By David N. Leff

Of all the kerzillion cells in a human body, only a few, such as those of the adult heart muscle - the cardiomyocytes - can't divide and multiply. Molecular cardiologist Jagat Narula tells why:

"These heart cells are terminally differentiated," he explained. "Cardiac cells rarely grow. They can only increase in size, they can become big, but they seldom proliferate, as the other cells of the body do. In other words," Narula went on, "whatever a person's age is, the age of his or her heart muscle is the same.

"The important thing," he pointed out, "is that if the heart could just keep on enlarging it would never be able to maintain its size, shape and other special features. All the dividing cells in the body, which are producing similar cells, their own progeny, have to have a lot of machinery for synthesizing that kind of daughter cells.

"In the heart, what we have is not more synthetic machinery but more contractile machinery - contractile proteins where the heart muscle contracts. Because that is what you need of the heart," Narula observed. "You don't want it to be wasting its efforts towards producing new cells. Rather, you want it to be committed more to contraction - a kind of incessant pumping activity that it has to maintain for, say, 80 or 90 years of life." During those four-score years and 10, a healthy heart, at 72 strokes per minute, beats 3,405,888,000 times.

Narula made the point that because heart muscle cells are terminally differentiated, it used to be generally believed that they did not undergo programmed cell death - apoptosis. In 1996, he demonstrated that the contrary is true. "We showed that in congestive heart failure and in end-stage heart failure, the cardiac muscle cells do indeed commit cell death by apoptosis."

That finding, now widely accepted, points toward eventual pharmacological or genetic interventions to prevent or mitigate those apoptosis-triggered heart diseases.

"The important thing is that cell death is of two types," Narula observed. "One is necrosis, quite like a murder. The other is apoptosis, which is quite like a suicide. Necrosis," he explained, "is something in which you can not control things, unless you can avoid the insulting agent, typically ischemia. Similarly, inflammations and infections, like myocarditis. On the other side from necrosis is apoptosis, a programmed cell suicide. If that is occurring, you would have some ways to intervene at the right targets, to prevent the cell death, dysfunction of the heart, and heart failure.

"When congestive heart failure ensues," Narula recounted, "the cardiac muscle cells are forced to enlarge and grow, to compensate for the decrease in cardiac function. In such a pathophysiological conflict, the cells commit suicide, which contributes to heart failure."

Narula, a clinical cardiologist at Hahnemann University School of Medicine in Philadelphia, directs its Center for Molecular Cardiology, and heads research at its Heart Failure and Transplantation Center. He and a team of international investigators have just announced discovery of a mechanism inside the cardiomyocyte that triggers heart failure. Their paper in the current issue of the Proceedings of the National Academy of Sciences (PNAS), dated July 6, 1999, bears the title: "Apoptosis in heart failure: Release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy."

"This PNAS paper," Narula said, "demonstrates the upstream cascade, or chain of events, that is occurring in apoptosis. And our next attempt is going to be how can we intervene in this chain. Where can we attack, to prevent the apoptosis in heart failure?"

That attack must begin with the release of cytochroma c (cyt c) from its confinement inside the heart cell's mitochondria. Cyt c is a protein involved in the mitochondrion-initiated respiratory chain that is necessary for cellular respiration. That cascade is the relay-like transfer of electrons that powers the cell's energy source. (See BioWorld Today, Aug. 11, 1998, p. 1.)

"The moment a mitochondrion releases its cyt c," Narula related, "that protein goes on to activate various proteases - protein-cleaving enzymes - which can go to various contractile proteins in the cell. So if you have these proteases, which cut the contractile proteins, the cell should not be able to function. And if these specific protein- cleaving enzymes go into the nuclei, they would cut down the DNA, which would lead to cell death by apoptosis."

How To Keep Cyt C Locked Up

"Eventually the most important question would be: Can we prevent the release of cyt c in the heart muscle cells? If we are able to do that, we should be able to prevent apoptosis, and develop novel therapeutic regimens," he said. To answer such questions, Narula and his co-authors explanted the diseased hearts of 16 patients undergoing cardiac transplant, plus five healthy control organs from people who had died of road accidents, and tissues from three donor hearts. They found evidence of apoptosis in the cardiomyopathic hearts but none in the normal controls.

"There are over 1.5 million people in this country who have congestive heart failures," Narula observed. "Some 400,000 new patients are diagnosed every year with heart failure. We know that this number is increasing, and will continue to increase, because the age of the country's population is increasing; longevity is increasing, as well as heart attacks, which eventually can lead to their heart failure. Previously, people used to die early of the disease. Now, with improved management, deaths are down, so there are more chances that these people would develop the complications of heart attacks, and will have more heart failure.

"The ultimate management strategy that we have," Narula pointed out, "is cardiac organ transplantation. But it's available to not more than 2,500 patients in a year. So we need to explore these apoptosis-preventing pharmacological or genetic strategies that are able to prevent congestive heart failure, because the five-year survival outcome after the diagnosis is dismal."