The effect of novel immunosuppressants on extracellular matrix remodelling and the expression of fibrosis associated genes in an experimental model of allograft vasculopathy

Background: Chronic allograft dysfunction (CAD), the leading cause of solid organ transplant failure, is characterised by histological evidence of parenchymal extracellular matrix (ECM) accumulation (fibrosis) and allograft vasculopathy. The aim of this study was to compare the effects of rapamycin and cyclosporin therapy, individually as well as in combination, on fibrosis associated gene expression and ECM remodeling in an experimental model of allograft vasculopathy. Methods: Vascular remodeling and ECM accumulation (picrosirius red) were measured by computerised histomorphometry of F344 to Lewis rat aortic allograft sections harvested at serial time points. Expression of fibrosis associated genes was studied by means of semi-quantitative RT-PCR. Results: Rapamycin (0.5mg/kg/day) or cyclosporin (5mg/kg/day) inhibited intimal hyperplasia, medial ECM accumulation and expansive vascular remodeling (increasing vessel circumference) in rat aortic allografts. This was associated with attenuation of the graft inflammatory infiltrate and a reduction in intra-graft gelatinase, collagen III and TIMP 1 mRNA levels. At a lower dose (0.25mg/kg/day) Rapamycin inhibited intimal hyperplasia and medial ECM accumulation however there was a lesser effect on vascular remodeling compared to cyclosporin or rapamycin 0.5mg/kg/day. Combined rapamycin and cyclosporin also inhibited intimal hyperplasia however there was a lesser effect on both vascular remodeling and medial extracellular matrix accumulation. Combined treatment or rapamycin 0.25mg/kg/day monotherapy aortic allografts were also seen to have a more severe inflammatory infiltrate and larger amounts of intra-graft MMP 9, TGFp and TIMP 1 mRNA than cyclosporin or rapamycin 0.5mg/kg/day monotherapy. Conclusion: These data suggest that in addition to the tissue response to injury, the alloimmune injury itself may directly contribute to vascular and ECM remodeling. In this experimental model rapamycin inhibited vascular remodeling and ECM accumulation only in the presence of effective immunosuppression

Effects of cerebral near-infrared spectroscopy on the outcome of patients undergoing cardiac surgery: a systematic review of randomised trials

Objectives Goal-directed optimisation of cerebral oxygenation using near-infrared spectroscopy (NIRS) during cardiopulmonary bypass is widely used. We tested the hypotheses that the use of NIRS cerebral oximetry results in reductions in cerebral injury (neurocognitive function, serum biomarkers), injury to other organs including the heart and brain, transfusion rates, mortality and resource use. Design Systematic review and meta-analysis. Setting Tertiary cardiac surgery centres in North America, Europe and Asia. Participants A search of Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Medline, Embase, and the Cumulative Index to Nursing and Allied Health Literature Plus from inception to November 2016 identified 10 randomised trials, enrolling a total of 1466 patients, all in adult cardiac surgery. Interventions NIRS-based algorithms designed to optimise cerebral oxygenation versus standard care (non-NIRS-based) protocols in cardiac surgery patients during cardiopulmonary bypass. Outcome measures Mortality, organ injury affecting the brain, heart and kidneys, red cell transfusion and resource use. Results Two of the 10 trials identified in the literature search were considered at low risk of bias. Random-effects meta-analysis demonstrated similar mortality (risk ratio (RR) 0.76, 95% CI 0.30 to 1.96), major morbidity including stroke (RR 1. 08, 95% CI 0.40 to 2.91), red cell transfusion and resource use in NIRS-treated patients and controls, with little or no heterogeneity. Grades of Recommendation, Assessment, Development and Evaluation of the quality of the evidence was low or very low for all of the outcomes assessed. Conclusions The results of this systematic review did not support the hypotheses that cerebral NIRS-based algorithms have clinical benefits in cardiac surgery

Transfusion triggers in cardiac surgery: Where do we go from here?

Defining the appropriate indications for the transfusion of allogenic red cells is an area of intense study. Cardiac surgery utilizes a significant proportion (over 6%) of all red cells transfused in the United Kingdom1 where demographic changes have reduced donor pools; it is also expensive. Indeed, the total societal cost for a single unit of red cells is estimated to be well over 600 CAD.2 In a patient who is bleeding profusely following surgery, the indication for red cell transfusion is clear. In this setting, red cell transfusion helps to maintain oxygen delivery and reverse the oxygen supply-demand imbalance. Nevertheless, in the anemic patient who is not actively bleeding, the risks and benefits of this costly intervention remain uncertain. Définir les bonnes indications d’une transfusion de globules rouges allogéniques constitue un domaine d’études intensif. La chirurgie cardiaque utilise un pourcentage significatif (plus de 6 %) de tous les globules rouges transfusés au Royaume-Uni1 où les caractéristiques démographiques ont réduit le nombre potentiel de donneurs; les transfusions sont également dispendieuses. De fait, le coût total d’une unité de globules rouges est estimé à plus de 600 dollars canadiens.2 L’indication d’une transfusion de globules rouges est évidente chez un patient qui saigne abondamment après une chirurgie. Dans ce cas, la transfusion de globules rouges aide à maintenir l’apport d’oxygène et à combler le déséquilibre de la demande en oxygène. Néanmoins, chez un patient anémique ne présentant pas d’hémorragie active, les risques et avantages de cette intervention coûteuse restent mal établis

Liberal or Restrictive Transfusion after Cardiac Surgery. The authors reply.

Liberal or Restrictive Transfusion after Cardiac Surgery. The authors reply

Vascular endothelial cell changes in postcardiac surgery acute kidney injury

Acute kidney injury (AKI) is common complication of cardiac surgery; however, the phenotype of this condition is poorly defined. The aim of this study was to characterize changes in endothelial structure and function that underlie postcardiopulmonary bypass (post-CPB) AKI. Adult pigs (n = 16) were randomized to undergo the following procedures (n = 8 per group): group 1: sham operation, neck dissection with 2.5 h of general anesthesia; and group 2: CPB, 2.5 h of cardiopulmonary bypass. CPB resulted in the depletion of specific epitopes of glycosaminoglycans side chains of the endothelial glycocalyx: Dolichos biflorus agglutinin: mean difference (MD) [95% confidence interval (CI)], P value: −0.26 (−0.42, −0.09), P = 0.0024, Triticum vulgaris (wheat germ) agglutinin: −0.83 (−1.2, −0.38), P = 0.0005, and Ulex europaeus agglutinin 1: −0.25 (−0.49, −0.009), P = 0.041; endothelial membrane protein: thrombomodulin: −3.13 (−5.6, −0.65), P = 0.02; and adherens junction: VE-cadherin: −1.06 (−1.98, −0.145), P = 0.02. CPB also resulted in reductions in microvascular cortical perfusion: −0.62 (−1.02, −0.22), P = 0.006, and increased renal cortex adenosine levels: 2.32 (0.83, 3.8), P = 0.0059. These changes were accompanied by significant reduction in creatinine clearance at 1.5 h postintervention, MD 95% CI; −51.7 (−99.7, −3.7), P = 0.037, and at 24 h, MD (95% CI): −47.3 (−87.7, −7.6), P = 0.023, and proteinuria immediately postintervention MD (95% CI): 18.79 (2.17, 35.4), P = 0.03 vs. sham. In our experimental CPB model, endothelial injury was associated with loss of autoregulation, increase in microvascular permeability, and reduced glomerular filtration. Interventions that promote endothelial homeostasis may have clinical utility in the prevention of postcardiac surgery AKI

Systematic review of studies that have evaluated screening tests in relatives of patients affected by nonsyndromic thoracic aortic disease

Background Nonsyndromic thoracic aortic diseases (NS‐TADs) are often silent entities until they present as life‐threatening emergencies. Despite familial inheritance being common, screening is not the current standard of care in NS‐TADs. We sought to determine the incidence of aortic diseases, the predictive accuracy of available screening tests, and the effectiveness of screening programs in relatives of patients affected by NS‐TADs. Methods and Results A systematic literature search on PubMed/MEDLINE, Embase, and the Cochrane Library was conducted from inception to the end of December 2017. The search was supplemented with the Online Mendelian Inheritance in Man database. A total of 53 studies were included, and a total of 2696 NS‐TAD relatives were screened. Screening was genetic in 49% of studies, followed by imaging techniques in 11% and a combination of the 2 in 40%. Newly affected individuals were identified in 33%, 24%, and 15% of first‐, second‐, and third‐degree relatives, respectively. Familial NS‐TADs were primarily attributed to single‐gene mutations, expressed in an autosomal dominant pattern with incomplete penetrance. Specific gene mutations were observed in 25% of the screened families. Disease subtype and genetic mutations stratified patients with respect to age of presentation, aneurysmal location, and aortic diameter before dissection. Relatives of patients with sporadic NS‐TADs were also found to be affected. No studies evaluated the predictive accuracy of imaging or genetic screening tests, or the clinical or cost‐effectiveness of an NS‐TAD screening program. Conclusions First‐ and second‐degree relatives of patients affected by both familial and sporadic NS‐TADs may benefit from personalized screening programs

Nonlinear association of BMI with all-cause and cardiovascular mortality in type 2 diabetes mellitus: a systematic review and meta-analysis of 414,587 participants in prospective studies

Aims/hypothesis: The relationship between BMI and mortality has been extensively investigated in the general population; however, it is less clear in people with type 2 diabetes. We aimed to assess the association of BMI with all-cause and cardiovascular mortality in individuals with type 2 diabetes mellitus. Methods: We searched electronic databases up to 1 March 2016 for prospective studies reporting associations for three or more BMI groups with all-cause and cardiovascular mortality in individuals with type 2 diabetes mellitus. Study-specific associations between BMI and the most-adjusted RR were estimated using restricted cubic splines and a generalised least squares method before pooling study estimates with a multivariate random-effects meta-analysis. Results: We included 21 studies including 24 cohorts, 414,587 participants, 61,889 all-cause and 4470 cardiovascular incident deaths; follow-up ranged from 2.7 to 15.9 years. There was a strong nonlinear relationship between BMI and all-cause mortality in both men and women, with the lowest estimated risk from 31–35 kg/m2 and 28–31 kg/m2 (p value for nonlinearity <0.001) respectively. The risk of mortality at higher BMI values increased significantly only in women, whilst lower values were associated with higher mortality in both sexes. Limited data for cardiovascular mortality were available, with a possible inverse linear association with BMI (higher risk for BMI <27 kg/m2). Conclusions/interpretation: In type 2 diabetes, BMI is nonlinearly associated with all-cause mortality with lowest risk in the overweight group in both men and women. Further research is needed to clarify the relationship with cardiovascular mortality and assess causality and sex differences

Adherence to transfusion strategies in a randomized controlled trial: experiences from the TITRe2 trial

Adherence to transfusion strategies in a randomized controlled trial: experiences from the TITRe2 tria

Body Mass Index and Mortality Among Adults Undergoing Cardiac Surgery: A Nationwide Study With a Systematic Review and Meta-Analysis.

BACKGROUND: In an apparent paradox, morbidity and mortality are lower in obese patients undergoing cardiac surgery, although the nature of this association is unclear. We sought to determine whether the obesity paradox observed in cardiac surgery is attributable to reverse epidemiology, bias, or confounding. METHODS: Data from the National Adult Cardiac Surgery registry for all cardiac surgical procedures performed between April 2002 and March 2013 were extracted. A parallel systematic review and meta-analysis (MEDLINE, Embase, SCOPUS, Cochrane Library) through June 2015 were also accomplished. Exposure of interest was body mass index categorized into 6 groups according to the World Health Organization classification. RESULTS: A total of 401 227 adult patients in the cohort study and 557 720 patients in the systematic review were included. A U-shaped association between mortality and body mass index classes was observed in both studies, with lower mortality in overweight (adjusted odds ratio, 0.79; 95% confidence interval, 0.76-0.83) and obese class I and II (odds ratio, 0.81; 95% confidence interval, 0.76-0.86; and odds ratio, 0.83; 95% confidence interval, 0.74-0.94) patients relative to normal-weight patients and increased mortality in underweight individuals (odds ratio, 1.51; 95% confidence interval, 1.41-1.62). In the cohort study, a U-shaped relationship was observed for stroke and low cardiac output syndrome but not for renal replacement therapy or deep sternal wound infection. Counter to the reverse epidemiology hypotheses, the protective effects of obesity were less in patients with severe chronic renal, lung, or cardiac disease and greater in older patients and in those with complications of obesity, including the metabolic syndrome and atherosclerosis. Adjustments for important confounders did not alter our results. CONCLUSIONS: Obesity is associated with lower risks after cardiac surgery, with consistent effects noted in multiple analyses attempting to address residual confounding and reverse causation

A Comparison of Red Cell Rejuvenation versus Mechanical Washing for the Prevention of Transfusion-associated Organ Injury in Swine

BACKGROUND: We evaluated the effects of two interventions that modify the red cell storage lesion on kidney and lung injury in experimental models of transfusion. METHODS: White-landrace pigs (n = 32) were allocated to receive sham transfusion (crystalloid), 14-day stored allogeneic red cells, 14-day red cells washed using the red cells washing/salvage system (CATS; Fresenius, Germany), or 14-day red cells rejuvenated using the inosine solution (Rejuvesol solution; Zimmer Biomet, USA) and washed using the CATS device. Functional, biochemical, and histologic markers of organ injury were assessed for up to 24 h posttransfusion. RESULTS: Transfusion of 14 day red cells resulted in lung injury (lung injury score vs. sham, mean difference -0.3 (95% CIs -0.6, -0.1; P = 0.02), pulmonary endothelial dysfunction, and tissue leukocyte sequestration. Mechanical washing reduced red cell-derived microvesicles but increased cell-free hemoglobin in 14-day red cell units. Transfusion of washed red cells reduced leukocyte sequestration but did not reduce the lung injury score (mean difference -0.2; 95% CI -0.5, 0.1; P = 0.19) relative to 14-day cells. Transfusion of washed red cells also increased endothelial activation and kidney injury. Rejuvenation restored adenosine triphosphate to that of fresh red cells and reduced microvesicle concentrations without increasing cell-free hemoglobin release. Transfusion of rejuvenated red cells reduced plasma cell-free hemoglobin, leukocyte sequestration, and endothelial dysfunction in recipients and reduced lung and kidney injury relative to 14-day or washed 14-day cells. CONCLUSIONS: Reversal of the red cell storage lesion by rejuvenation reduces transfusion-associated organ injury in swine