Molecular understanding of atrial fibrillation progression may enable earlier treatment
Atrial fibrillation, the most common form of sustained abnormal heart rhythm, occurs when the two upper chambers of the heart called the atria beat fast and erratically, reducing the organ¹s ability to pump blood. When it first occurs, it often resolves on its own. In a later form called paroxysmal, it can last for as long as seven days and then reoccur. In its most serious form, atrial fibrillation becomes virtually permanent without treatment.
Why this progression occurs has been a mystery, but now an international team of researchers led by those at Baylor College of Medicine think the problem occurs at the molecular level, where a leak of calcium ions from an organelle known as the sarcoplasmic reticulum is mediated by the ryanodine receptor 2. A report on their work appears online in the journal Circulation.
Progressive form of condition
"What is the molecular fuel that makes the atria become more dysfunctional over time and permissive of chronic atrial fibrillation?" said Dr. Xander Wehrens, professor of Molecular Physiology and Biophysics and director of the Cardiovascular Research Institute at BCM.
In studies in mice that have this progressive form of atrial fibrillation, Wehrens and his colleagues found that a molecular event - phosphorylation increases, which sparks activity of the ryanodine receptor 2. If the mouse is bred to a mouse that has a mutation that blocks this phosphorylation, it prevents atrial remodeling, which is thought to be the central mechanism underlying the recurrence and maintenance of atrial fibrillation; ultimately, this mutation prevents atrial fibrillation.
Understanding how this progression occurs answers an important question, said Wehrens.
"Now people may wait until patients have more severe disease to do an ablation (a procedure to eradicate the malfunctioning cells in the heart) to treat the problem," said Wehrens, who holds the Juanita P. Quigley Endowed Chair in Cardiology. "If we can find a way to prevent this, people may never develop the more serious form of the disease. There is an active program to develop those kinds of drugs."
A recent report on which Wehrens and his colleagues were also authors showed that this kind of calcium leak occurs in people in the early stages of atrial fibrillation.
"This research was only possible because of the team work that involved some of the best known researchers in the world in atrial fibrillation," he said.
Others who took part in this work include: Na Li, David Chiang, Qiongling Wang, Liang Sun, Jonathan Respress, Sameer Ather, Darlene Skapura, Valerie Jordan and Frank Horrigan, all of BCM; Sufen Wang and Miguel Valderrabano of The Methodist Hospital; Niels Voigt and Dobromir Dobrev of the University Duisburg-Essen in Germany; Wilhelm Schmitz and Frank Müller of the University of Münster in Germany; and Stanley Nattel of the Montreal Heart Institute and Université de Montréal in Canada.
This work was funded by the American Heart Association (Grants 09POST2260300, 12BGIA12050207, 12PRE11700012 and 13EIA1456006), the National Heart, Lung and Blood Institute (Grants R01-HL089598 and R01- HL091947), the Fondation Leducq (‘Alliance for CaMKII Signaling in Heart’ and ‘European North-American Atrial Fibrillation Research Alliance’) the German Center for Cardiovascular Research and the Deutsche Forschungsgemeinschaft (Grant DFG MU 1376/11-1), the IZKF Münster (Grant Mü1/014/11) the Canadian Institutes of Health Research (Grants MGP6957 and MOP44365) and the Heart and Stroke Foundation of Canada. Chiang was also supported by the Baylor College of Medicine Medical Scientist Training Program Caskey Scholarship.