A key advance in research could lead to new treatments for heart disease

Scientists examining the beating heart have solved a fundamental decades-old mystery about how the heart works. This revelation could herald the development of new treatments for heart disease, the leading cause of death worldwide.

Researchers from Eastern Virginia Medical School, Florida State University and the University of Virginia have observed a tiny muscle filament during a crucial stage of a beating heart for the first time. The research has been published in Proceedings of the National Academy of Sciences.

The heart is a single muscle that contracts and relaxes about once per second in most people. Each heartbeat relies on cyclical interactions between the thick and thin filaments of heart muscle — a process orchestrated by increasing and decreasing levels of calcium, said Vitold Galkin, associate professor of physiological sciences at Eastern Virginia Medical School and author of the study.

During the “systolic” phase, calcium binds to the thin filaments and allows interactions with the thick filaments to produce the force necessary for the contraction of the heart muscle.

“For decades, the structure of the fine filament at this important point was unknown,” Galkin said. “This has significantly limited our understanding of the regulation of fine filaments by calcium.”

The researchers worked for two years to overcome the technical challenges presented by the complex structure of the thin filament and the difficulty of preparing the sample for examination.

With these challenges overcome, the team used cryo-electron microscopy to directly observe the structure of the thin filament as the heart contracts and beats, findings that open a new avenue for heart disease research.

“We can now fully understand how inherited diseases of the heart affect its ability to function,” said Jose R. Pinto, associate professor of biomedical sciences at Florida State University. “Basically, we have created a new structural model for the cardiac thin filament, and based on this, we can now answer several existing questions about how the heart works in health and disease.”

The research team’s data reveals how parts of the thin filament cooperate to move from the diastole phase of the heartbeat – when the heart muscle is relaxed – to systole, when the heart muscle contracts and pumps blood.

“Advancing our fundamental knowledge of cardiac muscle regulation opens the way to the rational design of tailored therapeutic interventions that can improve cardiac muscle function in diseased hearts,” Galkin said.

The research was groundbreaking for several reasons, said co-investigator P. Bryant Chase, professor of biological sciences at Florida State University. This includes the identification of individual structures along thin filaments at three calcium concentrations – including a previously unknown structure at systolic calcium – and the use of thin filaments from a pig’s heart, whose size and heart rates are very similar to those of a human heart.

“Our results provide a fundamental new basis for understanding and modeling the thin filament in health and disease, as a number of genetic heart diseases affect thin filament proteins,” he said.

This research was funded by the National Heart, Lung, and Blood Institute.

The EVMS research team included Galkin; Cristina Risi, researcher in physiological sciences; Ian Pepper, graduate student; Betty Belknap, research associate in physiological sciences; and Howard White, professor of physiological sciences. The FSU research team included Pinto, Chase, and graduate student Maicon Landim-Vieira. The University of Virginia researcher was Kelly A. Dryden, associate professor of research, molecular physiology and biological physics.