Rakesh K. Chaturvedi

Mechanical Ventilation–induced Diaphragm Disuse in Humans Triggers Autophagy

RATIONALE Controlled mechanical ventilation (CMV) results in atrophy of the human diaphragm. The autophagy-lysosome pathway (ALP) contributes to skeletal muscle proteolysis, but its contribution to diaphragmatic protein degradation in mechanically ventilated patients is unknown. OBJECTIVES To evaluate the autophagy pathway responses to CMV in the diaphragm and limb muscles of humans and to identify the roles of FOXO transcription factors in these responses. METHODS Muscle biopsies were obtained from nine control subjects and nine brain-dead organ donors. Subjects were mechanically ventilated for 2 to 4 hours and 15 to 276 hours, respectively. Activation of the ubiquitin-proteasome system was detected by measuring mRNA expressions of Atrogin-1, MURF1, and protein expressions of UBC2, UBC4, and the α subunits of the 20S proteasome (MCP231). Activation of the ALP was detected by electron microscopy and by measuring the expressions of several autophagy-related genes. Total carbonyl content and HNE-protein adduct formation were measured to assess oxidative stress. Total AKT, phosphorylated and total FOXO1, and FOXO3A protein levels were also measured. MEASUREMENTS AND MAIN RESULTS Prolonged CMV triggered activation of the ALP as measured by the appearance of autophagosomes in the diaphragm and increased expressions of autophagy-related genes, as compared with controls. Induction of autophagy was associated with increased protein oxidation and enhanced expression of the FOXO1 gene, but not the FOXO3A gene. CMV also triggered the inhibition of both AKT expression and FOXO1 phosphorylation. CONCLUSIONS We propose that prolonged CMV causes diaphragm disuse, which, in turn, leads to activation of the ALP through oxidative stress and the induction of the FOXO1 transcription factor.

Mitochondrial Dysfunction and Lipid Accumulation in the Human Diaphragm during Mechanical Ventilation

RATIONALE Mechanical ventilation (MV) is associated with adverse effects on the diaphragm, but the cellular basis for this phenomenon, referred to as ventilator-induced diaphragmatic dysfunction (VIDD), is poorly understood. OBJECTIVES To determine whether mitochondrial function and cellular energy status are disrupted in human diaphragms after MV, and the role of mitochondria-derived oxidative stress in the development of VIDD. METHODS Diaphragm and biceps specimens obtained from brain-dead organ donors who underwent MV (15-176 h) and age-matched control subjects were compared regarding mitochondrial enzymatic function, mitochondrial DNA integrity, lipid content, and metabolic gene and protein expression. In addition, diaphragmatic force and oxidative stress after exposure to MV for 6 hours were evaluated in mice under different conditions. MEASUREMENTS AND MAIN RESULTS In human MV diaphragms, mitochondrial biogenesis and content were down-regulated, with a more specific defect of respiratory chain cytochrome-c oxidase. Laser capture microdissection of cytochrome-c oxidase-deficient fibers revealed mitochondrial DNA deletions, consistent with damage from oxidative stress. Diaphragmatic lipid accumulation and responses of master cellular metabolic sensors (AMP-activated protein kinase and sirtuins) were consistent with energy substrate excess as a possible stimulus for these changes. In mice, induction of hyperlipidemia worsened diaphragmatic oxidative stress during MV, whereas transgenic overexpression of a mitochondria-localized antioxidant (peroxiredoxin-3) was protective against VIDD. CONCLUSIONS Our data suggest that mitochondrial dysfunction lies at the nexus between oxidative stress and the impaired diaphragmatic contractility that develops during MV. Energy substrate oversupply relative to demand, resulting from diaphragmatic inactivity during MV, could play an important role in this process.

Initial Results of Posterior Leaflet Extension for Severe Type IIIb Ischemic Mitral Regurgitation

Background— Management of severe ischemic mitral regurgitation remains difficult with disappointing early and intermediate-term surgical results of valve repair. Methods and Results— Forty-four patients with severe (4+) Carpentier type IIIb ischemic mitral regurgitation underwent mitral valve repair, with or without surgical revascularization, by posterior leaflet extension with a patch of bovine pericardium and a remodeling annuloplasty. Serial echocardiography was performed preoperatively, intraoperatively, and postoperatively to assess mitral valve competence. The postoperative functional status of patients was assessed. The average Parsonnet score was 38±13. Thirty-day mortality was 11%, and late mortality was 14%. Mean follow-up was 38 months. The actuarial freedom from moderate or severe recurrent mitral regurgitation was 90% at 2 years, whereas 90% of patients were in New York Heart Association class I at 2 years. Conclusion— Posterior leaflet extension with annuloplasty of the mitral valve for severe type IIIb ischemic regurgitation is a safe, effective method that provides good early and intermediate-term competence of the mitral valve and therefore good functional status.

Preoperative hospital length of stay as a modifiable risk factor for mediastinitis after cardiac surgery

BackgroundAs high-risk cardiac patients frequently remain within hospital while waiting for surgery, the aim of the present study was to determine the role of preoperative length of hospital stay on mediastinitis, and also, to assess contemporary risk factors for this complication.MethodsThe source population consisted of 6653 consecutive patients undergoing coronary bypass surgery, valve surgery, or both between September 2000 and September 2009 at a single tertiary care hospital. A retrospective cohort analysis was used to assess the effect of 18 preoperative variables, including length of stay, on mediastinitis.ResultsMediastinitis developed in 108 patients (1.6%) resulting in an in-hospital mortality rate of 13.9%. Independent predictors of mediastinitis included obesity (2.59, CI 1.58-4.23), COPD (2.44, CI 1.55-3.84), diabetes (2.16, CI 1.44-3.24), and impaired estimated glomerular filtration rate. Preoperative hospital stay was also found to be an independent risk factor leading to a 15% increased risk of mediastinitis per week of stay. The primary wound pathogen was coagulase negative staphylococcus (82%) followed by multi-flora isolates (49%), but was unrelated to hospital stay.ConclusionsIn addition to the traditional risk factors, prolonged preoperative hospital stay is also a significant and potentially modifiable predictor for the development of mediastinitis following cardiac surgery. All efforts should be made to minimize the delay in operating on hospitalized patients awaiting heart surgery.

Use of continuous negative pressure around the chest increases exercise performance in chronic obstructive pulmonary disease patients: a pilot study.

BACKGROUND Patients with severe chronic obstructive pulmonary disease (COPD) often have intrinsic positive end-expiratory pressure. Continuous positive airway pressure has been shown to decrease the inspiratory work of breathing and increases exercise capacity in these patients. OBJECTIVE To determine whether continuous negative pressure (CNP) around the chest is able to bring the positive end-expiratory pressure closer to atmospheric pressure, thereby reducing the threshold load and increasing exercise capability. METHODS A pilot study was undertaken with eight COPD patients who had been hospitalized for exacerbation and were close to discharge. For CNP, a shell (around the thorax from under the axillae to the mid abdomen) and wrap were used. Each of the eight patients was assessed with a 6 min walk test in three modes (in randomized order) with 30 min of rest in between: a control walk with no shell or wrap; a sham CNP in which the applied CNP was negligible; and CNP, with pressure chosen by the patient that provided maximal relief of dyspnea at rest. RESULTS At the end of each of the 6 min walk tests, there was no difference in heart rate, oxygen saturation or level of dyspnea among the three test modes. Respiratory rate was reduced with CNP compared with sham. The patients walked furthest with CNP compared with control (mean ± SD) (313 ± 66.2 m versus 257 ± 65.2 m; P<0.01) and compared with sham. CONCLUSIONS In the present pilot study, COPD patients improved their exercise performance with CNP.