release. Now there is another pathway of the SR calcium release, called 'Quarky Ca2+ release' (QCR) because of its very small size. This release is like a Ca2+ quark, the smallest unit of Ca2+ release. The occurrence of QCR is nearly invisible and can reduce the amount of calcium in the SR, the heart's Ca2+ storehouse between beats in ways that may affect the heart's ability to beat properly."
Brochet says a current research and therapeutic goal is the identification and characterization of a drug that can stop the quarky calcium release. He notes that such a drug will offer a new way to treat heart disease including arrhythmias and poor contraction and may lead to a healthier heart.
The new release event was termed "quarky" because it measures the opening of one or a few individual SR calcium release channels. Scientists had called the release of one normal channel a "calcium quark," but until now, no one has been able to see anything close to the hypothesized event.
The research team developed new imaging techniques with improved detection ability and sensitivity to probe animal heart cells. They were able to discover the smaller calcium release events, which are about a tenth of the size of Ca2+ sparks. They investigated QCR and Ca2+ spark events and their interplay. Surprisingly they found that the quarky events were much more frequent that common calcium sparks between heart beats, with the QRCs' total contribution to calcium release during this inter-beat period approximately equal in strength to the sparks. That fact is significant to further comparative study of healthy vs. unhealthy heart tissue.
Because cardiovascular disease─including cardiac arrhythmia and sudden cardiac death and stroke─is the leading cause of death worldwide, any significant new insight into the physiology of the heart is huge, said co-author W. Jonathan Lederer, M.D., Ph.D. director of BioMET.
"These small SR calcium releases were very significant. We were not expecting them," said Brochet. "The new imaging technique enabled us to detect subtle calcium release events that otherwise would be difficult to discriminate from noise."
Such faint events evidently play an important role in shaping how calcium is released from the heart cells. "They contribute to 'invisible' calcium release in health and disease," said Brochet
"Our results reveal that low-flux quarky calcium release events coexist and interplay with regular calcium sparks to provide rich calcium signaling substructure and complexity. We found that QCR events were 10 times more frequent than spontaneous Ca2+ sparks between beats. They are very significant."
The experiments were carried out in heart cells from healthy animals. Currently the team is running the same experiments on animal models of human disease. "That will give us the controls we need to gauge the extent to which the QRCs influence the health of the cells. That information will be useful to researchers developing new drugs to quiet quarky release," Brochet said.
"These quarky calcium release events are very abundant in health and also certainly in disease. The idea is to evaluate how important they are in the development of arrhythmia and heart failure." said Brochet.
"If we were able to specifically inhibit these quarky events, we then may be able to cure arrhythmia and heart failure without altering the contractile functions of the heart. In summary, we would get a better heart." That's what we all hope for!
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