Pubblicazioni - Vallerio Dott.ssa Paola

• Cardiovascular Remodeling after Endovascular Treatment for Thoracic Aortic Injury.
  Ann Vasc Surg

  2019 Nov;61():134-141. doi: S0890-5096(19)30468-6.
  
  Vallerio Paola, Maloberti Alessandro, D'Alessio Ilenia, Lista Alfredo, Varrenti Marisa, Castelnuovo Samuela, Marone Matteo, Piccinelli Enrico, Grassi Guido, Palmieri Bruno, Giannattasio Cristina
  
  Abstract
  
  BACKGROUND:
  Thoracic endovascular aortic repair (TEVAR) currently represents the gold standard of treatment for thoracic aortic injury (TAI). Nevertheless, there is an ongoing debate surrounding its safety and subsequent cardiovascular effects. Our aim is to assess heart and vascular structure and function remodeling after TEVAR in TAI young patients.
  
  METHODS:
  We evaluated 20 patients (18 men, age 41 ± 14 years, 11 treated with Gore CTAG, 9 with Medtronic Valiant) with office and 24-hr blood pressure (BP) with specific vascular stiffness analysis (Mobil-O-Graph), aortic diameters (computed tomography scan) and left ventricular mass index (LVMI echocardiogram). Evaluation was done after a median time of 5.0 ± 3.5 years from the trauma.
  
  RESULTS:
  After TAI 12 patients (55%) developed hypertension. When patients were divided according to treating time, those treated for more than 3 years show higher LVMI, PWV, and ascending aorta dilatation.
  
  CONCLUSIONS:
  Our study shows that TEVAR for TAI is associated with heart and vascular remodeling. The presence of TEVAR modifies aortic functional properties and could induce an increase in BP that can promote aortic and cardiac damage, even in young patients.
  
  Copyright © 2019 Elsevier Inc. All rights reserved.
  
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• Could two-dimensional radial strain be considered as a novel tool to identify pre-clinical hypertrophic cardiomyopathy mutation carriers?
  Int J Cardiovasc Imaging

  2019 Dec;35(12):2167-2175. doi: 10.1007/s10554-019-01668-9.
  
  Santambrogio Gloria Maria, Maloberti Alessandro, Vallerio Paola, Peritore Angelica, Spanò Francesca, Occhi Lucia, Musca Francesco, Belli Oriana, De Chiara Benedetta, Casadei Francesca, Facchetti Rita, Turazza Fabio, Manfredini Emanuela, Giannattasio Cristina, Moreo Antonella
  
  Abstract
  
  Treatment of overt form of hypertrophic cardiomyopathy (HCM) is often unsuccessful. Efforts are focused on a possible early identification in order to prevent or delaying the development of hypertrophy. Our aim was to find an echocardiographic marker able to distinguish mutation carriers without left ventricular hypertrophy (LVH) from healthy subjects. We evaluated 28 patients, members of eight families. Three types of mutation were recognized: MYBPC3 (five families), MYH7 (two families) and TNNT2 (one family). According to genetic (G) and phenotypic (Ph) features, patients were divided in three groups: Group A (10 patients), mutation carriers with LVH (G+/Ph+); Group B (9 patients), mutation carriers without LVH (G+/Ph-); Group C (9 patients), healthy subjects (G-/Ph-). Echocardiography examination was performed acquiring standard 2D, DTI and 2D-strain imaging. Global longitudinal strain (GLS) and global radial strain (GRS) at basal and mid-level were measured. GRS was significantly different between group B and C at basal level (32.18%?±?9.6 vs. 44.59%?±?12.67 respectively; p-value?
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• Pulse wave velocity progression over a medium-term follow-up in hypertensives: Focus on uric acid.
  J Clin Hypertens (Greenwich)

  2019 Jul;21(7):975-983. doi: 10.1111/jch.13603.
  
  Maloberti Alessandro, Rebora Paola, Andreano Anita, Vallerio Paola, De Chiara Benedetta, Signorini Stefano, Casati Marco, Besana Silvia, Bombelli Michele, Grassi Guido, Valsecchi Maria Grazia, Giannattasio Cristina
  
  Abstract
  
  The role of uric acid (UA) on the arterial stiffness progression has been evaluated only in three studies. Our aim was to evaluate its role as a possible determinant of the pulse wave velocity (PWV) progression over a 3.7 ± 0.5 years follow-up period in hypertensive patients. Specific sex analysis was done due to the well-known sex interaction with UA levels. We enrolled 422 consecutive hypertensive outpatients. At baseline anamnestic, blood pressure (BP) and laboratory data as well as PWV were assessed. PWV was performed again at follow-up examination. Hyperuricemia was defined as a UA > 6 mg/dL for women and > 7 mg/dL for men. Baseline age was 53.2 ± 13 years, 58% were males, systolic and diastolic BP (SBP/DBP) 141.7 ± 17.7/86.8 ± 10.8 mm Hg, UA 5.2 ± 1.4 mg/dL, and PWV 8.5 ± 1.9 m/s. At follow-up, despite better BP values (-8.5 ± 24.6 for SBP and -7.5 ± 15.4 for DBP), PWV increases to 9.1 ± 2.3 m/s (P < 0.001) with mean ?PWV of+ 0.5 ± 2.2 m/s. A total of 61 patients were hyperuricemic (14.4%), and they present higher PWV baseline (9.0 ± 2.5 vs 8.5 ± 1.8 m/s, P = 0.03) without significant differences in ?PWV. Hyperuricemic female (6.2%, 11 patients) presents higher baseline PWV without significant differences in ?PWV. No differences were found in arterial stiffness in hyperuricemic males (20.4%, 50 patients). UA showed association with baseline and ?PWV in the whole population but it loses statistical significance at the linear regression model. Same figures were also for sex analysis. Our findings provide evidence that baseline UA levels are not determinants of PWV progression over a median follow-up of 3.8 years' in hypertensive patients.
  
  ©2019 Wiley Periodicals, Inc.
  
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• Vascular Aging and Disease of the Large Vessels: Role of Inflammation.
  High Blood Press Cardiovasc Prev

  2019 Jun;26(3):175-182. doi: 10.1007/s40292-019-00318-4.
  
  Maloberti Alessandro, Vallerio Paola, Triglione Nicola, Occhi Lucia, Panzeri Francesco, Bassi Ilaria, Pansera Francesco, Piccinelli Enrico, Peretti Alessio, Garatti Laura, Palazzini Matteo, Sun Jinwei, Grasso Enzo, Giannattasio Cristina
  
  Abstract
  
  Structural and functional arterial properties commonly impair with aging process. These effects on vasculature could act at many levels from microcirculation to large vessels. Above normal aging process classic cardio-vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, etc.) accelerate the physiological process leading to premature structural and functional alterations that has also been termed early vascular aging. Target organ damage evaluation could be clinically important since these alterations precede by many years' cardiovascular events and so their assessment can predict the onset of more serious and costly events giving the opportunity to prevent CV events by earlier therapeutic intervention. This review will focus on large artery functional properties and particularly on the role of inflammation on the aortic stiffening process.
  
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• Cardio-oncology organization patterns in Italy: one size does not fit all.
  J Cardiovasc Med (Hagerstown)

  2018 May;19(5):229-233. doi: 10.2459/JCM.0000000000000642.
  
  Canale Maria Laura, Lestuzzi Chiara, Bisceglia Irma, Vallerio Paola, Parrini Iris,
  
  Abstract
  
  AIMS:
  Cardio-oncology is imposing as the specialty deputed to the management of a large and rapidly increasing population of cancer patients receiving anticancer treatments with cardiovascular side effects or presenting with cardiac and oncological comorbidities. Organization patterns dramatically vary across Italy.
  
  METHODS:
  On the behalf of ANMCO, we have analyzed the characteristics of cardio-oncology services across different hospital types in Italy. A questionnaire was sent out to all ANMCO divisions inquiring about inner organization, workload, multidisciplinary team and inter-hospital connections.
  
  RESULTS:
  Ninety-eight centers sent back the questionnaire. We summarize different paths into four reference assistance models (sizes XL, L, M and S) according to hospital characteristics, cardio-oncology population size, specialists availability, local facilities and the hospital-surrounding network. We define sizes of the proposed pathways highlighting the need to tailor the model in each single situation.
  
  CONCLUSION:
  No single cardio-oncology organization model can be applied to all hospitals. Each center could select the size/model that best fits its organization. Multidisciplinarity and networking play a crucial role.
  
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• Determinants of carotid-femoral pulse wave velocity progression in hypertensive patients over a 3.7 years follow-up.
  Blood Press

  2018 02;27(1):32-40. doi: 10.1080/08037051.2017.1378069.
  
  Meani Paolo, Maloberti Alessandro, Sormani Paola, Colombo Giulia, Giupponi Luca, Stucchi Miriam, Varrenti Marisa, Vallerio Paola, Facchetti Rita, Grassi Guido, Mancia Giuseppe, Giannattasio Cristina
  
  Abstract
  
  OBJECTIVE:
  The role of risk factors on the progression of arterial stiffness has not yet been extensively evaluated. The aim of the current longitudinal study was to evaluate the determinants of the PWV progression over a 4 years follow-up period in hypertensive subjects.
  
  MATERIALS AND METHODS:
  We enrolled 333 consecutive hypertensive outpatients 18-80 aged, followed by the Hypertension Unit of St. Gerardo Hospital (Monza, Italy). At baseline anamnestic, clinical, BP, laboratory data and cfPWV were assessed. We performed a PWV follow-up examination with a median time amounting to 3.75?±?0.53 years.
  
  RESULTS:
  At baseline the mean age was 54.5?±?12.6 years, SBP and DBP were 141.3?±?18.6 and 86.4?±?10.4?mmHg and PWV was 8.56?±?1.92 m/s. Despite an improvement in BP control (from 37 to 60%), at follow-up the population showed a PWV increase (?PWV 0.87?±?3.05 m/s). PWV and ?PWV gradually increased in age decades. In patients with uncontrolled BP values at follow-up ?PWV showed a greater increase as compared to patients with controlled BP (1.46?±?3.67 vs 0.62?±?2.61 m/s, p?
  CONCLUSIONS:
  the accelerated arterial aging in treated hypertensive subjects is in large measure explained by age and BP values. PWV changes over time would probably give important information that need further future research studies.
  
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• Perfusion CT Changes in Liver Metastases from Pancreatic Neuroendocrine Tumors During Everolimus Treatment.
  Anticancer Res

  2017 03;37(3):1305-1311.
  
  D'Onofrio Mirko, Cingarlini Sara, Ortolani Silvia, Crosara Stefano, DE Robertis Riccardo, Vallerio Paola, Grego Elisabetta, Ciaravino Valentina, Ruzzenente Andrea, Landoni Luca, Scarpa Aldo, Bassi Claudio, Tortora Giampaolo
  
  Abstract
  
  AIM:
  To evaluate modifications of perfusional parameters assessed by perfusion computed tomography (P-CT) of liver metastases (LM) from pancreatic neuroendocrine tumors (PanNETs) during everolimus treatment.
  
  PATIENTS AND METHODS:
  All patients with LMs from G1-2 PanNETs undergoing everolimus treatment between January 2013 and January 2015 were prospectively evaluated with P-CT at baseline, and after 2 and 4 months of therapy. Size, perfusion, blood volume (BV), peak enhancement intensity (PEI) and time to peak for each lesion were calculated.
  
  RESULTS:
  A total of 33 LMs in nine patients with G1-2 PanNETs were prospectively evaluated: 23/33 (69.7%) were responders, 10/33 (30.3%) were non-responders. Among perfusional parameters, only numerical peak enhancement intensity values significantly differed between the two groups at baseline (p=0.043). BV increase was the most significant perfusional modification identifying responding lesions, even at an early stage of treatment, with a high positive predictive value (89.47%).
  
  CONCLUSION:
  P-CT seems to be useful for prediction of response to everolimus of LMs from PanNETs.
  
  Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
  
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• Arterial Stiffness in Aortic Stenosis: Relationship with Severity and Echocardiographic Procedures Response.
  High Blood Press Cardiovasc Prev

  2017 Mar;24(1):19-27. doi: 10.1007/s40292-016-0176-x.
  
  Bruschi Giuseppe, Maloberti Alessandro, Sormani Paola, Colombo Giulia, Nava Stefano, Vallerio Paola, Casadei Francesca, Bruno Jolie, Moreo Antonella, Merlanti Bruno, Russo Claudio, Oliva Fabrizio, Klugmann Silvio, Giannattasio Cristina
  
  Abstract
  
  INTRODUCTION:
  Aortic stenosis (AS) is more than only a degenerative disease, it could be also an atherosclerotic-like process involving the valve instead of the vessels. Little is known about the relation of arterial stiffness and AS.
  
  AIM:
  We sought to determine wether pulse wave velocity (PWV), is related to AS severity and to the procedures response, both as surgical aortic-valve-replacement (AVR) and trascatheter-aortic-valve-implantation (TAVI).
  
  METHODS:
  30 patients with severe AS were treated (15 AVR, 15 TAVI). Before the procedures (t0) and after 1 week (t1) echocardiography and PWV were evaluated.
  
  RESULTS:
  On the whole population, subjects with higher PWV showed higher transvalvular pressure gradient at baseline (mean: 56.5 ± 15.1 vs 45.4 ± 9.5; peak: 93.3 ± 26.4 vs 73.3 ± 14.9, p = 0.02) and, a significantly greater response to the procedures (mean: -42.9 ± 17.2 vs -27.9 ± 10.1, peak: -68.7 ± 29.2 vs -42.8 ± 16.4, p = 0.02). When the two different procedures groups were separated, data were confirmed only in the TAVI subgroup.
  
  CONCLUSIONS:
  In patients undergoing procedures for AS, PWV is correlated with transvalvular gradient and, in TAVI subjects, is able to predict the echocardiographic response. Baseline evaluation of PWV in patients candidates to TAVI can help the selection of subjects, even if larger and longer studies are needed before definitive conclusion can be drawn.
  
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• Antiplatelet and Anticoagulation Treatment in Patients with Thrombocytopenia.
  Curr Pharm Des

  2017 ;23(9):1354-1365. doi: 10.2174/1381612822666161205113119.
  
  Morici Nuccia, Cantoni Silvia, Vallerio Paola, Cattaneo Marco, Savonitto Stefano
  
  Abstract
  
  Thrombocytopenia (TP) is a common finding in patients hospitalized for cardiovascular causes and needing antiplatelet and anticoagulant therapies. However, TP is not only a numeric parameter, but mostly a dynamic condition affected by the patients' underlying disorders and concomitant treatments. Platelets are important players in the hemostatic process, taking part to both primary and secondary hemostasis. Although both TP and antithrombotic treatment contribute to the risk of bleeding, the complexity of the pathogenesis of bleeding events makes it difficult to predict them accurately simply based on these two parameters. It should be considered that, under certain clinical conditions, TP may be associated with an increased risk of thrombosis. In order to manage antithrombotic therapies in patients with TP, the frail balance between bleeding and thrombotic complications needs to be estimated. A joint hematological and cardiological evaluation is mandatory in order to avoid stopping an otherwise lifesaving treatment and to decrease the individual patient risk for both thrombotic and/or bleeding events, in each different setting. The purpose of this review is to describe an operative work flow aimed at helping clinicians to face this challenging issue.
  
  Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
  
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• Role of Combined 68Ga-DOTATOC and 18F-FDG Positron Emission Tomography/Computed Tomography in the Diagnostic Workup of Pancreas Neuroendocrine Tumors: Implications for Managing Surgical Decisions.
  Pancreas

  2017 01;46(1):42-47.
  
  Cingarlini Sara, Ortolani Silvia, Salgarello Matteo, Butturini Giovanni, Malpaga Anna, Malfatti Veronica, D?Onofrio Mirko, Davì Maria Vittoria, Vallerio Paola, Ruzzenente Andrea, Capelli Paola, Citton Elia, Grego Elisabetta, Trentin Chiara, De Robertis Riccardo, Scarpa Aldo, Bassi Claudio, Tortora Giampaolo
  
  Abstract
  
  OBJECTIVES:
  Ga-DOTATOC (Ga) positron emission tomography (PET)/computed tomography (CT) is recommended in the workup of pancreas neuroendocrine tumors (PanNETs); evidence suggests that F-FDG (F) PET/CT can also provide prognostic information. Aims of this study were to assess the role of combined Ga- and F-PET/CT in the evaluation of grade (G) 1-2 PanNETs and to test the correlation between F-PET/CT positivity and tumor grade.
  
  METHODS:
  Preoperative Ga- and F-PET/CT of 35 patients with surgically resected G1-2 PanNETs were evaluated. For grading, the 2010 World Health Organization Classification was used; an ancillary analysis with Ki67 cutoffs at 5% to 20% was conducted. Correlation between F-PET/CT positivity (SUVmax > 3.5) and grade was assessed.
  
  RESULTS:
  Of 35 PanNETs, 28.6% and 71.4% were G1 and G2 as per World Health Organization. Ga-PET/CT showed high sensitivity (94.3%) in detecting G1-2 PanNETs. F-PET/CT was positive in 20% and 76% G1 and G2 tumors (P = 0.002). F-PET/CT identified G2 PanNETs with high positive predictive value (PPV, 90.5%). F-PET/CT correlated with tumor grade also in the ancillary analysis (P = 0.009).
  
  CONCLUSIONS:
  The high sensitivity of Ga-PET/CT in NET detection is known. The high PPV of F-PET/CT in the identification of G2 forms suggests its potential role in PanNETs prognostication and risk stratification.
  
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• Annexin A5 in treated hypertensive patients and its association with target organ damage.
  J Hypertens

  2017 01;35(1):154-161.
  
  Maloberti Alessandro, Meani Paolo, Vallerio Paola, Varrenti Marisa, Casadei Francesca, Musca Francesco, Facchetti Rita, Di Blasio Anna M, Ravassa Susanna, Mancia Giuseppe, Giannattasio Cristina
  
  Abstract
  
  OBJECTIVE:
  Annexin A5 (AnxA5) has been previously linked to the presence of carotid and cardiac target organ damage (TOD) in the context of heart failure and rheumatologic patients. However, information is scant in the context of hypertension. Aim of our study was to evaluate AnxA5 in treated hypertension patients compared with normotensive controls and to determine whether it is associated with vascular and heart TOD evaluated as arterial stiffness, carotid plaque and left ventricular hypertrophy.
  
  METHODS:
  We enrolled 123 consecutive treated hypertension and 124 normotensive controls. TOD was evaluated as pulse wave velocity (PWV, complior), left ventricular hypertrophy (echocardiography) and intima-media thickness and carotid plaque presence (ecographic methods). AnxA5 levels was dosed and compared in patients with and without hypertension and with and without TOD.
  
  RESULTS:
  With similar age hypertension patients showed higher SBP, DBP and AnxA5 levels (13.9?±?11.1 vs 10.1?±?8.4?ng/ml, P?
  CONCLUSION:
  Our data have shown that AnxA5 levels are increased in treated hypertension patients. In this condition, it is probably released in the plasma as a defensive mechanism through its anti-inflammatory and anticoagulants effects. We found a significant association with arterial stiffness, but AnxA5 was not found to be a significant predictor of TOD.
  
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• Nrf2 expression is increased in peripheral blood mononuclear cells derived from mild-moderate ex-smoker COPD patients with persistent oxidative stress.
  Int J Chron Obstruct Pulmon Dis

  2016 ;11():1733-43. doi: 10.2147/COPD.S102218.
  
  Fratta Pasini Anna Maria, Ferrari Marcello, Stranieri Chiara, Vallerio Paola, Mozzini Chiara, Garbin Ulisse, Zambon Giorgia, Cominacini Luciano
  
  Abstract
  
  Inadequacy of antioxidant nuclear factor-E2-related factor 2 (Nrf2) and endoplasmic reticulum stress-mediated unfolded protein response has been implicated in severe chronic obstructive pulmonary disease (COPD) and cigarette smoking-induced emphysema. As evidence suggests that the ability to upregulate Nrf2 expression may influence the progression of COPD and no data exist up to now in ex-smokers with mild-moderate COPD, this study was first aimed to evaluate Nrf2 and unfolded protein response expression in peripheral blood mononuclear cells (PBMC) of mild-moderate ex-smokers with COPD compared to smoking habit-matched non-COPD subjects. Then, we tested whether oxidative stress persists after cigarette smoking cessation and whether the concentrations of oxidized phospholipids (oxidation products of the phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine [oxPAPC]) in the PBMC of the same subjects may have a causative role in determining the upregulation of Nrf2. The expression (mRNA and protein) of Nrf2 and of its related gene heme oxygenase-1 was significantly increased in COPD group without differences in the unfolded protein response. Plasma malondialdehyde, the circulating marker of oxidative stress, and oxPAPC in PBMC were significantly higher in COPD than in non-COPD subjects. The fact that the expression of p47phox, a subunit of NADPH oxidase, was increased in PBMC of COPD patients and that it was directly correlated with oxPAPC may indicate that oxPAPC may be one of the determinants of oxidative stress-induced Nrf2 upregulation. Finally, we also demonstrated that lung function inversely correlated with plasma malondialdehyde and with Nrf2 and heme oxygenase-1 mRNA expression in all subjects. Our results indicate that mild-moderate ex-smokers with COPD may be able to counteract oxidative stress by increasing the expression of Nrf2/antioxidant-response elements. Because Nrf2 failure significantly contributes to the development of COPD, our findings suggest that the possibility to prevent Nrf2 reduction may open a new scenario in helping to prevent the oxidative stress-associated lung function decline.
  
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• Long-Term Effects of Radiotherapy on Arterial Stiffness in Breast Cancer Women.
  Am J Cardiol

  2016 09;118(5):771-6. doi: 10.1016/j.amjcard.2016.06.001.
  
  Vallerio Paola, Sarno Laura, Stucchi Miriam, Musca Francesco, Casadei Francesca, Maloberti Alessandro, Lestuzzi Chiara, Mancia Giuseppe, Moreo Antonella, Palazzi Mauro, Giannattasio Cristina
  
  Abstract
  
  Radiotherapy for breast cancer may expose heart and vessels to late radiation-induced complications. Although recent technical progress in radiation therapy (RT) has been associated with drastic reduction in cardiovascular (CV) mortality, the prolonged life expectancy of patients with cancer requires CV evaluation for many years. The aim of our study was to evaluate local changes in vascular and cardiac function because of previous breast RT. We enrolled 43 patients treated with RT 15 years ago for breast cancer. CV risk factors and atherosclerotic carotid damage were investigated in all women. We divided patients into 2 groups: R (n = 25) treated to right breast and L (n = 18) to left breast. All subjects were submitted to standard echocardiography and functional arteries evaluation by carotid-radial pulse-wave velocity (crPWV; Complior) and AIx (Sphygmocor; Atcor Medical). Global mean age was 69.5 ± 8 years old. CV risk factors were equally allocated in 2 groups. No patients had history of cardiac or artery disease. R had a significantly increased crPWV (9.9 ± 1.4 vs 8.9 ± 1.1, p = 0.001) on right arm compared with left arm, and in L group, crPWV was similarly higher on the left arm than on right arm (9.6 ± 1.5 vs 8.9 ± 1.4, p = 0.011). AIx was significantly increased in the ipsilateral arm only in L (32.1 ± 7.6 vs 28.3 ± 6.8, p = 0.05). Central blood pressure estimation was not different in the right and left arms. No correlations were found with hormone therapy or chemotherapy. Our data show a local arterial stiffening because of radiation that can be involved in increased CV risk in breast cancer-treated patients.
  
  Copyright © 2016 Elsevier Inc. All rights reserved.
  
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• Acute coronary syndrome: a rare case of multiple endocrine neoplasia syndromes with pheochromocytoma and medullary thyroid carcinoma.
  Cancer Biol Med

  2015 Sep;12(3):255-8. doi: 10.7497/j.issn.2095-3941.2015.0016.
  
  Maloberti Alessadro, Meani Paolo, Pirola Roberto, Varrenti Marisa, Boniardi Marco, De Biase Anna Maria, Vallerio Paola, Bonacina Edgardo, Mancia Giuseppe, Loli Paola, Giannattasio Cristina
  
  Abstract
  
  Pheochromocytoma is a tumor arising from neuroectodermal chromaffin tissues in the adrenal gland or extra-adrenal paraganglia (paragangliomas). The prevalence of the tumor is 0.1%-0.6% in the hypertensive population, of which 10%-20% are malignant. Pheochromocytoma produces, stores, and secretes catecholamines, as well as leads to hypertensive crisis, arrhythmia, angina, and acute myocardial infarction without coronary artery diseases. We report a case of acute coronary syndrome (ACS) with a final diagnosis of multiple endocrine neoplasia with pheochromocytoma and medullary thyroid carcinoma (MTC).
  
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• Endoplasmic reticulum stress and Nrf2 signaling in cardiovascular diseases.
  Free Radic Biol Med

  2015 Nov;88(Pt B):233-242. doi: S0891-5849(15)00238-5.
  
  Cominacini Luciano, Mozzini Chiara, Garbin Ulisse, Pasini Andrea, Stranieri Chiara, Solani Erika, Vallerio Paola, Tinelli Irene Alessandra, Fratta Pasini Anna
  
  Abstract
  
  Various cellular perturbations implicated in the pathophysiology of human diseases, including cardiovascular and neurodegenerative diseases, diabetes mellitus, obesity, and liver diseases, can alter endoplasmic reticulum (ER) function and lead to the abnormal accumulation of misfolded proteins. This situation configures the so-called ER stress, a form of intracellular stress that occurs whenever the protein-folding capacity of the ER is overwhelmed. Reduction in blood flow as a result of atherosclerotic coronary artery disease causes tissue hypoxia, a condition that induces protein misfolding and ER stress. In addition, ER stress has an important role in cardiac hypertrophy mainly in the transition to heart failure (HF). ER transmembrane sensors detect the accumulation of unfolded proteins and activate transcriptional and translational pathways that deal with unfolded and misfolded proteins, known as the unfolded protein response (UPR). Once the UPR fails to control the level of unfolded and misfolded proteins in the ER, ER-initiated apoptotic signaling is induced. Furthermore, there is considerable evidence that implicates the presence of oxidative stress and subsequent related cellular damage as an initial cause of injury to the myocardium after ischemia/reperfusion (I/R) and in cardiac hypertrophy secondary to pressure overload. Oxidative stress is counterbalanced by complex antioxidant defense systems regulated by a series of multiple pathways, including the UPR, to ensure that the response to oxidants is adequate. Nuclear factor-E2-related factor (Nrf2) is an emerging regulator of cellular resistance to oxidants; Nrf2 is strictly interrelated with the UPR sensor called pancreatic endoplasmic reticulum kinase. A series of studies has shown that interventions against ER stress and Nrf2 activation reduce myocardial infarct size and cardiac hypertrophy in the transition to HF in animals exposed to I/R injury and pressure overload, respectively. Finally, recent data showed that Nrf2/antioxidant-response element pathway activation may be of importance also in ischemic preconditioning, a phenomenon in which the heart is subjected to one or more episodes of nonlethal myocardial I/R before the sustained coronary artery occlusion.
  
  Copyright © 2015 Elsevier Inc. All rights reserved.
  
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• Effects of Cancer Therapy Targeting Vascular Endothelial Growth Factor Receptor on Central Blood Pressure and Cardiovascular System.
  Am J Hypertens

  2016 Feb;29(2):158-62. doi: 10.1093/ajh/hpv077.
  
  Moreo Antonella, Vallerio Paola, Ricotta Riccardo, Stucchi Miriam, Pozzi Mattia, Musca Francesco, Meani Paolo, Maloberti Alessandro, Facchetti Rita, Di Bella Sara, Giganti Maria Olga, Sartore-Bianchi Andrea, Siena Salvatore, Mancia Giuseppe, Giannattasio Cristina
  
  Abstract
  
  BACKGROUND:
  In the last 2 decades, new drugs that oppose the effects of vascular endothelial growth factor receptor (VEGFR), and thus angiogenesis, have considerably improved treatment of solid tumors. These anti-VEGFR drugs, however, are burdened by several side effects, particularly relevant on heart and vessels. The aim of this study was to analyze the changes in cardiovascular structure and function associated with use of anti-VEGFR drugs.
  
  METHODS:
  Twenty-nine patients (27 affected by renal and 2 by thyroid cancer), received treatment with anti-VEGFR drugs. Brachial blood pressure (BP), central BP, carotid-femoral pulse wave velocity (cfPWV), augmentation index (Aix), and several echocardiographic markers of systolic and diastolic left ventricular functions including global longitudinal strain were measured before starting treatment (T0), after 2 (T1), and 6 weeks (T2) of treatment.
  
  RESULTS:
  Anti-VEGFR treatment was accompanied by a significant increase of both peripheral (systolic BP +13±15.5mm Hg, diastolic BP +7.1±9.3mm Hg, P < 0.001) and central BP (systolic BP +14±14.2mm Hg, diastolic BP +7.3±10.4mm Hg, P < 0.001) and a significant raise of cfPWV (+1.3±1.8 m/sec, P = 0.003). There was also a significant alteration of markers of diastolic and subclinical left ventricular systolic function, including global longitudinal strain (-19.9±3.8% at T0, -17.8±2.6% at T2, P < 0.05). All the changes were already evident at T1, worsened at T2 in patients who maintained oncological treatment, but disappeared at T2 in patients in whom treatment was stopped.
  
  CONCLUSIONS:
  All the changes regarding BP and cfPWV appear early after treatment initiation and seem to be reversible if treatment is stopped, instead diastolic and systolic left ventricular function are persistently altered by anti-VEGFR drugs.
  
  © American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
  
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• Structural and Functional Abnormalities of Carotid Artery and Their Relation with EVA Phenomenon.
  High Blood Press Cardiovasc Prev

  2015 Dec;22(4):373-9. doi: 10.1007/s40292-015-0100-9.
  
  Maloberti Alessandro, Meani Paolo, Varrenti Marisa, Giupponi Luca, Stucchi Miriam, Vallerio Paola, Giannattasio Cristina
  
  Abstract
  
  Early vascular aging is a process characterized by a reduction in arterial elastin with an increase in collagen that has been related to cardiovascular risk factor and can determine an increased arterial stiffness and central blood pressure. It can be measured by several non invasive methods and in different arterial segment. The present paper will focus on functional (local stiffness parameter) and structural (intima media thickness) carotid arteries alterations typically evaluated by ultrasound methods. Methodological, research and clinical issue has been reviewed.
  
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• Renal artery stenosis as the cause of resistant arterial hypertension: an unusual technique for revascularization.
  J Clin Hypertens (Greenwich)

  2014 Jul;16(7):536-7. doi: 10.1111/jch.12331.
  
  De Biase Anna, Varrenti Marisa, Meani Paolo, Cesana Francesca, Pirola Roberto, Giupponi Luca, Alloni Marta, Vallerio Paola, Moreo Antonella, Rampoldi Antonio, Giannattasio Cristina
  
  
  
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• Do oxidized polyunsaturated Fatty acids affect endoplasmic reticulum stress-induced apoptosis in human carotid plaques?
  Antioxid Redox Signal

  2014 Aug;21(6):850-8. doi: 10.1089/ars.2014.5870.
  
  Garbin Ulisse, Stranieri Chiara, Pasini Andrea, Baggio Elda, Lipari Giovanni, Solani Erika, Mozzini Chiara, Vallerio Paola, Cominacini Luciano, Fratta Pasini Anna Maria
  
  Abstract
  
  Macrophage apoptosis is involved in atherosclerotic plaque development. The aim of this study was to evaluate the interrelationship between macrophage apoptosis and the endoplasmic reticulum (ER) stress in the tissue around the necrotic core (TANC) and in the periphery (P) of the same carotid plaques derived from patients undergoing carotid endarterectomy. Apoptosis was significantly higher in TANC than in P (p<0.001). mRNA and protein expression of the protein kinase-like ER kinase (Perk) and the nuclear erythroid-related factor 2 (Nrf2)-related survival genes was significantly higher in P than in TANC (p<0.01), while CCAAT/enhancer-binding protein homologous protein (Chop) and the apoptosis-related genes were higher in TANC than in P (p<0.01). The TANC extract was characterized by significantly higher concentrations of oxidized derivatives of polyunsaturated fatty acids (PUFAs) than the P extract (p<0.01). When THP-1 cells were incubated with P or TANC extracts there was a dose-dependent increase of Perk and Nrf2 or of Chop and of the apoptosis-related genes, respectively (p<0.01). Our observations lead to the hypothesis that ER stress induced by oxidized derivatives of PUFAs may promote macrophage apoptosis in TANC and favor the expansion of the necrotic core of the plaques, a major feature responsible for its disruption and acute luminal thrombosis.
  
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• Increased endoplasmic reticulum stress and Nrf2 repression in peripheral blood mononuclear cells of patients with stable coronary artery disease.
  Free Radic Biol Med

  2014 Mar;68():178-85. doi: 10.1016/j.freeradbiomed.2013.12.017.
  
  Mozzini Chiara, Fratta Pasini Anna, Garbin Ulisse, Stranieri Chiara, Pasini Andrea, Vallerio Paola, Cominacini Luciano
  
  Abstract
  
  Endoplasmic reticulum (ER) stress is involved in the pathophysiology of atherosclerosis. Insults interfering with ER function lead to the accumulation of unfolded and misfolded proteins in the ER that initiates the unfolded protein response (UPR). When the UPR fails to control the level of unfolded and misfolded proteins, ER-initiated apoptotic signaling is induced. We evaluated: (1) the UPR and ER-initiated apoptotic signaling in peripheral blood mononuclear cells (PBMCs) of stable coronary artery disease (CAD) patients; (2) PBMC content of oxidation products of phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC); (3) the possible origin of oxPAPC in PBMCs; and (4) the expression of nuclear erythroid-related factor 2 (Nrf2)/antioxidant-related element (ARE), a cellular defense mechanism. Twenty-nine CAD patients and 28 matched controls were enrolled. Expression of glucose-regulated protein 78kDa (GRP78/BiP), as a representative of the UPR, and of C/EBP homologous protein (CHOP), as a representative of ER apoptosis, was significantly higher in CAD than in controls (p<0.01). Concentrations of oxPAPC in PBMCs, in plasma, and in low-density lipoprotein (LDL) were significantly higher in CAD compared to controls (p<0.01). The oxPAPC in PBMCs may derive from circulating ox-LDL. Nrf2/ARE gene expression and circulating and cellular glutathione were significantly lower in CAD compared to controls (p<0.01). In in vitro studies, increasing amounts of oxPAPC induced a dose-dependent increase in CHOP and apoptosis-related protein expression (p<0.01) and a progressive decrease in Nrf2/ARE gene expression (p<0.01). In PBMCs of CAD patients there is an activation of the UPR and ER-initiated apoptotic signaling, possibly related to an abnormal concentration of oxPAPC in PBMCs.
  
  Copyright © 2013 Elsevier Inc. All rights reserved.
  
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• Lysophosphatidylcholine and carotid intima-media thickness in young smokers: a role for oxidized LDL-induced expression of PBMC lipoprotein-associated phospholipase A2?
  PLoS One

  2013 ;8(12):e83092. doi: 10.1371/journal.pone.0083092.
  
  Fratta Pasini Anna, Stranieri Chiara, Pasini Andrea, Vallerio Paola, Mozzini Chiara, Solani Erika, Cominacini Mattia, Cominacini Luciano, Garbin Ulisse
  
  Abstract
  
  BACKGROUND:
  Although cigarette smoking has been associated with carotid intima-media thickness (CIMT) the mechanisms are yet not completely known. Lysophosphatidylcholine (lysoPC), a main product of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, appears to be a major determinant of the pro-atherogenic properties of oxidized LDL (oxLDL) and to induce proteoglycan synthesis, a main player in intimal thickening. In this study we assessed whether cigarette smoking-induced oxidative stress may influence plasma Lp-PLA2 and lysoPC and Lp-PLA2 expression in peripheral blood mononuclear cells (PBMC), as well as the relationship between lysoPC and CIMT.
  
  METHODS/RESULTS:
  45 healthy smokers and 45 age and sex-matched subjects participated in this study. Smokers, compared to non-smokers, showed increased plasma concentrations of oxLDL, Lp-PLA2 and lysoPC together with up-regulation of Lp-PLA2 (mRNA and protein) expression in PBMC (P<0.001). Plasma Lp-PLA2 positively correlated with both lysoPC (r=0.639, P<0.001) and PBMC mRNA Lp-PLA2 (r=0.484, P<0.001) in all subjects. Moreover CIMT that was higher in smokers (P<0.001), positively correlated with lysoPC (r=0.55, P<0.001). Then in in vitro study we demonstrated that both oxLDL (at concentrations similar to those found in smoker's serum) and oxidized phospholipids contained in oxLDL, were able to up-regulate mRNA Lp-PLA2 in PBMC. This effect was likely due, at least in part, to the enrichment in oxidized phospholipids found in PBMC after exposure to oxLDL. Our results also showed that in human aortic smooth muscle cells lysoPC, at concentrations similar to those found in smokers, increased the expression of biglycan and versican, two main proteoglycans.
  
  CONCLUSIONS:
  In smokers a further effect of raised oxidative stress is the up-regulation of Lp-PLA2 expression in PBMC with subsequent increase of plasma Lp-PLA2 and lysoPC. Moreover the correlation between lysoPC and CIMT together with the finding that lysoPC up-regulates proteoglycan synthesis suggests that lysoPC may be a link between smoking and intimal thickening.
  
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• Role of MDCT coronary angiography in the clinical setting: economic implications.
  Radiol Med

  2013 Dec;118(8):1294-308. doi: 10.1007/s11547-013-0933-z.
  
  Malagò Roberto, Pezzato Andrea, Barbiani Camilla, Tavella Domenico, Vallerio Paola, Pasini Anna Fratta, Cominacini Luciano, Mucelli Roberto Pozzi
  
  Abstract
  
  PURPOSE:
  This study evaluated the incremental value and cost-effectiveness ratio of introducing coronary angiography (CA) with multidetector computed tomography (MDCT-CA) in the diagnostic management of patients with suspected coronary artery disease (CAD) compared with the traditional diagnostic workup.
  
  MATERIAL AND METHODS:
  Five hundred and fifty consecutive patients who underwent MDCT-CA between January 2009 and June 2011 were considered. Patients with atypical chest pain and suspected obstructive CAD were directed to one of two diagnostic pathways: the traditional protocol (examination, stress test, CA) and the current protocol (examination, stress test, MDCT-CA, and CA, if necessary). The costs of each protocol and for the individual method were calculated. Based on the results, the cost-effectiveness ratio of the two diagnostic pathways was compared. A third, modified, diagnostic pathway has been proposed with its relative cost-effectiveness ratio (examination, MDCT-CA, stress test, and CA, if necessary).
  
  RESULTS:
  Stress test vs. MDCT-CA had an accuracy of 66%, a sensitivity and specificity of 21% and 87%, respectively, and a positive (PPV) and negative (NPV) predictive value of 40% and 70%, respectively. Comparison between conventional CA (CCA) and MDCT-CA showed a sensitivity and specificity of 92% and 89%, respectively, a PPV and NPV of 89%, and an accuracy of 92%. The traditional protocol has higher costs than the second protocol: 1,645 euro against 322 euro (mean), but it shows a better cost-effectiveness ratio. The new proposed protocol has lower costs, mean 261 euro, with a better costeffectiveness ratio than the traditional protocol.
  
  CONCLUSIONS:
  The diagnostic protocol for patients with suspected CAD has been modified by the introduction of MDCT-CA. Our study confirms the greater diagnostic performance of MDCT-CA compared with stress test and its similar accuracy to CCA. The use of MDCT-CA to select patients for CCA has a favourable cost-effectiveness profile.
  
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• Expansion of necrotic core and shedding of Mertk receptor in human carotid plaques: a role for oxidized polyunsaturated fatty acids?
  Cardiovasc Res

  2013 Jan;97(1):125-33. doi: 10.1093/cvr/cvs301.
  
  Garbin Ulisse, Baggio Elda, Stranieri Chiara, Pasini Andrea, Manfro Stefania, Mozzini Chiara, Vallerio Paola, Lipari Giovanni, Merigo Flavia, Guidi Giancesare, Cominacini Luciano, Fratta Pasini Anna
  
  Abstract
  
  AIMS:
  Expansion of necrotic core (NC), a major feature responsible for plaque disruption, is likely the consequence of accelerated macrophage apoptosis coupled with defective phagocytic clearance (efferocytosis). The cleavage of the extracellular domain of Mer tyrosine kinase (Mertk) by metallopeptidase domain17 (Adam17) has been shown to produce a soluble Mertk protein (sMer), which can inhibit efferocytosis. Herein, we analysed the expression and localization of Mertk and Adam17 in the tissue around the necrotic core (TANC) and in the periphery (P) of human carotid plaques. Then we studied the mechanisms of NC expansion by evaluating which components of TANC induce Adam17 and the related cleavage of the extracellular domain of Mertk.
  
  METHODS AND RESULTS:
  We studied 97 human carotid plaques. The expression of Mertk and Adam17 was found to be higher in TANC than in P (P < 0.001). By immunohistochemistry, Mertk was higher than Adam17 in the area of TANC near to the lumen (P < 0.01) but much lower in the area close to NC (P < 0.01). The extract of this portion of TANC increased the expression (mRNA) of Adam17 and Mertk (P < 0.01) in macrophage-like THP-1 cells but it also induced the cleavage of the extracellular domain of Mertk, generating sMer in the medium (P < 0.01). This effect of TANC extract was most evoked by its content in F(2)-isoprostanes, hydroxyoctadecadienoic acids, and hydroxytetraenoic acids.
  
  CONCLUSION:
  Some oxidized derivatives of polyunsaturated fatty acids contained in TANC of human carotid plaques are strong inducers of Adam17, which in turn leads to the generation of sMer, which can inhibit efferocytosis.
  
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• Serum oxidative stress-induced repression of Nrf2 and GSH depletion: a mechanism potentially involved in endothelial dysfunction of young smokers.
  PLoS One

  2012 ;7(1):e30291. doi: 10.1371/journal.pone.0030291.
  
  Fratta Pasini Anna, Albiero Anna, Stranieri Chiara, Cominacini Mattia, Pasini Andrea, Mozzini Chiara, Vallerio Paola, Cominacini Luciano, Garbin Ulisse
  
  Abstract
  
  BACKGROUND:
  Although oxidative stress plays a major role in endothelial dysfunction (ED), the role of glutathione (GSH), of nuclear erythroid-related factor 2 (Nrf2) and of related antioxidant genes (ARE) are yet unknown. In this study we combined an in vivo with an in vitro model to assess whether cigarette smoking affects flow-mediated vasodilation (FMD), GSH concentrations and the Nrf2/ARE pathway in human umbilical vein endothelial cells (HUVECs).
  
  METHODS AND RESULTS:
  52 healthy subjects (26 non-smokers and 26 heavy smokers) were enrolled in this study. In smokers we demonstrated increased oxidative stress, i.e., reduced concentrations of GSH and increased concentrations of oxidation products of the phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in serum and in peripheral blood mononuclear cells (PBMC), used as in vivo surrogates of endothelial cells. Moreover we showed impairment of FMD in smokers and a positive correlation with the concentration of GSH in PBMC of all subjects. In HUVECs exposed to smokers' serum but not to non-smokers' serum we found that oxidative stress increased, whereas nitric oxide and GSH concentrations decreased; interestingly the expression of Nrf2, of heme oxygenase-1 (HO-1) and of glutamate-cysteine ligase catalytic (GCLC) subunit, the rate-limiting step of synthesis of GSH, was decreased. To test the hypothesis that the increased oxidative stress in smokers may have a causal role in the repression of Nrf2/ARE pathway, we exposed HUVECs to increasing concentrations of oxPAPC and found that at the highest concentration (similar to that found in smokers' serum) the expression of Nrf2/ARE pathway was reduced. The knockdown of Nrf2 was associated to a significant reduction of HO-1 and GCLC expression induced by oxPAPC in ECs.
  
  CONCLUSIONS:
  In young smokers with ED a novel further consequence of increased oxidative stress is a repression of Nrf2/ARE pathway leading to GSH depletion.
  
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• Endothelial progenitor cells in patients with essential hypertension.
  J Hypertens

  2007 Jan;25(1):127-32.
  
  Delva Pietro, Degan Maurizio, Vallerio Paola, Arosio Enrico, Minuz Pietro, Amen Gabriella, Di Chio Marzia, Lechi Alessandro
  
  Abstract
  
  OBJECTIVE(S):
  The eventual role of blood pressure on the endothelial progenitor cell (EPC) has rarely been evaluated and data collected so far relate to patients with co-existing coronary heart disease.
  
  METHODS:
  We have studied the number and functional activity of EPC as well as the number of EPC endothelial colony-forming units (CFU) in a carefully selected group of 36 patients with essential hypertension and 24 normotensive control subjects.
  
  RESULTS:
  In patients with essential hypertension, the EPC number was not statistically different from that found in control subjects (mean +/- SD, essential hypertension 58 +/- 29, controls 53 +/- 20; EPC/high power field). CFU per well were not statistically different in patients with essential hypertension compared with normotensive controls (mean +/- SD, patients with essential hypertension 2.4 +/- 2.6, normotensive controls 3 +/- 3.3 CFU/well). In essential hypertension patients, the EPC number was inversely correlated with both total (R=0.635, P < 0.0001) and low-density lipoprotein (LDL)-cholesterol (R=0.486, P < 0.05). Neither the EPC number nor the EPC CFU were correlated with age, systolic blood pressure, diastolic blood pressure, body mass index, lipoprotein(a), high-sensitivity C-reactive protein or homocysteine.
  
  CONCLUSIONS:
  The present study shows that essential hypertension is not characterized by the altered number or functional activity of EPC. Plasma total and LDL-cholesterol are independent predictors of reduced numbers of circulating EPC in essential hypertension patients. The absence of any correlation between the characteristics of EPC and several markers predictive of cardiovascular damage merits further investigation.
  
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