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Purpose Inflammation and congestion persist after LVAD and may contribute to clinical outcomes. C-Reactive Protein (CRP) and N-terminal-pro B-type natriuretic peptide (proBNP) are established biomarkers of inflammation and congestion. We studied the association of these biomarkers measured at the first outpt visit after LVAD implant with: i) risk of readmission, and ii) days-alive-out-of-hospital (DAOH). Methods Serum CRP and proBNP were measured in LVAD pts implanted between 9/2014 and 11/2018. Readmissions and DAOH (based on % of total days) between first outpt visit and up to 2-year follow up were analyzed. CRP and proBNP values were categorized as ≥ vs Results 217 LVAD pts (99 HMII, 102 HM3, 16 others) were studied. 378 readmissions occurred in 155 pts. Median time to first readmission was 110 [29-233] d. Median DAOH% was 98.2% [94-100]. Median CRP and proBNP were 19.4 [8.9-43.6] mg/L and 1271 [456-3050] pg/mL. At 2-year follow up, freedom from readmission was higher in Conclusion Low levels of CRP and proBNP at the first outpt visit identify a low-risk subset of LVAD pts with lower probability of readmission and higher DAOH%. Based on these findings, studies investigating interventions to reduce inflammation and congestion are needed to evaluate their impact on readmissions and quality of life.

Purpose Malnutrition is common in heart failure (HF) and contributes to poor outcomes. Nutrient metabolism might be influenced by the complex interplay between HF progression, venous congestion, inflammation and gut dysbiosis. We investigated the association between nutritional status and: i) biomarkers of congestion and inflammation; ii) gut microbial diversity; and iii) perioperative infections among HF pts undergoing LVAD. Methods From 8/2016 to 8/2018, hospitalized pts with prospectively collected stool and blood samples prior to LVAD and a nutritional assessment were retrospectively reviewed. Nutritional status was assessed according to current guidelines. Pts were divided into 2 groups: no malnutrition vs malnutrition (≥moderate). Calorie and fiber consumption over 7-day period pre-LVAD was averaged. Serum biomarkers of congestion (NT-proBNP) and inflammation (CRP) were measured. Stool samples were analyzed using 16S rRNA sequencing and summarized both at the taxa level, and overall using the Shannon index (a composite metric of gut alpha-diversity). Regression analyses explored differences in Shannon index and individual taxa (via DESeq) by nutritional status. Results 37 pts (56 ±12.6 y, 92% M) were included. 10 (27%) had malnutrition. Malnourished pts had significantly lower Shannon Index (Fig 1A). A positive correlation was found between Shannon index and calorie (r =.36, p=.027) and fiber intake (r= .32, p=.05). We observed n=3 taxa, all with anti-inflammatory properties, to be significantly enriched in pts without malnutrition (Fig 1B). Pre-LVAD levels of NT-proBNP and CRP were similar between groups. Perioperative infections were more prevalent in pts with malnutrition (Fig 1C); specifically, pre-LVAD 50% vs 18% and post-LVAD infections 60% vs 26%, both p=.05. Conclusion Malnutrition is associated with gut dysbiosis and perioperative infections in HF pts undergoing LVAD. Proof of principle trials to increase fiber intake and reduce gut dysbiosis and infection are justified.

Management of dredged materials disposal is regulated by several environmental normative requirements, and it is often supported by the integration of chemical data with ecotoxicological characterization. The reliability of a bioassay to assess the potential toxicity of dredged sediments requires the selection of quality criteria that should be based on simple analytical methods and easily understandable hazard for politicians and environmental managers. The sea urchin embryo-toxicity bioassay is considered an essential component for evaluating the quality of sediments in harbour areas but its use, when based exclusively on the observation of normal vs. abnormal embryos, may alter the interpretation of the results, overestimating the risk assessment. To improve the reliability of this assay in establishing a causative relationship between quality of sediments and sea urchin embryonic development, here we developed and validated three Integrative Toxicity Indexes (ITI 2.0, ITI 3.0, ITI 4.0), modifying the already-known ITI (here ITI 1.0). Based on this aim, we used Taranto harbour as a model pilot-study to compare results to those obtained from standard criteria. Among the tested indexes, the ITI 4.0, discriminating strictly developmental delay and morphological defects from fertilized egg to gastrula stage, resulted in the most promising.

The sea urchin embryo toxicity test is classically used to assess the noxious effects of contaminated marine waters and sediments. In Italian guidelines on quality of dredged sediments, the standard toxicity criteria used for this assay are based on a single endpoint at 48 hours of development, corresponding to the pluteus stage. Different typologies of abnormalities, including those which occur at earlier stages, are not categorized, thus preventing the evaluation of the actual teratogenic hazards. A new integrative toxicity index has been developed in this study based on the analysis of two developmental stages, at 24 and 48h post-fertilization, and the differentiation between development delays and germ layers impairments: the new toxicity index is calculated by integrating the frequency of abnormal embryos with the severity of such abnormalities. When tested on dredged sediments, the evaluation of increasing levels of toxicity affecting embryonic outcomes enhanced the capability to discriminate different samples, appearing particularly relevant to validate the sea urchin embryo toxicity assay, and supporting its utility in practical applications such as the sediments classification in harbor areas.

Introduction Accuracy of serum creatinine (sCr) in the estimation of renal function among heart transplant (HT) pts may be limited by changes in muscle mass. Cystatin C (CysC) is independent from muscle mass and provides an alternative measure of estimated glomerular filtration rate (eGFR). We hypothesized that: i) sCr would overestimate renal function due to muscle wasting; and ii) this would cause overdosing of valganciclovir (VGC) and, thereby, leukopenia. Herein, we aimed to: i) compare post-HT changes in CysC- and sCr-based eGFR; and ii) explore whether the use of CysC in lieu of sCr carries the potential to reduce the rate of VGC-induced leukopenia. Methods Pts transplanted between 6/2016 and 4/2019 had serial measurements of CysC and sCr pre- and post-HT. eGFR was assessed using CKD-EPI-CysC (eGFRCysC) and MDRD (eGFRsCr). Linear mixed models were used to regress post-HT changes in eGFRCysC, eGFRsCr and sCr/CysC ratio (a validated marker of muscle mass). In a subgroup of patients receiving VGC, eGFR was assessed as a time-varying covariate at 1-, 3-, and 6-months post-HT. The primary endpoint was rate of VGC-induced leukopenia within 1-month of renal function assessment. Appropriateness of VGC dosing for renal impairment was assessed using, in addition to eGFRCysC and eGFRsCr, creatinine clearance (CrCl) as per manufacturer's recommendation. Results A total of 309 samples were collected in 83 pts. eGFRCysC was markedly lower than eGFRsCr early post-HT (Figure A). While eGFRsCr declined long-term, eGFRCysC showed an opposite trend with a gradual improvement. The decline in eGFRsCr mirrored the rise in sCr/CysC ratio, suggesting that increase in muscle mass may contribute to this decline. Among 57 pts who were on VGC at 1-, 3-, and 6-months post-HT, 117 samples were available. Based on sCr-based equations (eGFRsCr and CrCl), VGC was appropriately dosed in the majority of samples (72% and 64%, respectively). However, based on eGFRCysC, VGC was inappropriately dosed in 54 (46%) samples: 11 (9%) underdosed, 43 (37%) overdosed (Figure B). Among 31 episodes of VGC-induced leukopenia within 1-month of sampling, 15 (48%) occurred in samples with VGC overdosed by eGFRCysC. In adjusted models, higher CysC but not sCr was associated with increased risk for leukopenia (OR: CysC: 1.47, 95%CI 1.04-2.06; sCr: 1.19, 95%CI 0.79-1.79). Conclusions eGFRCysC and eGFRsCr markedly differ early post-HT with critical implications in the dosing of VGC. The use of CysC in lieu of sCr may prevent VGC overdosing and reduce the rate of leukopenia in HT pts.

Purpose Serum creatinine (sCr) is routinely used in the assessment of renal function among heart transplant (HT) pts. However, changes in muscle mass and nutritional status early post-HT may affect the accuracy of sCr estimated glomerular filtration rate (eGFRsCr). While Cystatin C (CysC) is independent from the above mentioned confounders, an increase in CysC with steroid use has been reported. The ratio sCr/CysC has been validated as a marker of muscle mass. Herein, we aimed to: i) longitudinally compare post-HT changes in CysC eGFR (eGFRCysC) and eGFRsCr; and ii) investigate the relation of muscle mass, nutritional status and steroid use with the difference between eGFRCysC and eGFRsCr. Methods Pts transplanted between 6/2016 and 4/2019 had serial, concurrent measurements of CysC and sCr pre- and post-HT. Albumin (a marker of nutritional status) and prednisone dose at the time of sample collection were recorded. Adjusted linear mixed models were used to: i) regress post-HT changes in eGFRCysC, eGFRsCr and sCr/CysC ratio; ii) study associations of albumin and prednisone dose with the difference between eGFRsCr and eGFRCysC (ΔeGFRsCr-CysC = [eGFRsCr - eGFRCysC]/eGFRsCr). Results 313 samples were collected in 84 pts (age 54±12, 20% female). While eGFRsCr declined long-term, eGFRCysC showed an opposite trend with a gradual improvement (Figure). The temporal decline in eGFRsCr mirrored the progressive rise in sCr/CysC ratio, suggesting a contribution of an increase in muscle mass to this decline. Albumin was inversely related to ΔeGFRsCr-CysC (β= -0.51, p Conclusion eGFRCysC and eGFRsCr markedly differ early post-HT. Changes in muscle mass and nutritional status as well as steroid use may account for the observed discrepancies. Future studies are warranted to address these inconsistencies as accurate estimation of renal function carries important clinical implications (e.g. medication dosing).

Purpose Creatinine clearance (CrCl) is the accepted clinical standard for the assessment of renal function and dosing of renally-excreted medications such as valganciclovir (VGC) among heart transplant (HT) pts. Cystatin C (CysC) has recently shown superiority to serum creatinine (sCr) for the estimation of renal function in advanced diseases. We hypothesize that CysC-estimated glomerular filtration rate (Cys-eGFR) more accurately guides VGC dosing than CrCL, and thereby may prevents drug overdosing and leukopenia in HT pts. Methods Pts transplanted between 11/2016 and 4/2019 who received VGC for CMV prophylaxis were included. eGFR was assessed using CrCl and CysC-eGFR as a time-varying covariate at 1-,3-, and 6-months post-HT. The primary endpoint was rate of leukopenia (WBC Results 119 samples were available in 58 pts (age 54±13 y, 20% female). Based on CrCl, VGC was inappropriately dosed in 43 samples: 21 underdosed, 22 overdosed. Based on CysC-eGFR, VGC was inappropriately dosed in 62 samples: 12 underdosed, 50 overdosed (Figure 1). 32 episodes of leukopenia were observed in 27 pts within 1-month of sampling. Half (n=16) of the events occurred in samples with VGC overdosed by CysC-eGFR. In adjusted models, CysC but not sCr was associated with a significant 1.48 times greater odds of leukopenia (per 0.3 mg/L CysC 95%CI 1.05-2.08; OR per 0.3 mg/dL sCr 1.17, 95%CI 0.78-1.73.) Conclusion CysC-eGFR may more accurately estimate VGC dosing compared to CrCL thereby resulting in lower rates of leukopenia after HT.

Purpose We previously showed that cerebrovascular reactivity (CVR) is reduced in heart failure (HF) patients and does not improve after left ventricular assist device (LVAD) HeartMate II (HMII) implantation, possibly because of low pulsatile physiology. Therefore, it is possible that the artificial pulse of the latest generation LVAD, the HeartMate3 (HM3), restores normal CVR. HM3 patients will have an increased CVR to a CO2-retention challenge compared with HF and HMII. Methods A total of 79 subjects (17 healthy, 30 HF, 15 HMII and 17 HM3) underwent angle-corrected transcranial Doppler sonography. Middle cerebral artery (MCA) velocity profiles were recorded before and at the end of a 30s breath hold. Mean flow velocity (MFV), peak flow velocity (Vmax), minimal flow velocity (Vmin), Pulsatility Index (PI) and Resistance Index (RI) were quantified. Statistical differences were determined using 2-way ANOVA (Breathhold x group). Results At baseline, HF patients with and without LVAD implantation had a decreased Vmax, MFV, PI and RI compared to healthy (all P Conclusion HM3 patients have a significantly improved CVR to a CO2-retention challenge compared with HMII patients. However, the acute CVR is not altered by the artificial pulse. Since CVR of HM3 patients remains reduced compared with healthy controls, further research is needed to understand the pathophysiology of cerebrovascular complications in LVAD.

Purpose Lack of nocturnal blood pressure (BP) reduction (BP dipping) has been associated with cerebrovascular and cardiovascular events in the general population. However, the effect of a deranged circadian BP variability between day and night has never been studied in patients on left ventricular assist device (LVAD) support, where stroke still represents a major complication. We hypothesized that decreased BP dipping significantly increases the risk of stroke in patients on LVAD support. Methods HeartMate II (HMII) outpatients were prospectively studied with an ambulatory BP monitor (Mobil-O-Graph) previously validated in this patient population. Systolic BP (SBP), diastolic BP (DBP) and mean arterial pressure (MAP) were recorded every 30 minutes during the day and every hour during the night for 24 hours. Circadian patterns, expressed as the percentage of nocturnal SBP, DBP, and MAP reduction from daytime values, were assessed in Cox regression models with stroke as primary endpoint. Results 29 patients were studied (age 59 ±15 yrs, 76% male, 38% ischemic, 69% DT). 6 patients (20%) experienced a stroke 879±591 days post LVAD implant. Nocturnal reductions of SBP, DBP, and MAP were 5.0 ± 6.1%, 5.0 ± 5.6% and 5.0 ± 5.5%, respectively. Preserved nocturnal reductions of SBP (HR 0.790 [95% CI 0.658 - 0.949]), DBP (HR 0.707 [95% CI 0.559 - 0.894]) and MAP (HR 0.703 [95% CI 0.554 - 0.894]) were associated with a decreased risk of stroke. When patients were grouped by the median nocturnal reduction in MAP (5.4%), patients with reduced dipping had a significantly greater risk of stroke (Figure 1). Conclusion This study is the first to indicate that reduced BP dipping at night increases the risk of stroke in patients on HMII support. Further studies are warranted to investigate, mechanistically, the relationship between reduced BP dipping and sympathetic nervous system activation, and, clinically, its association with the risk of stroke in patients on HM3 support.

Purpose The optimal method for blood pressure (BP) measurement among pts implanted with HeartMate 3 (HM3), a centrifugal pump that features an artificial pulse, is presently unknown. We aimed to: 1) assess success rate and validity of Doppler opening BP (DOBP) and automated BP (ABP) monitor; 2) test a novel approach to estimate mean arterial pressure (MAP) by combining DOBP and HM3 parameters. Methods BP and HM3 parameters (Speed, Power, Pulsatility Index [PI], Flow) were prospectively collected in a derivation cohort (DC, n=50) and a validation cohort (VC, n=11). BP was measured by arterial line (A-line) in all pts. DOBP and ABP were concurrently measured in a subgroup of DC (DCs, n=31) and in VC. In DC, a multiple linear regression model was fit with A-line systolic BP (SBP) and HM3 parameters as predictor variables and A-line MAP as the dependent variable to derive the HM3 MAP Formula. In DCs and VC, the accuracy of the Formula in estimating A-line MAP was tested using DOBP as non-invasive equivalent of A-line SBP. Mean observed differences (MOD) and mean absolute differences (MAD) against A-line were calculated for each method. Results The success rate for Doppler and ABP monitor was 100% and 49%, respectively. In DCs, DOBP reflected A-line SBP (MAD 4.6, MOD +1.7 mmHg) but markedly overestimated A-line MAP (Fig A). MAD and MOD of ABP monitor were 7.7 and +3.5 and 7.0 and +1.1 mmHg for SBP and MAP, respectively (Fig B). In DC, the best model to predict A-line MAP included PI and Flow in addition to A-line SBP (HM3 MAP Formula, r2=0.77). In DCs, the Formula accurately predicted A-line MAP when using A-line SBP (Fig C) and DOBP (Fig D). In a preliminary analysis of VC, the accuracy of the Formula was similar (MAD: A-line SBP 4.1, DOBP 6.8 mmHg). Conclusion In HM3 pts, DOBP accurately estimates SBP, but overestimates MAP. ABP monitor has limited success rate and accuracy, possibly due to the artificial pulse. The HM3 MAP Formula represents a uniformly successful and valid tool to estimate MAP by combining DOBP and pump parameters.

Purpose It is well established that continuous-flow left ventricular assist devices (LVAD) reduce pulsatility in the circulation. Consequently, the addition of an ‘artificial pulse’ to the HeartMate3 (HM3) LVAD has been expected to increase pulsatility. Yet, there has been no prospective study that has examined arterial hemodynamics of HM3 patients across the whole circulation, from large to muscular and microcirculatory arteries.Compared with HMII patients, HM3 patients will have a significantly increased arterial pulsatility across the whole circulation, and similar pulsatility to healthy individuals. Methods Pulsatility index (PI), peak systolic velocity (PSV), minimum velocity (Vmin) and mean flow velocity (MFV) of the common carotid, middle cerebral and central retinal arteries were quantified with angle-corrected 2D ultrasound in 141 volunteers (32 healthy controls, 42 heart failure (HF), 28 HM II, and 39 HM3 patients). To test the study hypothesis, data were statistically evaluated using 1-way ANOVA with Tukey's honestly significant difference test. Results Across all three artery locations, both PI and PSV of HM3 patients were significantly lower compared with healthy controls and HF (all P 0.05, Fig.1). Similarly, Vmin and MFV were not significantly different between HM3 and HMII (all P>0.05). Conclusion Despite the presence of an ‘artificial pulse’, pulsatility in patients implanted with the HM3 remains significantly lower than healthy controls and similar to HM II patients. Importantly, the lack of increased pulsatility in HM3 was explained by the flow pattern caused by the artificial pulse, which did not increase peak systolic velocity. These findings add insight into the remaining cardiovascular complications in HM3 patients and warrant further investigation.

Purpose Serum creatinine (sCr) is routinely used in the evaluation of left ventricular assist device (LVAD) candidates. However, the prognostic value of sCr may be limited by the high prevalence of sarcopenia in this population. Cystatin C (CysC) is an alternative marker of renal function, which is less dependent on muscle mass. We aimed to investigate the association of pre-LVAD CysC and sCr with early post-operative outcomes and long-term mortality. Methods CysC and sCr were concurrently measured prior to LVAD implant in 130 consecutive pts (age 59 ± 13, 15% F, 80% HM3) from 2/2016 to 8/2019. The primary endpoints were: 1) a composite of early post-LVAD outcomes, and 2) long-term mortality. The former included: i) death during index admission; ii) right ventricular failure (RVF) - need for right ventricular assist device or inotropic support ≥14 days; iii) acute kidney injury (AKI) - need for renal replacement therapy or sCr increase ≥4 mg/dL or ≥x3 times baseline. Secondary endpoints were the individual components of the composite endpoint and prolonged length of stay (pLOS), defined as LOS ≥ 30 d post-LVAD. Logistic and Cox proportional models regressed the endpoints on CysC and sCr. Results In pre-LVAD samples, median CysC and sCr were 1.40 (IQR: 1.10,1.87) mg/L and 1.39 (IQR: 1.07,1.79) mg/dL, respectively. The composite of early outcomes occurred in 72 (55%) pts: 10 (8%) in-hospital deaths, 43 (33.1%) RVF and 47 (36.2%) AKI. CysC outperformed sCr in the prediction of the composite of early post-LVAD outcomes. CysC, but not sCr, was associated with RVF and pLOS (Table). Death occurred in 20 (15%) pts over a median follow-up of 13 months. Pre-LVAD CysC, but not sCr was associated with an increased risk of long-term mortality (Table). Conclusion In a contemporary cohort of LVAD pts, pre-LVAD CysC was associated with early post-operative outcomes as well as with long-term mortality. The use of CysC in the pre-operative assessment of LVAD candidates may improve risk stratification compared to sCr.

Background: The MOMENTUM3 trial1 has revealed superiority of the novel HeartMate3 (HM3) left ventricular assist device (LVAD) compared with the HM2, with a significantly reduced occurrence of cerebrovascular accidents. Thus, cerebral autoregulation may be improved in HM3 compared with HM II patients, possibly because of altered microcirculatory haemodynamics associated with the in-built speed modulation (‘pulsatility’) of the HM3 device. Methods: Angle-corrected Doppler ultrasound images of the middle cerebral artery (MCA) were recorded before and at the end of a 30s breathhold test in healthy controls (n = 17), heart failure (HF n = 18), HM2 (n = 10) and HM3 (n = 17) patients. Microcirculatory haemodynamics as represented by the central retinal artery (CRA) were also quantified (Controls = 33, HF = 27, HM2 = 23, HM3 = 31). Data were analysed for Time-Averaged Maximum flow velocity (TAMAX), peak flow velocity (Vmax), minimum flow velocity (Vmin), Pulsatility Index (PI) and Resistance Index (RI, Table 1). Table 1Haemodynamics in the middle cererbral artery (MCA) and the central retinal artery (CRA) between HeartMate2 and HeartMate3 patients Healthy controls (n = 33) Heart failure (n = 27) HeartMate II (n = 23) HeartMate3 (average) (n = 31) HeartMate3 (no speed modulation) (n = 31) HeartMate3 (with speed modulation) (n = 31) Middle Cerebral Artery TAMAX (cm/s) 58 ± 15 48 ± 13 45 ± 15 48 ± 19 48 ± 19 46 ± 18 Vmax (cm/s) 92 ± 22 78 ± 20 55 ± 19*# 55 ± 21*# 54 ± 21*# 55 ± 22*# Vmin (cm/s) 39 ± 12 29 ± 11 37 ± 16 39 ± 14 44 ± 16# 32 ± 13 Pulsatility index 0.88 ± 0.18 1.05 ± 0.31* 0.40 ± 0.24*# 0.34 ± 0.14*# 0.21 ± 0.12*#$ 0.56 ± 0.24*# Resistance index 0.57 ± 0.07 0.60 ± 0.11 0.29 ± 0.14*# 0.16 ± 0.09*#$ 0.17 ± 0.10*#$ 0.14 ± 0.09*#$ Central retinal artery TAMAX (cm/s) 6 ± 1 5 ± 2 6 ± 3 7 ± 3 7 ± 4 6 ± 4 Vmax (cm/s) 12 ± 3 11 ± 6 8 ± 4* 8 ± 4* 8 ± 4* 8 ± 4* Vmin (cm/s) 3 ± 1 3 ± 1 5 ± 2 5 ± 3 6 ± 3*# 4 ± 4 Pulsatility index 1.60 ± 0.45 1.42 ± 0.40 0.58 ± 0.26*# 0.49 ± 0.21*# 0.32 ± 0.17*# 0.79 ± 0.35*# Resistance index 0.75 ± 0.09 0.70 ± 0.11 0.38 ± 0.15*# 0.22 ± 0.11*#$ 0.24 ± 0.12*#$ 0.20 ± 0.13*#$ *p < 0.05 compared with healthy controls; #p < 0.05 compared with Heart Failure; $p < 0.05 compared with HeartMate II. Results: Breathhold significantly increased TAMAX, Vmax and Vmin in all groups except HM II patients (Figure 1A). Conversely, PI decreased slightly in all groups while RI was maintained. The greater breathhold response in HM3 compared with HM2 patients was not attributable to the in-built pump-speed modulation (Figure 1B), however, HM3 had a consistently lower RI in the MCA and CRA. Figure 1(A) Time-averaged maximum flow velocity in the middle cerebral artery of healthy controls and patient groups in response to a 30-s breathhold test. (B) Breakdown of the responses in HM3 patients, comparing beats with and without added pulsatility. Conclusion: Although reduced compared with healthy controls, HF and HM3 patients have a significantly greater metabolic cerebral vasoreactivity compared with HM2 patients. The 60% greater diastolic flow velocity in the microcirculation of both LVAD groups compared to healthy controls may alter gas exchange in the microcirculation. Future studies should examine the role of altered RI in HM3 patients.

The effects of ocean acidification, a major anthropogenic impact on marine life, have been mainly investigated in laboratory/mesocosm experiments. We used the CO

Purpose Accurate estimation of renal function using glomerular filtration rate (eGFR) is key for prediction of adverse events among HF pts undergoing LVAD implant. Changes in muscle mass are frequent among HF pts and represent a known confounder of serum creatinine (sCr) based equations. Cystatin C (CysC) is independent of muscle mass and provides an alternative measure of eGFR. We aimed to prospectively compare the value of CysC vs. sCr based eGFR in the prediction of postoperative outcomes among pts undergoing LVAD implant. Methods sCr and CysC were concurrently measured pre-LVAD in 73 pts (age 61±13, F 16%). CKD stages were defined by sCr-eGFR and CysC-eGFR using MDRD4 and CysC-CKD-EPI equations, respectively. The primary endpoint was a composite of severe right ventricular failure (sRVF) or renal replacement therapy (RRT) on the index admission. Predictive values of sCr-eGFR and CysC-eGFR were compared. The independent effect of sCr and CysC on the primary endpoint was assessed using multivariable models. Results Compared to pre-LVAD sCr-eGFR, CysC-eGFR reclassified 46 (63%) pts: 7 (16%) to earlier stage CKD and 39 (84%) to later stage CKD (Fig A). For every increase in CKD stage, there was a 60% increase in the risk of the primary endpoint using CysC-eGFR (p=.02) while the increase in risk did not reach statistical significance using sCr-eGFR (p=.19) (Fig B). CysC-eGFR outperformed sCr-eGFR as predictor of the primary endpoint (AUC 0.68 vs. 0.59, p=0.04, Fig C). In a model including both CysC and sCr: i) higher CysC was associated with an increased risk for the primary endpoint (OR: 1.60 per 0.5 mg/L increase, p=.01); ii) a trend towards a paradoxical association between higher sCr and lower risk was found (OR: 0.42 per 0.5 mg/dL increase, p=.08). Conclusion CysC-eGFR is a more reliable predictor of sRVF or need for RRT among pts undergoing LVAD implant. Higher sCr in relation to CysC may represent a marker of preserved muscle mass and thus might paradoxically confer improved prognosis.

Purpose Declining renal function portends poor prognosis in advanced HF. Hemodynamic optimization with diuretics, inotropes, and temporary mechanical circulatory support is frequently performed for optimization of end-organ function before LVAD surgery. We aimed to study the relationship between long- and short-term changes in serum creatinine (sCr) that occur prior to implant and postoperative outcome in LVAD pts. Methods We retrospectively identified 146 LVAD pts with sCr at 3 time points: 1-year (1y), day of index admission, and 1-day (1d) prior to LVAD. Pts were classified based on the changes in sCr that occurred between 1y and 1d prior to LVAD as: Improved = sCr reduction >10% (n=42); Stable = sCr change ≤10% (n=50); Worsened = sCr increase >10% (n=54). Pts were also classified as Optimized using the following exploratory cutoffs: sCr reduction of ≥10, 15, and 20% during the index admission. The primary endpoint was survival free from renal replacement therapy (RRT) after LVAD. Multivariable Cox models were developed to adjust for age, sex, race and sCr 1d pre-LVAD. Results On average, sCr increased from 1 y to the time of index admission, while subsequently declined prior to LVAD (Fig A). Among 147 pts, 47 (31%) met the primary endpoint. In univariable model, Stable 1y-1d sCr was associated with a reduced risk for the primary endpoint (Fig B). After adjustment, there was only a trend towards significance in Stable vs. Improved (p=0.06). Optimization of sCr during index admission was not associated with improved outcomes. Furthermore, in an adjusted model, a decrease in sCr≥15% was significantly associated with increased risk for the primary endpoint (Fig B). Conclusion In the year preceding LVAD implant, a stable renal function is associated with a trend towards improved post-LVAD survival free from RRT. Moreover, a decrease in sCr≥15% during index admission was associated with worse outcome. The effect of sarcopenia on sCr levels in advanced HF may explain these paradoxical findings.

Purpose Left ventricular assist devices (LVAD) are widely used as a bridge to heart transplantation or destination therapy for advanced heart failure. However, hemocompatibility-related complications such as pump thrombosis, stroke and bleeding remain frequent. We previously reported that LVAD implantation is followed by a sharp increase in serum levels of IgG natural antibodies (Nabs) recognizing oxidation-specific epitopes (OSE). Nabs have been implicated in inflammatory reactions related to atherosclerosis, ischemic stroke and primary graft dysfunction following heart transplantation. However, the consequence of IgG Nabs production following LVAD is not known. We hypothesized that Nabs generated following implant may contribute to LVAD complications by modulating the coagulation cascade. Methods We studied a cohort of adult patients who received a continuous flow LVAD at Columbia University/NewYork Presbyterian Hospital. Nabs and anti-phospholipid antibodies (aPL) were measured in pre- and post-LVAD sera at 1, 6 and 12 months by assessing IgG reactivity to the OSE malondialdehyde (MDA) or β2-glycoprotein complexes by ELISA. In a subset of patients, Nabs were measured at day 1 to 7 post-implant. The effect of IgG Nabs on hemostasis was tested by rotational thromboelastometry (ROTEM) by adding IgG purified from pre- and post-LVAD serum to ABO blood type-matched donor blood. Wilcoxon's signed rank test for matched pairs or Mann-Whitney U test was used to compare measurements. Results Mean IgG Nabs levels were significantly increased in post-LVAD sera at 1 (7040±1680 ELISA units, p Conclusion Our studies revealed that serum IgG Nabs reactive to oxidized epitopes are elevated following LVAD implant. Appearance of Nabs was not accompanied by aPL increase. IgG Nabs prolonged the clotting time of donor whole blood, suggesting that Nabs modulate the coagulation pathway. These findings suggest that IgG Nabs may contribute to hemocompatibility-related complications in LVAD recipients.

Background: High pulsatility index (PI) in the cerebral circulation has been associated with increased prevalence of stroke (1). Interestingly, heart failure (HF) patients implanted with continuous-flow left ventricular assist devices (CF-LVADs) have increased rates of stroke despite presenting with dramatically lower pulse pressures compared with healthy individuals (20 mmHg vs. 30–40 mmHg). Characterising and understanding flow velocity profiles of the middle cerebral artery (MCA) may provide a useful and local marker of pulsatile energy transmitted into the brain of HF and CF-LVAD patients. Methods: PI and resistance index (RI) were quantified from Duplex ultrasound images (2D and pulsed-wave Doppler) of the MCA obtained in four heart failure patients (HF; 68 ± 7 yrs), eight CF-LVAD patients (59 ± 4 yrs) and 20 healthy controls (51 ± 7 yrs). Results: Compared with healthy controls, PI of the MCA was actually higher in the HF group (0.72 ± 0.16 vs. 1.32 ± 0.17, P < 0.0001), but markedly lower in patients on CF-LVAD (0.36 ± 0.21, P < 0.0001). However, RI was similar between healthy controls and HF patients (P > 0.05), and only lower in CF-LVAD patients (P < 0.0001). Conclusions: PI in the MCA is significantly higher in HF but markedly lower in CF-LVAD patients, relative to healthy controls. The higher PI in HF does not appear to be associated with an altered RI. Future work should examine the cerebrovascular outcomes associated with varying levels of pulsatility and resistance in both HF and CF-LVAD patients.

Echinoderms, an ancient and very successful phylum of marine invertebrates, play a central role in the maintenance of ecosystem integrity and are constantly exposed to environmental pressure, including: predation, changes in temperature and pH, hypoxia, pathogens, UV radiation, metals, toxicants, and emerging pollutants like nanomaterials. The annotation of the sea urchin genome, so closely related to humans and other vertebrate genomes, revealed an unusually complex immune system, which may be the basis for why sea urchins can adapt to different marine environments and survive even in hazardous conditions. In this review, we give a brief overview of the morphological features and recognized functions of echinoderm immune cells with a focus on studies correlating stress and immunity in the sea urchin. Immune cells from adult Paracentrotus lividus, which have been introduced in the last fifteen years as sentinels of environmental stress, are valid tools to uncover basic molecular and regulatory mechanisms of immune responses, supporting their use in immunological research. Here we summarize laboratory and field studies that reveal the amenability of sea urchin immune cells for toxicological testing.

Polystyrene nanoparticles have been shown to pose serious risk to marine organisms including sea urchin embryos based on their surface properties and consequently behaviour in natural sea water. The aim of this study is to investigate the toxicity pathways of amino polystyrene nanoparticles (PS-NH2, 50 nm) in Paracentrotus lividus embryos in terms of development and signalling at both protein and gene levels. Two sub-lethal concentrations of 3 and 4 μg/mL of PS-NH2 were used to expose sea urchin embryos in natural sea water (PS-NH2 as aggregates of 143 ± 5 nm). At 24 and 48 h post-fertilisation (hpf) embryonic development was monitored and variations in the levels of key proteins involved in stress response and development (Hsp70, Hsp60, MnSOD, Phospho-p38 Mapk) as well as the modulation of target genes (Pl-Hsp70, Pl-Hsp60, Pl-Cytochrome b, Pl-p38 Mapk, Pl-Caspase 8, Pl-Univin) were measured. At 48 hpf various striking teratogenic effects were observed such as the occurrence of cells/masses random...

An increasing number of end-stage heart failure patients are now implanted with continuous-flow left ventricular assist devices (CF-LVADs). Although this therapeutic approach is associated with improved clinical outcomes, continuous flow physiology reduces arterial pulse pressure and pulsatility to an extent that is unique to this population. Recent data suggest that high blood pressure (BP) contributes to life-threatening complications such as pump thrombosis and stroke of CF-LVAD patients. However, limited understanding of the distinct hemodynamics of these pumps makes measurement and, consequently, medical management of BP quite challenging. Here, we review the evolution of LVAD design, the impact of CF-LVAD flow, and "artificial pulse" technology on hemodynamics and BP measurement, as well as suggest new approaches for the assessment and interpretation of the unique physiology of modern LVADs.

Among currently identified issues presenting risks and benefits to human and ocean health, engineered nanoparticles (ENP) represent a priority. Predictions of their economic and social impact appear extraordinary, but their release in the environment at an uncontrollable rate is in striking contrast with the extremely limited number of studies on environmental impact, especially on the marine environment. The sea urchin has a remarkable sensing environmental system whose function and diversity came into focus during the recent years, after sea urchin genome sequencing. The complex immune system may be the basis wherefore sea urchins can adapt to a dynamic environment and survive even in hazardous conditions both in the adult and in the embryonic life. This review is aimed at discussing the literature in nanotoxicological/ecotoxicological studies with a focus on stress and innate immune signaling in sea urchins. In addition, here we introduce our current development of in vitro-driven probes that could be used to dissect ENP aftermaths, suggesting their future use in immune-nanotoxicology.

Manganese (Mn) is a naturally abundant metal in marine sediments where it mainly occurs as MnO 2 . During hypoxic conditions it is converted into a bioavailable state, Mn 2+ , and can reach levels that previously have shown effects on immune competent cells of the crustacean, Nephrops norvegicus . Here we investigated if Mn also affects circulating coelomocytes and their renewal in the common sea star, Asterias rubens , when exposed to concentrations of Mn that can be found in nature. When the sea stars were exposed to Mn it accumulated in the coelomic fluid and the number of circulating coelomocytes, in contrast to what was recorded in Nephrops , increased significantly. By using the substitute nucleotide, 5-bromo-2′-deoxyuridine, BrdU, for tracing cell division and by recording mitotic index by nuclei staining, we found that Mn induced proliferation of cells from a putative haematopoietic tissue, the coelomic epithelium. In addition, the haematopoietic tissue and coelomocytes showed stress response in terms of changes in HSP70 levels and protein carbonyls, as judged by immunohistochemistry and Western blotting. Measurement of dehydrogenase activity, using MTS/PMS, revealed that Mn showed cytotoxic properties. We also found that the phagocytotic capacity of coelomocytes was significantly inhibited by Mn. It was concluded that the exposure of A. rubens to Mn induced renewal of coelomocytes and impaired their immune response.

The aim of the present study was to investigate on the suitability of the sea urchin as a sentinel organism for the assessment of the macro-zoobenthos health state in bio-monitoring programmes. A field study was carried out during two oceanographic campaigns using immuno-competent cells, the coelomocytes, from sea urchins living in a marine protected area. In particular, coelomocytes subpopulations ratio and heat shock protein 70 (HSC70) levels were measured in specimens of Paracentrotus lividus (Lamark, 1816) collected in two sampling sites, namely Pianosa and Caprara Islands, both belonging to the Tremiti Island Marine Protected Area (MPA) in the Southern Adriatic Sea, Italy. By density gradients separation performed on board the Astrea boat, we found an evident increase in red amoebocytes, a subpopulation increasing upon stress, in those specimens collected around Pianosa (strictly protected area with no human activities allowed), unlike those collected around Caprara (low restrictions for human activities). Likewise, we found higher HSC70 protein levels in the low impacted site (Pianosa) by Western blots on total coelomocyte lysates. The apparent paradox could be explained by the presence in the Pianosa sampling area of contaminating remains from Second World War conventional ammunitions and a merchant boat wreck. Metal determination performed using sea urchin gonads by inductively coupled plasma atomic emission spectrometry (ICP-AES) revealed higher Fe and lower Zn levels around Pianosa with respect to Caprara, in accordance with the persistent contaminating metal sources, and thus calling for remediation measures. Taken all together, our results confirm the feasibility of using sea urchin coelomocytes as biosensors of environmental stress.

Purpose Left ventricular assist device (LVAD) is an established treatment for advanced heart failure (aHF) with notable improvement in patient survival, yet complications remain. AHF is associated with gut microbial community dysbiosis (i.e. reduced diversity of microbial communities). Changes in gut diversity following LVAD might offer a precision medicine oriented approach to predicting the clinical trajectory of patients. In this analysis we explored longitudinal trends in gut microbial diversity before/after LVAD. Methods We prospectively enrolled 66 AHF patients (59.4±13.4 yrs old; 88% M; 56% White). A total of n=99 stool samples (n=34 pre-LVAD, n=36 LVAD 1 mo, n=29 LVAD 3-6 mo) were collected. 16S rRNA sequencing was performed on all samples. Alpha diversity metrics (number and evenness of bacterial taxa within samples) were estimated using Shannon index and the # of observed taxa. Repeated measures models were used to regress alpha diversity on time post-LVAD, adjusted for age, gender and race/ethnicity. Beta diversity (microbial difference between samples) was estimated by Bray-Curtis dissimilarity. DESeq regression analyses explored differences in individual taxa over time and the false discovery rate (FDR) adjusted for multiple comparisons Results Alpha diversity (# observed) increased by 3-6 mo following LVAD implantation (p=0.004, Figure 1). Trends were consistent for Shannon index (Figure 1). No differences in beta diversity were observed following LVAD (p=0.23). There were 32 taxa that differed between pre- vs. post-LVAD 3-6 mo with FDR Conclusion After an initial trend for decrease in gut microbial diversity at 1 mo, these metrics increased by 3-6 mo post-LVAD, which could be reflective of improved clinical status. Future studies are necessary to determine the relevance of these findings to clinical outcomes among LVAD patients and to explore the biological relevance of the taxa underlying these changes.