RESUMEN
Cardiomyocyte (CM) proliferation and maturation are highly linked processes, however, the extent to which these processes are controlled by a single signaling axis is unclear. Here, we show the previously undescribed role of Hedgehog (HH)-GLI2-CKS1B cascade in regulation of the toggle between CM proliferation and maturation. Here we show downregulation of GLI-signaling in adult human CM, adult murine CM, and in late-stage hiPSC-CM leading to their maturation. In early-stage hiPSC-CM, inhibition of HH- or GLI-proteins enhanced CM maturation with increased maturation indices, increased calcium handling, and transcriptome. Mechanistically, we identified CKS1B, as a new effector of GLI2 in CMs. GLI2 binds the CKS1B promoter to regulate its expression. CKS1B overexpression in late-stage hiPSC-CMs led to increased proliferation with loss of maturation in CMs. Next, analysis of datasets of patients with heart disease showed a significant enrichment of GLI2-signaling in patients with ischemic heart failure (HF) or dilated-cardiomyopathy (DCM) disease, indicating operational GLI2-signaling in the stressed heart. Thus, the Hh-GLI2-CKS1B axis regulates the proliferation-maturation transition and provides targets to enhance cardiac tissue engineering and regenerative therapies.
Asunto(s)
Proliferación Celular , Miocitos Cardíacos , Proteína Gli2 con Dedos de Zinc , Miocitos Cardíacos/metabolismo , Humanos , Proteína Gli2 con Dedos de Zinc/metabolismo , Proteína Gli2 con Dedos de Zinc/genética , Animales , Ratones , Proteínas Hedgehog/metabolismo , Transducción de Señal , Células Madre Pluripotentes Inducidas/metabolismo , Diferenciación CelularRESUMEN
Many efforts to design introductory "cultural competence" courses for medical students rely on an information delivery (competence) paradigm, which can exoticize patients while obscuring social context, medical culture, and power structures. Other approaches foster a general open-minded orientation, which can remain nebulous without clear grounding principles. Medical educators are increasingly recognizing the limitations of both approaches and calling for strategies that reenvision cultural competence training. Successfully realizing such alternative strategies requires the development of comprehensive models that specify and integrate theoretical frameworks, content, and teaching principles.In this article, the authors present one such model: Introduction to Medicine and Society (IMS), a required cultural competence course launched in 2013 for first-year medical students at the Perelman School of Medicine at the University of Pennsylvania. Building on critical pedagogy, IMS is centered on a novel specification of "critical consciousness" in clinical practice as an orientation to understanding and pragmatic action in three relational domains: internal, interpersonal, and structural. Instead of transmitting discrete "facts" about patient "types," IMS content provokes students to engage with complex questions bridging the three domains. Learning takes place in a small-group space specifically designed to spur transformation toward critical consciousness. After discussing the three key components of the course design and describing a representative session, the authors discuss the IMS model's implications, reception by students and faculty, and potential for expansion. Their early experience suggests the IMS model successfully engages students and prepares future physicians to critically examine experiences, manage interpersonal dynamics, and structurally contextualize patient encounters.
Asunto(s)
Estado de Conciencia , Competencia Cultural/educación , Curriculum , Educación de Pregrado en Medicina/organización & administración , Estudiantes de Medicina/psicología , Humanos , PennsylvaniaRESUMEN
OBJECTIVE: A concern with the initiation of totally endoscopic robotic mitral valve repair (TERMR) programs has been the risk for the learning curve. To minimize this risk, we initiated a TERMR program with a defined team and structured learning approach before clinical implementation. METHODS: A dedicated team (two surgeons, one cardiac anesthesiologist, one perfusionist, and two nurses) was trained with clinical scenarios, simulations, wet laboratories, and "expert" observation for 3 months. This team then performed a series of TERMRs of varying complexity. RESULTS: Thirty-two isolated TERMRs were performed during the first programmatic year. All operations included mitral valve repair, left atrial appendage exclusion, and annuloplasty device implantation. Additional procedures included leaflet resection, neochordae insertion, atrial ablation, and papillary muscle shortening. Longer clamp times were associated with number of neochordae (P < 0.01), papillary muscle procedures (P < 0.01), and leaflet resection (P = 0.06). Sequential case number had no impact on cross-clamp time (P = 0.3). Analysis of nonclamp time demonstrated a 71.3% learning percentage (P < 0.01; ie, 28.7% reduction in nonclamp time with each doubling of case number). There were no hospital deaths or incidences of stroke, myocardial infarction, unplanned reoperation, respiratory failure, or renal failure. Median length of stay was 4 days. All patients were discharged home. CONCLUSIONS: Totally endoscopic robotic mitral valve repair can be safely performed after a pretraining regimen with emphasis on experts' current practice and team training. After a pretraining regimen, cross-clamp times were not subject to learning curve phenomena but were dependent on procedural complexity. Nonclamp times were associated with a short learning curve.
Asunto(s)
Educación Médica Continua/métodos , Endoscopía/educación , Implantación de Prótesis de Válvulas Cardíacas/educación , Curva de Aprendizaje , Insuficiencia de la Válvula Mitral/cirugía , Robótica/educación , Adulto , Anciano , Endoscopía/métodos , Implantación de Prótesis de Válvulas Cardíacas/métodos , Humanos , Masculino , Persona de Mediana Edad , Robótica/métodos , Factores de Tiempo , Adulto JovenRESUMEN
In selected patients undergoing cardiac surgery, our research group previously showed that optimized temporary biventricular pacing can increase cardiac output one hour after weaning from cardiopulmonary bypass. Whether pacing is effective after beating-heart surgery is unknown. Accordingly, in this study we examined the feasibility of temporary biventricular pacing after off-pump coronary artery bypass grafting. The effects of optimized pacing on cardiac output were measured with an electromagnetic aortic flow probe at the conclusion of surgery in 5 patients with a preoperative mean left ventricular ejection fraction of 0.26 (range, 0.15-0.35). Atrioventricular (7) and interventricular (9) delay settings were optimized in randomized order. Cardiac output with optimized biventricular pacing was 4.2 ± 0.7 L/min; in sinus rhythm, it was 3.8 ± 0.5 L/min. Atrial pacing at a matched heart rate resulted in cardiac output intermediate to that of sinus rhythm and biventricular pacing (4 ± 0.6 L/min). Optimization of atrioventricular and interventricular delay, in comparison with nominal settings, trended toward increased flow. This study shows that temporary biventricular pacing is feasible in patients with preoperative left ventricular dysfunction who are undergoing off-pump coronary artery bypass grafting. Further study of the possible clinical benefits of this intervention is warranted.