The amount of cardiovascular support in the first 48 hrs after congenital heart surgery with cardiopulmonary bypass predicts eventual morbidity and mortality in young infants. The degree of support is best characterized by a maximum vasoactive-inotropic score obtained during this period. The usefulness of vasoactive-inotropic score as an independent predictor of clinical outcome in infants after cardiac surgery may have important implications for future cardiothoracic intensive care unit research.

Background Notch signaling has previously been shown to play an essential role in regulating cell fate decisions and differentiation during cardiogenesis in many systems including Drosophila, Xenopus and mammals. We hypothesized that Notch may also be involved in directing the progressive lineage restriction of cardiomyocytes into specialized conduction cells. Methods and Results In hearts where Notch signaling is activated within the myocardium from early development onwards, Notch promotes a conduction-like phenotype based on ectopic expression of conduction system-specific genes and cell autonomous changes in electrophysiology. Using an in vitro assay to activate Notch in newborn cardiomyocytes, we observed global changes in the transcriptome as well as in action potential characteristics consistent with reprogramming to a conduction-like phenotype. Conclusions Notch can instruct the differentiation of chamber cardiac progenitors into specialized conduction-like cells. Plasticity remains in late-stage cardiomyocytes, which has potential implications for engineering of specialized cardiovascular tissues.

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Notch signaling has previously been shown to play an essential role in regulating cell fate decisions in many systems. We hypothesized that Notch may be involved in directing the progressive lineage restriction of cardiomyocytes into specialized conduction cells. In murine hearts where Notch signaling is activated within the myocardium from early development onwards, Notch promotes a conduction‐like phenotype as evidenced by ectopic expression of conduction system‐specific genes, as well as cell autonomous changes in cellular electrophysiology. Activation of Notch in newborn ventricular cardiomyocytes from Contactin2‐EGFP transgenic mice, which specifically labels conduction cells, demonstrates Notch‐induced changes in “chamber” ventricular cardiomyocytes consistent with a phenotypic switch to Purkinje‐like cells, including transcriptional changes, action potential prolongation and hyperpolarization of the resting membrane potential. Taken together, this suggests that Notch can instruct the differentiation of cardiac progenitors into specialized conduction‐like cells and that this plasticity remains in late‐stage cardiomyocytes, which has potential implications for engineering of specialized cardiovascular tissues.Grant Funding Source: Career Award for Medical Scientists Burroughs Wellcome Fund and K08 HL107449‐01 to SR, U01 HL100405‐1 to JAE