Urinary extracellular vesicles and micro-RNA as markers of acute kidney injury after cardiac surgery.

We hypothesised that measuring changes in urinary levels of EV and miR will predict the onset of acute kidney injury in cardiac surgery patients. The study was performed in the cohort of the REVAKI-2 trial. Urine samples were collected before and 24 h after the procedure from 94 cardiac surgery patients. Urinary particle concentrations and size distribution were assessed using NanoSight. EV derivation and levels were measured using flow cytometry. Samples from 10 selected patients were sequenced, and verification was performed with advanced TaqMan assays in samples from all patients. Urinary particle concentrations significantly increased in patients with AKI after surgery, with the percentage of EV positive for CD105 and ß1-integrin also increasing. Pre-surgery podocalyxin-positive EV were significantly lower in patients with AKI. Their levels correlated with the severity of the injury. Pre-operative miR-125a-5p was expressed at lower levels in urine from patients with AKI when adjusted for urinary creatinine. Levels of miR-10a-5p were lower after surgery in AKI patients and its levels correlated with the severity of the injury. Pre-operative levels of podocalyxin EVs, urinary particle concentrations and miR-125a-5p had moderate AKI predictive value and, in a logistic model together with ICU lactate levels, offered good (AUC = 82%) AKI prediction.

Evaluating the Feasibility of Screening Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Diseases: The REST Study.

Background Diseases of the thoracic aorta are characterized by a familial etiology in up to 30% of the cases. Nonsyndromic thoracic aorta diseases (NS-TADs) lack overt clinical signs and systemic features, which hinder early detection and prompt surgical intervention. We hypothesize that tailored genetic testing and imaging of first-degree and second-degree relatives of patients affected by NS-TADs may enable early diagnosis and allow appropriate surveillance or intervention. Methods and Results We conducted a feasibility study involving probands affected by familial or sporadic NS-TADs who had undergone surgery, which also offered screening to their relatives. Each participant underwent a combined imaging (echocardiogram and magnetic resonance imaging) and genetic (whole exome sequencing) evaluation, together with physical examination and psychological assessment. The study population included 16 probands (8 sporadic, 8 familial) and 54 relatives (41 first-degree and 13 second-degree relatives) with median age 48 years (range: 18-85 years). No syndromic physical features were observed. Imaging revealed mild-to-moderate aortic dilation in 24% of relatives. A genetic variant of uncertain significance was identified in 3 families. Imaging, further phenotyping, or a form of secondary prevention was indicated in 68% of the relatives in the familial group and 54% in the sporadic group. No participants fulfilled criteria for aortic surgery. No differences between baseline and 3-month follow-up scores for depression, anxiety, and self-reported quality of life were observed. Conclusions In NS-TADs, imaging tests, genetic counseling, and family screening yielded positive results in up to 1 out of 4 screened relatives, including those in the sporadic NS-TAD group. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03861741.

Gene and metabolite expression dependence on body mass index in human myocardium.

We hypothesized that body mass index (BMI) dependent changes in myocardial gene expression and energy-related metabolites underlie the biphasic association between BMI and mortality (the obesity paradox) in cardiac surgery. We performed transcriptome profiling and measured a panel of 144 metabolites in 53 and 55, respectively, myocardial biopsies from a cohort of sixty-six adult patients undergoing coronary artery bypass grafting (registration: NCT02908009). The initial analysis identified 239 transcripts with biphasic BMI dependence. 120 displayed u-shape and 119 n-shape expression patterns. The identified local minima or maxima peaked at BMI 28-29. Based on these results and to best fit the WHO classification, we grouped the patients into three groups: BMI < 25, 25 ≤ BMI ≤ 32, and BMI > 32. The analysis indicated that protein translation-related pathways were downregulated in 25 ≤ BMI ≤ 32 compared with BMI < 25 patients. Muscle contraction transcripts were upregulated in 25 ≤ BMI ≤ 32 patients, and cholesterol synthesis and innate immunity transcripts were upregulated in the BMI > 32 group. Transcripts involved in translation, muscle contraction and lipid metabolism also formed distinct correlation networks with biphasic dependence on BMI. Metabolite analysis identified acylcarnitines and ribose-5-phosphate increasing in the BMI > 32 group and α-ketoglutarate increasing in the BMI < 25 group. Molecular differences in the myocardium mirror the biphasic relationship between BMI and mortality.

Activation of the innate immune response and organ injury after cardiac surgery: a systematic review and meta-analysis of randomised trials and analysis of individual patient data from randomised and non-randomised studies.

BACKGROUND: It is unclear whether the innate immune response represents a therapeutic target for organ protection strategies in cardiac surgery. METHODS: A systematic review of trials of interventions targeting the inflammatory response to cardiac surgery reporting treatment effects on both innate immune system cytokines and organ injury was performed. The protocol was registered at the International Prospective Register of Systematic Reviews: CRD42020187239. Searches of the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase were performed. Random-effects meta-analyses were used for the primary analysis. A separate analysis of individual patient data from six studies (n=785) explored sources of heterogeneity for treatment effects on cytokine levels. RESULTS: Searches to May 2020 identified 251 trials evaluating 24 interventions with 20 582 participants for inclusion. Most trials had important limitations. Methodological limitations of the included trials and heterogeneity of the treatment effects on cytokine levels between trials limited interpretation. The primary analysis demonstrated inconsistency in the direction of the treatment effects on innate immunity and organ failure or death between interventions. Analyses restricted to important subgroups or trials with fewer limitations showed similar results. Meta-regression, pooling available data from all trials, demonstrated no association between the direction of the treatment effects on inflammatory cytokines and organ injury or death. The analysis of individual patient data demonstrated heterogeneity in the association between the cytokine response and organ injury after cardiac surgery for people >75 yr old and those with some chronic diseases. CONCLUSIONS: The certainty of the evidence for a causal relationship between innate immune system activation and organ injury after cardiac surgery is low.

Intravenous sildenafil citrate and post-cardiac surgery acute kidney injury: a double-blind, randomised, placebo-controlled trial.

BACKGROUND: This study assessed whether i.v. sildenafil citrate prevented acute kidney injury in at-risk patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: In a double-blind RCT, adults at increased risk of acute kidney injury undergoing cardiac surgery in a single UK tertiary centre were randomised to receive sildenafil citrate 12.5 mg kg-1 i.v. over 150 min or dextrose 5% at the commencement of surgery. The primary outcome was serum creatinine measured at six post-randomisation time points. The primary analysis used a linear mixed-effects model adjusted for the stratification variables, baseline estimated glomerular filtration rate, and surgical procedure. Secondary outcomes considered clinical events and potential disease mechanisms. Effect estimates were expressed as mean differences (MDs) or odds ratios with 95% confidence intervals. RESULTS: The analysis population comprised eligible randomised patients that underwent valve surgery or combined coronary artery bypass graft and valve surgery, with cardiopulmonary bypass, between May 2015 and June 2018. There were 60 subjects in the sildenafil group and 69 in the placebo control group. The difference between groups in creatinine concentration was not statistically significant (MD: 0.88 µmol L-1 [-5.82, 7.59]). There was a statistically significant increase in multiple organ dysfunction scores in the sildenafil group (MD: 0.54 [0.02, 1.07]; P=0.044). Secondary outcomes, and biomarkers of kidney injury, endothelial function, and inflammatory cell activation, were not significantly different between the groups. CONCLUSIONS: These results do not support the use of i.v. sildenafil citrate for kidney protection in adult cardiac surgery. CLINICAL TRIAL REGISTRATION: ISRCTN18386427.

Biomarkers of Inflammation and Lung Recovery in Extracorporeal Membrane Oxygenation Patients With Persistent Pulmonary Hypertension of the Newborn: A Feasibility Study.

OBJECTIVES: Extracorporeal membrane oxygenation is a treatment for Persistent Pulmonary Hypertension of the Newborn with high mortality. HYPOTHESIS: the extracorporeal membrane oxygenation circuit results in inflammatory responses that mitigate against successful weaning. DESIGN: Single-center prospective observational feasibility study. SETTING: PICU. PATIENTS: Twenty-four neonates requiring extracorporeal membrane oxygenation support for Persistent Pulmonary Hypertension of the Newborn. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The reference outcome was death or more than 7 days of extracorporeal membrane oxygenation support. Other outcomes included serial measures of plasma-free hemoglobin and markers of its metabolism, leucocyte, platelet and endothelial activation, and biomarkers of inflammation. Of 24 participants recruited between February 2016 and June 2017, 10 died or required prolonged extracorporeal membrane oxygenation support. These patients were sicker at baseline with higher levels of plasma-free hemoglobin within 12 hours of cannulation (geometric mean ratio, 1.92; 95% CIs, 1.00-3.67; p = 0.050) but not thereafter, versus those requiring less than 7 days extracorporeal membrane oxygenation. Serum haptoglobin concentrations were significantly elevated in both groups. Patients who died or required prolonged extracorporeal membrane oxygenation support demonstrated elevated levels of platelet-leucocyte aggregation, but decreased concentrations of mediators of the inflammatory response: interleukin-8, C-reactive protein, and tumor necrosis factor α. CONCLUSIONS: Clinical status at baseline and not levels of plasma-free hemoglobin or the systemic inflammatory response may determine the requirement for prolonged extracorporeal membrane oxygenation support in neonates.

Systematic review and meta-analysis of experimental studies evaluating the organ protective effects of histone deacetylase inhibitors.

The clinical efficacy of organ protection interventions are limited by the redundancy of cellular activation mechanisms. Interventions that target epigenetic mechanisms overcome this by eliciting genome wide changes in transcription and signaling. We aimed to review preclinical studies evaluating the organ protection effects of histone deacetylase inhibitors (HDACi) with a view to informing the design of early phase clinical trials. A systematic literature search was performed. Methodological quality was assessed against prespecified criteria. The primary outcome was mortality, with secondary outcomes assessing mechanisms. Prespecified analyses evaluated the effects of likely moderators on heterogeneity. The analysis included 101 experimental studies in rodents (n = 92) and swine (n = 9), exposed to diverse injuries, including: ischemia (n = 72), infection (n = 7), and trauma (n = 22). There were a total of 448 comparisons due to the evaluation of multiple independent interventions within single studies. Sodium valproate (VPA) was the most commonly evaluated HDACi (50 studies, 203 comparisons). All of the studies were judged to have significant methodological limitations. HDACi reduced mortality in experimental models of organ injury (risk ratio = 0.52, 95% confidence interval 0.40-0.68, p < 0.001) without heterogeneity. HDACi administration resulted in myocardial, brain and kidney protection across diverse species and injuries that was attributable to increases in prosurvival cell signaling, and reductions in inflammation and programmed cell death. Heterogeneity in the analyses of secondary outcomes was explained by differences in species, type of injury, HDACi class (Class I better), drug (trichostatin better), and time of administration (at least 6 hours prior to injury better). These findings highlight a potential novel application for HDACi in clinical settings characterized by acute organ injury.