Verde Dott. Alessandro

Pubblicazioni su PubMed

• Case Report: A rare homozygous patient affected by systemic amyloidosis with a prominent heart involvement.
  Front Cardiovasc Med

  2023 ;10():1164916. doi: 1164916.
  
  Micaglio Emanuele, Santangelo Gloria, Moscardelli Silvia, Rusconi Daniela, Musca Francesco, Verde Alessandro, Campiglio Laura, Bursi Francesca, Guazzi Marco
  
  Abstract
  
  Hereditary transthyretin amyloidosis is a severe, adult-onset autosomal dominant inherited systemic disease predominantly affecting the peripheral and autonomic nervous system, heart, kidney, and the eyes. We present a case of a Caucasian 65-year-old man with cardiac amyloidosis and the homozygous mutation Val142Ile (classically, Val122Ile) in the transthyretin gene. We provide a genotype-phenotype correlation regarding the genetic status of both heterozygous and homozygous individuals and their clinical conditions at the time of genetic testing.
  
  © 2023 Micaglio, Santangelo, Moscardelli, Rusconi, Musca, Verde, Campiglio, Bursi and Guazzi.
  
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• Intravenous continuous home inotropic therapy in advanced heart failure: Insights from an observational retrospective study.
  Eur J Intern Med

  2023 Jun;():. doi: S0953-6205(23)00205-4.
  
  Gentile Piero, Masciocco Gabriella, Palazzini Matteo, Tedeschi Andrea, Ruzzenenti Giacomo, Conti Nicolina, D'Angelo Luciana, Foti Grazia, Perna Enrico, Verde Alessandro, Ammirati Enrico, Sinagra Gianfranco, Oliva Fabrizio, Garascia Andrea
  
  Abstract
  
  INTRODUCTION:
  Intravenous inotropic support represents an important therapeutic option in advanced heart failure (HF) as bridge to heart transplantation, bridge to mechanical circulatory support, bridge to candidacy or as palliative therapy. Nevertheless, evidence regarding risks and benefits of its use is lacking.
  
  METHODS:
  we conducted a retrospective single center study, analysing the effect of inotropic therapies in an outpatient cohort, evaluating the burden of hospitalizations, the improvement in quality of life, the incidence of adverse events and the evolution of organ damage.
  
  RESULTS:
  twenty-seven patients with advanced HF were treated in our Day Hospital service from 2014 to 2021. Nine patients were treated as bridge to heart transplant while eighteen as palliation. Comparing data regarding the year before and after the beginning of inotropic infusion, we observed a reduction of hospitalization (46 vs 25, p
  CONCLUSIONS:
  in a selected population of advanced HF patients, continuous home inotropic infusion were able to reduce hospitalizations, improving end organ damage and quality of life. We provide a practical guidance on starting and maintaining home inotropic infusion while monitoring a challenging group of patients.
  
  Copyright © 2023. Published by Elsevier B.V.
  
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• Immune checkpoint inhibitor-associated myocarditis: from pathophysiology to rechallenge of therapy - a narrative review.
  Future Cardiol

  2023 Feb;19(2):91-103. doi: 10.2217/fca-2022-0120.
  
  Tedeschi Andrea, Camilli Massimiliano, Ammirati Enrico, Gentile Piero, Palazzini Matteo, Conti Nicolina, Verde Alessandro, Masciocco Gabriella, Foti Grazia, Giannattasio Cristina, Garascia Andrea
  
  Abstract
  
  Even if immune checkpoint inhibitors have revolutionized the landscape of cancer therapy, their use may be complicated by immune-related adverse events. Among these, myocarditis is the most severe complication. The clinical suspicion often arises after clinical symptoms onset and increase in cardiac biomarkers or electrocardiographic manifestations. Echocardiography and cardiac magnetic resonance imaging are recommended for each patient. However, since they may be misleadingly normal, endomyocardial biopsy remains the gold standard for establishing the diagnosis. Until now, treatment has been based on glucocorticoids even if increasing interest has risen in other immunosuppressive agents. Although myocarditis currently imposes immunotherapy discontinuation, case reports have suggested a safety rechallenge in low-grade myocarditis paving the way for further studies to respond to this unmet clinical need.
  
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• Differential inhibition of T-cell receptor and STAT5 signaling pathways determines the immunomodulatory effects of dasatinib in chronic phase chronic myeloid leukemia.
  Haematologica

  2023 Jun;108(6):1555-1566. doi: 10.3324/haematol.2022.282005.
  
  Harrington Patrick, Dillon Richard, Radia Deepti, Rousselot Philippe, McLornan Donal P, Ong Mark, Green Anna, Verde Alessandro, Hussain Farzana, Raj Kavita, Kordasti Shahram, Harrison Claire, De Lavallade Hugues
  
  Abstract
  
  Dasatinib is a multi-kinase inhibitor with activity against the SRC kinase LCK, which plays a critical role in T-cell receptor signaling. Dasatinib, initially developed as an immunosuppressive agent, is by contrast, also noted to result in enhanced tumor immunity in a subset of patients. We studied the impact of dasatinib in chronic myeloid leukemia patients and compared it with patients taking other tyrosine kinase inhibitors (TKI) and healthy controls. We found that patients on dasatinib showed inhibition of both T-cell receptor (TCR) and STAT5 signaling pathways, and reduced expression of Teffector pro-inflammatory cytokines. In addition, dasatinib induced selective depletion of regulatory T cells (Tregs) and effector Tregs, particularly in patients with clonal expansion of effector CD8+ T cells, who demonstrated greater and preferential inhibition of Treg TCR intracellular signaling. In addition, we show that dasatinib selectively reduces Treg STAT5 phosphorylation via reduction of IL-2, in relation with the marked reduction of plasma IL-2 levels in patients taking dasatinib. Finally, patients on other TKI had significantly increased TCR signaling in TIM3+ cells compared to patients taking dasatinib, suggesting that chronic SRC kinase inhibition by dasatinib may play a role in preventing TIM-3-mediated T-cell exhaustion and preserve anti-tumor immunity. These data provide further insight into the selective immunomodulatory effects of dasatinib and its potential use for pharmacologic control of immunotherapies.
  
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• Haemodynamic effects of sacubitril/valsartan in advanced heart failure.
  ESC Heart Fail

  2022 Apr;9(2):894-904. doi: 10.1002/ehf2.13755.
  
  Gentile Piero, Cantone Rosaria, Perna Enrico, Ammirati Enrico, Varrenti Marisa, D'Angelo Luciana, Verde Alessandro, Foti Grazia, Masciocco Gabriella, Garascia Andrea, Frigerio Maria, Cipriani Manlio
  
  Abstract
  
  AIMS:
  The angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, has been shown to be effective in treatment of patients with heart failure (HF), but limited data are available in patients with advanced disease. This retrospective observational study assessed the effects of ARNI treatment in patients with advanced HF.
  
  METHODS AND RESULTS:
  We reviewed medical records of all advanced HF patients evaluated at our centre for unconventional therapies from September 2016 to January 2019. We studied 44 patients who started ARNI therapy and who had a haemodynamic assessment before beginning ARNI and after 6 ± 2 months. The primary endpoint was variation in pulmonary pressures and filling pressures at 6 months after starting ARNI therapy. Mean patient age was 51.6 ± 7.4 years; 84% were male. At 6 ± 2 months after starting ARNI, there was significant reduction of systolic pulmonary artery pressure [32 mmHg, interquartile range (IQR) 27-45 vs. 25 mmHg, IQR 22.3-36.5; P 
  CONCLUSIONS:
  Sacubitril/valsartan is effective in reducing filling pressures and pulmonary pressures in patients with advanced HF. The absence of adverse events during follow-up suggests that sacubitril/valsartan is safe and well-tolerated in this cohort of patients.
  
  © 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
  
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• Heart Rate in Patients with SARS-CoV-2 Infection: Prevalence of High Values at Discharge and Relationship with Disease Severity.
  J Clin Med

  2021 Nov;10(23):. doi: 5590.
  
  Maloberti Alessandro, Ughi Nicola, Bernasconi Davide Paolo, Rebora Paola, Cartella Iside, Grasso Enzo, Lenoci Deborah, Del Gaudio Francesca, Algeri Michela, Scarpellini Sara, Perna Enrico, Verde Alessandro, Santolamazza Caterina, Vicari Francesco, Frigerio Maria, Alberti Antonia, Valsecchi Maria Grazia, Rossetti Claudio, Epis Oscar Massimiliano, Giannattasio Cristina, On The Behalf Of The Niguarda Covid-Working Group
  
  Abstract
  
  The most common arrhythmia associated with COronaVIrus-related Disease (COVID) infection is sinus tachycardia. It is not known if high Heart Rate (HR) in COVID is simply a marker of higher systemic response to sepsis or if its persistence could be related to a long-term autonomic dysfunction. The aim of our work is to assess the prevalence of elevated HR at discharge in patients hospitalized for COVID-19 and to evaluate the variables associated with it. We enrolled 697 cases of SARS-CoV2 infection admitted in our hospital after February 21 and discharged within 23 July 2020. We collected data on clinical history, vital signs, laboratory tests and pharmacological treatment. Severe disease was defined as the need for Intensive Care Unit (ICU) admission and/or mechanical ventilation. Median age was 59 years (first-third quartile 49, 74), and male was the prevalent gender (60.1%). 84.6% of the subjects showed a SARS-CoV-2 related pneumonia, and 13.2% resulted in a severe disease. Mean HR at admission was 90 ± 18 bpm with a mean decrease of 10 bpm to discharge. Only 5.5% of subjects presented HR > 100 bpm at discharge. Significant predictors of discharge HR at multiple linear model were admission HR (mean increase = ? = 0.17 per bpm, 95% CI 0.11; 0.22,
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• Short- and long-term effects of a cardiac rehabilitation program in patients implanted with a left ventricular assist device.
  PLoS One

  2021 ;16(12):e0259927. doi: e0259927.
  
  Scaglione Anna, Panzarino Claudia, Modica Maddalena, Tavanelli Monica, Pezzano Antonio, Grati Paola, Racca Vittorio, Toccafondi Anastasia, Bordoni Bruno, Verde Alessandro, Cartella Iside, Castiglioni Paolo
  
  Abstract
  
  The efficacy of cardiac rehabilitation in heart-failure patients who received a left-ventricular assist device (LVAD) instead of heart transplantation (HTx) is still unclear. This study aims to evaluate whether cardiac rehabilitation is beneficial in LVAD as HTx patients in the short term and whether its effects in LVAD patients persist over time. Twenty-five LVAD patients were evaluated by functional and psychological tests at admission (T0) and discharge (T1) of a 4-week inpatient structured rehabilitation program, and follow-ups 3 (T2), 6 (T3), and 12 months (T4) after discharge. Twenty-five matched HTx patients were also studied from T0 to T1 to compare the improvements in the six-minute walk test (6MWT). The quality-of-life scores substantially improved in LVAD patients and the 6MWT showed the same functional recovery as in HTx patients from T0 to T1. After T1, numerous LVAD patients withdrew from the study. However, the 6MWT outcome increased further from T1 to T3, with a positive trend during the follow-ups. Hemoglobin and the ventilatory performance increased, and the psychological perception of heart-failure symptoms and pain further improved at T2. In conclusion, exercise-based rehabilitation programs provide similar beneficial effects in LVAD and HTx patients, without deterioration in LVAD patients up to 12 months after discharge.
  
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• Innate Memory Reprogramming by Gold Nanoparticles Depends on the Microbial Agents That Induce Memory.
  Front Immunol

  2021 ;12():751683. doi: 751683.
  
  Swartzwelter Benjamin J, Michelini Sara, Frauenlob Tobias, Barbero Francesco, Verde Alessandro, De Luca Anna Chiara, Puntes Victor, Duschl Albert, Horejs-Hoeck Jutta, Italiani Paola, Boraschi Diana
  
  Abstract
  
  Innate immune memory, the ability of innate cells to react in a more protective way to secondary challenges, is induced by exposure to infectious and other exogeous and endogenous agents. Engineered nanoparticles are particulate exogenous agents that, as such, could trigger an inflammatory reaction in monocytes and macrophages and could therefore be also able to induce innate memory. Here, we have evaluated the capacity of engineered gold nanoparticles (AuNPs) to induce a memory response or to modulate the memory responses induced by microbial agents. Microbial agents used were in soluble . particulate form (MDP and the gram-positive bacteria ; ?-glucan and the ?-glucan-producing fungi ), and as whole microrganisms that were either killed (, ) or viable (the gram-negative bacteria ). The memory response was assessed , by exposing human primary monocytes from 2-7 individual donors to microbial agents with or without AuNPs (primary response), then resting them for 6 days to allow return to baseline, and eventually challenging them with LPS (secondary memory response). Primary and memory responses were tested as production of the innate/inflammatory cytokine TNF? and other inflammatory and anti-inflammatory factors. While inactive on the response induced by soluble microbial stimuli (muramyl dipeptide -MDP-, ?-glucan), AuNPs partially reduced the primary response induced by whole microorganisms. AuNPs were also unable to directly induce a memory response but could modulate stimulus-induced memory in a circumscribed fashion, limited to some agents and some cytokines. Thus, the MDP-induced tolerance in terms of TNF? production was further exacerbated by co-priming with AuNPs, resulting in a less inflammatory memory response. Conversely, the -induced tolerance was downregulated by AuNPs only relative to the anti-inflammatory cytokine IL-10, which would lead to an overall more inflammatory memory response. These effects of AuNPs may depend on a differential interaction/association between the reactive particle surfaces and the microbial components and agents, which may lead to a change in the exposure profiles. As a general observation, however, the donor-to-donor variability in memory response profiles and reactivity to AuNPs was substantial, suggesting that innate memory depends on the individual history of exposures.
  
  Copyright © 2021 Swartzwelter, Michelini, Frauenlob, Barbero, Verde, De Luca, Puntes, Duschl, Horejs-Hoeck, Italiani and Boraschi.
  
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• SERS Sensing of Bacterial Endotoxin on Gold Nanoparticles.
  Front Immunol

  2021 ;12():758410. doi: 758410.
  
  Verde Alessandro, Mangini Maria, Managò Stefano, Tramontano Chiara, Rea Ilaria, Boraschi Diana, Italiani Paola, De Luca Anna Chiara
  
  Abstract
  
  Engineered gold nanoparticles (AuNPs) find application in several fields related to human activities (, food and cosmetic industry or water purification) including medicine, where they are employed for diagnosis, drug delivery and cancer therapy. As for any material/reagent for human use, the safety of AuNPs needs accurate evaluation. AuNPs are prone to contamination by bacterial endotoxin (lipopolysaccharide, LPS), a potent elicitor of inflammatory responses in mammals. It is therefore important, when assessing AuNP immunosafety and immune-related effects, to discriminate between inflammatory effects intrinsic to the NPs from those caused by an undeliberate and undetected LPS contamination. Detection of LPS contamination in AuNP preparations poses different problems when using the current LPS detection assays, given the general interference of NPs, similar to other particulate agents, with the assay reagents and endpoints. This leads to time-consuming search for optimal assay conditions for every NP batch, with unpredictable results, and to the use in parallel of different assays, each with its weaknesses and unpredictability. Thus, the development of highly sensitive, quantitative and accurate assays able to detect of LPS on AuNPs is very important, in view of their medical applications. Surface-enhanced Raman spectroscopy (SERS) is a label-free, sensitive, chemical-specific, nondestructive and fast technique that can be used to directly obtain molecular fingerprint information and a quantitative analysis of LPS adsorbed on AuNPs. Within this study, we describe the use of SERS for the label-free identification and quantitative evaluation - down to few attograms - of the LPS adsorbed on the surface of 50 nm AuNPs. We thus propose SERS as an efficient tool to detect LPS on the AuNP surface, and as the basis for the development of a new sensitive and specific LPS-detection sensor based on the use of AuNPs and SERS.
  
  Copyright © 2021 Verde, Mangini, Managò, Tramontano, Rea, Boraschi, Italiani and De Luca.
  
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• Long-term administration of intravenous inotropes in advanced heart failure.
  ESC Heart Fail

  2021 Oct;8(5):4322-4327. doi: 10.1002/ehf2.13394.
  
  Gentile Piero, Marini Claudia, Ammirati Enrico, Perna Enrico, Saponara Gianluigi, Garascia Andrea, D'Angelo Luciana, Verde Alessandro, Foti Grazia, Masciocco Gabriella, Frigerio Maria, Cipriani Manlio
  
  Abstract
  
  BACKGROUND:
  Patients in heart transplantation (HTx) waiting list for advanced heart failure (HF) are susceptible to acute deterioration refractory to standard HF medical therapies. Limited data are available on long-term in-hospital continuous intravenous (IV) inotropic therapy as bridge to definite therapies.
  
  METHODS AND RESULTS:
  We reviewed medical records of all heart transplant recipients treated in the pre-HTx phase with in-hospital continuous IV inotropes at our institution between 2012 and 2018. We analysed data before the beginning of continuous IV therapy and at the moment of HTx. We report data of 24 patients (mean age of 43.5 ± 15.7 years) treated with IV inotropes as bridge to HTx (median follow-up of 28 months after HTx). The main length of IV inotropic therapy was 84 ± 66 days (min 22; max 264 days). At the beginning, the most frequently used inotrope was dopamine (median dosage of 3 mcg/kg/min, interquartile range 2.5-3.75), alone (n = 11, 46%) or in combination with other inotropes (n = 13, 54%). In 18 patients, the class of inotropes was changed during the hospitalization. We registered a progressive improvement of perfusion markers and neuro-hormonal activation.
  
  CONCLUSION:
  In-hospital continuous parenteral inotropic therapy may serve as a temporary pharmacological bridge to HTx in patients with advanced HF that are actively listed to HTx with good reply in terms of prognosis and perfusion markers.
  
  © 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
  
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• Interaction of nanoparticles with endotoxin .
  Nanotoxicology

  2021 May;15(4):558-576. doi: 10.1080/17435390.2021.1898690.
  
  Mangini Maria, Verde Alessandro, Boraschi Diana, Puntes Victor F, Italiani Paola, De Luca Anna Chiara
  
  Abstract
  
  The interaction between engineered nanoparticles and the bacterial lipopolysaccharide, or endotoxin, is an event that warrants attention. Endotoxin is one of the most potent stimulators of inflammation and immune reactions in human beings, and is a very common contaminant in research labs. In nanotoxicology and nanomedicine, the presence of endotoxin on the nanoparticle surface affects their biological properties leading to misinterpretation of results. This review discusses the importance of detecting the endotoxin contamination on nanoparticles, focusing on the current method of endotoxin detection and their suitability for nanoparticulate materials. Conversely, the capacity of nanoparticles to bind endotoxin can be enhanced by functionalization with endotoxin-capturing molecules, opening the way to the development of novel endotoxin detection assays.
  
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• Interaction between Macrophages and Nanoparticles: In Vitro 3D Cultures for the Realistic Assessment of Inflammatory Activation and Modulation of Innate Memory.
  Nanomaterials (Basel)

  2021 Jan;11(1):. doi: 207.
  
  Swartzwelter Benjamin J, Verde Alessandro, Rehak Laura, Madej Mariusz, Puntes Victor F, De Luca Anna Chiara, Boraschi Diana, Italiani Paola
  
  Abstract
  
  Understanding the modes of interaction between human monocytes/macrophages and engineered nanoparticles is the basis for assessing particle safety, in terms of activation of innate/inflammatory reactions, and their possible exploitation for medical applications. In vitro assessment of nanoparticle-macrophage interaction allows for examining the response of primary human cells, but the conventional 2D cultures do not reproduce the three-dimensional spacing of a tissue and the interaction of macrophages with the extracellular tissue matrix, conditions that shape macrophage recognition capacity and reactivity. Here, we have compared traditional 2D cultures with cultures on a 3D collagen matrix for evaluating the capacity gold nanoparticles to induce monocyte activation and subsequent innate memory in human blood monocytes in comparison to bacterial LPS. Results show that monocytes react to stimuli almost in the same way in 2D and 3D cultures in terms of production of TNF? and IL-6, but that notable differences are found when IL-8 and IL-1Ra are examined, in particular in the recall/memory response of primed cells to a second stimulation, with the 3D cultures showing cell activation and memory effects of nanoparticles better. In addition, the response variations in monocytes/macrophages from different donors point towards a personalized assessment of the nanoparticle effects on macrophage activation.
  
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• Clarification of Misleading Perceptions of COVID-19 Fatality and Testing Rates in Italy: Data Analysis.
  J Med Internet Res

  2020 Jun;22(6):e19825. doi: e19825.
  
  Tosi Davide, Verde Alessandro, Verde Manuela
  
  Abstract
  
  BACKGROUND:
  The fatality rate of coronavirus disease (COVID-19) in Italy is controversial and is greatly affecting discussion on the impact of containment measures that are straining the world's social and economic fabric, such as instigating large-scale isolation and quarantine, closing borders, imposing limits on public gatherings, and implementing nationwide lockdowns.
  
  OBJECTIVE:
  The scientific community, citizens, politicians, and mass media are expressing concerns regarding data suggesting that the number of COVID-19-related deaths in Italy is significantly higher than in the rest of the world. Moreover, Italian citizens have misleading perceptions related to the number of swab tests that have actually been performed. Citizens and mass media are denouncing the coverage of COVID-19 swab testing in Italy, claiming that it is not in line with that in other countries worldwide.
  
  METHODS:
  In this paper, we attempt to clarify the aspects of COVID-19 fatalities and testing in Italy by performing a set of statistical analyses that highlight the actual numbers in Italy and compare them with official worldwide data.
  
  RESULTS:
  The analysis clearly shows that the Italian COVID-19 fatality and mortality rates are in line with the official world scenario, as are the numbers of COVID-19 tests performed in Italy and in the Lombardy region.
  
  CONCLUSIONS:
  This up-to-date analysis may elucidate the evolution of the COVID-19 pandemic in Italy.
  
  ©Davide Tosi, Alessandro Verde, Manuela Verde. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 17.06.2020.
  
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• Gold Nanoparticles Modulate BCG-Induced Innate Immune Memory in Human Monocytes by Shifting the Memory Response towards Tolerance.
  Cells

  2020 Jan;9(2):. doi: 284.
  
  Swartzwelter Benjamin J, Barbero Francesco, Verde Alessandro, Mangini Maria, Pirozzi Marinella, De Luca Anna Chiara, Puntes Victor F, Leite Luciana C C, Italiani Paola, Boraschi Diana
  
  Abstract
  
  Innate immune memory is characterized by a modulation in the magnitude with which innate immune cells such as monocytes and macrophages respond to potential dangers, subsequent to previous exposure to the same or unrelated agents. In this study, we have examined the capacity of gold nanoparticles (AuNP), which are already in use for therapeutic and diagnostic purposes, to modulate the innate memory induced by bacterial agents. The induction of innate memory was achieved in vitro by exposing human primary monocytes to bacterial agents (lipopolysaccharide -LPS-, or live Bacille Calmette-Guérin -BCG) in the absence or presence of AuNP. After the primary activation, cells were allowed to return to a resting condition, and eventually re-challenged with LPS. The induction of memory was assessed by comparing the response to the LPS challenge of unprimed cells with that of cells primed with bacterial agents and AuNP. The response to LPS was measured as the production of inflammatory (TNF?, IL-6) and anti-inflammatory cytokines (IL-10, IL-1Ra). While ineffective in directly inducing innate memory per se, and unable to influence LPS-induced tolerance memory, AuNP significantly affected the memory response of BCG-primed cells, by inhibiting the secondary response in terms of both inflammatory and anti-inflammatory factor production. The reprogramming of BCG-induced memory towards a tolerance type of reactivity may open promising perspectives for the use of AuNP in immunomodulatory approaches to autoimmune and chronic inflammatory diseases.
  
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• Scheduled intermittent inotropes for Ambulatory Advanced Heart Failure. The RELEVANT-HF multicentre collaboration.
  Int J Cardiol

  2018 Dec;272():255-259. doi: 10.1016/j.ijcard.2018.08.048.
  
  Oliva Fabrizio, Perna Enrico, Marini Marco, Nassiacos Daniele, Cirò Antonio, Malfatto Gabriella, Morandi Fabrizio, Caico Ivan, Perna Gianpiero, Meloni Sabina, Vincenzi Antonella, Villani Alessandra, Vecchi Andrea Lorenzo, Minoia Chiara, Verde Alessandro, De Maria Renata,
  
  Abstract
  
  BACKGROUND:
  Ambulatory Advanced Heart Failure (AAHF) is characterized by recurrent HF hospitalizations, escalating diuretic requirements, intolerance to neurohormonal antagonists, end-organ dysfunction, short-term reduced life expectancy despite optimal medical management (OMM). The role of intermittent inotropes in AAHF is unclear. The RELEVANT-HF registry was designed to obtain insight on the effectiveness and safety of compassionate scheduled repetitive 24-hour levosimendan infusions (LEVO) in AAHF patients.
  
  METHODS:
  185 AAHF NYHA class III-IV patients, with ?2 HF hospitalizations/emergency visits in the previous 6?months and systolic dysfunction, were treated with LEVO at tailored doses (0.05-0.2??g/kg/min) without prior bolus every 3-4?weeks. We compared data on HF hospitalizations (percent days spent in hospital, DIH) in the 6?months before and after treatment start.
  
  RESULTS:
  Infusion-related adverse events occurred in 23 (12.4%) patients the commonest being ventricular arrhythmias (16, 8.6%). During follow-up, 37 patients (20%) required for clinical instability treatment adjustments (decreases in infusion dose, rate of infusion or interval). From the 6?months before to the 6?months after treatment start we found lower DIH (9.4 (8.2) % vs 2.8 (6.6) %, p?0.0001), cumulative number (1.3 (0.6) vs 1.8 (0.8), p?=?0.0001) and length of HF admissions (17.4 (15.6) vs 21.6 (13.4) days, p?=?0.0001). One-year survival was 86% overall and 78% free from death/LVAD/urgent transplant.
  
  CONCLUSIONS:
  In AAHF patients, who remain symptomatic despite OMM, LEVO is well tolerated and associated with lower overall length of hospital stay during six months. This multicentre clinical experience underscores the need for a randomized controlled trial of LEVO impact on outcomes in AAHF patients.
  
  Copyright © 2018 Elsevier B.V. All rights reserved.
  
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• Differences in biochemical markers between Heart-transplanted and Left Ventricular Assist Device implanted patients, during cardiac rehabilitation.
  Sci Rep

  2018 Jul;8(1):10816. doi: 10816.
  
  Racca Vittorio, Castiglioni Paolo, Panzarino Claudia, Saresella Marina, Marventano Ivana, Verde Alessandro, Oliva Fabrizio, Ferratini Maurizio
  
  Abstract
  
  Heart transplant (HTx) and left ventricular assist device (LVAD) implant are the best options for symptomatic end stage heart failure, but LVAD patients show lower rehabilitative outcome than HTx patients. To investigate the causes, we compared biomarkers levels and their association with rehabilitative outcome in 51 HTx and in 46 LVAD patients entering the same cardiac rehabilitation program. In both groups, routine biomarkers were measured at start (T1) and end (T2) of cardiac rehabilitation while homocysteine, leptine and IGF-1 were measured at T1 only. HTx patients had lower lymphocyte, platelets, glucose, total proteins and albumin at T1; differences with LVAD patients vanished during rehabilitation when new cases of diabetes were observed in HTx. By contrast, total cholesterol, LDL and HDL fractions, leptin and IGF-1 were higher in HTx patients. The increase from T1 to T2 in six-minute walking test distance, measure of functional rehabilitation outcome, was positively associated with homocysteine and IGF-1 levels in HTx patients. In conclusion, during rehabilitation care should be paid to the early occurrence of dyslipidemia and hyperglycemia in HTx patients, which also require a proper protein dietary support. IGF-1, dangerously low in LVAD patients, might contribute to their lower rehabilitative outcome.
  
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• Graphene-Based Raman Spectroscopy for pH Sensing of X-rays Exposed and Unexposed Culture Media and Cells.
  Sensors (Basel)

  2018 Jul;18(7):. doi: 2242.
  
  Camerlingo Carlo, Verde Alessandro, Manti Lorenzo, Meschini Roberta, Delfino Ines, Lepore Maria
  
  Abstract
  
  Graphene provides a unique way of sensing the local pH level of substances on the micrometric scale, with important implications for the monitoring of cellular metabolic activities where proton excretion could occur. Accordingly, an innovative biosensing approach for the quantification of the pH value of biological fluids, to be used also with small amounts of fluids, was realized and tested. It is based on the use of micro-Raman spectroscopy to detect the modifications of the graphene doping level induced by the contact of the graphene with the selected fluids. The approach was preliminarily tested on aqueous solutions of known pH values. It was then used to quantify the pH values of cell culture media directly exposed to different doses of X-ray radiation and to media exposed to X-ray-irradiated cells. The Raman response of cells placed on graphene layers was also examined.
  
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• [Psychological evaluation and support in patients with left ventricular assist devices: preliminary data at 6-month follow-up].
  G Ital Cardiol (Rome)

  2016 Nov;17(11):940-946. doi: 10.1714/2498.26204.
  
  Voltolini Alessandra, Minotti Anna, Verde Alessandro, Cipriani Manlio, Garascia Andrea, Turazza Fabio, Macera Francesca, Perna Enrico, Russo Claudio F, Fumagalli Emilia, Frigerio Maria
  
  Abstract
  
  BACKGROUND:
  Heart disease has an impact on patient's identity and self-perception. Taking into account the wide literature about psychological aspects before and after heart transplant, it clearly emerges that there is a lack of data and results for patients up to implantation of ventricular assist devices (VAD). The aim of the present study was to explore quality of life and factors correlated with psychological adjustment in patients supported with VAD.
  
  METHODS:
  From February 2013 to August 2014, 18 patients (17 male, mean age 57 years) under clinical evaluation before and after VAD implantation were enrolled. During interviews, patients were assessed with EuroQoL-5D questionnaire to monitor improvement of quality of life before implantation and at 3 and 6 months; critical issues, needs and point of views of patients have been described.
  
  RESULTS:
  A significant improvement in the quality of life score was observed at 3 (score 38 [interquartile range 30-40] vs 75 [60-80], p
  CONCLUSIONS:
  Successful treatment and efficient psychological care are closely related to assessment and continuous clinical support. This approach ensures a better selection of patients and improves their compliance. Further data are needed to support our preliminary observations and to explore long-term quality of life.
  
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• Low incidence of gastrointestinal bleeding and pump thrombosis in patients receiving the INCOR LVAD system in the long-term follow-up.
  Int J Artif Organs

  2015 Oct;38(10):542-7. doi: 10.5301/ijao.5000441.
  
  Iacovoni Attilio, Centofanti Paolo, Attisani Matteo, Verde Alessandro, Terzi Amedeo, Senni Michele, Maiani Massimo, Baronetto Andrea, Livi Ugo, Frigerio Maria, Rinaldi Mauro
  
  Abstract
  
  BACKGROUND:
  Left ventricular assist device (LVAD) implantation improves survival and quality of life in patients with advanced heart failure (HF). Despite these advantages, LVADs are not free from risks. Among all adverse events (AE), pump thrombosis and bleeding, especially of the gastrointestinal (GI) tract, have been reported to occur with increasing frequency in some CF-LVADs. The INCOR LVAD system is a third-generation, continuous flow, axial pump with active magnetic levitation, avoiding the potential downsides of mechanical bearings.
  
  METHODS:
  The aim of this retrospective study was to review the Italian clinical experience with the INCOR LVAD and to determine the prevalence of GI bleeding and pump thrombosis. All patients implanted between January 2006 and May 2012 were considered eligible.
  
  RESULTS:
  The total population consisted of 42 patients. LVAD indication was BTT in 36 (86%) and DT in 6 (14%) patients; 31 patients (74%) were INTERMACS class 1 or 2. Mean support time was 525 ± 570 days. The 1-year and 2-year survival rates were 74% and 60%, respectively. The most frequent AE was driveline infection (0.33 events PPY) followed by stroke with consequence (0.17 events PPY), sepsis (0.07 events PPY), and right HF (0.05 events PPY). No episodes of pump thrombosis or GI bleeding were observed.
  
  CONCLUSIONS:
  In this cohort of high-risk, advanced HF patients, the INCOR LVAD provided effective support with improved survival. Moreover, the absence of GI bleeding and pump thrombosis demonstrates a favorable characteristic of this device. Further prospective studies are needed to confirm these data.
  
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• Mid-term survival after continuous-flow left ventricular assist device versus heart transplantation.
  Heart Vessels

  2016 May;31(5):722-33. doi: 10.1007/s00380-015-0654-4.
  
  Ammirati Enrico, Oliva Fabrizio G, Colombo Tiziano, Russo Claudio F, Cipriani Manlio G, Garascia Andrea, Guida Valentina, Colombo Giulia, Verde Alessandro, Perna Enrico, Cannata Aldo, Paino Roberto, Martinelli Luigi, Frigerio Maria
  
  Abstract
  
  There is a paucity of data about mid-term outcome of patients with advanced heart failure (HF) treated with left ventricular assist device (LVAD) in Europe, where donor shortage and their aging limit the availability and the probability of success of heart transplantation (HTx). The aim of this study is to compare Italian single-centre mid-term outcome in prospective patients treated with LVAD vs. HTx. We evaluated 213 consecutive patients with advanced HF who underwent continuous-flow LVAD implant or HTx from 1/2006 to 2/2012, with complete follow-up at 1 year (3/2013). We compared outcome in patients who received a LVAD (n = 49) with those who underwent HTx (n = 164) and in matched groups of 39 LVAD and 39 HTx patients. Patients that were treated with LVAD had a worse risk profile in comparison with HTx patients. Kaplan-Meier survival curves estimated a one-year survival of 75.5 % in LVAD vs. 82.3 % in HTx patients, a difference that was non-statistically significant [hazard ratio (HR) 1.46; 95 % confidence interval (CI) 0.74-2.86; p = 0.27 for LVAD vs. HTx]. After group matching 1-year survival was similar between LVAD (76.9 %) and HTx (79.5 %; HR 1.15; 95 % CI 0.44-2.98; p = 0.78). Concordant data was observed at 2-year follow-up. Patients treated with LVAD as bridge-to-transplant indication (n = 22) showed a non significant better outcome compared with HTx with a 95.5 and 90.9 % survival, at 1- and 2-year follow-up, respectively. Despite worse preoperative conditions, survival is not significantly lower after LVAD than after HTx at 2-year follow-up. Given the scarce number of donors for HTx, LVAD therapy represents a valid option, potentially affecting the current allocation strategy of heart donors also in Europe.
  
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• Differential regulation of microRNAs in end-stage failing hearts is associated with left ventricular assist device unloading.
  Biomed Res Int

  2015 ;2015():592512. doi: 592512.
  
  Barsanti Cristina, Trivella Maria Giovanna, D'Aurizio Romina, El Baroudi Mariama, Baumgart Mario, Groth Marco, Caruso Raffaele, Verde Alessandro, Botta Luca, Cozzi Lorena, Pitto Letizia
  
  Abstract
  
  Mechanical unloading by left ventricular assist devices (LVADs) in advanced heart failure (HF), in addition to improving symptoms and end-organ perfusion, is supposed to stimulate cellular and molecular responses which can reverse maladaptive cardiac remodeling. As microRNAs (miRNAs) are key regulators in remodeling processes, a comparative miRNA profiling in transplanted hearts of HF patients with/without LVAD assistance could aid to comprehend underlying molecular mechanisms. Next generation sequencing (NGS) was used to analyze miRNA differential expression in left ventricles of HF patients who underwent heart transplantation directly (n = 9) or following a period of LVAD support (n = 8). After data validation by quantitative real-time PCR, association with functional clinical parameters was investigated. Bioinformatics' tools were then used for prediction of putative targets of modulated miRNAs and relative pathway enrichment. The analysis revealed 13 upregulated and 10 downregulated miRNAs in failing hearts subjected to LVAD assistance. In particular, the expression level of some of them (miR-338-3p, miR-142-5p and -3p, miR-216a-5p, miR-223-3p, miR-27a-5p, and miR-378g) showed correlation with off-pump cardiac index values. Predicted targets of these miRNAs were involved in focal adhesion/integrin pathway and in actin cytoskeleton regulation. The identified miRNAs might contribute to molecular regulation of reverse remodeling and heart recovery mechanisms.
  
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• Caspase-1 transcripts in failing human heart after mechanical unloading.
  Cardiovasc Pathol

  2015 ;24(1):11-8. doi: 10.1016/j.carpath.2014.08.002.
  
  Prescimone Tommaso, D'Amico Andrea, Caselli Chiara, Cabiati Manuela, Viglione Federica, Caruso Raffaele, Verde Alessandro, Del Ry Silvia, Trivella Maria Giovanna, Giannessi Daniela
  
  Abstract
  
  BACKGROUND:
  Caspase (Casp)-1 has been indicated as a molecular target capable of preventing the progression of cardiovascular diseases, including heart failure (HF), due to its central role in promoting inflammation and cardiomyocyte loss. The aim of this study was to assess whether Left Ventricular Assist Device (LVAD) implantation modifies the inflammatory and apoptotic profile in the heart through the modulation of Casp-1 expression level.
  
  METHODS:
  Cardiac tissue was collected from end-stage HF patients before LVAD implant (pre-LVAD group, n=22) and at LVAD removal (post-LVAD, n=6), and from stable HF patients on medical therapy without prior circulatory support (HTx, n=7) at heart transplantation, as control. The cardiac expression of Casp-1, of its inhibitors caspase recruitment domain (CARD) only protein (COP) and CARD family, member 18 (ICEBERG), was evaluated by real-time PCR in the three groups of patients.
  
  RESULTS:
  Casp-1 was increased in the pre-LVAD group compared to HTx (p=0.006), while on the contrary the ICEBERG level was significantly decreased in pre-LVAD with respect to HTx patients (p
  CONCLUSIONS:
  This study describes a specific pattern of the Casp-1 system associated with inflammation and apoptosis markers in patients who require LVAD insertion. The inflammation could be the key process regulating, in a negative loop, Casp-1 signaling and its down-stream effects, apoptosis included.
  
  Copyright © 2014 Elsevier Inc. All rights reserved.
  
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• Relationship between early inflammatory response and clinical evolution of the severe multiorgan failure in mechanical circulatory support-treated patients.
  Mediators Inflamm

  2014 ;2014():281790. doi: 281790.
  
  Caruso Raffaele, Campolo Jonica, Verde Alessandro, Botta Luca, Cozzi Lorena, Parolini Marina, Milazzo Filippo, Nonini Sandra, Martinelli Luigi, Paino Roberto, Marraccini Paolo, Frigerio Maria
  
  Abstract
  
  BACKGROUND:
  The mechanical circulatory support (MCS) is an effective treatment in critically ill patients with end-stage heart failure (ESHF) that, however, may cause a severe multiorgan failure syndrome (MOFS) in these subjects. The impact of altered inflammatory response, associated to MOFS, on clinical evolution of MCS postimplantation patients has not been yet clarified.
  
  METHODS:
  Circulating cytokines, adhesion molecules, and a marker of monocyte activation (neopterin) were determined in 53?MCS-treated patients, at preimplant and until 2 weeks. MOFS was evaluated by total sequential organ failure assessment score (tSOFA).
  
  RESULTS:
  During MCS treatment, 32 patients experienced moderate MOFS (tSOFA?11; A group), while 21 patients experienced severe MOFS (tSOFA???11) with favorable (B group) or adverse (n = 13, C group) outcomes. At preimplant, higher values of left ventricular ejection fraction (LVEF) and estimated glomerular filtration rate (eGFR) were the only parameter independently associated with A group. In C group, during the first postoperative week, high levels of interleukin-8 (IL-8) and tumor necrosis factor (TNF)-?, and an increase of neopterin and adhesion molecules, precede tSOFA worsening and exitus.
  
  CONCLUSIONS:
  The MCS patients of C group show an excessive release to IL-8 and TNF-?, and monocyte-endothelial activation after surgery, that might contribute to the unfavourable evolution of severe MOFS.
  
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• Cardiac molecular markers of programmed cell death are activated in end-stage heart failure patients supported by left ventricular assist device.
  Cardiovasc Pathol

  2014 ;23(5):272-82. doi: 10.1016/j.carpath.2014.04.003.
  
  Prescimone Tommaso, Masotti Silvia, D'Amico Andrea, Caruso Raffaele, Cabiati Manuela, Caselli Chiara, Viglione Federica, Verde Alessandro, Del Ry Silvia, Giannessi Daniela
  
  Abstract
  
  BACKGROUND:
  Cardiomyocyte apoptosis increases in heart failure (HF) and is implicated in disease progression. The apoptotic cell is not inevitably committed to death, and appropriate therapy like left ventricular assist device (LVAD) support could offer a rescue of cellular functions. Literature data regarding the modulation of the apoptotic process during LVAD support are still controversial.
  
  METHODS:
  To assess whether LVAD implantation modifies the apoptotic profile in the heart, cardiac tissue was collected from end-stage HF patients before LVAD implant (pre-LVAD, n=22) and at LVAD removal (post-LVAD, n=6) and from stable HF patients on medical therapy without prior circulatory support (HTx, n=7) at heart transplantation as control. Caspase (Casp)-3, Bax, Bcl-2, and Hsp72 cardiac mRNA and protein expression were evaluated by real-time polymerase chain reaction and Western blotting (WB) in the three groups of patients. Immunohistochemical analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and DNA laddering analysis were performed; cellular size and interstitial fibrosis content were also determined.
  
  RESULTS:
  All the apoptotic indices were increased in the post-LVAD group compared to pre-LVAD, specially antiapoptotic Hsp72 and proapoptotic Bax (Hsp72: 3.27±0.41 vs. 0.76±0.14, P<.001 bax: vs. p=".035;" post-lvad pre-lvad respectively the significant increase in hsp72 was confirmed by wb and immunohistochemical analysis.>
  CONCLUSION:
  LVAD appears to induce an activation of apoptotic mediators, mainly at the mitochondrial level, while the following activation of Casp-3 is reduced by the significant increase of Hsp72, whose enhancement could be an important factor in cardiac remodeling associated with LVAD support.
  
  Copyright © 2014 Elsevier Inc. All rights reserved.
  
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• Relationship between pre-implant interleukin-6 levels, inflammatory response, and early outcome in patients supported by left ventricular assist device: a prospective study.
  PLoS One

  2014 ;9(3):e90802. doi: e90802.
  
  Caruso Raffaele, Botta Luca, Verde Alessandro, Milazzo Filippo, Vecchi Irene, Trivella Maria Giovanna, Martinelli Luigi, Paino Roberto, Frigerio Maria, Parodi Oberdan
  
  Abstract
  
  PURPOSE:
  The immune response is crucial in the development of multi-organ failure (MOF) and complications in end-stage heart failure patients supported by left ventricular assist device (LVAD). However, at pre-implant, the association between inflammatory state and post-LVAD outcome is not yet clarified. Aim of the study was to assess the relationship among pre-implant levels of immune-related cytokines, postoperative inflammatory response and 3-month outcome in LVAD-patients.
  
  METHODS:
  In 41 patients undergoing LVAD implantation, plasma levels of interleukin (IL)-6, IL-8, crucial for monocyte modulation, and urine neopterin/creatinine ratio (Neo/Cr), marker of monocyte activation, were assessed preoperatively, at 3 days, 1 and 4 weeks post-LVAD. MOF was evaluated by total sequential organ failure assessment (tSOFA) score. Intensive care unit (ICU)-death and/or post-LVAD tSOFA ?11 was considered as main adverse outcome. Length of ICU-stay, 1 week-tSOFA score, hospitalisation and 3-month survival were considered additional end-points.
  
  RESULTS:
  During ICU-stay, 8 patients died of MOF, while 8 of the survivors experienced severe MOF with postoperative tSOFA score ?11. Pre-implant level of IL-6 ? 8.3 pg/mL was identified as significant marker of discrimination between patients with or without adverse outcome (OR 6.642, 95% CI 1.201-36.509, p?=?0.030). Patients were divided according to pre-implant IL-6 cutoff of 8.3 pg/ml in A [3.5 (1.2-6.1) pg/mL] and B [24.6 (16.4-38.0) pg/mL] groups. Among pre-implant variables, only white blood cells count was independently associated with pre-implant IL-6 levels higher than 8.3 pg/ml (OR 1.491, 95% CI 1.004-2.217, p?=?0.048). The ICU-stay and hospitalisation resulted longer in B-group (p?=?0.001 and p?=?0.030, respectively). Postoperatively, 1 week-tSOFA score, IL-8 and Neo/Cr levels were higher in B-group.
  
  CONCLUSIONS:
  LVAD-candidates with elevated pre-implant levels of IL-6 are associated, after intervention, to higher release of monocyte activation related-markers, a clue for the development of MOF, longer clinical course and poor outcome.
  
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• Adrenomedullin and intermedin gene transcription is increased in leukocytes of patients with chronic heart failure at different stages of the disease.
  Peptides

  2014 May;55():13-6. doi: 10.1016/j.peptides.2014.01.028.
  
  Cabiati Manuela, Sabatino Laura, Svezia Benedetta, Caruso Raffaele, Verde Alessandro, Caselli Chiara, Prescimone Tommaso, Giannessi Daniela, Del Ry Silvia
  
  Abstract
  
  Adrenomedullin (ADM) is a vasodilatory peptide expressed in many tissues. Its levels are elevated in various diseases including chronic heart failure (CHF) and it has been suggested that the up-regulation of ADM in cardiac disease represents a protective mechanism. Similarly, intermedin (IMD), a novel member of the calcitonin/calcitonin gene-related peptide family, is considered a potential endogenous protector of the heart. Previous studies demonstrated that in CHF patients, elevated plasma concentrations of ADM and IMD reflect the patient's disease severity and prognosis, while the behavior of mRNA expression is not known. The aim of this study was to evaluate ADM/IDM transcriptomic profiling in human leukocytes of CHF patients as a function of clinical severity, assessing possible changes with respect to healthy subjects (C). mRNA expression was evaluated by Real-Time PCR and total RNA was extracted from leukocytes of C (n=8) and from CHF patients (NYHA I-II n=10; NYHA III-IV n=14) with PAXgene Blood RNA Kit. Significantly higher levels of ADM and IMD mRNA were found in CHF as a function of clinical severity (ADM: C=0.03 ± 0.013, NYHA I-II=0.11 ± 0.084, NYHA III-IV=11.46 ± 4.72, p=0.037 C vs NYHA III-IV, p=0.028 NYHA I-II vs NYHA III-IV; IMD: C=0.158 ± 0.041, NYHA I-II=0.93 ± 0.40, NYHA III-IV=2.6 ± 0.67, p=0.014 C vs NYHA III-IV, p=0.014 NYHA I-II vs NYHA III-IV). This study highlights, for the first time, the possibility of evaluating ADM and IMD mRNA expression in human whole blood samples by Real-Time PCR study providing further relevant information and providing a more complete interpretation of the pathophysiology of the disease.
  
  Copyright © 2014 Elsevier Inc. All rights reserved.
  
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• Adverse event prediction in patients with left ventricular assist devices.
  Annu Int Conf IEEE Eng Med Biol Soc

  2013 ;2013():1314-7. doi: 10.1109/EMBC.2013.6609750.
  
  Tsipouras Markos G, Karvounis Evaggelos C, Tzallas Alexandros T, Katertsidis Nikolaos S, Goletsis Yorgos, Frigerio Maria, Verde Alessandro, Trivella Maria G, Fotiadis Dimitrios I
  
  Abstract
  
  This work presents the Treatment Tool, which is a component of the Specialist's Decision Support Framework (SDSS) of the SensorART platform. The SensorART platform focuses on the management of heart failure (HF) patients, which are treated with implantable, left ventricular assist devices (LVADs). SDSS supports the specialists on various decisions regarding patients with LVADs including decisions on the best treatment strategy, suggestion of the most appropriate candidates for LVAD weaning, configuration of the pump speed settings, while also provides data analysis tools for new knowledge extraction. The Treatment Tool is a web-based component and its functionality includes the calculation of several acknowledged risk scores along with the adverse events appearance prediction for treatment assessment.
  
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• Transcriptomic profiling of the four adenosine receptors in human leukocytes of heart failure patients.
  Biomed Res Int

  2013 ;2013():569438. doi: 569438.
  
  Cabiati Manuela, Caruso Raffaele, Verde Alessandro, Sabatino Laura, Morales Maria-Aurora, Del Ry Silvia
  
  Abstract
  
  In this study the transcriptomic profiling of adenosine receptors (ARs) in human leukocytes of heart failure (HF) patients as a function of clinical severity, assessing the possible changes with respect to healthy subjects (C), was evaluated. Total RNA was extracted from leukocytes of C (n = 8) and of HF patients (NYHA I-II n = 9; NYHA III-IV n = 14) with a PAXgene Blood RNA Kit. An increase as a function of clinical severity was observed in each AR (A1R: C = 0.02 ± 0.009, NYHA I-II = 0.21 ± 0.09, NYHA III-IV = 3.6 ± 1.3, P = 0.03 C versus NYHA III-IV, P = 0.02 NYHA I-II versus NYHA III-IV; A2aR: C = 0.2 ± 0.05, NYHA I-II = 0.19 ± 0.04, NYHA III-IV = 1.32 ± 0.33, P = 0.005 C versus NYHA III-IV, P = 0.003 NYHA I-II versus NYHA III-IV; A2bR: C = 1.78 ± 0.36, NYHA I-II = 1.35 ± 0.29, NYHA III-IV = 4.07 ± 1.21, P = 0.03: NYHA I-II versus NYHA III-IV; A3R: C = 0.76 ± 0.21, NYHA I-II = 0.94 ± 0.19, NYHA III-IV = 3.14 ± 0.77, P = 0.01 C versus NYHA III-IV and NYHA I-II versus NYHA III-IV, resp.). The mRNA expression of the ectonucleoside triphosphate diphosphohydrolase (CD39) and the ecto-5'-nucleotidase (CD73) were also evaluated. They resulted up-regulated. These findings show that components of adenosine metabolism and signalling are altered to promote adenosine production and signalling in HF patients. Thus, HF may benefit from adenosine-based drug therapy after confirmation by clinical trials.
  
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• Levosimendan reverted severe pulmonary hypertension in one patient on waiting list for heart transplantation.
  Int J Cardiol

  2013 Oct;168(4):4518-9. doi: 10.1016/j.ijcard.2013.06.106.
  
  Ammirati Enrico, Musca Francesco, Oliva Fabrizio, Garascia Andrea, Pacher Valentina, Verde Alessandro, Cipriani Manlio, Moreo Antonella, Martinelli Luigi, Frigerio Maria
  
  
  
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• High peripheral levels of h-FABP are associated with poor prognosis in end-stage heart failure patients with mechanical circulatory support.
  Biomark Med

  2013 Jun;7(3):481-92. doi: 10.2217/bmm.13.6.
  
  Cabiati Manuela, Caselli Chiara, Caruso Raffaele, Prescimone Tommaso, Verde Alessandro, Botta Luca, Parodi Oberdan, Del Ry Silvia, Giannessi Daniela
  
  Abstract
  
  AIM:
  To associate the time-course of h-FABP and N-terminal pro B-type natriuretic peptide (NT-proBNP)after left ventricular assist device (LVAD) implantation to outcome in end-stage heart failure patients.
  
  MATERIALS & METHODS:
  Patients (n = 14, NYHA class III/IV; left ventricular ejection fraction
  RESULTS:
  h-FABP significantly increases after surgery, decreasing since 72 h in all patients. At 72 h all survivor patients present h-FABP lower than the median value. N-terminal pro B-type natriuretic peptide is not associated with patient outcome at any time.
  
  CONCLUSION:
  High h-FABP levels, indicating the presence of more severe myocardial damage, are associated with a poor prognosis in patients with LVAD, suggesting that an early cardiac injury marker could improve the prediction of clinical outcome.
  
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• [Treatment of advanced heart failure in women: heart transplantation and ventricular assist devices].
  G Ital Cardiol (Rome)

  2012 May;13(5 Suppl 1):35S-41S.
  
  Cipriani Manlio, Macera Francesca, Verde Alessandro, Bruschi Giuseppe, del Medico Marta, Oliva Fabrizio, Martinelli Luigi, Frigerio Maria
  
  Abstract
  
  Women candidates for heart transplantation are definitely less than men, just 20% of all patients transplanted; even in the INTERMACS registry they represent only 21% of all ventricular assist devices (VAD) implanted. The reasons for this big difference are discussed in this article. Why women are less frequently assessed for unconventional therapies? Are they sicker or just less regarded? Our experience and the literature show us clear epidemiological, clinical and treatment differences that could lead to a lower prevalence of end-stage disease in women of an age suitable for unconventional therapies. Once on the transplant list, women wait less than men for a heart transplant, because they present with more severe disease, have a lower body mass index and undergo less VAD implants. After transplantation women's survival is comparable to men's, although they usually complain of a lower quality of life. Females receive less often a VAD than men. The main reasons for this include presentation with advanced heart failure at an older age than men, worse outcomes related to small body surface area, and lower survival rates on VAD when implanted as bridge to heart transplantation.
  
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• Limited changes in severe functional mitral regurgitation and pulmonary hypertension after left ventricular assist device implantation: a clue to consider concurrent mitral correction?
  Int J Cardiol

  2013 Jul;167(2):e35-7. doi: 10.1016/j.ijcard.2013.03.098.
  
  Ammirati Enrico, Musca Francesco, Cannata Aldo, Garascia Andrea, Verde Alessandro, Pacher Valentina, Moreo Antonella, Oliva Fabrizio, Martinelli Luigi, Frigerio Maria
  
  
  
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• [Proposal for updated listing criteria for heart transplantation and indications to implant of left ventricular assist devices].
  G Ital Cardiol (Rome)

  2013 Feb;14(2):110-9. doi: 10.1714/1218.13523.
  
  Ammirati Enrico, Oliva Fabrizio, Colombo Tiziano, Botta Luca, Cipriani Manlio, Cannata Aldo, Verde Alessandro, Turazza Fabio M, Russo Claudio F, Paino Roberto, Martinelli Luigi, Frigerio Maria
  
  Abstract
  
  Heart transplantation (HTx) is considered to be the gold standard treatment for advanced heart failure (HF) but it is available only for a minority of patients, due to paucity of donor hearts (278 HTx were performed in 2011 in Italy). Patients listed for HTx have a prolonged waiting time (that is about 2.3 years in the 2006-2010 time period in Italy) that is superior compared with patients who receive HTx (median time around 6 months), to underline the presence of an allocation system that prioritizes candidates in critical conditions. Patients listed for HTx have a poor quality of life and their annual mortality is around 8-10%. Another 10-15% of HTx candidates are removed from the waiting list each year because they are no longer suitable for transplantation. On the other hand, continuous-flow left ventricular assist devices (LVADs) have been demonstrated to improve survival and quality of life of patients with advanced/refractory HF. LVAD therapy can represent a valid alternative to HTx, and it is recommended for patients with advanced HF in the recent edition of the European Society of Cardiology guidelines on HF management. In the United States, a larger number of centers compared with European ones started to apply a strategy of LVAD implant for many patients who meet clinical criteria for listing for HTx. Data from our center concerning the last 6 years of LVAD implant (51 implants since 2006) reported a 75.5% survival rate at 1 year. In Italian series, as in our center, current HTx survival is only slightly superior (83% survival rate at 1 year), based on data from the Italian National Transplant Center. We report a proposal for updated listing criteria for HTx and indications for LVAD implant in patients with advanced acute and chronic HF. Criteria for identifying suitable patients for HTx and/or LVAD considering the shortage of donors are discussed.
  
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• Severity of oxidative stress and inflammatory activation in end-stage heart failure patients are unaltered after 1 month of left ventricular mechanical assistance.
  Cytokine

  2012 Jul;59(1):138-44. doi: 10.1016/j.cyto.2012.04.018.
  
  Caruso Raffaele, Verde Alessandro, Campolo Jonica, Milazzo Filippo, Russo Claudio, Boroni Chiara, Parolini Marina, Trunfio Salvatore, Paino Roberto, Martinelli Luigi, Frigerio Maria, Parodi Oberdan
  
  Abstract
  
  This study investigates the impact of early left ventricular (LV)-mechanical unloading on systemic oxidative stress and inflammation in terminal heart failure patients and their impact both on multi organ failure and on intensive care unit (ICU) stay. Circulating levels of urinary 15-isoprostane-F(2t) (8-epi-PGF2(?)) and pro-inflammatory markers [plasma interleukin (IL)-6, IL-8, and urinary neopterin, a monocyte activation index] were analyzed in 20 healthy subjects, 22 stable end-stage heart failure (ESHF) patients and in 23 LV assist device (LVAD) recipients at pre-implant and during first post-LVAD (PL) month. Multi-organ function was evaluated by total Sequential Organ Failure Assessment (tSOFA) score. In LVAD recipients the levels of oxidative-inflammatory markers and tSOFA score were higher compared to other groups. After device implantation 8-epi-PGF2(?) levels were unchanged, while IL-6, and IL-8 levels increased during first week, and at 1month returned to pre-implant values, while neopterin levels increased progressively during LVAD support. The tSOFA score worsened at 1 PL-week with respect to pre-implant value, but improved at 1 PL-month. The tSOFA score related with IL-6 and IL-8 levels, while length of ICU stay related with pre-implant IL-6 levels. These data suggest that hemodynamic instability in terminal HF is associated to worsening of systemic inflammatory and oxidative milieu that do not improve in the early phase of hemodynamic recovery and LV-unloading by LVAD, affecting multi-organ function and length of ICU stay. This data stimulate to evaluate the impact of inflammatory signals on long-term outcome of mechanical circulatory support.
  
  Copyright © 2012 Elsevier Ltd. All rights reserved.
  
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• Association of pre-operative interleukin-6 levels with Interagency Registry for Mechanically Assisted Circulatory Support profiles and intensive care unit stay in left ventricular assist device patients.
  J Heart Lung Transplant

  2012 Jun;31(6):625-33. doi: 10.1016/j.healun.2012.02.006.
  
  Caruso Raffaele, Verde Alessandro, Cabiati Manuela, Milazzo Filippo, Boroni Chiara, Del Ry Silvia, Parolini Marina, Vittori Claudia, Paino Roberto, Martinelli Luigi, Giannessi Daniela, Frigerio Maria, Parodi Oberdan
  
  Abstract
  
  BACKGROUND:
  Inflammatory mechanisms are associated with worse prognosis in end-stage heart failure (ESHF) patients who require left ventricular assist device (LVAD) support. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles describe patient condition at pre-implant and outcome. This study assessed the relationship among inflammation patterns and INTERMACS profiles in LVAD recipients.
  
  METHOD:
  Thirty ESHF patients undergoing LVAD implantation as bridge to transplant were enrolled. Blood and urine samples were collected pre-operatively and serially up to 2 weeks post-operatively for assessment of inflammatory markers (plasma levels of interleukin [IL]-6, IL-8, IL-10, and osteopontin, a cardiac inflammatory-remodeling marker; and the urine neopterin/creatinine ratio, a monocyte activation marker). Multiorgan function was evaluated by the total sequential organ failure assessment (tSOFA) score. Outcomes of interest were early survival, post-LVAD tSOFA score, and intensive care unit (ICU) length of stay.
  
  RESULTS:
  Fifteen patients had INTERMACS profiles 1 or 2 (Group A), and 15 had profiles 3 or 4 (Group B). At pre-implant, only IL-6 levels and the IL-6/IL-10 ratio were higher in Group A vs B. After LVAD implantation, neopterin/creatinine ratio and IL-8 levels increased more in Group A vs B. Osteopontin levels increased significantly only in Group B. The tSOFA score at 2 weeks post-LVAD and ICU duration were related with pre-implant IL-6 levels.
  
  CONCLUSIONS:
  The INTERMACS profiles reflect the severity of the pre-operative inflammatory activation and the post-implant inflammatory response, affecting post-operative tSOFA score and ICU stay. Therefore, inflammation may contribute to poor outcome in patients with severe INTERMACS profile.
  
  Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
  
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• Preventing restenosis after implantation of bare stents with oral rapamycin: a randomized angiographic and intravascular ultrasound study with a 5-year clinical follow-up.
  Cardiology

  2010 ;115(1):77-86. doi: 10.1159/000253854.
  
  Cernigliaro Carmelo, Sansa Mara, Vitrella Giancarlo, Verde Alessandro, Bongo Angelo Sante, Giuliani Luigi, Novelli Eugenio
  
  Abstract
  
  OBJECTIVES:
  To establish the efficacy of oral rapamycin at a dose of 2 mg for 1 month at reducing the 6-month restenosis rate after the implantation of bare metal stents.
  
  METHODS:
  A prospective, 1:1 randomized, single-blind, placebo-controlled study was conducted in 108 consecutive patients assigned immediately after stent implantation to oral rapamycin (4 mg loading dose followed by 2 mg daily for 30 days) or a placebo.
  
  RESULTS:
  Rapamycin was maintained in 98% of patients. Angiographic in-stent binary restenosis was 14.3% in the rapamycin group versus 32.1% in the placebo group, with a relative risk (RR) of 0.45 (95% CI 0.24-0.84, p = 0.015). The rapamycin blood concentration at 15 days correlated with binary restenosis (p = 0.044). The volume obstructions found by intravascular ultrasound for the rapamycin and the placebo groups were 18.1+/-10.7 and 27.1+/-15.7% (p = 0.002), respectively. Major adverse cardiac events at a 5-year follow-up were 31.5% for the rapamycin group and 50.0% for the placebo group (RR 0.63, 95% CI 0.39-1.01, p = 0.078).
  
  CONCLUSIONS:
  Oral rapamycin significantly reduces the incidence of restenosis at follow-up compared to a placebo.We believe these findings deserve further testing in larger trials.
  
  (c) 2009 S. Karger AG, Basel.
  
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• [Management of advanced chronic heart failure].
  G Ital Cardiol (Rome)

  2008 Oct;9(10 Suppl 1):112S-117S.
  
  Oliva Fabrizio, Macera Francesca, Verde Alessandro, Frigerio Maria
  
  Abstract
  
  Because of the progressive ageing of the population and the extensive use of recommended drugs, the number of patients with advanced chronic heart failure constantly increases. Several studies showed the efficacy of neurohormonal antagonists and electric devices in NYHA class III-IV patients; however, there is no agreement on the management of refractory heart failure, especially for patients who are not candidates for heart transplantation, because of age or comorbidity. The treatment with intravenous inotropic agents is considered a palliative care. The growing experience with implant of left ventricular assist devices, on the other hand, is encouraging and suggests more extensive use of these devices, both as bridge to transplant and as destination therapy.
  
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• [Changes in patient survival and quality of life after heart transplantation].
  G Ital Cardiol (Rome)

  2008 Jul;9(7):461-71.
  
  Frigerio Maria, Oliva Fabrizio, Turazza Fabio M, Macera Francesca, Galvanin Silvia, Verde Alessandro, Bruschi Giuseppe, Pedrazzini Giovanna
  
  Abstract
  
  Heart transplantation was performed firstly in 1967, but it became a valuable option in the 1980s, due to the availability of cyclosporine and of the technique for rejection monitoring by means of serial endomyocardial biopsies. Post-transplant survival improved over the years, mainly due to a reduction in early mortality for infection or acute rejection. Expected 1-year and 5-year survivals are around 85% and 70%, respectively. During the past 20-30 years, better therapies for heart failure have been developed, leading to restriction of heart transplant candidacy to truly refractory heart failure. On the contrary, the criteria for donor acceptance have been liberalized, due to the discrepancy between heart transplant candidates and available organs. It must be kept in mind that renal and/or hepatic insufficiency that may be a consequence of heart failure, pulmonary hypertension, and donor age, all remain risk factors for mortality after transplantation. In order to maintain and possibly improve the results of heart transplantation, effective strategies to increase safely the donor pool are of utmost importance. Moreover, long-term post-transplant recipients present new challenges to research and clinical practice. Mechanical circulatory support devices represent a surgical bridge or an alternative to transplantation; their expansion is limited by costs, organizational burden, and by patient difficulties in accepting this therapy.
  
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• Cardiac angio-CT scan for planning MIDCAB.
  Heart Surg Forum

  2004 Apr;7(2):E113-6.
  
  Caimmi Philippe-Primo R, Fossaceca Rita, Lanfranchi Marco, Kapetanakis Emmanouil I, Verde Alessandro, Panella Alessandro, Bernardi Massimo, Fiume Cosimo, Vivirito Mario, Carriero Alessandro, Micalizzi Ezio
  
  Abstract
  
  Precise evaluation of the cardiac and thoracic anatomy of the patient is mandatory for planning safe minimally invasive direct coronary artery bypass (MIDCAB). Three-dimensional images obtained with a computed tomographic coronary angiography (angio-CT) scan make it possible to accurately visualize the intrathoracic surgical anatomy in order to check the feasibility of the direct exposure of the anatomical structures involved in the surgical procedure. Particular morphological parameters of coronary arteries such as diameter, wall calcification, and intramyocardial position as well as bypass grafts and internal thoracic artery (ITA) displacement can all be precisely defined with this method. We present our preliminary experience using cardiac angio-CT scan as a method for selecting patients for MIDCAB in order to avoid possible surgical complications to minimize the necessity for conversion to the standard surgical approach as well as for choosing the best surgical access.
  
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