Editors' ChoiceHeart Disease

The Pacemaker Goes Organic

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Science Translational Medicine  14 Mar 2012:
Vol. 4, Issue 125, pp. 125ec44
DOI: 10.1126/scitranslmed.3003978

Pacemakers are popular: Approximately 3 million people worldwide sport these devices, and ~600,000 are implanted each year. But if we’ve learned anything from overly revealing Facebook posts, it’s that “popular” doesn’t mean unequivocally good. In addition to the potential surgical and mechanical problems associated with electronic pacemakers—infection, need for replacement, interference from other devices—implanted generators are unable to respond to input from the autonomic nerves in response to physiological conditions. Thus, researchers have sought to develop biological pacemakers. Mandel et al. now show that human embryonic stem cell–derived cardiomyocytes (HE-CMs) and induced pluripotent stem cell–derived cardiomyocytes (IP-CMs) might serve this purpose.

Pacemakers are usually implanted in order to treat slow beating of the heart, which can occur because of either malfunction of the physiological pacemaker (sinoatrial node) or blockade in the electrical conduction system. Functionality of the sinoatrial node is complex: Essential characteristics include the exerting of dominance over the underlying myocardium, spontaneous activity with reactivity to rate-modifying drugs, and beat-to-beat variability (“sinus rhythm arrhythmia”).

In vitro, HE-CMs and IP-CMs displayed spontaneous contractions with a consistent frequency throughout a 15-day follow-up period that was reactive to treatment with rate-increasing and -reducing drugs. When the authors applied power-law relations by plotting short-term versus long-term interbeat variability, both cell types exhibited intrinsic variability and showed oscillations in rate fluctuations, both traits that resemble characteristics of the sinoatrial node. Furthermore, Mandel et al. elegantly demonstrated that analysis of the power-law relations might be a useful tool to screen for the suitability of cells to act as biological pacemakers.

The paper by Mandel et al. is of special interest, not only because it documents the general ability of HE-CMs and IP-CMs to display critical features of the sinoatrial node, but also because it provides tools with which to evaluate the necessary structural and functional organization of cells in culture. Although the results are promising, the work sheds light on the immense complexity that accompanies the fabrication of a successful biological pacemaker. Challenges span the experimental terrain from the unknown behavior of pluripotent heterogenous cells over the long term and within a living organism to problems of incorporating transplanted cells within the myocardial structure and the conductive system. These challenges need to be addressed before the organic pacemaker becomes a phenomenon.

Y. Mandel et al., Human embryonic and induced pluripotent stem cell−derived cardiomyocytes exhibit beat rate variability and power-law behavior. Circulation 125, 883–893 (2012). [Abstract]

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