In the confines of the thoracic chamber, a heart has lost its rhythm. Its two upper chambers, the atria, are beating out of sync with the two lower chambers, the ventricles. The resulting chaos is called atrial fibrillation and is a major concern because it prevents the heart from pumping effectively and is with serious complications including heart failure, dementia and a five fold increase in the risk of stroke.
The laboratories of Dr. Xander Wehrens at Baylor College of Medicine and Dr. Stephan Lehnart at the University of Goettingen in Germany are making headway into understanding the molecular mechanisms that underlie this devastating rhythm disorder. “At the molecular level, calcium is essential for maintaining a healthy heart beat,” said Wehrens, professor of molecular physiology and biophysics and the Juanita P. Quigley Endow Chair in Cardiology at Baylor.
The atrial fibrillation
Proper contraction and relaxation of the heart depends on the coordinate flux of calcium ions in; also out of individual cardiac muscle cells. Research in our lab focuses on understanding how these calcium dynamics are regulate in normal and disease hearts. Cardiac cells store calcium in a specialize compartment called the sarcoplasmic reticulum, or SR.
Using an unbias strategy for analysis, they identify a super complex of two essential protein machines; so a calcium release channel and a calcium reuptake pump; also find that both are actually regulate by the same molecular mechanism in heart cells.” As Wehrens, Alsina, Lehnart and their colleagues explore the molecular players; which involve in regulating SR calcium cycling, they discover a new piece of the puzzle that has change the field’s understanding of the molecular mechanisms leading to atrial fibrillation.
Using an unbiase technique called complexome profiling, Wehrens and colleagues found that a phosphatase regulatory subunit known as PPP1R3A binds to both the SR calcium release and reuptake complexes; forming one big super-complex that is present in atrial cells from both mice and humans. Furthermore, using a new imaging technique called ‘Stimulated Emission Depletion’ (STED) super-resolution microscopy; the team visually confirm that these two complexes are very close to each other.
Traditional confocal microscopy
“With traditional confocal microscopy they see blurry spots; but with STED they can clearly see individual molecules and estimate the distance between them,” said Wehrens; who is the director of the Cardiovascular Research Institute. “They find that components of the calcium release complex overlap with components of the calcium reuptake complex; also that this super-complex is also present in tissue samples from human atria.”
In addition, the researchers found that levels of PPP1R3A were decrease and the super-complex disrupt in atria of human patients with atrial fibrillation. These findings may have exciting implications for the future of atrial fibrillation treatments. As Wehrens explained, “a reduction in the amount of PPP1R3A may explain two defects in calcium handling in atrial fibrillation, opening the possibility of treating both defects at the same time.”
Lehnart emphasize that these findings were only possible through the combine efforts of multiple labs across the world. “Our joint work, which originate through independent efforts and methodologies in different laboratories; also shows the importance of international collaboration to understand; also eventually develop new therapies for complex diseases such as atrial fibrillation.”