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Objective: Hands-on surgical training (HOST) for congenital heart surgery (CHS), utilizing silicone-molded models created from 3D-printing of patients' imaging data, was shown to improve surgical skills. However, the impact of repetition and frequency of repetition in retaining skills has not been previously investigated. We aimed to longitudinally evaluate the outcome for HOST on two example procedures of different technical difficulties with repeated attempts over a 15-week period. Methods: Five CHS trainees were prospectively recruited. Repair of coarctation of the aorta (CoA) and arterial switch operation (ASO) were selected as example procedures of relatively low and high technical difficulty. Procedural time and technical performance (using procedure-specific assessment tools by the participant, a peer-reviewer, and the proctor) were measured. Results: Coarctation repair performance scores improved after the first repetition but remained unchanged at the follow-up session. Likewise, CoA procedural time showed an early reduction but then remained stable (mean [standard deviation]: 29[14] vs 25[15] vs 23[9] min at 0, 1, and 4 weeks). Conversely, ASO performance scores improved during the first repetitions, but decreased after a longer time delay (>9 weeks). Arterial switch operation procedural time showed modest improvements across simulations but significantly reduced from the first to the last attempt: 119[20] versus 106[28] min at 0 and 15 weeks, P = .049. Conclusions: Complex procedures require multiple HOST repetitions, without excessive time delay to maintain long-term skills improvement. Conversely, a single session may be planned for simple procedures to achieve satisfactory medium-term results. Importantly, a consistent reduction in procedural times was recorded, supporting increased surgical efficiency.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Competência Clínica , Humanos , Estudos Prospectivos , Procedimentos Cirúrgicos Cardíacos/métodos , Modelos Anatômicos , Cardiopatias Congênitas/cirurgia , Silicones , Impressão Tridimensional , Masculino , Feminino , Estudos Longitudinais , Coartação Aórtica/cirurgia , Educação de Pós-Graduação em Medicina/métodosRESUMO
3D printing allows the most realistic perception of the surgical anatomy of congenital heart diseases without the requirement of physical devices such as a computer screen or virtual headset. It is useful for surgical decision making and simulation, hands-on surgical training (HOST) and cardiovascular morphology teaching. 3D-printed models allow easy understanding of surgical morphology and preoperative surgical simulation. The most common indications for its clinical use include complex forms of double outlet right ventricle and transposition of the great arteries, anomalous systemic and pulmonary venous connections, and heterotaxy. Its utility in congenital heart surgery is indisputable, although it is hard to "scientifically" prove the impact of its use in surgery because of many confounding factors that contribute to the surgical outcome. 3D-printed models are valuable resources for morphology teaching. Educational models can be produced for almost all different variations of congenital heart diseases, and replicated in any number. HOST using 3D-printed models enables efficient education of surgeons in-training. Implementation of the HOST courses in congenital heart surgical training programs is not an option but an absolute necessity. In conclusion, 3D printing is entering the stage of maturation in its use for congenital heart surgery. It is now time for imagers and surgeons to find how to effectively utilize 3D printing and how to improve the quality of the products for improved patient outcomes and impact of education and training.
RESUMO
BACKGROUND: The monthly in-house Hands-On Surgical Training (HOST) program was incorporated into the congenital heart surgery (CHS) curriculum for surgical trainees within our institution. This study evaluated whether there was an improvement and retention of technical skills throughout the curriculum via objective assessment methods. METHODS: Twelve 3-dimensional-printed surgical heart models were included into the year-long curriculum. The monthly sessions were attended by all trainees and staff surgeons. Proctors demonstrated the operation on a model, which was followed by 2 attempts by each trainee. Attempts were recorded for objective assessment. On completion of the curriculum trainees repeated 4 procedures an additional 2 times after a delay to assess skill retention. RESULTS: Twelve sessions were completed by 7 trainees within the curriculum. Objective assessments were performed in 7 sessions. Eighty-one percent of trainees' scores improved between the 2 attempts, with a mean improvement of 13% (attempt 1: HOST-CHS score of 79, attempt 2: HOST-CHS score of 89; P < .001). Similarly, 91% of procedural times improved by a mean of 25% (attempt 1, 1:22:00 [hours:minutes:seconds]; attempt 2, 1:01:21; P < .001). During individual procedure analysis, statistical significance remained in 3 of 7 procedures (P < .05). Four procedures were assessed for skill retention after a delay (2-14 months). Scores decreased by 4% in 47% of trainees during attempt 3 (attempt 2: HOST-CHS score of 94, attempt 3: HOST-CHS score of 91; P = .34) but improved in 79% during attempt 4 (attempt 3: HOST-CHS score of 91, attempt 4: HOST-CHS score of 99; P = .004), matching their previous performance. CONCLUSIONS: The monthly HOST course was successfully incorporated into a training curriculum for CHS surgeons using objective assessments to measure technical performance. Trainees demonstrated an improvement across all evaluated procedures and retained their skills when reassessed after a delay highlighting its value in CHS training.
Assuntos
Currículo , Educação de Pós-Graduação em Medicina/métodos , Cardiopatias Congênitas/cirurgia , Modelos Anatômicos , Cirurgia Torácica/educação , Humanos , Impressão TridimensionalRESUMO
OBJECTIVES: The hands-on surgical training course utilizes 3-dimensional (3D)-printed heart models to simulate complex congenital heart operations. This study aimed to validate a model and assessment tool in the simulation of 2 techniques of the Norwood operation and investigate whether technical performance improves following rehearsal with or without proctor presence. METHODS: Five 'experienced' and 5 'junior' surgeons performed 2 techniques of the Norwood operation on 3D-printed models of hypoplastic left heart syndrome. Performances were retrospectively assessed by 10 raters with varying experience in congenital heart surgery (CHS) (Medical Doctorate versus non-Medical Doctorate). Assessments were made with the procedure-specific Hands-On Surgical Training-CHS tool. Results were analysed for technical performance and rater consistency. Following validation, 30 surgeons (24 with proctor guidance and 6 with training videos and objective feedback only) simulated the Norwood operation twice. RESULTS: Performance scores were consistently higher for experienced surgeons and raters discriminated clearly between the experienced and junior surgeons (P ≤ 0.001). The hands-on surgical training-CHS tool showed high inter-rater (0.86) and intra-rater (0.80) reliability among all raters. Scores for both experienced and junior surgeons were highly consistent across all raters, with no statistically significant difference (P = 0.50). All surgeons successfully performed the Norwood operation. Sixty attempts were scored in total. Eighty-seven percentage (26/30) of surgeons' scores (mean: attempt 1 = 92, attempt 2 = 104) and times [mean: attempt 1 = 1:22:00, attempt 2 = 1:08:00 (h:mm:ss)] improved between the 2 attempts by 9% and 15% respectively (P ≤ 0.001). Total scores of all surgeons in the non-proctored subgroup (6) improved by 15% on average (mean: attempt 1 = 86, attempt 2 = 105, P = 0.002). CONCLUSIONS: Procedure-specific assessment tools can be developed to evaluate technical performance for complex CHS simulation and be performed reliably by non-expert raters. Rehearsal both under supervision and independently leads to technical skill improvement further supporting its value in CHS training.
RESUMO
OBJECTIVE: Data supporting the use of hands-on simulation in congenital heart surgery are promising but primarily qualitative. This study aimed to demonstrate if there was an objective improvement in time and technical performance of the arterial switch procedure on 3-dimensional printed heart models by surgeons using a validated assessment method. METHODS: A total of 30 surgeons of varying experience performed the arterial switch procedure twice on 3-dimensional printed models with transposition of the great arteries during the Hands-on Surgical Training courses. Surgeons' performances were recorded and retrospectively assessed for both time and performance using the Hands-on Surgical Training-Congenital Heart Surgery tool, a validated procedure-specific assessment tool for the arterial switch. RESULTS: A total of 60 videos were scored. Eighty percent of surgeons (24/30) had improved from their first attempt. The mean total score of the first attempt performance compared with the second was 103 and 120, respectively, with a mean difference in score of 17 (95% confidence interval, 10-24). All surgeons were statistically significantly quicker in their second attempt. The mean time for the first attempt compared with the second was 1 hour, 28 minutes, 4 seconds and 1 hour, 5 minutes, and 45 seconds, respectively, with a mean difference of 0 hours, 22 minutes, 19 seconds (95% confidence interval, 0 hours, 15 minutes, 22 seconds to 0 hours, 25 minutes, 34 seconds). CONCLUSIONS: This is the first study to demonstrate an objective improvement in time and technical performance of the arterial switch procedure on 3-dimensional printed heart models. This supports the evidence that simulation in the form of deliberate practice with constructive, objective feedback is fundamental in the training of future congenital heart surgeons. These simulations and assessments should be incorporated to create structured, standardized training curricula within congenital heart surgery.
Assuntos
Transposição das Grandes Artérias/educação , Educação de Pós-Graduação em Medicina , Cardiopatias Congênitas/cirurgia , Modelos Anatômicos , Impressão Tridimensional , Cirurgiões/educação , Transposição das Grandes Artérias/efeitos adversos , Competência Clínica , Cardiopatias Congênitas/patologia , Humanos , Curva de Aprendizado , Duração da Cirurgia , Estudos Retrospectivos , Análise e Desempenho de Tarefas , Fatores de Tempo , Gravação em VídeoRESUMO
BACKGROUND: Hands-on surgical simulation has been sought to address training limitations within congenital heart surgery (CHS). However, there is a need for objective assessment methods to measure surgeons' performance to justify its global adoption. This study aimed to validate a procedure-specific assessment tool for the simulation of the arterial switch operation on 3D-printed models and to evaluate the consistency of scoring among evaluators with different levels of experience in CHS. METHODS: Five "expert" and 5 "junior" surgeons performed the arterial switch procedure on 3D-printed models with transposition of the great arteries during 2 hands-on surgical training courses. Their performance was retrospectively assessed by 9 evaluators with varying experience in CHS (staff surgeons, resident surgeons, and non-MD raters). Assessments were done using 2 assessment tools: the Hands-On Surgical Training-Congenital Heart Surgery (HOST-CHS) assessment tool and the global rating scale (GRS). RESULTS: The HOST-CHS tool showed a higher interrater and intrarater reliability compared with the GRS. Total scores for expert surgeons were highly consistent across all evaluators. Non-MD raters' total scores for junior surgeons were slightly higher than those of residents and staff evaluators. All grades of evaluator were able to discriminate between junior and expert surgeons. CONCLUSIONS: This study demonstrates the development and validation of an objective, procedure-specific assessment tool for the arterial switch operation with consistency among evaluators with different experience. There is now a platform for quantifying and accurately evaluating performance, which will be highly beneficial in training and developing the next generation of congenital heart surgeons.
Assuntos
Transposição das Grandes Artérias/educação , Avaliação Educacional/métodos , Treinamento por Simulação/métodos , Cirurgiões/educação , Transposição dos Grandes Vasos/cirurgia , Humanos , Impressão Tridimensional , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Congenital heart surgery is a technically demanding specialty resulting in a prolonged training period. With the growing expectation of perfect patient outcomes, there is a need for improved training methods by implementing simulation. We assess the utilization of simulation in the training of congenital heart surgeons and discuss its future implications. A keyword-based PubMed literature search was conducted for hands-on surgical simulation in congenital heart surgery. The abstracts/titles of the search were reviewed and papers using simulation specific to congenital cardiac surgery were selected. Studies that did not include surgeons operating on the simulator, or did not incorporate assessment methods were excluded. Analysis included the problem addressed, simulator-type, methodology, assessment methods, results, benefits/limitations, and reproducibility. Five papers fulfilled our selection criteria of hands-on surgical simulation in congenital heart surgery with an assessment of the simulator or procedural performance. One simulation used animal models and 4 utilized 3D-printed models. Simulators covered either single or multiple complex procedures. All studies highlight usefulness of simulation; however, only 1 study has been replicated with >10 participants. The studies demonstrate how hands-on surgical simulation is possible within congenital heart surgery. Although primarily proof of concept studies, the next step would involve using a greater number of participants and demonstrate how repetition and deliberate practice will improve outcomes. Congenital heart surgery is one of the most technically demanding surgical specialties; therefore, we should lead the way in utilizing simulation to complement the training of our surgeons as we face the challenges ahead.
Assuntos
Procedimentos Cirúrgicos Cardíacos/educação , Educação de Pós-Graduação em Medicina , Cardiopatias Congênitas/cirurgia , Internato e Residência , Treinamento por Simulação , Cirurgiões/educação , Animais , Competência Clínica , Simulação por Computador , Currículo , Cardiopatias Congênitas/diagnóstico por imagem , Humanos , Modelos Animais , Modelos Cardiovasculares , Impressão TridimensionalRESUMO
OBJECTIVE: We sought to define the intrinsic stem cell capacity in pediatric heart lesions, and the effects of diagnosis and of age, in order to inform evidence-based use of potential autologous stem cell sources for regenerative medicine therapy. METHODS: Ventricular explants derived from patients with hypoplastic left heart syndrome (HLHS), tetralogy of Fallot (TF), dilated cardiomyopathy (DCM) and ventricular septal defect (VSD) were analyzed following standard in vitro culture conditions, which yielded cardiospheres (C-spheres), indicative of endogenous stem cell capacity. C-sphere counts generated per 5 mm3 tissue explant and the presence of cardiac progenitor cells were correlated to patient age, diagnosis and echocardiographic function. RESULTS: Cardiac explants from patients less than one year of age with TF and DCM robustly generated c-kit- and/or vimentin-positive cardiac mesenchymal cells (CMCs), populating spontaneously forming C-spheres. Beyond one year of age, there was a marked reduction or absence of cardiac explant-derivable cardiac stem cell content in patients with TF, VSD and DCM. Stem cell content in HLHS and DCM strongly correlated to the echocardiographic function in the corresponding ventricular chamber, with better echocardiographic function correlating to a more robust regenerative cellular content. CONCLUSIONS: We conclude that autologous cardiomyogenic potential in pediatric heart lesions is robust during the first year of life and uniformly declines thereafter. Depletion of stem cell content occurs at an earlier age in HLHS with the onset of ventricular failure in a chamber-specific pattern that correlates directly to ventricular dysfunction. These data suggest that regenerative therapies using autologous cellular sources should be implemented in the neonatal period before the potentially rapid onset of single ventricle failure in HLHS or the evolution of biventricular failure in DCM.
Assuntos
Cardiomiopatia Dilatada/fisiopatologia , Comunicação Interventricular/fisiopatologia , Ventrículos do Coração/fisiopatologia , Síndrome do Coração Esquerdo Hipoplásico/fisiopatologia , Regeneração , Tetralogia de Fallot/fisiopatologia , Adolescente , Envelhecimento/patologia , Envelhecimento/fisiologia , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/cirurgia , Células Cultivadas , Criança , Pré-Escolar , Eletrocardiografia , Comunicação Interventricular/diagnóstico por imagem , Comunicação Interventricular/patologia , Comunicação Interventricular/cirurgia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Ventrículos do Coração/cirurgia , Humanos , Síndrome do Coração Esquerdo Hipoplásico/diagnóstico por imagem , Síndrome do Coração Esquerdo Hipoplásico/patologia , Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Lactente , Recém-Nascido , Células-Tronco Mesenquimais/patologia , Células-Tronco Mesenquimais/fisiologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Regeneração/fisiologia , Tetralogia de Fallot/diagnóstico por imagem , Tetralogia de Fallot/patologia , Tetralogia de Fallot/cirurgia , Técnicas de Cultura de TecidosRESUMO
BACKGROUND: Two different surgical techniques are used to repair anomalous pulmonary venous connection or pulmonary vein (PV) stenosis: the classic repair (CR) and the sutureless repair (SR). The purpose of this study was to compare the prevalence of PV stenosis between the two surgical approaches. METHODS: Patients were prospectively recruited irrespective of symptoms or previous imaging findings. Cardiac magnetic resonance imaging and echocardiography were performed in a blinded fashion on the same day. RESULTS: Twenty-five patients (13 male) after PV repair completed the study. Twelve patients had undergone CR and 13 SR (in 1 patient as a reoperation after CR). The median age at operation was 2 months (range: 1 day to 5 years) and was similar for both groups; the median age at the time of cardiac magnetic resonance was 9 years (range: 6 to 17 years) and 9 years (range: 6 to 14 years) for the CR and SR, respectively. Four patients had PV stenosis. All 4 patients had had total anomalous pulmonary venous connection, 1 patient had undergone repair with the CR and 2 with a primary SR; 1 patient had first undergone a CR, followed by a SR for stenosis. Echocardiography provided complete visualization of all PVs in only 11 patients (44%). Notable stenosis of at least one PV was missed by echocardiography in 2 patients. CONCLUSIONS: This pilot study indicates that not only CR but also SR may be burdened by a risk of postoperative PV stenosis. Magnetic resonance imaging should be used routinely for the postoperative monitoring for the development of PV obstruction.
Assuntos
Imageamento por Ressonância Magnética , Complicações Pós-Operatórias/diagnóstico por imagem , Síndrome de Cimitarra/cirurgia , Estenose de Veia Pulmonar/diagnóstico por imagem , Técnicas de Sutura , Adolescente , Criança , Estudos Transversais , Ecocardiografia , Feminino , Humanos , Masculino , Projetos Piloto , Complicações Pós-Operatórias/epidemiologia , Prevalência , Estudos Prospectivos , Estenose de Veia Pulmonar/epidemiologiaRESUMO
BACKGROUND: We sought to evaluate the incidence of Fontan failure or complication and its relation to death in patients having contemporary Fontan strategies over 2 decades. METHODS: Five hundred patients who underwent Fontan completion (extracardiac, n = 326; lateral tunnel, n = 174) from 1985 to 2012 were reviewed. Patient characteristics, modes of Fontan failure/complication and death, and predictors for Fontan failure/complication and death were analyzed. RESULTS: There were 23 early deaths (4.6%) and 17 late deaths (3.4%), with no early death since 2000. Survival has improved over time (p < 0.001). Twenty-three of 40 patients who died were identified as Fontan failure before death, including ventricular dysfunction (n = 14), pulmonary vascular dysfunction (n = 4), thromboembolism (n = 2), and arrhythmia (n = 4). Mode of death was circulatory failure (n = 18), multiorgan failure (n = 6), pulmonary failure (n = 3), cerebral/renal (n = 5), and sudden death (n = 4). Modes of failure/complication were directly (65%) or conceivably (10%) related to death in 30 of 40 patients (75%). Forty-eight percent of survivors had late Fontan complication(s). Five-year freedom from late Fontan complication was lower among patients who died compared with patients who survived (29.4% versus 53.3%, p < 0.001). Ventricular dysfunction (p = 0.001) and higher pulmonary artery pressures (p < 0.001) after Fontan were predictors for death. Longer cardiopulmonary bypass time (p = 0.032) and reinterventions (p < 0.001) were predictors for late Fontan complication. CONCLUSIONS: Early death in the early era has been overcome. Yet the incidence and causes of late death remain unchanged. There was a strong causative relationship between the mode of Fontan failure/complication and death, indicating the importance of early recognition and treatment of Fontan failure/complication.
Assuntos
Técnica de Fontan/efeitos adversos , Cardiopatias Congênitas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Masculino , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Falha de TratamentoRESUMO
BACKGROUND: The purpose of this study was to evaluate the clinical utility of intraoperative aortic blood flow measurements on clinical outcome in patients undergoing pulmonary artery banding (PAB). METHODS: We reviewed 12 patients who underwent a PAB between September 2008 and March 2013 who also had intraoperative aortic blood flow measurements. Diagnosis included biventricular physiology in 6, single-ventricle physiology in 4, and inadequate systemic ventricle in 2 patients. Aortic blood flow was measured at the time of surgery by Transonic flow probe (Transonic Systems Inc, Ithaca, NY). Aortic flow, intraoperative hemodynamics, and clinical outcomes were analyzed to determine the potential predictive utility of intraoperative variables on postoperative outcomes. RESULTS: The aortic flow increased after PAB from 1.56 ± 0.73 to 2.20 ± 1.10 L · min(-1) · m(-2) (41.0% increase; p = 0.001). The efficacy of the PAB procedure was found to be directly related to the percentage increase in aortic blood flow measured intraoperatively. Three patients with less than 20% increase in aortic blood flow died, required re-PAB, or developed ventricular dysfunction, while patients with successful PAB had more than 40% increase in aortic blood flow. The percentage increase in aortic blood flow was not predictable based on pre-band or post-band absolute aortic blood flow measurements. The percentage increase in aortic blood flow was inversely correlated to the tightness of the PAB as defined relative to that predicted by the Trusler formula (r = 0.67; p = 0.01). CONCLUSIONS: This study identifies the change in the aortic blood flow as a new, physiologically based parameter to help predict PAB outcome.
Assuntos
Aorta Torácica/fisiopatologia , Determinação da Pressão Arterial/estatística & dados numéricos , Cardiopatias Congênitas/cirurgia , Artéria Pulmonar/cirurgia , Velocidade do Fluxo Sanguíneo/fisiologia , Feminino , Seguimentos , Cardiopatias Congênitas/fisiopatologia , Humanos , Lactente , Recém-Nascido , Masculino , Valor Preditivo dos Testes , Artéria Pulmonar/fisiopatologia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Resistência Vascular , Procedimentos Cirúrgicos VascularesRESUMO
BACKGROUND: Patients with single-ventricle physiology frequently develop left-sided pulmonary vein obstruction (PVO), in which the pulmonary veins traverse the descending thoracic aorta. We hypothesized that a combination of cardiomegaly and an anteriorly positioned descending aorta is associated with PVO. METHODS: Among 494 consecutive single-ventricle patients, 15 were diagnosed with PVO by cardiac magnetic resonance, defined as anatomically localized narrowing of the pulmonary vein diameter. Using axial slices at the level of the left lower pulmonary vein, normalized dimensions were obtained to characterize the anatomic relationships of intrathoracic structures. Measurements were compared between patients with PVO and "control" patients (single-ventricle patients with normal pulmonary veins, n = 12). RESULTS: Patients with cardiac magnetic resonance-diagnosed PVO had larger cardiac size and more antero-laterally located descending aorta when compared with controls (normalized dimensions: cardiac/thoracic area ratio: 0.43 vs 0.38, P = .035, distance from vertebra to descending aorta normalized by the horizontal dimension of thoracic cavity: 0.09 vs 0.08, P = .049). Seven (47%) patients underwent PV sutureless repair, and 3 (of 7) failed to achieve Fontan. Patients who failed to achieve Fontan had a larger normalized cardiac size than those who achieved Fontan (cardiac/thoracic area ratio: 0.49 vs 0.39, P = .001). CONCLUSIONS: The combination of relative cardiomegaly within the context of the thoracic cavity at the level of the pulmonary veins and antero-lateral displacement of the aorta is associated with left-sided PVO and subsequent failure to achieve Fontan completion. Further characterization of these unique geometric relationships may help inform both surveillance strategies and decision making in the timing of interventions, and guide the intraoperative objectives at the time of PVO repair.
Assuntos
Técnica de Fontan , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/cirurgia , Ventrículos do Coração/cirurgia , Pneumopatia Veno-Oclusiva/etiologia , Pneumopatia Veno-Oclusiva/cirurgia , Aorta Torácica/anormalidades , Cardiomegalia/complicações , Técnica de Fontan/efeitos adversos , Técnica de Fontan/mortalidade , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/mortalidade , Cardiopatias Congênitas/fisiopatologia , Ventrículos do Coração/anormalidades , Ventrículos do Coração/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Valor Preditivo dos Testes , Pneumopatia Veno-Oclusiva/diagnóstico , Pneumopatia Veno-Oclusiva/mortalidade , Pneumopatia Veno-Oclusiva/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Malformações Vasculares/complicaçõesRESUMO
Human dilated cardiomyopathy (DCM) manifests as a profound reduction in biventricular cardiac function that typically progresses to death or cardiac transplantation. There is no effective mechanism-based therapy currently available for DCM, in part because the transduction of mechanical load into dynamic changes in cardiac contractility (termed mechanotransduction) remains an incompletely understood process during both normal cardiac function and in disease states. Here we show that the mechanoreceptor protein integrin-linked kinase (ILK) mediates cardiomyocyte force transduction through regulation of the key calcium regulatory protein sarcoplasmic/endoplasmic reticulum Ca(2+)ATPase isoform 2a (SERCA-2a) and phosphorylation of phospholamban (PLN) in the human heart. A non-oncogenic ILK mutation with a synthetic point mutation in the pleckstrin homology-like domain (ILK(R211A)) is shown to enhance global cardiac function through SERCA-2a/PLN. Thus, ILK serves to link mechanoreception to the dynamic modulation of cardiac contractility through a previously undiscovered interaction with the functional SERCA-2a/PLN module that can be exploited to rescue impaired mechanotransduction in DCM.
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Proteínas de Ligação ao Cálcio/metabolismo , Mecanotransdução Celular/genética , Contração Miocárdica/genética , Miócitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinases/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Animais , Humanos , Células-Tronco Pluripotentes Induzidas , Mecanotransdução Celular/fisiologia , Camundongos , Camundongos Knockout , Contração Miocárdica/fisiologia , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Retículo Sarcoplasmático/metabolismoRESUMO
OBJECTIVES: Pulmonary vein stenosis (PVS) is a relentless disease with a poor prognosis. Although surgical repair can effectively treat "downstream" (near left atrial junction) PVS, residual "upstream" (deep in lung parenchyma) PVS commonly dictates long-term survival. Our initial studies revealed an association between PVS and transforming growth factor-ß signaling, which led us to investigate the effect of losartan on upstream pulmonary vein vasculopathy in a piglet model of PVS. METHODS: Neonatal Yorkshire piglets underwent sham surgical banding (sham, n = 6), staged bilateral pulmonary vein banding of all pulmonary veins except the right middle pulmonary vein (banded, n = 6), and staged pulmonary vein banding with losartan treatment (losartan, 1 mg/kg/d, n = 7). After 7 weeks, the hemodynamic data were obtained and the piglets killed. RESULTS: Pulmonary vein banding (compared with sham) was associated with continuous turbulent flow in banded pulmonary veins, pulmonary hypertension (pulmonary artery/systemic blood pressure ratio 0.51 ± 0.06 vs 0.23 ± 0.02, P < .001), and diffuse pulmonary vein intimal hyperplasia in the upstream pulmonary veins (P < .001). Losartan administration decreased the pulmonary artery/systemic blood pressure ratios compared with those in the banded piglets (0.36 ± 0.08 vs 0.51 ± 0.06, P = .007) but it remained greater than those in the sham group (P = .001). Losartan was also associated with diminished pulmonary vein intimal hyperplasia compared with that in the banded piglets (P < .001) but still remained more than that in the sham group (P = .035). Pulmonary vein banding reduced vascular endothelial-cadherin expression, indicative of diminished endothelial integrity, which was restored with losartan. CONCLUSIONS: Losartan treatment improved PVS-associated pulmonary hypertension and intimal hyperplasia and might be a beneficial prophylactic therapy for patients at high risk of developing PVS after pulmonary vein surgery.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Losartan/farmacologia , Veias Pulmonares/efeitos dos fármacos , Pneumopatia Veno-Oclusiva/tratamento farmacológico , Túnica Íntima/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Antígenos CD/metabolismo , Caderinas/metabolismo , Constrição Patológica , Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Hiperplasia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/tratamento farmacológico , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/fisiopatologia , Neointima , Veias Pulmonares/metabolismo , Veias Pulmonares/patologia , Veias Pulmonares/fisiopatologia , Pneumopatia Veno-Oclusiva/metabolismo , Pneumopatia Veno-Oclusiva/patologia , Pneumopatia Veno-Oclusiva/fisiopatologia , Suínos , Fatores de Tempo , Túnica Íntima/metabolismo , Túnica Íntima/patologiaRESUMO
BACKGROUND: We sought to evaluate the medium-term implications of fenestration status. METHODS: Between 1994 and 2012, 326 patients received an extracardiac Fontan (hospital mortality n = 6, 1.8%). A fenestration was routinely created (n = 306, 94%) unless there was technical difficulty. Three hundred patients discharged with an open fenestration were included. The primary end points were death and Fontan failure. Secondary outcomes were Fontan complications such as venovenous collaterals, protein-losing enteropathy, pacemaker requirement, and arrhythmias. RESULTS: The fenestration was closed in 260 patients: 185 as a catheter intervention (62%) and 75 (25%) spontaneously. Forty patients (13%) had the fenestration open at a median follow-up period of 5.05 years. Of these patients, catheter-based closure failed in 10 (3%). There was no statistically significant difference in pre-Fontan hemodynamic parameters, such as pulmonary artery pressure and pulmonary vascular resistance between the patients with open fenestration and the ones with closed fenestration. Patients with an open fenestration had significantly more late deaths (P < .001), Fontan failure (P = .021), and Fontan complications (P = .011) compared with those with a closed fenestration. Multivariable Cox regression revealed open fenestration (P < .001) and indeterminate ventricular morphology (P = .002) as risk factors for death/Fontan failure, and ventricular dysfunction (P = .014) and open fenestration (P = .009) as risk factors for Fontan complications. CONCLUSIONS: Persistent fenestration was a marker for physiologic intolerance as noted by increased rates of mortality and a higher incidence of Fontan failure/complications. The specificity of pre-Fontan physiologic data for fenestration status may not have the fidelity needed for long-term care and thus, the consequences of decision making regarding fenestration status may not be determined until well after the operation.