Failing hearts develop interference in their communication channels, according to research conducted at Washington University School of Medicine in St. Louis. The problem involves a subtle change in the pores that connect heart muscle cells. When the scientists duplicated this change in mice, the mice became susceptible to ventricular tachycardia, a dangerous heart rhythm disorder that can lead to sudden cardiac death.
The research was published in the January issue of the American Journal of Physiology-Heart and Circulatory Physiology.
“We identified an alteration in heart cell connections when we studied muscle samples from the hearts of patients who had undergone heart transplants,” says Kathryn A. Yamada, Ph.D., research associate professor of medicine in the Center for Cardiovascular Research. “We saw that these failing hearts had higher than normal amounts of a particular protein that is abundant in fetal hearts, but decreases as the heart matures. We found that it increases again in failing hearts.”
The protein is part of the heart’s system of signal conduction. In healthy hearts, the electrical signal required for the heart to contract properly propagates efficiently through pores called gap junctions that connect one muscle cell to another. Gap junctions are made of proteins called connexins, and the abnormally abundant protein measured by Yamada and her colleagues is connexin45.
In healthy adult heart cells, the majority of gap junctions are made up of another protein called connexin43. But the researchers found that in failing hearts, connexin45 was present in gap junctions in amounts 80 percent higher than usual while connexin43 levels fell.
“It seems that connexin45 has the ability to form hybrid pores or gap junctions with connexin43, and that reduces the coupling between cells,” Yamada says. “This abnormality in signal transmission may set up conditions for a reentrant circuit—a situation in which the electrical signal that stimulates ventricular muscle contraction loops back instead of moving across the heart. This can cause abnormal heart beats, or arrhythmias.”
The team engineered transgenic mice that overproduce connexin45 in their heart muscle. The heart cells of these mice showed altered cell-to-cell communication, and the mice had an increased tendency to experience ventricular tachycardia, a potentially dangerous increase in the excitation and contraction rate of the heart’s ventricles.
“Interestingly, it has been shown that the proteins that comprise gap junctions in the heart are replaced every few hours or so,” Yamada says. “This rapid turnover means that small changes in the formation or degradation of connexins in response to injury or disease can affect the function of heart cells dramatically, making connexin expression a significant marker of heart health and disease.”
Future studies in Yamada’s laboratory will use voltage-sensitive dyes to map electrical activity, enabling the researchers to locate precisely alterations of electrical signals in the hearts of transgenic mice that have excess connexin45. The research group also will study how changes in gap junction proteins affect the passage of other signals and influence the metabolism of muscle cells in failing hearts.
Betsuyaku T, Nnebe NS, Sundset R, Patibandla S, Krueger CM, Yamada KA. Overexpression of cardiac connexin45 increases susceptibility to ventricular tachyarrhythmias in vivo. American Journal of Physiology-Heart and Circulatory Physiology 2006 Jan;290(1):H163-H171.
Funding from the National Institutes of Health (Heart, Lung, and Blood Institute) and an American Heart Association Fellowship supported this research.
Washington University School of Medicine’s full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.