Mar. 6, 2008 Using pacemakers to electrically retune a heart damaged by long bouts of a wobbling heartbeat, where one heart muscle wall is beating sooner than the other, leads to fast improvements in the tissue levels of more than a dozen proteins key to the organ's health, scientists at Johns Hopkins report in experiments in dogs.
The team's findings, published online this week in the journal Circulation, are believed to be the first detailed chemical analysis of the pacemaker's biological effects on the heart and could serve as the basis for more strategic use of combined device-plus-drug treatments for people with congestive heart failure.
"Our results really help explain how pacemakers act much like a drug, actually changing the biology of the heart, and also explain why people can feel so much better after just two to six months with the device," says study senior study investigator and cardiologist David Kass, M.D., a professor at the Johns Hopkins University School of Medicine and its Heart Institute.
"We are learning that pacemaker therapy does profoundly more than just mechanically correct how the heart beats; in fact, it produces major chemical changes that benefit the muscle," says lead investigator Khalid Chakir, Ph.D., a postdoctoral cardiology research fellow at Hopkins.
Each year, more than a half-million Americans are diagnosed with congestive heart failure, when the heart weakens and cannot pump enough blood to the rest of the body. One-quarter of those affected, typically men and women over age 50, will suffer from a pendulating, non-uniform contraction, requiring implantation of a pacemaker. The device electrically stimulates both sides of the heart at the same time, as part of so-called cardiac resynchronization therapy to restore unison to the heartbeat.
Current treatments with pacemakers, scientists say, can block the ill effects of an uneven heartbeat, extending people's lives for months to years or helping them return to daily activities. But these benefits do not directly fix the cause for the delayed conduction; they merely circumvent it.
"Now that we have found that resynchronization is doing more fundamental things to the heart muscle, we should be able to better combine these devices with drugs to maximize long-term survival and outcomes," says Kass.
Chakir says previous research has shown that a year after implantation, pacemaker resynchronization has been effective at reducing mortality in some heart failure patients by as much as 36 percent, but researchers have not until now really understood the biological effect of the devices beyond the physical mechanics of contraction.
In the current study, the Hopkins team determined the biological effects of pacemaker treatment on the hearts of 22 dogs with heart failure induced by making the heart beat faster. A key nervelike, electrical pathway that normally assures the muscle's harmonious beat was also damaged, producing a wobbly, discoordinated contraction. The asymmetric heart-failure condition was allowed to take its natural progressive course in half the dogs; the others had cardiac resynchronization therapy with implantation of a pacemaker.
Results from tissue analysis in these two groups of dogs were then compared to a third group of six dogs with healthy hearts.
In the heart failure groups, the scientists report major ups and downs in production or activity levels in 17 out of more than two dozen proteins known to be involved with heart cell stress, survival and death.
The alterations were especially notable in the group that did not have their hearts retuned. But tissue levels and activity of these proteins were restored toward normal in those with pacemakers that were tuned to reestablish an even, coordinated contraction, with both sides beating at the same time.
Among the stand-out proteins was one that prevents heart muscle cells from dying, an enzyme called phospho-BCL2 antagonist of cell death, or pBAD for short, which was found to be five times more active in the pacemaker-treated group than in the untreated group.
A second protein, p38 MAP kinase, known to stimulate fibrosis and cell death, was twice as active in late-contracting parts of failing hearts in untreated dogs, than in the same heart zone of dogs who underwent pacemaker resynchronization therapy.
Other proteins that lead to heart cell death and worsen contraction were overexpressed in dogs with untreated heart failure, but not in the pacemaker-treated group. These included calcium-calmodulin-dependent kinase (CaMKII), which is linked to arrhythmia, and tumor necrosis factor-alpha (TNFá), which is also tied to damaging inflammation and cell death.
The enzyme Akt, a promoter of cell survival when turned on, was markedly less active in the group whose hearts continued to beat out of sync.
Researchers next plan to look at how pacemakers stimulate biological changes in the heart, with the aim of developing treatments that bring the heart back to a normal, healthy state.
In cardiac resynchronization therapy, both major pumping chambers, known as the right and left ventricles, are stimulated at the same time with a biventricular pacemaker to optimize the muscle's beat so that one side does not beat a short time before the other.
The American Heart Association estimates that more than 5 million Americans have some form of congestive heart failure, marked by symptoms such as shortness of breath and fatigue.
Funding for the study was provided by the National Institutes of Health and the Peter Belfer Laboratory Foundation.
Besides Kass and Chakir, other researchers involved in this study, conducted solely at Hopkins, were Samantapudi Daya, M.D.; Richard Tunin, B.S.; Robert Helm, M.D.; Melissa Byrne, Ph.D.; Veronica Dimaano, M.D.; Albert C. Lardo, Ph.D.; Theodore Abraham, M.D.; and Gordon Tomaselli, M.D. Kass is also the Abraham and Virginia Weiss Professor of Cardiology at Hopkins.
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