PhD student, Monash University
The search for therapeutic targets to prevent intensive care unit acquired weakness.
The molecular mechanisms responsible for ICU Acquired Weakness (ICUAW) are poorly understood. Novel biomarkers may provide potential therapeutic targets, and assist in the identification of patients at risk of ICUAW. Activin A is a strong negative regulator of muscle mass, is elevated in sepsis and predicts mortality in acute respiratory failure. It is unclear whether muscle wasting in critically ill humans is related to elevated activin A levels.
To investigate the relationship between serum activin A levels and physical function at ICU and hospital discharge.
This study was a prospective longitudinal observational cohort study. To date, 16 participants have been recruited from 2 tertiary ICUs from metropolitan hospitals in Melbourne, Australia. Participants were included if they were mechanically ventilated > 48 hours and were expected to have a total ICU stay of > 5 days. Total serum activin A levels were measured daily in ICU by specific assays. Grip strength and Medical Research Council Sum Score (MRC-SS) were completed daily in ICU. Physical Function in ICU Test Scored, Six-Minute Walk Test and Timed Up and Go Test were completed on ICU discharge and hospital discharge.
Nine of the sixteen participants survived to complete at least one physical outcome measure. Median serum activin A levels were lower in the participants who survived to ICU discharge (pseudo-R2 0.0822, p=0.021) but were not related to in hospital mortality (pseudo-R2 0.0422, p=0.078). Initial activin A levels were lower in participants who survived to hospital discharge (pseudo-R2 0.0614, p=0.048). Serum activin A levels were not related to any of the physical outcome measures at any time point.
High serum activin A levels were associated with increased mortality but not worse physical function in critically ill patients.
Abstract: 30 day mortality in patients with Acute Respiratory Failure (ARF) is approximately 30%, defined as patients requiring ventilator support for more than 6 hours. Novel biomarkers are needed to predict patient outcomes and to guide potential future therapies. The activins A and B, members of the Transforming Growth Factor β family of proteins, and their binding protein, follistatin, have recently been shown to be important regulators of inflammation and fibrosis but no substantial data are available concerning their roles in ARF.Specific assays for activin A, B and follistatin were used and the results analyzed according to diagnostic groups as well as according to standard measures in intensive care. Multivariable logistic regression was used to create a model to predict death at 90 days and 12 months from the onset of the ARF.Serum activin A and B were significantly elevated in most patients and in most of the diagnostic groups. Patients who had activin A and/or B concentrations above the reference maximum were significantly more likely to die in the 12 months following admission [either activin A or B above reference maximum: Positive Likelihood Ratio [LR+] 1.65 [95% CI 1.28-2.12, P = 0.00013]; both activin A and B above reference maximum: LR + 2.78 [95% CI 1.96-3.95, P < 0.00001]. The predictive model at 12 months had an overall accuracy of 80.2% [95% CI 76.6-83.3%].The measurement of activin A and B levels in these patients with ARF would have assisted in predicting those at greatest risk of death. Given the existing data from animal studies linking high activin A levels to significant inflammatory challenges, the results from this study suggest that approaches to modulate activin A and B bioactivity should be explored as potential therapeutic agents.
Pub.: 01 Nov '13, Pinned: 30 Aug '17
Abstract: Activin A and its binding protein follistatin (FS) are increased in inflammatory disorders and sepsis. Overexpression of activin A in the lung causes similar histopathological changes as acute respiratory distress syndrome (ARDS). ARDS and severe respiratory failure are complications of influenza A(H1N1) infection. Interleukin 6 (IL-6), which in experimental studies increases after activin A release, is known to be related to the severity of H1N1 infection. Our aim was to evaluate the levels of activin A, activin B, FS, IL-6 and IL-10 and their association with the severity of respiratory failure in critically ill H1N1 patients.A substudy of a prospective, observational cohort of H1N1 patients in Finnish intensive care units (ICU). Clinical information was recorded during ICU treatment, and serum activin A, activin B, FS, IL-6 and IL-10 were measured at admission to ICU and on days 2 and 7.Blood samples from 29 patients were analysed. At the time of admission to intensive care unit, elevated serum levels above the normal range for respective age group and sex were observed in 44% for activin A, 57% for activin B, and 39% for FS. In 13 of the 29 patients, serial samples at all time points were available and in these the highest activin A, activin B and FS were above the normal range in 85%, 100% and 46% of the patients, respectively. No difference in baseline or highest activin A or activin B was found in patients with or without acute lung injury (ALI) or ARDS (P > 0.05 for all). Peak levels of IL-6 were significantly elevated in ALI/ARDS patients. Peak activin A and activin A/FS were associated with ventilatory support free-days, severity of acute illness and length of ICU stay (P < 0.05 for all).Higher than normal values of these proteins were common in patients with H1N1 infection but we found no association with the severity of their respiratory failure.
Pub.: 03 Jun '14, Pinned: 30 Aug '17
Abstract: Lung transplantation exposes the donated lung to a period of anoxia. Re-establishing the circulation after ischemia stimulates inflammation causing organ damage. Since our published data established that activin A is a key pro-inflammatory cytokine, we assessed the roles of activin A and B, and their binding protein, follistatin, in patients undergoing lung transplantation.Sera from 46 patients participating in a published study of remote ischemia conditioning in lung transplantation were used. Serum activin A and B, follistatin and 11 other cytokines were measured in samples taken immediately after anaesthesia induction, after remote ischemia conditioning or sham treatment undertaken just prior to allograft reperfusion and during the subsequent 24 hours.Substantial increases in serum activin A, B and follistatin occurred after the baseline sample, taken before anaesthesia induction and peaked immediately after the remote ischemia conditioning/sham treatment. The levels remained elevated 15 minutes after lung transplantation declining thereafter reaching baseline 2 hours post-transplant. Activin B and follistatin concentrations were lower in patients receiving remote ischemia conditioning compared to sham treated patients but the magnitude of the decrease did not correlate with early transplant outcomes.We propose that the increases in the serum activin A, B and follistatin result from a combination of factors; the acute phase response, the reperfusion response and the use of heparin-based anti-coagulants.
Pub.: 29 Jan '16, Pinned: 30 Aug '17
Abstract: Growth and differentiation factor 8 (GDF8) is a TGF-β superfamily member, and negative regulator of skeletal muscle mass. GDF8 inhibition results in prominent muscle growth in mice, but less impressive hypertrophy in primates, including man. Broad TGF-β inhibition suggests another family member negatively regulates muscle mass, and its blockade enhances muscle growth seen with GDF8-specific inhibition. Here we show that activin A is the long-sought second negative muscle regulator. Activin A specific inhibition, on top of GDF8 inhibition, leads to pronounced muscle hypertrophy and force production in mice and monkeys. Inhibition of these two ligands mimics the hypertrophy seen with broad TGF-β blockers, while avoiding the adverse effects due to inhibition of multiple family members. Altogether, we identify activin A as a second negative regulator of muscle mass, and suggest that inhibition of both ligands provides a preferred therapeutic approach, which maximizes the benefit:risk ratio for muscle diseases in man.
Pub.: 30 Apr '17, Pinned: 30 Aug '17
Abstract: Several experimental evidences pinpoint the possible role of Activin A (ActA) as a driver of cancer cachexia. Supporting this hypothesis, we showed recently that human cancer cachexia is associated with high ActA levels. Moreover, ActA levels were correlated with body weight loss and skeletal muscle density, two prognostic factors in cancer patients. Our goal was therefore to investigate the value of ActA to predict survival in cancer patients.Patients with colorectal or lung cancer were prospectively enrolled at the time of diagnosis or relapse between January 2012 and March 2014. At baseline, patients had clinical, nutritional, and functional assessment. Body composition and skeletal muscle density were measured by CT scan, and plasma ActA concentrations were determined. Overall survival (OS) was analysed since inclusion to 24 months later.Survival data were available for 149 patients out of 152. Patients with high ActA (≥408 pg/mL) had lower OS than those with low levels, regardless the type of cancer (OS in colorectal cancer, 50% vs. 79%, P < 0.05; and in lung cancer, 27% vs. 67%, P = 0.001). The multivariable analysis confirmed the prognostic value of ActA independently of tumour stage or inflammatory markers, particularly in lung cancer. Low muscularity was also an independent prognostic factor.Our study demonstrates that high ActA level is an independent prognosis factor of survival in cancer patients. More than a basic marker of the severity of the neoplastic disease or of the inflammatory process, ActA seems to influence survival by contributing to the development of cachexia and loss of skeletal muscle mass.
Pub.: 15 Jul '17, Pinned: 30 Aug '17
Abstract: Does preoperative intervention in people undergoing cardiac surgery reduce pulmonary complications, shorten length of stay in the intensive care unit (ICU) or hospital, or improve physical function?Systematic review with meta-analysis of (quasi) randomised trials.People undergoing coronary artery bypass grafts and/or valvular surgery.Any intervention, such as education, inspiratory muscle training, exercise training or relaxation, delivered prior to surgery to prevent/reduce postoperative pulmonary complications or to hasten recovery of function.Time to extubation, length of stay in ICU and hospital (reported in days). Postoperative pulmonary complications and physical function were measured as reported in the included trials.The 17 eligible trials reported data on 2689 participants. Preoperative intervention significantly reduced the time to extubation (MD -0.14 days, 95% CI -0.26 to -0.01) and the relative risk of developing postoperative pulmonary complications (RR 0.39, 95% CI 0.23 to 0.66). However, it did not significantly affect the length of stay in ICU (MD -0.15 days, 95% CI -0.37 to 0.08) or hospital (MD -0.55 days, 95% CI -1.32 to 0.23), except among older participants (MD -1.32 days, 95% CI -2.36 to -0.28). When the preoperative interventions were separately analysed, inspiratory muscle training significantly reduced postoperative pulmonary complications and the length of stay in hospital. Trial quality ranged from good to poor and considerable heterogeneity was present in the study features. Other outcomes did not significantly differ.For people undergoing cardiac surgery, preoperative intervention reduces the incidence of postoperative pulmonary complications and, in older patients, the length of stay in hospital.
Pub.: 24 Jun '14, Pinned: 30 Aug '17
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