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The disorganized and inefficient tumor vasculature is a major obstacle to the delivery and efficacy of antineoplastic treatments. Antiangiogenic agents can normalize the tumor vessels, improving vessel function and boosting the distribution and activity of chemotherapy. The type III repeats (T3R) domain of thrombospondin-1 contains different potential antiangiogenic sequences. We therefore hypothesized that it might affect the tumor vasculature. Ectopic expression of the T3R domain by the tumor cells or by the host, or administration of recombinant T3R, delayed the in vivo growth of experimental tumors. Tumors presented marked reorganization of the vasculature, with abundant but smaller vessels, associated with substantially less necrosis. Mechanistically, the use of truncated forms of the domain, containing different active sequences, pointed to the FGF2/FGFR/ERK axis as a target for T3R activity. Along with reduced necrosis, the expression of T3R promoted tumor distribution of chemotherapy (paclitaxel), with a higher drug concentration and more homogeneous distribution, as assessed by HPLC and MALDI imaging mass spectrometry. T3R-expressing tumors were more responsive to paclitaxel and cisplatin. This study shows that together with its known role as a canonical inhibitor of angiogenesis, thrombospondin-1 can also remodel tumor blood vessels, affecting the morphological and functional properties of the tumor vasculature. The ability of T3R to reduce tumor growth and improve the response to chemotherapy opens new perspectives for therapeutic strategies based on T3R to be used in combination therapies.

Weaning from the extracorporeal support represents the ultimate objective of assistance. Native lung function must have recovered to a certain degree to make weaning possible, and a weaning trial is performed to ascertain the patient’s independence from extracorporeal membrane oxygenation (ECMO). This test can be performed in various ways, the common feature being a progressive increase in the respiratory workload. Once the patient has succeeded a weaning trial, decannulation can occur. This can be performed surgically or with direct decannulation, depending on the cannulation techniques and patient’s characteristics. Not all patients are ultimately weaned off ECMO. While for some patients (e.g., those bridged to lung transplant) this might be evident from the beginning, in some others the extracorporeal support can become a bridge to nowhere and futility ensues. In these patients, ECMO should be discontinued while ensuring patients’ comfort. Weaning represents a very challenging period, and even once decannulation has been obtained complications can occur, and those must be prevented and promptly treated.

Road traffic is one of the main sources of particulate emissions into the environment and has an increasing, negative impact on the release of potentially dangerous materials. Vehicle brakes release a significant amount of wear particles, and knowledge regarding their possible adverse effects is limited. One of the most dangerous elements contained in brake pads is copper (Cu), known to be toxic for human health. Therefore, our aim was to study the cell toxicity of particulate matter (PM) produced by different combinations of braking discs and pads containing different amounts of Cu. We investigated whether brake-derived microparticles have toxic effects on lung cells proportionally to their Cu content. Analyte content was measured in friction materials by XRFS and in PM2.5 captured during braking tests using SEM/EDX. The biological impact of brake-derived PM2.5 was investigated on a human epithelial alveolar cell line (A549). Cell viability, oxidative stress, mitochondrial membrane potential, apoptosis, and the pro-inflammatory response of the cells, as well as gene expression, were assessed following exposure to increasing PM2.5 concentrations (1, 10, 100, 200, and 500 µg/ml). The brake debris with the lowest Cu content did not induce significant changes in biological effects on A549 cells compared to normal controls, except for ROS production and IL6 gene expression. PM2.5 containing higher Cu quantities induced cell toxicity that correlated with Cu concentration. Our data suggest that the toxicity of PM2.5 from the brake system is mainly related to Cu content, thus confirming that eliminating Cu from brake pads will be beneficial for human health in urbanized environments.

Autosomal Dominant Polycystic Kidney Disease is a genetic disease that causes uncontrolled growth of fluid-filled cysts in the kidney. Kidney enlargement resulting from the expansion of cysts is continuous and often associated with decreased renal function and kidney failure. Mouse and rat models are necessary to discover new drugs able to halt the progression of the disease. The analysis of the effects of pharmacological interventions in these models is based on renal morphology and quantification of changes in total renal volume and cyst volume. This requires a proper, reproducible and fast segmentation of the kidney images. We propose a set of fully convolutional networks for kidney and cyst segmentation in micro-CT images, based on the U-Net architecture, to compare them and analyze which ones perform better on contrast-enhanced micro-CT images from normal rats and rats with Autosomal Dominant Polycystic Kidney Disease. Networks have been tested on a series images, and the performance has been evaluated in terms of Intersection over Union and Dice coefficients. Results showed that the best performing networks are the U-Net in which a batch normalization layer is applied after each pair of 3 × 3 convolutions, and the U-Net in which convolutional layers are replaced by inception blocks. Results also showed accurate cyst-to-kidney volume ratios obtained from the segmented images, which is one of main metrics of interest. Finally, segmentation performance has been found to be stable as the images in the training set vary. Therefore, the proposed automatic methodology is suitable and immediately applicable to segment cysts and kidney from micro-CT images, and directly provides the cyst-to-kidney volume ratio.

To address the need of alternatives to autologous vessels for small-calibre vascular applications (e.g. cardiac surgery), a bio-hybrid semi-degradable material composed of silk fibroin (SF) and polyurethane (Silkothane®) was herein used to fabricate very small-calibre grafts (Ø

Vasoactive therapy represents a pivotal yet debated topic in critically ill patients and in those with chronic heart failure. Levosimendan, a calcium sensitizer agent with inodilating properties, has been in the market for 27 years and new indications came out over time. The aim of the present review is to highlight what is actually proven and what is debated on the use of levosimendan in light of its pharmacologic features and the pathophysiological evidence. Levosimendan was firstly seen as an inodilator acting through calcium sensitization in myocytes both in the myocardium and in vascular smooth muscle. Over the years, its anti-inflammatory properties became clearer and a role in preconditioning and weaning from mechanical circulatory support was postulated. More recently, a possible action on other muscular fibers, namely, diaphragmatic myocytes, was observed, leading to a possible application in mechanical ventilation-related diaphragmatic dysfunction. Preliminary data showed promising effects of levosimendan in patients with sepsis-related and stress-related (Takotsubo) myocardial dysfunction, in those difficult-to-wean from mechanical circulatory support and in ventilator-associated diaphragmatic dysfunction. Moreover, its vasodilating, anti-oxidant, and neuroendocrine properties pave the way to a number of additional possible applications. Larger studies yielding to more conclusive results on these indications are under way or need to be planned in the future.

To address the need of alternatives to autologous vessels for small-calibre vascular applications (e.g. cardiac surgery), a bio-hybrid semi-degradable material composed of silk fibroin (SF) and polyurethane (Silkothane®) was herein used to fabricate very small-calibre grafts (Øin = 1.5 mm) via electrospinning. Bio-hybrid grafts were in vitro characterized in terms of morphology and mechanical behaviour, and compared to similar grafts of pure SF. Similarly, two native vessels from a rodent model (abdominal aorta and vena cava) were harvested and characterized. Preliminary implants were performed on Lewis rats to confirm the suitability of Silkothane® grafts for small-calibre applications, specifically as aortic insertion and femoral shunt. The manufacturing process generated pliable grafts consisting of a randomized fibrous mesh and exhibiting similar geometrical features to rat aortas. Both Silkothane® and pure SF grafts showed radial compliances in the range from 1.37 ± 0.86 to 1.88 ± 1.01% 10−2 mmHg−1, lower than that of native vessels. The Silkothane® small-calibre devices were also implanted in rats demonstrating to be adequate for vascular applications; all the treated rats survived the surgery for three months after implantation, and 16 rats out of 17 (94%) still showed blood flow inside the graft at sacrifice. The obtained results lay the basis for a deeper investigation of the interaction between the Silkothane® graft and the implant site, which may deal with further analysis on the potentialities in terms of degradability and tissue formation, on longer time-points.

Objective: To quantify how the first public announcement of confirmed coronavirus disease 2019 (COVID-19) in Italy affected a metropolitan region's emergency medical services (EMS) call volume and how rapid introduction of alternative procedures at the public safety answering point (PSAP) managed system resources. Methods: PSAP processes were modified over several days including (1) referral of non-ill callers to public health information call centers; (2) algorithms for detection, isolation, or hospitalization of suspected COVID-19 patients; and (3) specialized medical teams sent to the PSAP for triage and case management, including ambulance dispatches or alternative dispositions. Call volumes, ambulance dispatches, and response intervals for the 2 weeks after announcement were compared to 2017-2019 data and the week before. Results: For 2 weeks following outbreak announcement, the primary-level PSAP (police/fire/EMS) averaged 56% more daily calls compared to prior years and recorded 9281 (106% increase) on Day 4, averaging ∼400/hour. The secondary-level (EMS) PSAP recorded an analogous 63% increase with 3863 calls (∼161/hour; 264% increase) on Day 3. The COVID-19 response team processed the more complex cases (n = 5361), averaging 432 ± 110 daily (∼one-fifth of EMS calls). Although community COVID-19 cases increased exponentially, ambulance response intervals and dispatches (averaging 1120 ± 46 daily) were successfully contained, particularly compared with the week before (1174 ± 40; P = 0.02). Conclusion: With sudden escalating EMS call volumes, rapid reorganization of dispatch operations using tailored algorithms and specially assigned personnel can protect EMS system resources by optimizing patient dispositions, controlling ambulance allocations and mitigating hospital impact. Prudent population-based disaster planning should strongly consider pre-establishing similar highly coordinated medical taskforce contingencies.

Appropriate weaning is of crucial importance for critically ill patients requiring respiratory support. However, a remarkable proportion of them are difficult to wean. Levosimendan is a positive inotropic agent characterized by vasodilatory properties, which is used for the treatment of acute decompensated heart failure or in patients needing inotropic treatment, including cardiogenic shock, septic shock, pulmonary hypertension and right ventricular dysfunction, needed for hemodynamic support in patients with diuretic resistance, and weaning either from ventilator or from extracorporeal membrane oxygenation. This position paper will discuss the use of levosimendan in facilitating weaning from cardiorespiratory support in critically ill patients, according to available evidence and the personal experience of a group of Italian Experts.

This study aimed to assess if clampless off-pump coronary artery bypass grafting (OPCAB) decreases the incidence of perioperative stroke (POS) rate and in-hospital mortality. The secondary aim was to evaluate 12-year rates of overall mortality. Between January 2003 to December 2015, data of 645 consecutive patients undergoing isolated CABG were retrospectively collected. 363 underwent aortic no-touch OPCAB (No-touch group) and 282 underwent OPCAB with the Heartstring device (HS group). In-hospital mortality and perioperative stroke rate as primary endpoint, as well as long-term follow-up outcome were analysed. In-hospital mortality was lower into No-touch group compared with HS group but without significant statistical difference (1.7 vs. 3.2%, p = 0.19, respectively); the rate of postoperative stroke was higher in No-touch group compared with HS group, although this difference did not reach statistically significance. Delirium was reported with higher presentation rate in HS group (3.9 vs. 0.8%, p = 0.01). Blood transfusions rate was higher in HS subjects (23.4 vs. 16.1%, p = 0.01). Intubation time, ICU, and hospital length of stay were increased in the HS group (p = 0.008, p = 0.001 and p = 0.003, respectively). Over a 12-year follow-up period, survival probabilities at 1, 5, and 10 years were 93.6 ± 1.3 vs. 93.2 ± 1.5, 80.4 ± 2.6 vs. 80.3 ± 2.2, and 57.9 ± 5 vs. 58.4 ± 3.8% in the No-touch and HS group, respectively (p = 0.97). In this retrospective study, clampless off-pump CABG lowers perioperative stroke rate whose incidence is, however, not inferior compared with No-touch technique, and no statistically significance was detected. Delirium has a higher presentation rate in clampless off-pump CABG.

OBJECTIVES: Left ventricular free wall rupture (LVFWR) is a catastrophic complication following acute myocardial infarction with an estimated incidence of 0.2–7.6% and mortality can be as high as 60%. This study aimed to identify the risk factors for morbidity and mortality in patients affected by LVFWR. METHODS: This is a retrospective study of 35 patients who underwent surgery for LVFWR between January 2000 and December 2016 at our institution. RESULTS: The mean age of patients was 68.3 years. The in-hospital survival was 65.7% (n = 23), and 13% of survived patients presented with cardiac arrest. The following characteristics were associated with in-hospital mortality at univariable analysis: pre-existing hypertension (P = 0.02), need for inotropes (P = 0.02) and cardiac arrest (P

Background: Venoarterial extracorporeal membrane oxygenation support is a well-established tool in the care of severe refractory cardiac and respiratory failure. The application of this support may serve as a bridge to transplant, recovery or to implantation of a ventricular assist device. Venoarterial extracorporeal membrane oxygenation support can be administered through an open surgical access via the common femoral or axillary artery or a percutaneous approach using Seldinger technique. Both techniques may obstruct the blood flow to the lower limb and may cause a significant ischemia with possible limb loss. Malperfusion of the distal limb can be avoided using an ipsilateral distal limb perfusion, which may be established by adding a single-lumen catheter during venoarterial extracorporeal membrane oxygenation treatment to overcome the obstruction. The aim of this study is to distinguish the presence or absence of a distal limb perfusion regarding the incidence of distal limb ischemia. Furthermore, expected risk factors of open and percutaneous femoral venoarterial extracorporeal membrane oxygenation installation were evaluated for the development of distal limb ischemia. Methods: Between January 2012 and September 2015, 489 patients received venoarterial extracorporeal membrane oxygenation support at our institution. In total, 307 patients (204 male, 103 female) with femoral cannulation were included in the analysis. The cohort was distinguished by the presence (group A; n = 237) or absence (group B; n = 70) of a distal limb perfusion during peripheral venoarterial extracorporeal membrane oxygenation treatment. Furthermore, a risk factor analysis for the development of distal limb ischemia was performed. Results: The main indications for venoarterial extracorporeal membrane oxygenation therapy were a low cardiac output syndrome (LCOS) (53%) and failed weaning of extracorporeal circulation (23%). A total of 23 patients (7.49%) under venoarterial extracorporeal membrane oxygenation support developed severe distal limb malperfusion (3.38% in group A vs 21.42% in group B). Preemptive installation of distal limb perfusion extended the intervention-free intervals to 7.8 ± 19.3 days in group A and 6.3 ± 12.5 in group B. A missing distal limb perfusion (p = 0.001) was identified as a main risk factor for critical limb ischemia. Other comorbidities such as arterial occlusion disease (p = 0.738) were not statistically significantly associated. Surgical intervention due to vascular complications after extracorporeal membrane oxygenation explantation was needed in 14 cases (4.22% in group A and 5.71% in group B). Conclusion: We were able to identify the absence of distal limb perfusion as an independent risk factor for the development of critical distal limb ischemia during femoral venoarterial extracorporeal membrane oxygenation treatment. The application of a distal limb perfusion should be considered as a mandatory approach in the context of femoral venoarterial extracorporeal membrane oxygenation treatment regardless of the implantation technique.

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Early and long-term outcomes in elderly patients who underwent isolated aortic valve replacement (iAVR) are well defined. Conflicting data exist in elderly patients who underwent AVR plus coronary artery bypass grafting (CABG). We sought to evaluate the early and long-term outcomes of combined AVR + CABG in patients older than 75years of age. From June 1999 to June 2018, 402 patients ≥ 75years who underwent iAVR (n = 200; 49.7%) or combined AVR plus CABG (n = 202; 50.3%) were retrospectively analysed. AVR + CABG patients were older than iAVR patients (78.5 ± 2.5 vs 77.6 ± 2.8years; p 48h (OR 8.92) as independent predictors of 30-day mortality; preoperative cerebrovascular events (OR 3.43), creatinine (OR 7.27) and extracorporeal circulation time (OR 1.01) were independent predictors of in-hospital major adverse cardiovascular and cerebral events (MACCE). Treatment was not an independent predictor of 30-day mortality and in-hospital MACCE. Survival at 1, 5 and 10years was 94.7 ± 1.6%, 72.6 ± 3.6% and 31.7 ± 4.8% for iAVR patients and 89.1 ± 2.3%, 73.9 ± 3.5% and 37.2 ± 4.8% for AVR + CABG subjects (p = 0.99). Using adjusted Cox regression model, creatinine [hazard ration (HR) 1.50; p = 0.018], COPD (HR 1.97; p = 0.003) and NYHA class (HR 1.39; p

Levosimendan is an inodilator that promotes cardiac contractility primarily through calcium sensitization of cardiac troponin C and vasodilatation via opening of adenosine triphosphate-sensitive potassium (KATP) channels in vascular smooth muscle cells; the drug also exerts organ-protective effects through a similar effect on mitochondrial KATP channels. This pharmacological profile identifies levosimendan as a drug that may have applications in a wide range of critical illness situations encountered in intensive care unit medicine: hemodynamic support in cardiogenic or septic shock; weaning from mechanical ventilation or from extracorporeal membrane oxygenation; and in the context of cardiorenal syndrome. This review, authored by experts from 9 European countries (Austria, Belgium, Czech republic, Finland, France, Germany, Italy, Sweden, and Switzerland), examines the clinical and experimental data for levosimendan in these situations and concludes that, in most instances, the evidence is encouraging, which is not the case with other cardioactive and vasoactive drugs routinely used in the intensive care unit. The size of the available studies is, however, limited and the data are in need of verification in larger controlled trials. Some proposals are offered for the aims and designs of these additional studies., SCOPUS: ar.j, info:eu-repo/semantics/published

Chronic renal insufficiency inexorably progresses in patients, such as it does after partial renal ablation in rats. However, the progression of renal diseases can be delayed by angiotensin II blockers that stabilize renal function or increase GFR, even in advanced phases of the disease. Regression of glomerulosclerosis can be induced by angiotensin II antagonism, but the effect of these treatments on the entire vascular tree is unclear. Here, using microcomputed tomography and scanning electron microscopy, we compared the size and extension of kidney blood vessels in untreated Wistar rats with those in untreated and angiotensin II antagonist-treated Munich Wistar Frömter (MWF) rats that spontaneously develop kidney disease with age. The kidney vasculature underwent progressive rarefaction in untreated MWF rats, substantially affecting intermediate and small vessels. Microarray analysis showed increased Tgf-β and endothelin-1 gene expression with age. Notably, 10-week inhibition of the renin-angiotensin system regenerated kidney vasculature and normalized Tgf-β and endothelin-1 gene expression in aged MWF rats. These changes were associated with reduced apoptosis, increased endothelial cell proliferation, and restoration of Nrf2 expression, suggesting mechanisms by which angiotensin II antagonism mediates regeneration of capillary segments. These results have important implications in the clinical setting of chronic renal insufficiency.

Objective There is increasing burnout incidence among medical disciplines, and physicians working in emergency settings seem at higher risk. Cardiac anesthesiology is a stressful anesthesiology subspecialty dealing with high-risk patients. The authors hypothesized a high risk of burnout in cardiac anesthesiologists. Design National survey conducted on burnout. Setting Italian cardiac centers. Participants Cardiac anesthesiologists. Interventions The authors administered via email an anonymous questionnaire divided into 3 parts. The first 2 parts evaluated workload and private life. The third part consisted of the Maslach Burnout Inventory test with its 3 constituents: high emotional exhaustion, high depersonalization, and low personal accomplishment. Measurements and Main Results The authors measured the prevalence and risk of burnout through the Maslach Burnout Inventory questionnaire and analyzed factors influencing burnout. Among 670 contacts from 71 centers, 382 cardiac anesthesiologists completed the survey (57%). The authors found the following mean Maslach Burnout Inventory values: 14.5 ± 9.7 (emotional exhaustion), 9.1 ± 7.1 (depersonalization), and 33.7 ± 8.9 (personal accomplishment). A rate of 34%, 54%, and 66% of respondents scored in “high” or “moderate-high” risk of burnout (emotional exhaustion, depersonalization, and personal accomplishment, respectively). The authors found that, if offered to change subspecialty, 76% of respondents would prefer to remain in cardiac anesthesiology. This preference and parenthood were the only 2 investigated factors with a protective effect against all components of burnout. Significantly lower burnout scores were found in more experienced anesthesiologists. Conclusion A relatively high incidence of burnout was found in cardiac anesthesiologists, especially regarding high depersonalization and low personal accomplishment. Nonetheless, most of the respondents would choose to remain in cardiac anesthesiology.

Objective Management of pain, agitation and delirium (PAD) remains to be a true challenge in critically ill patients. The pharmacological proprieties of dexmedetomidine (DEX) make it an ideal candidate drug for light and cooperative sedation, but many practical questions remain unanswered. This structured consensus from 17 intensivists well experienced on PAD management and DEX use provides indications for the appropriate use of DEX in clinical practice. Methods A modified RAND/UCLA appropriateness method was used. In four predefined patient populations, the clinical scenarios do not properly cope by the current recommended pharmacological strategies (except DEX), and the possible advantages of DEX use were identified and voted for agreement, after reviewing literature data. Results Three scenarios in medical patients, five scenarios in patients with acute respiratory failure undergoing non-invasive ventilation, three scenarios in patients with cardiac surgery in the early postoperative period and three scenarios in patients with overt delirium were identified as challenging with the current PAD strategies. In these scenarios, the use of DEX was voted as potentially useful by most of the panellists owing to its specific pharmacological characteristics, such as conservation of cognitive function, lack of effects on the respiratory drive, low induction of delirium and analgesia effects. Conclusion DEX might be considered as a first-line sedative in different scenarios even though conclusive data on its benefits are still lacking.

Objective Cardiopulmonary bypass (CPB) exerts several deleterious effects on inflammatory pathways. Most of these can be related to an endothelial insult leading to endothelial dysfunction. To date, the degree of endothelial damage only has been evaluated on a cellular and molecular level, but no studies exist looking at the functional effects of CPB on the endothelium. Design Previous studies hypothesized a negative effect of continuous flow as opposed to the physiologic pulsatile flow. The aim of the present retrospective study was to investigate how different perfusion modalities during CPB (ie, continuous v pulsatile flow) or its avoidance differently impact endothelial function. Setting Cardiovascular operating room and intensive care unit of a large tertiary University Hospital in Monza, Italy. Participants Flow-mediated dilatation (FMD) of the brachial artery was assessed in 29 patients undergoing elective myocardial revascularization. Ten patients receiving continuous-flow CPB, 10 receiving pulsatile-flow CPB, and 9 scheduled for beating-heart revascularization were studied. Interventions Patients were studied at baseline (after induction of general anesthesia), after CPB upon intensive care unit (ICU) admission after surgery, and on the first postoperative day before discharge from the ICU (on average, 24 hours after CPB discontinuation). Measurements and Main Results The continuous-flow CPB group demonstrated a significant reduction in FMD after CPB, (12.8%±9.7% v 1.6%±1.5%, p

Myocardial failure is generally considered to be a progressive, irreversible medical condition with characteristic ventricular enlargement, spatial alteration of the heart chambers, diminished cardiac inotropy and resultant dysfunctional, mechanically inefficient heart. The Jarvik 2000®, similar to the mechanical pump, is an electrically powered, axial-flow left ventricular assist device (LVAD) designed to enhance the function of the chronically failing heart and, consequently, normalize the cardiac output for a long period of time. We report the case of 70-year-old man with congestive dilated cardiomyopathy and bioprosthetic mitral valve who underwent surgical implantation of the Jarvik 2000® LVAD, using the miniaturized extracorporeal circulation (MECC) system. The LVAD was implanted through a left thoracotomy and the MECC system was used to avoid intraoperative spontaneous hemodynamic instability and/or malignant ventricular arrhythmia. The circulatory support with the MECC system was optimal and no complication in terms of hemodynamic instability and perioperative bleeding was recorded. The MECC system obliterated the adverse effects associated with conventional extracorporeal circulation, which are often fatal in critically-ill patients.

We present the case of a woman assisted with veno-arterial extracorporeal membrane oxygenation (v-a ECMO) for postischemic cardiogenic shock, who developed left ventricular thrombosis despite systemic anticoagulation and left ventricular apical venting. We successfully achieved local thrombolysis with tenecteplase administered through the venting cannula to obtain local thrombolysis while reducing systemic effects to a minimum. The procedure was effective with mild systemic bleeding and the patient was successfully weaned off the extracorporeal support a few days thereafter.

Inflammatory response and hemodilution are the main drawbacks of extracorporeal circulation. We hypothesize that the use of miniaturized extracorporeal circulation (MECC) might lower the systemic and myocardial inflammatory patterns compared with a standard system (SECC) and off-pump coronary artery bypass grafting (OPCABG). Sixty-one patients undergoing isolated coronary artery bypass graft were prospectively randomized to MECC (n = 19), SECC (n = 20), or OPCABG (n = 22). Blood samples were collected from radial artery and coronary sinus to analyze blood lactate, hemodilution, and markers for inflammation and endothelial activation such as tumor necrosis factor (TNF)-α, interleukin-6, monocyte chemotactic protein-1, and E-selectin. No differences were observed in early clinical outcome. Interleukin -6 levels increased in every group during and after cardiac surgery, whereas TNF-α values grew in the SECC group (p = 0.05). E-selectin systemic values decreased during and after operation (p = 0.001) in every group. Monocyte chemotactic protein-1 systemic and cardiac levels raised only in SECC group (p = 0.014). In conclusion, MECC is comparable to SECC and OPCABG in the clinical outcome of low-risk patients, and it might be extensively used with no additional intraoperative risk. The analysis of the inflammatory patterns of endothelial activation shows MECC as effective as OPCABG, suggesting further studies to clarify MECC recommendation in high-risk patients.

Bardoxolone methyl is an antioxidant inflammation modulator acting through induction of Keap1-Nrf2 pathway. Results from a recent phase IIb clinical trial reported that bardoxolone methyl was associated with improvement in the estimated glomerular filtration rate in patients with advanced chronic kidney disease and Type 2 diabetes. However, increases in albuminuria, serum transaminase, and frequency of adverse events were noted. We studied the effect of 3-mo treatment with RTA 405, a synthetic triterpenoid analog of bardoxolone methyl in Zucker diabetic fatty rats with overt Type 2 diabetes. Rats were treated from 3 mo of age with vehicle, RTA 405, ramipril, or RTA 405 plus ramipril. RTA 405 caused severe changes in food intake and diuresis with decline in body weight, worsening of dyslipidemia, and increase in blood pressure. Early elevation in serum transaminase was followed by liver injury. RTA 405 worsened proteinuria, glomerulosclerosis, and tubular damage. Ramipril was renoprotective, but when given with RTA 405 it was not able to limit its worsening effects. These data could be due to degradation products in the drug substance used, as disclosed by the company once the study was concluded. To overcome such a drawback, the company offered to test dh404, a variant of RTA 405, in Zucker diabetic fatty rats. The dh404 did not display beneficial effects on proteinuria, glomerulosclerosis, and interstitial inflammation. Rather, kidneys from three rats receiving dh404 showed the presence of a granulomatous and inflammatory process reminiscent of a pseudotumor. Altogether these data raise serious concerns on the use of bardoxolone analogs in Type 2 diabetic nephropathy.

Objective Weaning from veno-arterial extracorporeal life support is challenging. The objective of this trial was to investigate the endothelial and hemodynamic effects of levosimendan in cardiogenic shock patients supported with veno-arterial extracorporeal life support. Design This was a prospective observational trial. Setting Cardiovascular intensive care unit of a large tertiary care university hospital in Monza, Italy. Participants and Interventions Flow-mediated dilatation of the brachial artery and hemodynamic parameters were assessed in 10 cardiogenic shock patients supported with veno-arterial extracorporeal life support, before and after the infusion of levosimendan. Measurements and Results Flow-mediated dilatation increased both as absolute value and as a percentage after levosimendan, from 0.10±0.12 to 0.61±0.21 mm (p

The contribution of microRNA (miRNA) to the pathogenesis of renal fibrosis is not well understood. Here, we investigated whether miRNA modulates the fibrotic process in Munich Wistar Fromter (MWF) rats, which develop spontaneous progressive nephropathy. We analyzed the expression profile of miRNA in microdissected glomeruli and found that miR-324-3p was the most upregulated. In situ hybridization localized miR-324-3p to glomerular podocytes, parietal cells of Bowman's capsule, and most abundantly, cortical tubules. A predicted target of miR-324-3p is prolyl endopeptidase (Prep), a serine peptidase involved in the metabolism of angiotensins and the synthesis of the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). In cultured tubular cells, transient transfection with a miR-324-3p mimic reduced Prep protein and activity, validating Prep as a target of this miRNA. In MWF rats, upregulation of miR-324-3p associated with markedly reduced expression of Prep in both glomeruli and tubules, low urine Ac-SDKP, and increased deposition of collagen. ACE inhibition downregulated glomerular and tubular miR-324-3p, promoted renal Prep expression, increased plasma and urine Ac-SDKP, and attenuated renal fibrosis. In summary, these results suggest that dysregulation of the miR-324-3p/Prep pathway contributes to the development of fibrosis in progressive nephropathy. The renoprotective effects of ACE inhibitors may result, in part, from modulation of this pathway, suggesting that it may hold other potential therapeutic targets.

There is no consensus on which drugs/techniques/strategies can affect mortality in the perioperative period of cardiac surgery. With the aim of identifying these measures, and suggesting measures for prioritized future investigation we performed the first International Consensus Conference on this topic. The consensus was a continuous international internet-based process with a final meeting on 28 June 2010 in Milan at the Vita-Salute University. Participants included 340 cardiac anesthesiologists, cardiac surgeons, and cardiologists from 65 countries all over the world. A comprehensive literature review was performed to identify topics that subsequently generated position statements for discussion, voting, and ranking. Of the 17 major topics with a documented mortality effect, seven were subsequently excluded after further evaluation due to concerns about clinical applicability and/or study methodology. The following topics are documented as reducing mortality: administration of insulin, levosimendan, volatile anesthetics, statins, chronic β-blockade, early aspirin therapy, the use of pre-operative intra-aortic balloon counterpulsation, and referral to high-volume centers. The following are documented as increasing mortality: administration of aprotinin and aged red blood cell transfusion. These interventions were classified according to the level of evidence and effect on mortality and a position statement was generated. This International Consensus Conference has identified the non-surgical interventions that merit urgent study to achieve further reductions in mortality after cardiac surgery: insulin, intra-aortic balloon counterpulsation, levosimendan, volatile anesthetics, statins, chronic β-blockade, early aspirin therapy, and referral to high-volume centers. The use of aprotinin and aged red blood cells may result in increased mortality.

In the present study, we evaluated the effect of simultaneously blocking angiotensin II synthesis and endothelin (ET)-1 activity as a multimodal intervention to implement renoprotection in overt diabetic nephropathy. Mechanisms underlying combined therapy effectiveness were addressed by investigating podocyte structure and function and glomerular barrier size-selective properties. Uninephrectomized rats made diabetic by streptozotocin received orally placebo, lisinopril (12.5 mg/l), the ETAreceptor antagonist avosentan (30 mg/kg), or their combination from 4 (when animals had proteinuria) to 8 mo. Proteinuria, renal damage, podocyte number, nephrin expression, and glomerular size selectivity by graded-size Ficoll molecule fractional clearance were assessed. Combined therapy normalized proteinuria, provided complete protection from tubulointerstitial damage, and induced regression of glomerular lesions, while only a partial renoprotection was achieved by each drug alone. Lisinopril plus avosentan restored to normal values the number of podocytes. Single therapies only limited podocyte depletion. Defective nephrin expression of diabetes was prevented by each drug. Altered glomerular size selectivity to large macromolecules of diabetic rats was remarkably improved by lisinopril and the combined treatment. Avosentan ameliorated peritubular capillary architecture and reduced interstitial inflammation and fibrosis. The ACE inhibitor and ETAreceptor antagonist induced regression of glomerular lesions in overt diabetic nephropathy. Regression of renal disease was conceivably the result of the synergistic effect of the ACE inhibitor of preserving glomerular permselective properties and the ETAantagonist in improving tubulointerstitial changes. These findings provide mechanistic insights to explain the antiproteinuric effect of this combined therapy in diabetes.

Angiotensin-converting enzyme (ACE) inhibition induces glomerular repair in the Munich Wistar Frömter (MWF) rat, a model of spontaneous glomerular injury. In this study, we investigated whether this effect is related to changes in glomerular cell number, particularly of podocytes, which are progressively lost with age. MWF rats with advanced nephropathy were studied at both 40 weeks and after 20 weeks of observation either with or without treatment with the ACE inhibitor lisinopril. Forty-week-old Wistar rats were used as controls. In untreated MWF rats, proteinuria, hypertension, glomerulosclerosis, and renal function worsened, while lisinopril induced regression of both functional and structural changes. Despite glomerular hypercellularity in untreated MWF rats, the number of endothelial cells per glomerulus did not change, and podocyte number even decreased. ACE inhibition halted the progressive increase in glomerular cell number and enhanced endothelial cell volume density. Surprisingly, lisinopril not only halted age-related podocyte loss but also increased the number of glomerular podocytes above baseline, which was associated with an increased number of proliferating Wilms tumor 1-positive cells, loss of cyclin-dependent kinase inhibitor p27 expression, and increased number of parietal podocytes. These data indicate that ACE inhibition restructures glomerular capillary, primarily by restoring the podocyte population in this model of glomerular injury. Increased parietal podocyte number in lisinopril-treated MWF rats suggests that the remodeling of Bowman’s capsule epithelial cells contributes to this effect.

PURPOSE: Non-invasive continuous positive airway pressure (CPAP) is effective in reducing intubation rate and mortality of patient with acute cardiogenic pulmonary edema (ACPE). We report our experience on pre-hospital application of CPAP by helmet as an adjunct to medical therapy or as a stand alone procedure in patient with presumed ACPE. METHODS: In pre-hospital treatment of 62 patients with presumed ACPE, CPAP was added to standard medical treatment while in another 59 patients, CPAP was used as a sole therapy. RESULTS: Helmet CPAP was feasible in all patients. No patient required pre-hospital intubation. In both groups, CPAP significantly improved oxygenation (SpO(2) went from 79 +/- 12 to 97 +/- 3% and from 81 +/- 13 to 98 +/- 3%), reduced respiratory rate (from 26 +/- 4 to 21 +/- 3 bpm and from 30 +/- 9 to 22 +/- 8 bpm) and improved hemodynamics, with a more pronounced decrease in blood pressure in the group with medical treatment than in the one without it. In the two cohorts, four and five patients were, respectively, intubated in Emergency Department and 11 and 9 eventually died. CONCLUSIONS: Helmet CPAP is feasible, efficient and safe in pre-hospital treatment of presumed ACPE. A significant improvement of physiological variables was observed also in the group treated with CPAP in the absence of a drug therapy. We propose helmet CPAP as first line pre-hospital treatment of presumed severe ACPE.

Objective Patients undergoing cardiac surgery are at risk of perioperative low cardiac output syndrome due to postoperative myocardial dysfunction. Myocardial dysfunction in patients undergoing cardiac surgery is a potential indication for the use of levosimendan, a calcium sensitizer with 3 beneficial cardiovascular effects (inotropic, vasodilatory, and anti-inflammatory), which appears effective in improving clinically relevant outcomes. Design Double-blind, placebo-controlled, multicenter randomized trial. Setting Tertiary care hospitals. Interventions Cardiac surgery patients (n = 1,000) with postoperative myocardial dysfunction (defined as patients with intraaortic balloon pump and/or high-dose standard inotropic support) will be randomized to receive a continuous infusion of either levosimendan (0.05-0.2 μg/[kg min]) or placebo for 24-48 hours. Measurements and main results The primary end point will be 30-day mortality. Secondary end points will be mortality at 1 year, time on mechanical ventilation, acute kidney injury, decision to stop the study drug due to adverse events or to start open-label levosimendan, and length of intensive care unit and hospital stay. We will test the hypothesis that levosimendan reduces 30-day mortality in cardiac surgery patients with postoperative myocardial dysfunction. Conclusions This trial is planned to determine whether levosimendan could improve survival in patients with postoperative low cardiac output syndrome. The results of this double-blind, placebo-controlled randomized trial may provide important insights into the management of low cardiac output in cardiac surgery.

Extracorporeal membrane oxygenation (VA ECMO) demonstrated an advantage in survival and neurological outcome in patients with cardiogenic shock and, in selected population, in victims of refractory cardiac arrest. The incidence of vascular complications ranges in recent series from 10 to 70% including both early and late complications. The aim of the present study was to determine the incidence of early vascular complications and the effectiveness of the prevention of limb ischemia by the insertion of a catheter for distal perfusion.Data from our registry of 100 patients treated with VA ECMO implanted via percutaneous femoral approach for cardiogenic shock or refractory cardiac arrest were analyzed. If the leg perfusion was inadequate, an additional 7-9 Fr percutaneous catheter distal to the ECMO arterial cannula was placed into the femoral artery to prevent limb ischemia.Thirty-five patients had early vascular complications. Thirty patients with early ischemia were cannulated with a small reperfusion cannula to obtain antegrade perfusion of the limb. Twenty-six had an effective reperfusion. Seven patients developed a compartment syndrome of the leg requiring urgent fasciotomy that led to clinical improvement and recovery in five, while the other two patients progressed to irreversible ischemia requiring amputation of the limb.The majority of ischemic episodes were resolved with the insertion of a distal perfusion catheter. We did not observe any mortal vascular complication, nor any of the observed complications was related to increased mortality.

Sudden cardiac arrest is a complex, life-threatening event involving a multidisciplinary approach. Despite the use of conventional cardiopulmonary resuscitation, survival rate continues to be low for both in-hospital and out-of-hospital cardiac arrest. In refractory cardiac arrest, defined by the absence of return of spontaneous circulation despite resuscitation manoeuvres, mortality approaches 100%. In the last years, an increasing number of case series, and few propensity-matched cohort studies have reported encouraging results on the use of venoarterial extracorporeal membrane oxygenation for refractory cardiac arrest. Extracorporeal circulation ensures an adequate blood flow, to perform diagnostic and therapeutic interventions even before a return of spontaneous circulation is achieved and to rest the heart by unloading the ventricle while ensuring myocardial perfusion after return of spontaneous circulation. This study reviews the rational, indications, evidence and management of extracorporeal support for cardiac arrest.

We present the case of a woman assisted with veno-arterial extracorporeal membrane oxygenation (v-a ECMO) for postischemic cardiogenic shock, who developed left ventricular thrombosis despite systemic anticoagulation and left ventricular apical venting. We successfully achieved local thrombolysis with tenecteplase administered through the venting cannula to obtain local thrombolysis while reducing systemic effects to a minimum. The procedure was effective with mild systemic bleeding and the patient was successfully weaned off the extracorporeal support a few days thereafter.

Differently from most transformed cells, cutaneous melanoma expresses the pleiotropic factor thrombospondin-1 (TSP-1). Herein, we show that TSP-1 (RNA and protein), undetectable in four cultures of melanocytes and a RGP melanoma, was variously present in 13 cell lines from advanced melanomas or metastases. Moreover, microarray analysis of 55 human lesions showed higher TSP-1 expression in primary melanomas and metastases than in common and dysplastic nevi. In a functional enrichment analysis, the expression of TSP-1 correlated with motility-related genes. Accordingly, TSP-1 production was associated with melanoma cell motility in vitro and lung colonization potential in vivo. VEGF/VEGFR-1 and FGF-2, involved in melanoma progression, regulated TSP-1 production. These factors were coexpressed with TSP-1 and correlated negatively with Slug (SNAI2), a cell migration master gene implicated in melanoma metastasis. We conclude that TSP-1 cooperates with FGF-2 and VEGF/VEGFR-1 in determining melanoma invasion and metastasis, as part of a Slug-independent motility program.

Today angiotensin II inhibition is primarily used to slow the rate of progression of kidney diseases. There is evidence that these therapies can induce a partial regression of glomerular lesions. However, we do not know yet the extent of sclerotic lesion regression and whether new glomerular tissue is formed to help support the renal function. We used male Munich Wistar Fromter (MWF) rats, an experimental model for progressive kidney disease, to quantify kidney structural lesions upon angiotensin-converting enzyme (ACE) inhibition therapy. Animals were studied at 50 weeks of age, when renal function and structure are severely altered, and after a 10-week observation period, without or with treatment with lisinopril (80 mg/l in drinking water). A group of untreated Wistar rats was used as controls. With age, proteinuria, and serum creatinine worsen, but lisinopril almost normalized proteinuria and stabilized serum creatinine. Serial section analysis of whole glomerular tufts showed that at baseline, glomerulosclerosis affected the entire glomerular population, and that these changes further increased with age. Lisinopril significantly reduced incidence and extent of glomerulosclerosis, with the presence of glomerular tufts not affected by sclerosis (23% of glomeruli). Glomerular volume was not significantly affected by treatment, and glomerular mass spared from sclerosis increased from 46.9 to 65.5% upon treatment, indicating consistent regeneration of glomerular tissue. Lisinopril normalized baseline glomerular transforming growth factor-beta and alpha-smooth muscle actin overexpression, and prevented worsening of interstitial changes. Hence, ACE inhibition, which is widely used in human kidney disease, may not only halt the progression of renal failure, but also actually induce the regeneration of new renal tissue.

Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies.BackgroundProteinuria predicts renal disease progression, and its reduction by angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor antagonists (ARA) is renoprotective.MethodsIn this prospective, randomized, cross-over study of 24 patients with nondiabetic, chronic nephropathies, we compared the effects on proteinuria, renal hemodynamics, and glomerular permselectivity of 8 weeks with comparable blood pressure control achieved by benazepril (10 mg/day) and valsartan (80 mg/day) combined therapy with those achieved by benazepril (20 mg/day) or valsartan (160 mg/day) alone.ResultsDespite comparable changes in blood pressure and glomerular filtration rate (GFR), combined therapy decreased proteinuria more than benazepril (-56% vs. -45.9%, P = 0.02) and valsartan (-41.5%, P = 0.002). Changes in urinary protein to creatinine ratio followed the same trend. Filtration fraction and renal vascular resistances (RVR) decreased more with combined (-14.7%,-23.7%) or benazepril (-12.4%, -20.5%) than with valsartan (-2.7%, -12.5%, P < 0.05 vs. both). RVR changes, adjusted for GFR changes, were associated with those in proteinuria (P < 0.05). Changes in glomerular permeability were comparable and did not predict different changes in proteinuria in the three groups.ConclusionAt comparable blood pressure, combined ACEi and ARA decreased proteinuria better than ACEi and ARA. The greater antiproteinuric effect most likely depended on an ACEi-related hemodynamic effect, in addition to glomerular size selectivity amelioration. Long-term combined ACEi and ARA therapy may be more renoprotective than treatment with each agent alone.