Prenatal microRNA miR-200b Therapy Improves Nitrofen-induced Pulmonary Hypoplasia Associated With Congenital Diaphragmatic Hernia.

OBJECTIVE: We aimed to evaluate the use of miR-200b as a prenatal transplacental therapy in the nitrofen rat model of abnormal lung development and congenital diaphragmatic hernia (CDH). BACKGROUND: Pulmonary hypoplasia (PH) and pulmonary hypertension determine mortality and morbidity in CDH babies. There is no safe medical prenatal treatment available. We previously discovered that higher miR-200b is associated with better survival in CDH babies. Here, we investigate the role of miR-200b in the nitrofen rat model of PH and CDH and evaluate its use as an in vivo prenatal therapy. METHODS: We profiled miR-200b expression during nitrofen-induced PH using RT-qPCR and in situ hybridization in the nitrofen rat model of PH and CDH. The effects of nitrofen on downstream miR-200b targets were studied in bronchial lung epithelial cells using a SMAD luciferase assay, Western blotting and Immunohistochemistry. We evaluated miR-200b as a lung growth promoting therapy ex vivo and in vivo using lung explant culture and transplacental prenatal therapy in the nitrofen rat model. RESULTS: We show that late lung hypoplasia in CDH is associated with (compensatory) upregulation of miR-200b in less hypoplastic lungs. Increasing miR-200b abundance with mimics early after nitrofen treatment decreases SMAD-driven TGF-ß signaling and rescues lung hypoplasia both in vitro and in vivo. Also, prenatal miR-200b therapy decreases the observed incidence of CDH. CONCLUSIONS: Our data indicate that miR-200b improves PH and decreases the incidence of CDH. Future studies will further exploit this newly discovered prenatal therapy for lung hypoplasia and CDH.

Pre-Operative Frailty Status Is Associated with Cardiac Rehabilitation Completion: A Retrospective Cohort Study.

While previous investigations have demonstrated the benefit of cardiac rehabilitation (CR) on outcomes after cardiac surgery, the association between pre-operative frailty and post-operative CR completion is unclear. The purpose of this retrospective cohort study was to determine if pre-operative frailty scores impacted CR completion post-operatively and if CR completion influenced frailty scores in 114 cardiac surgery patients. Frailty was assessed with the use of the Clinical Frailty Scale (CFS), the Modified Fried Criteria (MFC), the Short Physical Performance Battery (SPPB), and the Functional Frailty Index (FFI). A Mann-Whitney test was used to compare frailty scores between CR completers and non-completers and changes in frailty scores from baseline to 1-year post-operation. CR non-completers were more frail than CR completers at pre-operative baseline based on the CFS (p = 0.01), MFC (p < 0.001), SPPB (p = 0.007), and the FFI (p < 0.001). A change in frailty scores from baseline to 1-year post-operation was not detected in either group using any of the four frailty assessments. However, greater improvements from baseline to 1-year post-operation in two MFC domains (cognitive impairment and low physical activity) and the physical domain of the FFI were found in CR completers as compared to CR non-completers. These data suggest that pre-operative frailty assessments have the potential to identify participants who are less likely to attend and complete CR. The data also suggest that frailty assessment tools need further refinement, as physical domains of frailty function appear to be more sensitive to change following CR than other domains of frailty.

The impact of frailty on functional survival in patients 1 year after cardiac surgery.

OBJECTIVE: This study determined whether frailty provides incremental value to the European System for Cardiac Operative Risk Evaluation II in identifying patients at risk of poor 1-year functional survival. METHODS: This prospective study in patients undergoing cardiac surgery defined frailty using 3 common definitions: (1) the Modified Fried Criteria; (2) the Short Physical Performance Battery; and (3) the Clinical Frailty Scale. The primary outcome was functional survival, defined as being alive at 1 year postsurgery with a health-related quality of life score greater than 60 on the EuroQol-Visual Analogue Scale. RESULTS: Of the 188 participants, 49.5%, 52.6%, and 31.9% were deemed frail according to the Modified Fried Criteria, Short Physical Performance Battery, and Clinical Frailty Scale, respectively. The median age of our cohort was 71.0 years (29.3% female). The probability of functional survival at 1 year for the entire cohort was 73.9%. After adjusting for the European System for Cardiac Operative Risk Evaluation II, patients deemed frail under the Modified Fried Criteria, Short Physical Performance Battery, and Clinical Frailty Scale had an increased odds ratio for poor functional survival of 3.44, 3.47, and 2.08, respectively. When compared with the European System for Cardiac Operative Risk Evaluation II alone, the Modified Fried Criteria, Short Physical Performance Battery, and Clinical Frailty Scale showed an absolute improvement in the discrimination slope of 6.7%, 6.5%, and 2.4% with a category-free classification improvement of 59.6%, 59.2%, and 35.1%, respectively. CONCLUSIONS: Preoperative frailty was associated with a 2- to 3.5-fold higher risk of poor functional survival 1 year after cardiac surgery. The addition of frailty to the European System for Cardiac Operative Risk Evaluation II provides incremental value in identifying patients at risk of poor functional survival 1 year postsurgery, regardless of frailty definition.