Editors' ChoiceCongestive Heart Failure

Like a Bridge over Troubled Waters: Innervation Changes in the Malfunctioning Heart

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Science Translational Medicine  10 Feb 2010:
Vol. 2, Issue 18, pp. ec21
DOI: 10.1126/scitranslmed.3000922

The sympathetic nervous system allows us to increase our cardiac output rapidly—an effect we all appreciate when we run up stairs. The stimulatory effects of sympathetic nerves (which produce the neurotransmitter norepinephrine) are balanced by the parasympathetic nervous system, which produces acetylcholine and reduces cardiac performance. In congestive heart failure, increased activation of the sympathetic nervous system causes damage to the heart muscle, a decline in heart function, and potentially lethal arrhythmias. β blockers, a major pillar of therapy for congestive heart failure, function by inhibiting sympathetic nervous system activity. Now, Kanazawa et al. demonstrate how a failing heart tries to keep these deleterious effects of sympathetic innervation at bay.

In an apparent cry for help, failing rat heart muscle cells secrete cytokines such as leukemia inhibitory factor, a member of the interleukin-6 family that signals through cytokine receptors containing the gp130 subunit. In response, the sympathetic nervous system itself offers a helping hand. Kanazawa et al. showed that norepinephrine-secreting fibers of these nerves respond to the cytokines by transdifferentiating into fibers that release acetylcholine instead. This same transdifferentiation was seen when gp130 was overexpressed solely in sympathetic neurons. Because earlier studies had shown that stimulation of the heart with acetylcholine enhances survival of animals with congestive heart failure, these results suggest that transdifferentiation protects an ailing heart.

Is this result relevant in humans? It appears so, because hearts from patients with congestive heart failure showed evidence of a similar neurotransmitter switch. The question arises whether such transdifferentiation plays a role in other diseases, such as diabetes, in which the ability of the sympathetic and parasympathetic systems to regulate glucose and lipid metabolism is impaired. The current study exemplifies transdifferentiation of the sympathetic nervous system and how to study it.

H. Kanazawa et al., Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-signaling cytokines in rodents. J. Clin. Invest. 120, 408–421 (2010). [Full Text]

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