Pacemaker tune-up works chemical wonders on damaged hearts in dogs

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.