G-CSF treatment restores the expression of connexin 43 on cardiomyocytes near areas of heart attack–induced damage (arrows).

Cytokine therapy post–heart attack restores the expression of gap junction proteins and thus restores electrical connections between heart cells, according to a new study by Kuhlmann and colleagues (page 87). These heart cells, with better electrical connections, are able to pump with a more normal rhythm.

Restoring the function of damaged heart tissue is a new approach to the treatment of myocardial infarctions, or heart attacks. The scar tissue from heart attacks creates a roadblock for electrical conduction and can cause the heart to beat erratically. Indeed, erratic heartbeats—or arrhythmias—are the primary cause of death in patients who have had heart attacks.

Heart attack treatments range from blood-thinning and cholesterol-lowering drugs, which reduce the likelihood of developing blocked arteries, to implanted defibrillators that shock erratically beating hearts into line. But the idea of repairing damaged heart tissue is new. One promising repair approach involves the intravenous injection of two cytokines—G-CSF (granulocyte colony-stimulating factor) and SCF (stem cell factor)—which mobilize stem cells from the bone marrow (BM). Early studies suggested that these stem cells travel to the damaged heart and differentiate into functional heart cells called cardiomyocytes. Other studies, however, found no evidence that stem cells can become cardiomyocytes.

Kuhlmann and colleagues now confirm that G-CSF/SCF treatment in mice with heart damage causes BM-derived cells to enter the heart, but they show that virtually none of these cells become bona fide heart cells. The benefit of this treatment—which improved the heart's pump function and protected against induced arrhythmias—instead correlated with enhanced expression of the gap junction protein connexin 43 on the surface of heart cells adjacent to the injured tissue. The expression of connexin 43, which provides the electrical connection between neighboring cells, is decreased after heart injury, thus reducing the conductive capacity between cells.

The connexin-inducing effect of G-CSF might be direct, as cardiomyocyte expression of the G-CSF receptor was increased in response to injury. But this possibility is difficult to test in vitro, as mouse cardiomyocytes grow poorly in culture. The authors are also investigating G-CSF–independent signaling pathways that induce the expression of connexin 43 in other cell types.