Background Acute kidney injury ( AKI ) after cardiac surgery is associated with adverse outcomes. Venous congestion can impair kidney function, but few tools are available to assess its impact at the ...bedside. The objective of this study was to determine whether portal flow pulsatility and alterations in intrarenal venous flow assessed by Point-Of-Care ultrasound are associated with AKI after cardiac surgery. Methods and Results This single-center prospective cohort study recruited patients undergoing cardiac surgery with cardiopulmonary bypass. Hepatic and renal Doppler ultrasound assessments were performed before surgery, at the intensive care unit admission, and daily for 3 days after surgery. The primary statistical analysis was performed using proportional hazards model for time-dependent variables. Among the 145 patients included, 49 patients (33.8%) developed AKI after cardiac surgery. The detection of portal flow pulsatility was associated with an increased risk of AKI (hazard ratio: 2.09, confidence interval, 1.11-3.94, P=0.02), as were severe alterations of intrarenal venous flow (hazard ratio: 2.81, confidence interval, 1.42-5.56, P=0.003). These associations remained significant in multivariable models. The addition of these markers to preoperative risk factors and central venous pressure measurement at intensive care unit admission improved the prediction of AKI . (Continuous net reclassification improvement: 0.364, confidence interval, 0.081-0.652 for portal Doppler and net reclassification improvement: 0.343, confidence interval, 0.081-0.628 for intrarenal Doppler) Conclusions Portal flow pulsatility and intrarenal flow alterations are markers of venous congestion and are independently associated with AKI after cardiac surgery. These tools might offer valuable information to develop strategies aimed at treating or preventing congestive cardiorenal syndrome after cardiac surgery. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02831907.
Studies of the effect of right ventricular ejection fraction (RVEF) on outcomes in heart failure (HF) are limited by small sample size and short follow-up.
We examined the effect of baseline RVEF on ...outcomes in 2008 Beta-Blocker Evaluation of Survival Trial (BEST) participants with HF and left ventricular ejection fraction <or=35% during 24 months of mean follow-up. RVEF, estimated by gated-equilibrium radionuclide ventriculography, was used to categorize patients into 4 RVEF groups: >or=40% (n=733), 30% to 39% (n=531), 20% to 29% (n=473), and <20% (n=271). Unadjusted rates for all-cause mortality in patients with RVEF >or=40%, 30% to 39%, 20% to 29%, and <20% were 27%, 32%, 35%, and 47%, respectively. When compared with patients with RVEF >or=40%, unadjusted hazard ratios and 95% confidence intervals for all-cause mortality for those with RVEF 30% to 39%, 20% to 29%, and <20% were 1.19 (0.97 to 1.46; P=0.087), 1.45 (1.17 to 1.78; P=0.001), and 1.98 (1.59 to 2.47; P<0.0001), respectively. Respective multivariable-adjusted hazard ratios (95% confidence intervals) for all-cause mortality associated with RVEF 30% to 39%, 20% to 29%, and <20% were 1.07 (0.87 to 1.32; P=0.518), 1.12 (0.89 to 1.40; P=0.328), and 1.32 (1.02 to 1.71; P=0.034), respectively. Adjusted hazard ratios (95% confidence intervals) for other outcomes associated with RVEF <20% (compared with >or=40%) were as follows: cardiovascular mortality, 1.33 (1.01 to 1.76; P=0.041); HF mortality, 1.61 (1.03 to 2.52; P=0.037); sudden cardiac death, 1.29 (0.87 to 1.91; P=0.212); all-cause hospitalization, 1.21 (1.00 to 1.47; P=0.056); and HF hospitalization, 1.39 (1.10 to 1.77; P=0.007).
Baseline RVEF <20% is a significant independent predictor of mortality and HF hospitalization in systolic HF.
Type 2 diabetes (T2D) is characterized by low-grade inflammation. Low-density neutrophils (LDNs) represent normally less than 2% of total neutrophils but increase in multiple pathologies, releasing ...inflammatory cytokines and neutrophil extracellular traps (NETs). We assessed the count and role of high-density neutrophils (HDNs), LDNs, and NET-related activities in patients with T2D. HDNs and LDNs were purified by fluorescence-activated cell sorting (FACS) and counted by flow cytometry. Circulating inflammatory and NETs biomarkers were measured by ELISA (Enzyme Linked Immunosorbent Assay). NET formation was quantified by confocal microscopy. Neutrophil adhesion onto a human extracellular matrix (hECM) was assessed by optical microscopy. We recruited 22 healthy volunteers (HVs) and 18 patients with T2D. LDN counts in patients with diabetes were significantly higher (160%), along with circulating NETs biomarkers (citrullinated H3 histone (H3Cit), myeloperoxidase (MPO), and MPO-DNA (137%, 175%, and 69%, respectively) versus HV. Circulating interleukins (IL-6 and IL-8) and C-Reactive Protein (CRP) were significantly increased by 117%, 171%, and 79%, respectively, in patients compared to HVs. Isolated LDNs from patients expressed more H3Cit, MPO, and NETs, formed more NETs, and adhered more on hECM compared to LDNs from HVs. Patients with T2D present higher levels of circulating LDN- and NET-related biomarkers and associated pro-inflammatory activities.
ABSTRACT
Informed consent is a cornerstone of ethical human research. However, as cluster randomized trials (CRTs) are increasingly popular to evaluate health service interventions, especially as ...health systems aspire toward the learning health system, questions abound how research teams and research ethics boards (REBs) should navigate intertwining consent and data‐use considerations. Methodological and ethical questions include who constitute the participants, whose and what types of consent are necessary, and how data from people who have not consented to participation should be managed to optimize the balance of trust in the research enterprise, respect for persons, the promotion of data integrity, and the pursuit of the public good in the research arena. In this paper, we report the findings and lessons learned from a qualitative study examining how researchers and REB members consider the ethical dimensions of when data can be collected and used in CRTs in the evolving research landscape.
The primary cause of mortality at 5 years following a cardiac transplantation is the development of atherosclerosis, termed coronary allograft vasculopathy （CAV）. This pathology is characterized by ...diffused intimal hyperplasia and emanates from coronary arterial injuries caused by immune inflammatory cells. Neutrophils play an important role in this inflammatory process; however, their potential participation in the pathogenesis of CAV is poorly understood. Despite their essential contribution to the prevention of graft rejection, immunosuppressive drugs could have detrimental effects owing to their pro-inflammatory activities. Thus, we investigated the impact of different immunosuppressive drugs on the inflammatory response of neutrophils isolated from the blood of healthy volunteers. Under basal conditions, mammalian target of rapamycin （mTOR） inhibitors （sirolimus and everolimus） had the most potent anti-inflammatory effect, decreasing both IL-8 release （≈-80%） and vascular endothelial growth factor （VEGF） release （≈-65%） and preserving the release of the anti-inflammatory cytokine interleukin-1 receptor antagonist （IL-1RA）. In TNF-α-treated neutrophils, pre-incubation with everolimus provided the most potent effect, simultaneously reducing the release of both VEGF and IL-8 while doubling the release of IL-1RA. This latter effect of everolimus was maintained even when administered in combination with other immunosuppressive drugs. Sirolimus and everolimus decreased the tumor necrosis factor （TNF）-α-induced adhesion of neutrophils to human endothelial cells and human extracellular matrix. This effect was largely dependent on the ability of these compounds to alter P2-integrin/CD18 activation. Our results suggest a potential mechanism for the beneficial effect of everolimus in the prevention of CAV in heart transplant recipients.
Abstract Objective Hospitalization for worsening heart failure (HF) is common and associated with high mortality. However, the effect of incident HF hospitalization (compared with no HF ...hospitalization) on subsequent mortality has not been studied in a propensity-matched population of chronic HF patients. Methods In the Digitalis Investigation Group trial, 5501 patients had no HF hospitalizations (4512 alive at 2 years after randomization) and 1732 patients had HF hospitalizations during the first 2 years (1091 alive at 2 years). Propensity scores for incident HF hospitalization during the first 2 years after randomization were calculated for each patient and used to match 1057 patients (97%) who had 2-year HF hospitalization with 1057 patients who had no HF hospitalization. We used matched Cox regression analysis to estimate the effect of incident HF hospitalization during the first 2 years after randomization on post–2-year mortality. Results Compared with 153 deaths (rate, 420/10,000 person-years) in the no HF hospitalization group, 334 deaths (rate, 964/10,000 person-years) occurred in the HF hospitalization group (hazard ratio 2.49; 95% confidence interval 1.97–3.13; P < .0001). The hazard ratios (95% confidence intervals) for cardiovascular and HF mortality were 2.88 (2.23–3.74; P < .0001) and 5.22 (3.34–8.15; P < .0001), respectively. Conclusions Hospitalization for worsening HF was associated with increased risk of subsequent mortality in ambulatory patients with chronic HF. These results highlight the importance of HF hospitalization as a marker of disease progression and poor outcomes in chronic HF, reinforcing the need for prevention of HF hospitalizations and strategies to improve postdischarge outcomes.
Abstract Background There are little data on the optimization of high-intensity aerobic interval exercise (HIIE) protocols in patients with chronic heart failure (CHF). Therefore, we compared acute ...cardiopulmonary responses to 4 different HIIE protocols to identify the optimal one. Methods and Results Twenty men with stable systolic CHF performed 4 different randomly ordered single HIIE sessions with measurement of gas exchange. For all protocols (A, B, C, and D) exercise intensity was set at 100% of peak power output (PPO). Interval duration was 30 seconds (A and B) or 90 seconds (C and D), and recovery was passive (A and C) or active (50% of PPO in B and D). Time spent above 85% of VO2peak and time above the ventilatory threshold were similar across all 4 HIIE protocols. Total exercise time was significantly longer in protocols with passive recovery intervals (A: 1,651 ± 347 s; C: 1,574 ± 382 s) compared with protocols with active recovery intervals (B: 986 ± 542 s; D: 961 ± 556 s). All protocols appeared to be safe, with exercise tolerance being superior during protocol A. Conclusion Among the 4 HIIE protocols tested, protocol A with short intervals and passive recovery appeared to be superior.
Background Heart failure is the leading cause for 30-day all-cause readmission, the reduction of which is a goal of the Affordable Care Act. There is a growing interest in understanding the impact of ...evidence-based heart failure therapy on 30-day all-cause readmission. In the current study, we examined the impact of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI-ARBs) on 30-day all-cause readmission in heart failure. Methods Of the 1384 hospitalized Medicare beneficiaries with heart failure and left ventricular ejection fraction <45% discharged alive from 106 Alabama hospitals (1998–2001) without prior ACEI-ARB use and without known contraindications to ACEI-ARB use, 734 received new pre-discharge prescriptions for these drugs. Using propensity scores for ACEI-ARB initiation, we assembled a matched cohort of 477 pairs of patients balanced on 32 baseline characteristics (mean age 75 years, 46% women, 26% African American). Results 30-day all-cause readmissions occurred in 18% and 24% of matched patients receiving and not receiving ACEI-ARBs, respectively (hazard ratio {HR}, 0.74; 95% confidence interval {CI}, 0.56–0.97; p=0.030). ACEI-ARB use was also associated with lower risk of 30-day all-cause mortality (HR, 0.56; 95% CI, 0.33–0.98; p=0.041) and of the combined endpoint of 30-day all-cause readmission or 30-day all-cause mortality (HR, 0.73; 95% CI, 0.56–0.94; p=0.017). All associations remained significant at 1-year post-discharge. Conclusions –Among hospitalized patients with heart failure and reduced ejection fraction, the use of ACEI-ARBs was associated with a significantly lower risk of 30-day all-cause readmission and 30-day all-cause mortality; both beneficial associations persisted during long-term follow-up.
Background Heart failure is the leading cause for 30-day all-cause readmission. We examined the impact of 30-day all-cause readmission on long-term outcomes and cost in a propensity score matched ...study of hospitalized patients with heart failure. Methods Of the 7578 Medicare beneficiaries discharged with a primary diagnosis of heart failure from 106 Alabama hospitals (1998–2001) and alive at 30-day post-discharge, 1519 had 30-day all-cause readmissions. Using propensity scores for 30-day all-cause readmission, we assembled a matched cohort of 1516 pairs of patients with and without 30-day all-cause readmissions, balanced on 34 baseline characteristics (mean age 75 years, 56% women, 24% African American). Results During 2-12 months of follow-up after discharge from index hospitalization, all-cause mortality occurred in 41% and 27% of matched patients with and without 30-day all-cause readmission, respectively (hazard ratio {HR}, 1.68; 95% confidence interval {CI}, 1.48–1.90; p<0.001). This harmful association of 30-day all-cause readmission with mortality persisted during an average follow-up of 3.1 (maximum, 8.7) years (HR, 1.33; 95% CI, 1.22–1.45; p<0.001). Patients with a 30-day all-cause readmission had higher cumulative all-cause readmissions (mean, 6.9 vs. 5.1; p<0.001), a longer cumulative length of stay (mean, 51 vs. 43 days; p<0.001) and a higher cumulative cost (mean, $38,972 vs. $34,025; p=0.001) during 8.7 years of follow-up. Conclusions Among Medicare beneficiaries hospitalized for heart failure, 30-day all-cause readmission was associated with a higher risk of subsequent all-cause mortality, higher number of cumulative all-cause and heart failure readmissions, longer cumulative length of stay and higher cumulative cost.
We reported the expression of angiopoietin Tie2 receptor on human neutrophils and the capacity of angiopoietins (Ang1 and Ang2) to induce pro-inflammatory activities, such as platelet-activating ...factor synthesis, β2-integrin activation and neutrophil migration. Recently, we observed differential effects between both angiopoietins, namely, the capacity of Ang1, but not Ang2, to promote rapid interleukin-8 synthesis and release, as well as neutrophil viability. Herein, we addressed whether Ang1 and/or Ang2 could modulate the synthesis and release of macrophage inflammatory protein-1β (MIP-1β) by neutrophils. Neutrophils were isolated from blood of healthy volunteers; intracellular and extracellular MIP-1β protein concentrations were assessed by ELISA. After 24 hours, the basal intracellular and extracellular MIP-1β protein concentrations were ≈500 and 100 pg/106 neutrophils, respectively. Treatment with Ang1 (10 nM) increased neutrophil intracellular and extracellular MIP-1β concentrations by 310 and 388% respectively. Pretreatment with PI3K (LY294002), p38 MAPK (SB203580) and MEK (U0126) inhibitors completely inhibited Ang1-mediated increase of MIP-1β intracellular and extracellular protein levels. Pretreatment with NF-κB complex inhibitors, namely Bay11-7085 and IKK inhibitor VII or with a transcription inhibitor (actinomycin D) and protein synthesis inhibitor (cycloheximide), did also abrogate Ang1-mediated increase of MIP-1β intracellular and extracellular protein levels. We validated by RT-qPCR analyses the effect of Ang1 on the induction of MIP-1β mRNA levels. Our study is the first one to report Ang1 capacity to induce MIP-1β gene expression, protein synthesis and release from neutrophils, and that these effects are mediated by PI3K, p38 MAPK and MEK activation and downstream NF-κB activation.
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