Deadly Path to a Large Heart

Like the waistband in your favorite old pajamas, overstressed hearts often lose their elasticity and their ability to pump blood efficiently--a condition called congestive heart failure. The tired hearts are prone to arrhythmias that cause sudden death. Now researchers reporting in tomorrow's issue of the journal Cell have found an internal signaling pathway that causes a closely related form of heart failure in mice. The finding could lead to new drugs to keep stressed hearts from sagging.

Hearts try to compensate for abnormal stress on their walls by growing larger. That works for a while, but eventually the muscle cells get long and thin, and they fail like stretched elastic. Fibrous deposits also form and can cause arrhythmic beating and death. Scientists have long suspected that calcium in heart cells might play a role in this tragic transformation. So Eric Olson, a biologist at the University of Texas Southwestern Medical Center at Dallas, and colleagues were excited when they found a calcium regulating protein called NF-AT3 that also seemed to turn on the genes that caused enlargement of the heart.

To see if NF-AT3 could cause heart failure by itself, the researchers created mice that made an enzyme which kept the NF-AT3 pathway active, regardless of calcium levels. To the group's surprised satisfaction, the mice "recapitulate every physiological and pathological aspect of human heart failure," says Olson, including fibrous growth, arrhythmia, and sudden death.

Researchers caution that there may be other mechanisms that cause hearts to grow and fail in humans, but many are optimistic the finding may lead to new drug treatments. Indeed, Olsen's group gave the same mutant mice an immunosuppressant drug (cyclosporin) to block the NF-AT3 activity and found that it kept them healthy. Because the pathway seems specific to the heart, it could also be used to develop heart drugs with few side effects, says Stanford University Medical Center researcher Jerry Crabtree. "I would be very, very surprised if some drug company didn't immediately jump on this."