Aging and Disease Bring Symmetry to Heartbeat

Structural biologists rhapsodize about the beautiful symmetry of molecules, but when it comes to the rhythm of a beating heart, symmetry spells aging and disease.

Researchers at Beth Israel Deaconess Medical Center came to this conclusion after analyzing the heartbeat dynamics of 124 people with and without heart disease. More specifically, they found that the healthiest biological signals cannot be read backward.

Image courtesy of Ary Goldberger

Long-term cardiac recordings of healthy people (a, top) do not read the same way in reverse (b). But severe heart disease results in heartbeat patterns that look similar when read forward (c) and backward (d).

Signals from a normal heart have certain one-way dynamics. The heart takes more time to speed up during exercise than it does to recover to a resting heart rate, for example. And at rest, the heart quickens ever so slightly with each breath in and imperceptibly slows on exhalation.

But as a person becomes sicker, these cycles become more symmetric, according to postdoctoral fellow Madalena Costa, first author of a study in the Nov. 4 Physical Review Letters.

Most of the time asymmetry—or lack thereof—is too subtle to see with the naked eye. Using long-term cardiac recordings publicly available at PhysioNet, an NIH web resource, Costa and her co-authors developed a computational tool to put a number on the difference between signals read forward and those read backward.

Interestingly, the technique yields consistent results for aging and disease whether the fluctuations are analyzed second-by-second, beat-by-beat, or minute-by-minute. A previous analysis by other researchers based on only one time scale suggested that asymmetry increased with disease.

In contrast, Costa and her colleagues found the highest asymmetry, also called time irreversibility, in the heart recordings of healthy young people. Asymmetry decreased in healthy elderly people and plummeted in people with congestive heart failure and atrial fibrillation.

Such asymmetry is a fundamental feature of nonequilibrium systems, which are those that need to consume energy to keep functioning, said senior author Chung-Kang “CK” Peng, an assistant professor of medicine at BID and HMS.

“People talk about being in equilibrium as an enviable state of health,” said co-author Ary Goldberger, director of the Margret and H.A. Rey Institute for Nonlinear Dynamics in Medicine at BID and HMS professor of medicine. “Equilibrium is six feet under.”

The discovery will help guide efforts to understand the basis of heart rate control and may offer a simple way of monitoring the aging process and identifying individuals at high risk of cardiac and other life-threatening diseases, Goldberger said.

—Carol Cruzan Morton

Salmonella Block T Cells with a Touch

It is well known that T cells are necessary for controlling Salmonella infection, which causes typhoid and an estimated 1.4 million cases of food poisoning annually in the United States. But salmonella can overcome the T cell response, establishing infection that in some individuals can persist indefinitely, as in the case of the infamous Typhoid Mary, a silent carrier who caused several typhoid outbreaks.

Two years ago, Michael Starnbach, HMS associate professor of microbiology and molecular genetics, and colleagues showed that salmonella can kill dendritic cells, which activate T cells. In the Proceedings of the National Academy of Sciences published online the week of Nov. 21, Starnbach and colleagues, including postdoctoral fellow Adrianus van der Velden, report that Salmonella disables T cells directly merely by touching them.

“If the factor disabling the T cells can be identified, drugs might be designed that could interfere with Salmonella’s inhibition of immunity—possibly enabling the immune system to eradicate salmonella without the use of traditional antibiotics,” said Starnbach. The specificity of such a drug would be a hedge against the spread of antibiotic resistance. Additionally, the results suggest that a vaccine against Salmonella would need to be designed to overcome the inhibition of T cells.

The researchers began by engineering salmonella to produce a peptide from the egg protein ovalbumin so the immune systems of the laboratory mice would react against it. In vitro, these modified bacteria stimulated ovalbumin-specific T cells, as expected, but infection of whole animals failed to stimulate proliferation of these same T cells.

The question was, why? The researchers initially suspected that the lack of proliferation was once again the result of dendritic-cell destruction. But, said Starnbach, “We found in addition to killing the dendritic cell, Salmonella is also able to affect the T cell in a way that prevents the T cell from replicating in response to antigens.”

To inhibit T cell replication, salmonella had to touch the T cell. “If we separate the T cells from the salmonella with a little filter keeping them apart, but allowing the growth medium to go back and forth, we don’t get inhibition,” Starnbach said.

The researchers then showed that when salmonella touch the T cells, they secrete a factor into the assay medium that can prevent the T cells from proliferating in the absence of the -bacteria. “We are attempting to purify the factor and identify it biochemically,” Starnbach explained.
The researchers also have been trying to determine the gene encoding the T cell inhibitor by knocking out suspect genes.

—David Holzman

Proteasome Inhibitor Chokes Multiple Myeloma

A biologically active compound derived from ocean bacteria shows promising anticancer properties against the incurable bone marrow cancer multiple myeloma, Dana–Farber Cancer Institute researchers report in the November Cancer Cell. About 14,000 Americans are diagnosed annually with the disease.

The compound, NPI-0052, acts against this cancer by interfering with the activity of proteasomes, cellular garbage disposals that eliminate malfunctioning and unneeded cellular proteins. If the proteasomes do not work, these proteins accumulate inside the cell. In response, the cell commits suicide.

Since cancer cells multiply faster than normal cells, they build up defective and used proteins more rapidly. “In multiple myeloma, the proteasomes are working overtime,” said Dharminder Chauhan, first author of the study and HMS principal associate in medicine at DFCI. This renders cancer cells more susceptible to programmed cell death due to proteasome inhibition. This theory led researchers to investigate the use of proteasome inhibitors in cancer therapy in the first place.

Recently, the U.S. Food and Drug Administration approved a proteasome inhibitor, bortezomib (Velcade), to be used against refractory and relapsed multiple myeloma. But under prolonged use, patients have developed toxicities—the compound kills some normal cells as well as cancer cells—and resistance to the drug, rendering it ineffective.

NPI-0052 kills even bortezomib-resistant myeloma cells. And in animal studies, it appears to be highly effective. “Fifty-seven percent of mice treated with NPI-0052 showed no recurrence of tumor after stopping treatment,” Chauhan said.

One possible explanation of the new compound’s effectiveness is that proteasomes have three different activities for disposing of proteins. In both cell culture and in mice, bortezomib mostly disrupted just one of these activities, while NPI-0052 obstructed all three.

NPI-0052 also appears to be less toxic to normal cells than bortezomib. In the mouse studies, “the compound was well tolerated,” said Chauhan. It also can be taken by mouth, while bortezomib must be administered intravenously.

Because NPI-0052 causes programmed cell death via different pathways than bortezomib does, the two might be complementary. “The findings provide a rationale for clinical protocols evaluating NPI-0052 alone, and coupled with other novel agents, to improve myeloma patient outcome,” said senior author Kenneth Anderson, the Kraft family professor of medicine at HMS and DFCI.

Nereus Pharmaceuticals plans to file an investigational new drug (IND) application with the FDA by the end of the year, with trials at several centers, including Dana–Farber, starting in early 2006.

—David Holzman

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