RESUMO
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 onward, Notch promotes a conduction-like phenotype based on ectopic expression of conduction system-specific genes and cell autonomous changes in electrophysiology. With the use of an in vitro assay to activate Notch in newborn cardiomyocytes, we observed global changes in the transcriptome, and 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.
Assuntos
Nó Atrioventricular/citologia , Regulação da Expressão Gênica no Desenvolvimento , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Receptor Notch1/fisiologia , Potenciais de Ação , Adenoviridae/genética , Animais , Animais Recém-Nascidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem da Célula , Contactina 2/biossíntese , Contactina 2/genética , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Camundongos , Miócitos Cardíacos/ultraestrutura , Canal de Sódio Disparado por Voltagem NAV1.5 , Plasticidade Neuronal , Técnicas de Patch-Clamp , Fenótipo , Ramos Subendocárdicos/citologia , Receptor Notch1/genética , Proteínas Recombinantes de Fusão/fisiologia , Transdução de Sinais/fisiologia , Canais de Sódio/biossíntese , Canais de Sódio/genética , Proteínas com Domínio T/biossíntese , Proteínas com Domínio T/genética , Fatores de Transcrição HES-1 , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genéticaRESUMO
OBJECTIVE: Inotrope score has been proposed as a marker of illness severity after pediatric cardiac surgery despite a lack of data to support its use as such. The goal of this study was to determine the association between inotropic/vasoactive support and clinical outcome in infants after cardiac surgery. DESIGN: Retrospective chart review. SETTING: Dedicated pediatric cardiothoracic intensive care unit at an academic, tertiary care medical center. PATIENTS: One hundred seventy-four patients 0 to 6 months of age admitted to the cardiothoracic intensive care unit after cardiac surgery with cardiopulmonary bypass between August 2007 and June 2008. Forty-three percent were neonates, and 39% had functional single ventricle physiology. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hourly doses of all vasoactive medications were recorded for the first 48 hrs after admission to the cardiothoracic intensive care unit and a vasoactive-inotropic score was calculated. The maximum vasoactive-inotropic score level over the first 48 hrs was a good predictor of poor clinical outcome (death, cardiac arrest, mechanical circulatory support, renal replacement therapy, and/or neurologic injury). After controlling for diagnosis, high maximum vasoactive-inotropic score was strongly associated with a poor outcome with an adjusted odds ratio of 8.1 (95% confidence interval, 3.4-19.2; p < .001) compared with patients with a low maximum vasoactive-inotropic score. High vasoactive-inotropic score was also associated with prolonged cardiothoracic intensive care unit stay, duration of mechanical ventilation, and time to negative fluid balance. CONCLUSIONS: 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.
