Perna Dott. Enrico

Pubblicazioni su PubMed

• Fulminant Lymphocytic Myocarditis During Pregnancy Treated With Temporary Mechanical Circulatory Supports and Aggressive Immunosuppression.
  Circ Heart Fail

  2022 Oct;():e009810. doi: 10.1161/CIRCHEARTFAILURE.122.009810.
  
  Veronese Giacomo, Nonini Sandra, Cannata Aldo, Aresta Francesca, Olivieri Guido, Montrasio Elisa, De Caria Daniele, Perna Enrico, Calini Angelo, Bottiroli Maurizio, Cislaghi Francesca, Pedrazzini Giovanna, Baltaro Federica, Quattrocchi Giuseppina, Pedrotti Patrizia, Russo Claudio F, Garascia Andrea, Mondino Michele, Ammirati Enrico
  
  
  
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• Endothelial Dysfunction in Patients with Advanced Heart Failure Treated with Levosimendan Periodic Infusion Compared with Optimal Medical Therapy: A Pilot Study.
  Life (Basel)

  2022 Aug;12(9):. doi: 1322.
  
  Maloberti Alessandro, Sun Jinwei, Zannoni Jessica, Occhi Lucia, Bassi Ilaria, Fabbri Saverio, Colombo Valentina, Gualini Elena, Algeri Michela, Varrenti Marisa, Masciocco Gabriella, Perna Enrico, Oliva Fabrizio, Cipriani Manlio, Frigerio Maria, Giannattasio Cristina
  
  Abstract
  
  Endothelial dysfunction (ED) is frequently found in patients with heart failure (HF). Among several pharmacological agents reported to improve endothelial function, levosimendan seems to be a promising one, even though, to date, only two previously published studies have evaluated its effects on ED in these patients. The aim of our pilot study was to further investigate the role of periodic levosimendan infusion on endothelial function in patients affected by advanced HF. In this cross-sectional study, three different groups were enrolled: 20 patients with advanced HF treated with periodic levosimendan (LEVO), 20 patients with HF on optimal medical therapy (OMT), and 20 healthy subjects (control group). ED was evaluated through flow-mediated dilation (FMD) at the level of the brachial artery. The three groups presented similar ages with significant differences in gender distribution, systolic blood pressure, and chronic kidney disease (eGFR < 30 mL/min). In HF patients, ischaemic aetiology was more prevalent in the LEVO group than in the OMT group (60 vs. 40%, < 0.001). The New York Heart Association (NYHA) functional class was worse in the LEVO group, as well as in NT-proBNP (5636.7 ± 6164.6 ng/dL and 1243.7 ± 1487.2 ng/dL, in the LEVO and OMT groups, respectively, = 0.005). The FMD was significantly higher in the healthy control group compared to that of the OMT group (15.7 ± 6.4 vs. 9.1 ± 6.0%, = 0.007) while it showed an intermediate value in LEVO patients (12.4 ± 7.1%) (ANOVA = 0.010). In conclusion, levosimendan therapy seems to ameliorate endothelial dysfunction related to heart failure. Longitudinal studies in patients on periodic therapy are needed in order to confirm the long-term effects of levosimendan on ED.
  
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• Does moderate hyperkalemia influence survival in HF? Insights from the MECKI score data base.
  Int J Cardiol

  2022 Sep;():. doi: S0167-5273(22)01340-7.
  
  Toto Federica, Salvioni Elisabetta, Magrì Damiano, Sciomer Susanna, Piepoli Massimo, Badagliacca Roberto, Galotta Arianna, Baracchini Nikita, Paolillo Stefania, Corrà Ugo, Raimondo Rosa, Lagioia Rocco, Filardi Pasquale Perrone, Iorio Annamaria, Senni Michele, Correale Michele, Cicoira Mariantonietta, Perna Enrico, Metra Marco, Guazzi Marco, Limongelli Giuseppe, Sinagra Gianfranco, Parati Gianfranco, Cattadori Gaia, Bandera Francesco, Bussotti Maurizio, Mapelli Massimo, Cipriani Manlio, Bonomi Alice, Cunha Gonçalo, Re Federica, Vignati Carlo, Garascia Andrea, Lombardi Carlo, Scardovi Angela B, Passantino Andrea, Emdin Michele, Passino Claudio, Santolamazza Caterina, Girola Davide, Zaffalon Denise, Vizza Dario, De Martino Fabiana, Agostoni Piergiuseppe,
  
  Abstract
  
  BACKGROUND:
  The prognostic role of moderate hyperkalemia in reduced ejection fraction (HFrEF) patients is still controversial. Despite this, it affects the use of renin-angiotensin-aldosterone system inhibitors (RAASi) with therapy down-titration or discontinuation.
  
  OBJECTIVES:
  Aim of the study was to assess the prognostic impact of moderate hyperkalemia in chronic HFrEF optimally treated patients.
  
  METHODS AND RESULTS:
  We retrospectively analyzed MECKI (Metabolic Exercise test data combined with Cardiac and Kidney Indexes) database, with median follow-up of 4.2 [IQR 1.9-7.5] years. Data on K levels were available in 7087 cases. Patients with K plasma level ? 5.6 mEq/L and 4 and 
  CONCLUSIONS:
  Moderate hyperkalemia does not influence patients' outcome in a large cohort of ambulatory HFrEF patients.
  
  Copyright © 2022 Elsevier B.V. All rights reserved.
  
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• Revisiting a Prognosticating Algorithm from Cardiopulmonary Exercise Testing in Chronic Heart Failure (from the MECKI Score Population).
  Am J Cardiol

  2022 Oct;180():65-71. doi: 10.1016/j.amjcard.2022.06.034.
  
  Corrà Ugo, Piepoli Massimo Francesco, Giordano Andrea, Doni Francesco, Magini Alessandra, Bonomi Alice, Salvioni Elisabetta, Lagioia Rocco, Limongelli Giuseppe, Paolillo Stefania, Magrì Damiano, Filardi Pasquale Perrone, Sinagra Gianfranco, Scardovi Angela B, Metra Marco, Senni Michele, Scrutinio Domenico, Raimondo Rosa, Emdin Michele, Cattadori Gaia, Parati Gianfranco, Re Federica, Cicoira Mariantonietta, Minà Chiara, Correale Michele, Frigerio Maria, Perna Enrico, Bussotti Maurizio, Battaia Elisa, Guazzi Marco, Bandera Francesco, Badagliacca Roberto, Lenarda Andrea Di, Maggioni Aldo, Passino Claudio, Sciomer Susanna, Pacileo Giuseppe, Mapelli Massimo, Vignati Carlo, Clemenza Francesco, Lombardi Carlo, Agostoni Piergiuseppe,
  
  Abstract
  
  Cardiopulmonary exercise testing is a prognostic tool in heart failure with reduced left ventricular ejection fraction (HFrEF). Prognosticating algorithms have been proposed, but none has been validated. In 2017, a predictive algorithm, based on peak oxygen consumption (VO₂), ventilatory response to exercise (ventilation [VE] carbon dioxide production [VCO2], the VE/VCO₂ slope), exertional oscillatory ventilation (EOV), and peak respiratory exchange ratio, was recommended, according treatment with ? blockers: patients with HFrEF registered in the metabolic exercise test data combined with cardiac and kidney indexes (MECKIs) database were used to validated this algorithm. According to the inclusion/exclusion criteria, 4,683 MECKI patients with HFrEF were enrolled. At 3 years follow-up, the end point was cardiovascular death and urgent heart transplantation (cardiovascular events [CV]). CV events occurred in 25% in patients without ? blockers, whereas those with ?-blockers had 11% (p <0.0001). In patients without ? blockers, 36%, 24%, and 7% CV events were observed in those with peak VO2 ?10, with peak VO2 >10 <18, and with peak VO2 ?18 ml/kg/min (p = 0.0001), respectively; in MECKI patients with peak VO2 ?10 and patients with intermediate exercise capacity, a peak respiratory exchange ratio (?1.15) and VE/VCO₂ slope (?35) were diriment, respectively (p = 0.0001). EOV, when occurred, increased risk. In MECKI patients on ? blockers, 29%, 17%, and 8% CV events were noticed in those with a peak VO2 ?8, with peak VO2 = 8 to 12, and patients with peak VO2 ?12 ml/kg/min, respectively (p = 0.0000); when EOV was monitored an increment of risk was witnessed. In conclusion, the outcome of this algorithm was confirmed with the MECKI cohort.
  
  Copyright © 2022 Elsevier Inc. All rights reserved.
  
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• Pick Your Threshold: A Comparison Among Different Methods of Anaerobic Threshold Evaluation in Heart Failure Prognostic Assessment.
  Chest

  2022 Nov;162(5):1106-1115. doi: 10.1016/j.chest.2022.05.039.
  
  Salvioni Elisabetta, Mapelli Massimo, Bonomi Alice, Magrì Damiano, Piepoli Massimo, Frigerio Maria, Paolillo Stefania, Corrà Ugo, Raimondo Rosa, Lagioia Rocco, Badagliacca Roberto, Filardi Pasquale Perrone, Senni Michele, Correale Michele, Cicoira Mariantonietta, Perna Enrico, Metra Marco, Guazzi Marco, Limongelli Giuseppe, Sinagra Gianfranco, Parati Gianfranco, Cattadori Gaia, Bandera Francesco, Bussotti Maurizio, Re Federica, Vignati Carlo, Lombardi Carlo, Scardovi Angela B, Sciomer Susanna, Passantino Andrea, Emdin Michele, Passino Claudio, Santolamazza Caterina, Girola Davide, Zaffalon Denise, De Martino Fabiana, Agostoni Piergiuseppe,
  
  Abstract
  
  BACKGROUND:
  In clinical practice, anaerobic threshold (AT) is used to guide training and rehabilitation programs, to define risk of major thoracic or abdominal surgery, and to assess prognosis in heart failure (HF). AT of oxygen uptake (V.O; V.OAT) has been reported as an absolute value (V.OATabs), as a percentage of predicted peak V.O (V.OAT%peak_pred), or as a percentage of observed peak V.O (V.OAT%peak_obs). A direct comparison of the prognostic power among these different ways to report AT is missing.
  
  RESEARCH QUESTION:
  What is the prognostic power of these different ways to report AT?
  
  STUDY DESIGN AND METHODS:
  In this observational cohort study, we screened data of 7,746 patients with HF with a history of reduced ejection fraction (
  RESULTS:
  This study considered 6,157 patients with HF with identified AT. Follow-up was median, 4.2 years (25th-75th percentiles, 1.9-5.0 years). Both V.OATabs (mean ± SD, 823 ± 305 mL/min) and V.OAT%peak_pred (mean ± SD, 39.6 ± 13.9%), but not V.OAT%peak_obs (mean ± SD, 69.2 ± 17.7%), well stratified the population regarding prognosis (composite end point: cardiovascular death, urgent heart transplant, or left ventricular assist device). Comparing area under the receiver operating characteristic curve (AUC) values, V.OATabs (0.680) and V.OAT%peak_pred (0.688) performed similarly, whereas V.OAT%peak_obs (0.538) was significantly weaker (P 
  INTERPRETATION:
  In HF, V.OAT%peak_pred is the best way to report V.O at AT in relationship to prognosis, with a prognostic power comparable to that of peak V.O and, remarkably, in patients with severe HF.
  
  Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
  
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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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• Cardiovascular implantable electronic device therapy in patients with left ventricular assist devices: insights from TRAViATA.
  Int J Cardiol

  2021 Oct;340():26-33. doi: 10.1016/j.ijcard.2021.08.033.
  
  Darden Douglas, Ammirati Enrico, Brambatti Michela, Lin Andrew, Hsu Jonathan C, Shah Palak, Perna Enrico, Cikes Maja, Gjesdal Grunde, Potena Luciano, Masetti Marco, Jakus Nina, Van De Heyning Caroline, De Bock Dina, Brugts Jasper J, Russo Claudio F, Veenis Jesse F, Rega Filip, Cipriani Manlio, Frigerio Maria, Liviu Klein, Hong Kimberly N, Adler Eric, Braun Oscar Ö
  
  Abstract
  
  BACKGROUND:
  There is conflicting observational data on the survival benefit cardiac implantable electronic devices (CIED) in patients with LVADs.
  
  METHODS:
  Patients in whom an LVAD was implanted between January 2008 and April 2017 in the multinational Trans-Atlantic Registry on VAD and Transplant (TRAViATA) registry were separated into four groups based on the presence of CIED prior to LVAD implantation: none (n = 146), implantable cardiac defibrillator (ICD) (n = 239), cardiac resynchronization without defibrillator (CRT-P) (n = 28), and CRT with defibrillator (CRT-D) (n = 111).
  
  RESULTS:
  A total of 524 patients (age 52 years ±12, 84.4% male) were followed for 354 (interquartile range: 166-701) days. After multivariable adjustment, there were no differences in survival across the groups. In comparison to no device, only CRT-D was associated with late right ventricular failure (RVF) (hazard ratio 2.85, 95% confidence interval [CI] 1.42-5.72, p = 0.003). There was no difference in risk of early RVF across the groups or risk of ICD shocks between those with ICD and CRT-D.
  
  CONCLUSION:
  In a multinational registry of patients with LVADs, there were no differences in survival with respect to CIED subtype. However, patients with a pre-existing CRT-D had a higher likelihood of late RVF suggesting significant long-term morbidity in those with devices capable of LV?lead pacing post LVAD implantation.
  
  Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.
  
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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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• Outcome of patients on heart transplant list treated with a continuous-flow left ventricular assist device: Insights from the TRans-Atlantic registry on VAd and TrAnsplant (TRAViATA).
  Int J Cardiol

  2021 Feb;324():122-130. doi: 10.1016/j.ijcard.2020.09.026.
  
  Ammirati Enrico, Brambatti Michela, Braun Oscar Ö, Shah Palak, Cipriani Manlio, Bui Quan M, Veenis Jesse, Lee Euyhyun, Xu Ronghui, Hong Kimberly N, Van de Heyning Caroline M, Perna Enrico, Timmermans Philippe, Cikes Maja, Brugts Jasper J, Veronese Giacomo, Minto Jonathan, Smith Saige, Gjesdal Grunde, Gernhofer Yan K, Partida Cynthia, Potena Luciano, Masetti Marco, Boschi Silvia, Loforte Antonio, Jakus Nina, Milicic Davor, Nilsson Johan, De Bock Dina, Sterken Caroline, Van den Bossche Klaartje, Rega Filip, Tran Hao, Singh Ramesh, Montomoli Jonathan, Mondino Michele, Greenberg Barry, Russo Claudio F, Pretorius Victor, Liviu Klein, Frigerio Maria, Adler Eric D
  
  Abstract
  
  BACKGROUND:
  Geographic variations in management and outcomes of individuals supported by continuous-flow left ventricular assist devices (CF-LVAD) between the United States (US) and Europe (EU) is largely unknown.
  
  METHODS:
  We created a retrospective, multinational registry of 524 patients who received a CF-LVAD (either HVAD or Heartmate II) between January 2008 and April 2017. Follow up spanned from date of CF-LVAD implant to post-HTx period with a median follow up of 44.8 months.
  
  RESULTS:
  The cohort included 299 (57.1%) EU and 225 (42.9%) US patients. Although the US cohort was significantly older with a higher prevalence of comorbidities, survival was similar between the cohorts (US 63.1%, EU 68.4% at 5 years, unadjusted log-rank test p = 0.43).Multivariate analyses suggested that older age, higher body mass index, elevated creatinine, use of temporary mechanical circulatory support prior CF-LVAD, and implantation of HVAD were associated with increased mortality. Among CF-LVAD patients undergoing HTx, the median time on CF-LVAD support was shorter in the US, meanwhile US donors were younger. Finally, the pattern of adverse events (stroke, gastrointestinal bleedings, late right ventricular failure, and driveline infection) during support differed significantly between US and EU.
  
  CONCLUSIONS:
  Although waitlisted patients in the US on CF-LVAD have higher risk comorbid conditions, the overall outcome is similar in US and EU. Geographic variations with regards to donor characteristics, duration of CF-LVAD support prior to transplant, and adverse events on support can explain the disparity in the utilization of mechanical bridge to transplant strategy between US and EU.
  
  Copyright © 2020 Elsevier B.V. All rights reserved.
  
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• Long-term prognostic role of diabetes mellitus and glycemic control in heart failure patients with reduced ejection fraction: Insights from the MECKI Score database.
  Int J Cardiol

  2020 Oct;317():103-110. doi: 10.1016/j.ijcard.2020.04.079.
  
  Paolillo Stefania, Salvioni Elisabetta, Perrone Filardi Pasquale, Bonomi Alice, Sinagra Gianfranco, Gentile Piero, Gargiulo Paola, Scoccia Alessandra, Cosentino Nicola, Gugliandolo Paola, Badagliacca Roberto, Lagioia Rocco, Correale Michele, Frigerio Maria, Perna Enrico, Piepoli Massimo, Re Federica, Raimondo Rosa, Minà Chiara, Clemenza Francesco, Bussotti Maurizio, Limongelli Giuseppe, Gravino Rita, Passantino Andrea, Magrì Damiano, Parati Gianfranco, Caravita Sergio, Scardovi Angela B, Arcari Luca, Vignati Carlo, Mapelli Massimo, Cattadori Gaia, Cavaliere Carlo, Corrà Ugo, Agostoni Piergiuseppe,
  
  Abstract
  
  BACKGROUND:
  The prognostic role of diabetes mellitus (DM) in heart failure (HF) patients is undefined, since DM is outweighed by several DM-related variables when confounders are considered. We determined the prognostic role of DM, treatment, and glycemic control in a real-life HF population.
  
  METHODS:
  3927 HF patients included in the Metabolic Exercise Cardiac Kidney Index (MECKI) score database were evaluated with a median follow-up of 3.66 years (IQR 1.70-6.67). Data analysis considered survival between DM (n = 897) vs. non-DM (n = 3030) patients, and, in diabetics, between insulin (n = 304), oral antidiabetics (n = 479), and dietary only (n = 88) treatments. The role of glycemic control was evaluated grouping DM patients according to glycated hemoglobin (HbA1c): 8% (n = 149). All analyses were performed also adjusting for ejection fraction, renal function, hemoglobin, sodium, exercise peak oxygen uptake, and ventilation/carbon dioxide relationship slope. Study primary endpoint was the composite of cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation. Secondary endpoints were cardiovascular and all causes death.
  
  RESULTS:
  For all endpoints, upon adjustment for confounders, DM status and insulin treatment or dietary regimen were not significantly associated with adverse long-term prognosis compared to non-DM and oral antidiabetic treated patients, respectively. A worse prognosis was observed in HbA1c >8% patients (Log-Rank p 
  CONCLUSION:
  In HF patients, DM, insulin treatment and dietary regimen are not adverse outcome predictors. The only condition related to long-term prognosis, considering potential confounders, is poor glycemic control.
  
  Copyright © 2020 Elsevier B.V. All rights reserved.
  
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• Exercise oscillatory ventilation and prognosis in heart failure patients with reduced and mid-range ejection fraction.
  Eur J Heart Fail

  2019 Dec;21(12):1586-1595. doi: 10.1002/ejhf.1595.
  
  Rovai Sara, Corrà Ugo, Piepoli Massimo, Vignati Carlo, Salvioni Elisabetta, Bonomi Alice, Mattavelli Irene, Arcari Luca, Scardovi Angela B, Perrone Filardi Pasquale, Lagioia Rocco, Paolillo Stefania, Magrì Damiano, Limongelli Giuseppe, Metra Marco, Senni Michele, Scrutinio Domenico, Raimondo Rosa, Emdin Michele, Lombardi Carlo, Cattadori Gaia, Parati Gianfranco, Re Federica, Cicoira Mariantonietta, Villani Giovanni Q, Minà Chiara, Correale Michele, Frigerio Maria, Perna Enrico, Mapelli Massimo, Magini Alessandra, Clemenza Francesco, Bussotti Maurizio, Battaia Elisa, Guazzi Marco, Bandera Francesco, Badagliacca Roberto, Di Lenarda Andrea, Pacileo Giuseppe, Maggioni Aldo, Passino Claudio, Sciomer Susanna, Sinagra Gianfranco, Agostoni Piergiuseppe,
  
  Abstract
  
  AIMS:
  Exercise oscillatory ventilation (EOV) is a pivotal cardiopulmonary exercise test parameter for the prognostic evaluation of patients with chronic heart failure (HF). It has been described in patients with HF with reduced ejection fraction (50%, HFpEF), but no data are available for patients with HF with mid-range ejection fraction (40-49%, HFmrEF). The aim of the study was to evaluate the prognostic role of EOV in HFmrEF patients.
  
  METHODS AND RESULTS:
  We analysed 1239 patients with HFmrEF and 4482 patients with HFrEF, enrolled in the MECKI score database, with a 2-year follow-up. The study endpoint was the composite of cardiovascular death, urgent heart transplant, and ventricular assist device implantation. We identified EOV in 968 cases (16% and 17% of cases in HFmrEF and HFrEF, respectively). HFrEF EOV+ patients were significantly older, and their parameters suggested a more severe HF than HFrEF EOV- patients. A similar behaviour was found in HFmrEF EOV+ vs. EOV- patients. Kaplan-Meier analysis, irrespective of ejection fraction, showed that EOV is associated with a worse survival, and that patients with HFrEF and HFmrEF EOV+ had a significantly worse outcome than the EOV- of the same ejection fraction groups. EOV-associated survival differences in HFmrEF patients started after 18?months of follow-up.
  
  CONCLUSION:
  Exercise oscillatory ventilation has a similar prevalence and ominous prognostic value in both HFmrEF and HFrEF patients, indicating a group of patients in need of a more intensive follow-up and a more aggressive therapy. In HFmrEF, the survival curves between EOV+ and EOV- patients diverged only after 18?months.
  
  © 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.
  
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• Psychological outcomes of left ventricular assist device long-term treatment: A 2-year follow-up study.
  Artif Organs

  2020 Jan;44(1):67-71. doi: 10.1111/aor.13531.
  
  Voltolini Alessandra, Salvato Gerardo, Frigerio Maria, Cipriani Manlio, Perna Enrico, Pisu Mirella, Mazza Umberto
  
  Abstract
  
  Left ventricular assist device (LVAD) is an effective therapy for patients with advanced or refractory heart failure. It may represent a temporary treatment in heart transplant (HTX) candidates (Bridge-To-Transplant-BTT), or a permanent therapy for patients unsuitable for HTX (Destination Therapy-DT). Living with the device may be stressful for both the patients and their caregivers. Currently, evidence on the psychological assessment of LVAD recipients, and factors influencing the patients' psychological adaptation to the device in the long-term period is limited. Here, we explored the quality of life in 20 patients who were treated with LVAD with BTT (n = 13) or DT indication (n = 7) before (T0), 1 year (T1) and 2 years (T2) after implantation, using the EuroQoL-5D-5L test. We also analyzed the influence of sociodemographic (eg, age, gender) and clinical variables (eg, the INTERMACS level and number of hospital admissions) on the quality of life at T2. We found a significant improvement in the self-perceived quality of life 2 years after LVAD implantation. Patients significantly improved in the domains of physical activity and anxiety and depression symptoms. Interestingly, we also demonstrated that the treatment indication was related to changes in self-assessed quality of life, which improved over time in patients implanted with DT indication, whereas it decreased from T1 to T2 in patients with BTT indication. Taken together, these findings suggest that LVAD-related emotional distress and coping strategies need to be carefully evaluated before and in the long-term after LVAD implantation.
  
  © 2019 International Center for Artificial Organ and Transplantation and Wiley Periodicals, Inc.
  
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• Safety of centrifugal left ventricular assist device in patients previously treated with MitraClip system.
  Int J Cardiol

  2019 May;283():131-133. doi: 10.1016/j.ijcard.2019.02.039.
  
  Ammirati Enrico, Van De Heyning Caroline M, Musca Francesco, Brambatti Michela, Perna Enrico, Cipriani Manlio, Cannata Aldo, Mondino Michele, Moreo Antonella, De Bock Dina, Pretorius Victor, Claeys Marc J, Adler Eric D, Russo Claudio F, Frigerio Maria
  
  Abstract
  
  INTRODUCTION:
  No data regarding the safety of continuous-flow left ventricular assist device (CF-LVAD) implantation in patients with previous MitraClip have been reported. Thus, it remains unknown whether an initial treatment strategy with MitraClip therapy might complicate future heart failure management in patients who are also considered for CF-LVAD.
  
  METHODS:
  We retrospectively identified 6 patients (median age of 62?years; 2 women) who had been treated with MitraClip, that were eventually implanted with a CF-LVAD (all Heartware HVAD) in 3 hospitals between 2013 and 2018.
  
  RESULTS:
  Patients were treated in 4 cases with 2 clips, and in 2 cases with 1 clip. Median time from MitraClip implantation to CF-LVAD implant was 282?days (interquartile range 67 to 493), and median time on CF-LVAD support was 401?days (interquartile range 105 to 492?days). Two patients underwent a heart transplant, 3 patients died on support, and 1 is alive on support. In all cases, there was a reduction of functional mitral regurgitation without MitraClip-related complications.
  
  CONCLUSIONS:
  Based on this small case series, implantation of a CF-LVAD appears safe in patients with a previously positioned MitraClip system, at least, with 1 or 2 clips in place, with no need for additional mitral valve surgery.
  
  Copyright © 2019 Elsevier B.V. All rights reserved.
  
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• Antithrombotic therapy in ventricular assist device (VAD) management: From ancient beliefs to updated evidence. A narrative review.
  Int J Cardiol Heart Vasc

  2018 Sep;20():20-26. doi: 10.1016/j.ijcha.2018.06.005.
  
  Morici Nuccia, Varrenti Marisa, Brunelli Dario, Perna Enrico, Cipriani Manlio, Ammirati Enrico, Frigerio Maria, Cattaneo Marco, Oliva Fabrizio
  
  Abstract
  
  Platelets play a key role in the pathogenesis of ventricular assist device (VAD) thrombosis; therefore, antiplatelet drugs are essential, both in the acute phase and in the long-term follow-up in VAD management. Aspirin is the most used agent and still remains the first-choice drug for lifelong administration after VAD implantation. Anticoagulant drugs are usually recommended, but with a wide range of efficacy targets. Dual antiplatelet therapy, targeting more than one pathway of platelet activation, has been used for patients developing a thrombotic event, despite an increased risk of bleeding complications. Although different strategies have been attempted, bleeding and thrombotic events remain frequent and there are no uniform strategies adopted for pharmacological management in the short and mid- or long-term follow up. The aim of this article is to provide an overview of the evidence from randomized clinical trials and observational studies with a focus on the pathophysiologic mechanisms underlying bleeding and thrombosis in VAD patients and the best antithrombotic regimens available.
  
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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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• Dose-dependent efficacy of ?-blocker in patients with chronic heart failure and atrial fibrillation.
  Int J Cardiol

  2018 Dec;273():141-146. doi: 10.1016/j.ijcard.2018.08.012.
  
  Campodonico Jeness, Piepoli Massimo, Clemenza Francesco, Bonomi Alice, Paolillo Stefania, Salvioni Elisabetta, Corrà Ugo, Binno Simone, Veglia Fabrizio, Lagioia Rocco, Sinagra Gianfranco, Cattadori Gaia, Scardovi Angela B, Metra Marco, Senni Michele, Scrutinio Domenico, Raimondo Rosa, Emdin Michele, Magrì Damiano, Parati Gianfranco, Re Federica, Cicoira Mariantonietta, Minà Chiara, Limongelli Giuseppe, Correale Michele, Frigerio Maria, Bussotti Maurizio, Perna Enrico, Battaia Elisa, Guazzi Marco, Badagliacca Roberto, Di Lenarda Andrea, Maggioni Aldo, Passino Claudio, Sciomer Susanna, Pacileo Giuseppe, Mapelli Massimo, Vignati Carlo, Lombardi Carlo, Filardi Pasquale Perrone, Agostoni Piergiuseppe,
  
  Abstract
  
  BACKGROUND:
  The usefulness of ?-blockers in heart failure (HF) patients with permanent atrial fibrillation (AF) has been questioned.
  
  METHODS AND RESULTS:
  We analyzed data from HF patients (958 patients (801 males, 84%, age 67?±?11?years)) with AF enrolled in the MECKI score database. We evaluated prognosis (composite of cardiovascular death, urgent heart transplant, or left ventricular assist device) of patients receiving ?-blockers (n?=?777, 81%) vs. those not treated with ?-blockers (n?=?181, 19%). We also analyzed the role ?1-selectivity and the role of daily ?-blocker dose. To account for different HF severity, Kaplan-Meier survival curves were normalized for relevant confounding factors and for treatment strategies. Dose was available in 629 patients. Median follow-up was 1312 (577-2304) days in the entire population, 1203 (614-2420) and 1325 (569-2300) days in patients not receiving and receiving ?-blockers. 224 (23%, 54/1000?events/year), 163 (21%, 79/1000?events/year), and 61 (34%, 49/1000?events/year) events were recorded, respectively. At 10-year patients treated with ?-blockers had a better outcome (HR 0.447, p?0.01) with no effects as regards ?1selective drugs (53%) vs. ?1-?2 blockers (47%). Survival improved in parallel with ?-blocker dose increase (HR 0.296, 0.496, 0.490 for the high, medium, and low dose vs. no ?-blockers, p?0.0001).
  
  CONCLUSION:
  HF patients with AF taking a ?-blocker have a better outcome (with a survival improvement in parallel with daily dose but no differences as regards ?1 selectivity) but this does not mean that ?-blockers improve outcomes in these patients as we cannot control for all the potential confounders associated with ?-blocker use.
  
  Copyright © 2018. Published by Elsevier B.V.
  
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• Single-center outbreak of Pneumocystis jirovecii pneumonia in heart transplant recipients.
  Transpl Infect Dis

  2018 Jun;20(3):e12880. doi: 10.1111/tid.12880.
  
  Veronese Giacomo, Ammirati Enrico, Moioli Maria Cristina, Baldan Rossella, Orcese Carlo Andrea, De Rezende Gisele, Veronese Silvio, Masciocco Gabriella, Perna Enrico, Travi Giovanna, Puoti Massimo, Cipriani Manlio, Tiberi Simon, Cirillo Daniela, Frigerio Maria
  
  Abstract
  
  BACKGROUND:
  Pneumocystis jirovecii pneumonia (PJP) outbreaks are described in solid organ transplant recipients. Few reports suggest interhuman transmission with important infection control implications. We described a large PJP outbreak in heart transplant (HTx) recipients.
  
  METHODS:
  Six cases of PJP occurred in HTx recipients within 10 months in our hospital. Demographics, clinical characteristics, treatment and outcomes were described. To identify contacts among individuals a review of all dates of out-patient visits and patient hospitalizations was performed. Cross exposure was also investigated using genotyping on PJ isolates.
  
  RESULTS:
  At the time of PJP-related hospitalization, patients' mean age was 49 ± standard deviation 4 years, median time from HTx was 8 (25%-75% interquartile range [Q1-Q3] 5-12) months and none of the cases were on prophylaxis. At PJP-related admission, 5 patients had CMV reactivation, of whom 4 were on antiviral preemptive treatment. Median in-hospital stay was 30 (Q1-Q3, 28-48) days; and 2 cases required intensive care unit admission. All patients survived beyond 2 years. Transmission map analysis suggested interhuman transmission in all cases (presumed incubation period, median 90 [Q1-Q3, 64-91] days). Genotyping was performed in 4 cases, demonstrating the same PJ strain in 3 cases.
  
  CONCLUSIONS:
  We described a large PJP cluster among HTx recipients, supporting the nosocomial acquisition of PJP through interhuman transmission. Based on this experience, extended prophylaxis for more than 6 months after HTx could be considered in specific settings. Further work is required to understand its optimal duration and timing based on individual risk factor profiles and to define standardized countermeasures to prevent and limit PJP outbreaks.
  
  © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
  
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• End-stage heart failure: Two surgical approaches with different rehabilitative outcomes.
  PLoS One

  2017 ;12(10):e0185717. doi: e0185717.
  
  Racca Vittorio, Castiglioni Paolo, Panzarino Claudia, Oliva Fabrizio, Perna Enrico, Ferratini Maurizio
  
  Abstract
  
  BACKGROUND:
  A rising number of patients are surgically treated for heart failure at the more advanced stage, thanks to the increasing use of left ventricular assist device (LVAD) as a reliable alternative to heart transplantation (HTx). However, it is still unknown whether differences exist between the two surgical approaches in the efficacy of rehabilitation programmes. Therefore, aim of this study was to evaluate whether functional capacity and rehabilitative outcomes differ between HTx and implantation of LVAD.
  
  METHODS AND RESULTS:
  We enrolled 51 patients with HTx and 46 with LVAD upon admission to our rehabilitation-unit. We evaluated six-minute walking test (6MWT), resting oxygen saturation (SaO2) and nutritional assessment before and after a standardised cardiovascular rehabilitation programme. HTx and LVAD groups differed in age, anthropometric variables, gender distribution. Upon enrolment, 6MWT distance was similar in the two groups, whereas malnutrition was less frequent and the waist circumference/height ratio (WHtR) was greater in LVAD patients. SaO2 was greater in HTx patients. Rehabilitation improved SaO2, 6MWT distance and nutritional status. The difference in malnutrition disappeared, but WHtR remained higher in the LVAD and SaO2 higher in the HTx patients; the 6MWT distance improved more in the HTx patients. Multivariate linear regression analysis confirmed that the type of intervention was independent predictor of 6MWT distance after rehabilitation.
  
  CONCLUSIONS:
  HTx patients improve more rapidly and perform better after rehabilitation, suggesting the need for more tailored rehabilitation training for LVAD patients.
  
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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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• Ticagrelor for left ventricular assist device thrombosis: A new therapeutic option to be evaluated with caution.
  Int J Cardiol

  2016 Oct;221():58-9. doi: 10.1016/j.ijcard.2016.06.304.
  
  Morici Nuccia, Perna Enrico, Cipriani Manlio, Femia Eti Alessandra, Oliva Fabrizio, Frigerio Maria, Cattaneo Marco
  
  
  
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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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• Deletion of the activated protein-1 transcription factor JunD induces oxidative stress and accelerates age-related endothelial dysfunction.
  Circulation

  2013 Mar;127(11):1229-40, e1-21. doi: 10.1161/CIRCULATIONAHA.112.000826.
  
  Paneni Francesco, Osto Elena, Costantino Sarah, Mateescu Bogdan, Briand Sylvie, Coppolino Giuseppe, Perna Enrico, Mocharla Pavani, Akhmedov Alexander, Kubant Ruslan, Rohrer Lucia, Malinski Tadeusz, Camici Giovanni G, Matter Christian M, Mechta-Grigoriou Fatima, Volpe Massimo, Lüscher Thomas F, Cosentino Francesco
  
  Abstract
  
  BACKGROUND:
  Reactive oxygen species are major determinants of vascular aging. JunD, a member of the activated protein-1 family of transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to reactive oxygen species homeostasis in the vasculature remains unknown.
  
  METHODS AND RESULTS:
  Endothelium-dependent vasorelaxation was impaired in young and old JunD(-/-) mice (6 and 22 months old) compared with age-matched wild-type mice. JunD(-/-) mice displayed an age-independent decline in endothelial nitric oxide release and endothelial nitric oxide synthase activity and increased mitochondrial superoxide formation and peroxynitrite levels. Furthermore, vascular expression and activity of the free radical scavengers manganese and extracellular superoxide dismutase and aldehyde dehydrogenase 2 were reduced, whereas the NADPH oxidase subunits p47phox, Nox2, and Nox4 were upregulated. These redox changes were associated with premature vascular aging, as shown by reduced telomerase activity, increased ?-galactosidase-positive cells, upregulation of the senescence markers p16(INK4a) and p53, and mitochondrial disruption. Interestingly, old wild-type mice showed a reduction in JunD expression and transcriptional activity resulting from promoter hypermethylation and binding with tumor suppressor menin, respectively. In contrast, JunD overexpression blunted age-induced endothelial dysfunction. In human endothelial cells, JunD knockdown exerted a similar impairment of the O2(-)/nitric oxide balance that was prevented by concomitant NADPH inhibition. In parallel, JunD expression was reduced in monocytes from old versus young healthy subjects and correlated with mRNA levels of scavenging and oxidant enzymes.
  
  CONCLUSIONS:
  JunD provides protection in aging-induced endothelial dysfunction and may represent a novel target to prevent reactive oxygen species-driven vascular aging.
  
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• p66(Shc) protein, oxidative stress, and cardiovascular complications of diabetes: the missing link.
  J Mol Med (Berl)

  2009 Sep;87(9):885-91. doi: 10.1007/s00109-009-0499-3.
  
  Francia Pietro, Cosentino Francesco, Schiavoni Marzia, Huang Yale, Perna Enrico, Camici Giovani G, Lüscher Thomas F, Volpe Massimo
  
  Abstract
  
  Diabetes affects more than 150 million people worldwide, and it is estimated that this would increase to 299 million by the year 2025. The incidence of and mortality from cardiovascular disease are two- to eightfold higher in subjects with diabetes than in those without, coronary artery disease accounting for the large majority of deaths. Among the full spectrum of biochemical effects of high glucose, generation of oxygen-derived free radicals is one of the main pathophysiological mechanisms linking hyperglycemia to atherosclerosis, nephropathy, and cardiomyopathy. The adaptor protein p66(Shc) is implicated in mitochondrial reactive oxygen species (ROS) generation and translation of oxidative signals into apoptosis. Indeed, p66(Shc-/-) mice display prolonged lifespan, reduced production of intracellular oxidants, and increased resistance to oxidative stress-induced apoptosis. Accordingly, a series of studies defined the pathophysiological role of p66(Shc) in cardiovascular disease where ROS represent a substantial triggering component. As p66(Shc) modulates the production of cellular ROS, it represents a proximal node through which high glucose exerts its deleterious effects on different cell types; indeed, several studies tested the hypothesis that deletion of the p66(Shc) gene may confer protection against diabetes-related cardiovascular complications. The present review focuses on the reported evidence linking p66(Shc) signaling pathway to high glucose-associated endothelial dysfunction, atherogenesis, nephropathy, and cardiomyopathy.
  
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