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1. Serum endocan as a predictive biomarker of cardiovascular risk in obese pediatric patients

Author

Carmela Morace, Selenia Lorenza Curatola, Giuseppe Mandraffino, Michele Scuruchi, Angela Elvira Serrano’, Angelo Tropeano, Fortunato Lombardo, Giuseppina Salzano, Giovanni Squadrito, Antonio Giovanni Versace, and Mariella Valenzise

Subjects
Endocan, Obesity, Cardiovascular risk, Children, Pediatrics, RJ1-570
Abstract

Abstract Background Endocan is a soluble dermatan sulfate proteoglycan (50 kDa) secreted by endothelial cells and expressed by dermal, coronary, pulmonary and adipose tissue microvasculature. It plays an important role in the pathogenesis of vascular disorders, inflammatory state, endothelium dysfunction and neoangiogenesis. Aims of the study were to compare fasting serum endocan levels between children with obesity and healthy controls and to investigate the relationships between endocan, body mass index (BMI) and other indices of cardiometabolic risk. Methods This single-center, observational, retrospective study included 19 pediatric patients with obesity aged 11.94 ± 0.52 years and 19 lean matched controls. Each patient underwent clinical and auxological examination and laboratory investigations including routine organs function tests and lipid profile. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Fasting endocan serum levels were measured using an enzyme-linked immunosorbent assay (ELISA). Results Compared to healthy subjects, serum endocan levels were found to be significantly upraised in children with obesity. Endocan resulted significantly correlated with insulin levels (rho 0.47; p = 0.04); in addition, an association with HOMA-IR values with a trend toward the statistical significance (rho 0.43; p = 0.07) was found. No significant correlation with fasting blood glucose values and lipid serum levels was demonstrated. Although not statistically significant, a correlation between endocan and the presence and grading of liver steatosis on ultrasound (rho 0.51; p = 0.08 and rho 0.51; p = 0.08, respectively) was found. Conclusions These findings confirm the association between endothelial damage and insulin resistance in children with obesity. Endocan could be used as a biomarker of early endothelial dysfunction in children with obesity and could be a valid predictor of future cardiovascular risk in adulthood.

Published
2023
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2. Ketoacidosis and SGLT2 Inhibitors: A Narrative Review

Author

Carmela Morace, Giuseppe Lorello, Federica Bellone, Cristina Quartarone, Domenica Ruggeri, Annalisa Giandalia, Giuseppe Mandraffino, Letteria Minutoli, Giovanni Squadrito, Giuseppina T. Russo, and Herbert Ryan Marini

Subjects
diabetic ketoacidosis, SGLT2-i, adverse drug reaction, Microbiology, QR1-502
Abstract

An acute metabolic complication of diabetes mellitus, especially type 1, is diabetic ketoacidosis (DKA), which is due to an increase in blood ketone concentrations. Sodium/glucose co-transporter-2 inhibitor (SGLT2-i) drugs have been associated with the occurrence of a particular type of DKA defined as euglycemic (euDKA), characterized by glycemic levels below 300 mg/dL. A fair number of euDKA cases in SGLT2-i-treated patients have been described, especially in the last few years when there has been a significant increased use of these drugs. This form of euDKA is particularly insidious because of its latent onset, associated with unspecific symptomatology, until it evolves (progressing) to severe systemic forms. In addition, its atypical presentation can delay diagnosis and treatment. However, the risk of euDKA associated with SGLT2-i drugs remains relatively low, but it is essential to promptly diagnose and manage it to prevent its serious life-threatening complications. In this narrative review, we intended to gather current research evidence on SGLT2i-associated euDKA from randomized controlled trials and real-world evidence studies, its diagnostic criteria and precipitating factors.

Published
2024
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3. Clinical Approach in the Management of Paediatric Patients with Familial Hypercholesterolemia: A National Survey Conducted by the LIPIGEN Paediatric Group

Author

Cristina Pederiva, Marta Gazzotti, Marcello Arca, Maurizio Averna, Giuseppe Banderali, Giacomo Biasucci, Marta Brambilla, Paola Sabrina Buonuomo, Paolo Calabrò, Francesco Cipollone, Nadia Citroni, Sergio D’Addato, Maria Del Ben, Simonetta Genovesi, Ornella Guardamagna, Gabriella Iannuzzo, Lorenzo Iughetti, Giuseppe Mandraffino, Lorenzo Maroni, Giuliana Mombelli, Sandro Muntoni, Fabio Nascimbeni, Angelina Passaro, Fabio Pellegatta, Matteo Pirro, Livia Pisciotta, Roberta Pujia, Riccardo Sarzani, Roberto Scicali, Patrizia Suppressa, Sabina Zambon, Maria Grazia Zenti, Sebastiano Calandra, Alberico Luigi Catapano, Patrizia Tarugi, Federica Galimberti, Manuela Casula, and Maria Elena Capra

Subjects
familial hypercholesterolemia, paediatric, pathology register, survey, management, Nutrition. Foods and food supply, TX341-641
Abstract

Detection and treatment of patients with familial hypercholesterolemia (FH) starting from childhood is fundamental to reduce morbidity and mortality. The activity of National realities such as the LIPIGEN (LIpid transPort disorders Italian GEnetic Network) Paediatric Group, founded in 2018, is a milestone in this context. The aim of this exploratory survey, conducted in October 2021 among Italian lipid clinics included in the LIPIGEN Paediatric Group, was to investigate the current clinical approach in the management and treatment of paediatric patients with suspected FH. A digital questionnaire composed of 20 questions investigating nutritional treatment and nutraceutical and pharmacological therapy for children and adolescents with FH was proposed to the principal investigators of 30 LIPIGEN centres. Twenty-four centres responded to the section referring to children aged < 10 years and 30 to that referring to adolescents. Overall, 66.7% of children and 73.3% of adolescents were given lipid-lowering nutritional treatment as the first intervention level for at least 3–4 months (29.2% and 23.3%) or 6–12 months (58.3% and 53.3%). Nutraceuticals were considered in 41.7% (regarding children) and 50.0% (regarding adolescents) of the centres as a supplementary approach to diet. Lipid-lowering drug therapy initiation was mainly recommended (91.7% and 80.0%). In 83.3% of children and 96.7% of adolescents, statins were the most frequently prescribed drug. We highlighted several differences in the treatment of paediatric patients with suspected FH among Italian centres; however, the overall approach is in line with the European Atherosclerosis Society (EAS) recommendations for FH children and adolescents. We consider this survey as a starting point to reinforce collaboration between LIPIGEN centres and to elaborate in the near future a consensus document on the management of paediatric patients with suspected FH so as to improve and uniform detection, management, and treatment of these patients in our country.

Published
2023
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5. The Role of Registers in Increasing Knowledge and Improving Management of Children and Adolescents Affected by Familial Hypercholesterolemia: the LIPIGEN Pediatric Group

Author

Marta Gazzotti, Manuela Casula, Stefano Bertolini, Maria Elena Capra, Elena Olmastroni, Alberico Luigi Catapano, Cristina Pederiva, the LIPIGEN Paediatric Group, Massimiliano Allevi, Marcello Arca, Renata Auricchio, Maurizio Averna, Davide Baldera, Giuseppe Banderali, Andrea Bartuli, Giacomo Biasucci, Claudio Borghi, Patrizia Bruzzi, Raffaele Buganza, Paola Sabrina Buonuomo, Paolo Calabrò, Sebastiano Calandra, Francesca Carubbi, Arturo Cesaro, Francesco Cipollone, Nadia Citroni, Giuseppe Covetti, Annalaura Cremonini, Sergio D’Addato, Maria Del Ben, Maria Donata Di Taranto, Giuliana Fortunato, Roberto Franceschi, Federica Galimberti, Simonetta Genovesi, Antonina Giammanco, Liliana Grigore, Ornella Guardamagna, Arcangelo Iannuzzi, Gabriella Iannuzzo, Lorenzo Iughetti, Lidia Lascala, Fabiana Locatelli, Sara Madaghiele, Giuseppe Mandraffino, Massimo Raffaele Mannarino, Bucci Marco, Lorenzo Maroni, Ilenia Minicocci, Giuliana Mombelli, Sandro Muntoni, Fabio Nascimbeni, Gianfranco Parati, Angelina Passaro, Chiara Pavanello, Fabio Pellegatta, Francesco Massimo Perla, Matteo Pirro, Livia Pisciotta, Arturo Pujia, Francesco Purrello, Elisabetta Rinaldi, Riccardo Sarzani, Roberto Scicali, Patrizia Suppressa, Patrizia Tarugi, Sabrina Verachtert, Giovanni Battista Vigna, Josè Pablo Werba, Alberto Zambon, Sabina Zambon, and Maria Grazia Zenti

Subjects
familial hypercholesterolemia, pediatric cohort, genetic diagnosis, pathology register, clinical diagnosis, cardiovascular genetics, Genetics, QH426-470
Abstract

Pathology registers can be a useful tool to overcome obstacles in the identification and management of familial hypercholesterolemia since childhood. In 2018, the LIPIGEN pediatric group was constituted within the Italian LIPIGEN study to focus on FH subjects under 18 years. This work aimed at discussing its recent progress and early outcomes. Demographic, biochemical, and genetic baseline characteristics were collected, with an in-depth analysis of the genetic defects. The analysis was carried out on 1,602 children and adolescents (mean age at baseline 9.9 ± 4.0 years), and almost the whole cohort underwent the genetic test (93.3%). Overall, the untreated mean value of LDL-C was 220.0 ± 97.2 mg/dl, with an increasing gradient from subjects with a negative (N = 317; mean untreated LDL-C = 159.9 ± 47.7 mg/dl), inconclusive (N = 125; mean untreated LDL-C = 166.4 ± 56.5 mg/dl), or positive (N = 1,053; mean untreated LDL-C = 246.5 ± 102.1 mg/dl) genetic diagnosis of FH. In the latter group, the LDL-C values presented a great variability based on the number and the biological impact of involved causative variants. The LIPIGEN pediatric group represents one of the largest cohorts of children with FH, allowing the deepening of the characterization of their baseline and genetic features, providing the basis for further longitudinal investigations for complete details.

Published
2022
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6. Endocan Knockdown Down-Regulates the Expression of Angiogenesis-Associated Genes in Il-1ß Activated Chondrocytes

Author

Michele Scuruchi, Federica Aliquò, Angela Avenoso, Giuseppe Mandraffino, Giovanna Vermiglio, Aurelio Minuti, Salvatore Campo, Giuseppe Maurizio Campo, and Angela D’Ascola

Subjects
endocan, proteoglycans, chondrocytes, inflammation, angiogenic factors, Microbiology, QR1-502
Abstract

Endocan is a small soluble proteoglycan (PG) known to be involved in inflammation and angiogenesis. Increased endocan expression was found in the synovia of arthritic patients and chondrocytes stimulated with IL-1ß. Considering these findings, we aimed to investigate the effects of endocan knockdown on the modulation of pro-angiogenic molecules expression in a model of IL-1ß-induced inflammation in human articular chondrocytes. Endocan, VEGF-A, MMP-9, MMP-13, and VEGFR-2 expression was measured in both normal and endocan knockdown chondrocytes stimulated with IL-1ß. VEGFR-2 and NF-kB activation were also measured. Results have shown that endocan, VEGF-A, VEGFR-2, MMP-9, and MMP-13 were significantly up-regulated during IL-1ß-induced inflammation; interestingly, the expression of such pro-angiogenic molecules and NF-kB activation were significantly reduced by endocan knockdown. These data support the hypothesis that endocan released by activated chondrocytes may be involved in the mechanisms that stimulate cell migration and invasion, as well as angiogenesis, in the pannus of arthritic joints.

Published
2023
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7. Hybrid Palliation for Hypoplastic Borderline Left Ventricle: One More Chance to Biventricular Repair

Author

Lilia Oreto, Giuseppe Mandraffino, Rita Emanuela Calaciura, Daniela Poli, Placido Gitto, Michele Benedetto Saitta, Ermanno Bellanti, Scipione Carerj, Concetta Zito, Fiore Salvatore Iorio, Paolo Guccione, and Salvatore Agati

Subjects
hybrid palliation, hypoplastic left heart syndrome, echocardiography, borderline left ventricle, biventricular repair, Pediatrics, RJ1-570
Abstract

Treatment options for hypoplastic borderline left ventricle (LV) are critically dependent on the development of the LV itself and include different types of univentricular palliation or biventricular repair performed at birth. Since hybrid palliation allows deferring major surgery to 4–6 months, in borderline cases, the decision can be postponed until the LV has expressed its growth potential. We aimed to evaluate anatomic modifications of borderline LV after hybrid palliation. We retrospectively reviewed data from 45 consecutive patients with hypoplastic LV who underwent hybrid palliation at birth between 2011 and 2015. Sixteen patients (mean weight 3.15 Kg) exhibited borderline LV and were considered for potential LV growth. After 5 months, five patients underwent univentricular palliation (Group 1), eight biventricular repairs (Group 2) and three died before surgery. Echocardiograms of Groups 1 and 2 were reviewed, comparing LV structures at birth and after 5 months. Although, at birth, all LV measurements were far below the normal limits, after 5 months, LV mass in Group 2 was almost normal, while in Group 1, no growth was evident. However, aortic root diameter and long axis ratio were significantly higher in Group 2 already at birth. Hybrid palliation can be positively considered as a “bridge-to-decision” for borderline LV. Echocardiography plays a key role in monitoring the growth of borderline LV.

Published
2023
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8. Endocan Promotes Pro-Tumorigenic Signaling in Lung Cancer Cells: Modulation of Cell Proliferation, Migration and lncRNAs H19 and HULC Expression

Author

Federica Aliquò, Aurelio Minuti, Angela Avenoso, Giuseppe Mandraffino, Giuseppe Maurizio Campo, Salvatore Campo, Angela D‘Ascola, and Michele Scuruchi

Subjects
endocan, proteoglycans, tumors, NSCLC, angiogenesis, long non-coding RNAs, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Endocan is a circulating proteoglycan secreted by several cell lines and identified as a potential biomarker of inflammation and angiogenesis. Endocan-increased expression has been found in a broad spectrum of human tumors, including lung cancer, and is associated with a poor prognosis. To elucidate the possible mechanism, this study aimed to investigate the role of endocan in non-small-cell lung carcinoma (NSCLC) using an in vitro model of cultured cells. Endocan expression was knocked down by using a specific small interfering RNA. The effects of endocan knockdown have been evaluated on VEGF-A, VEGFR-2, HIF-1α, the long non-coding RNAs H19 and HULC expression, and AKT and ERK 1/2 degree of activation. Cell migration and proliferation have been studied as well. VEGF-A, VEGFR-2, HIF-1α, and the long non-coding RNAs H19 and HULC expression were significantly affected by endocan knockdown. These effects correlated with a reduction of cell migration and proliferation and of AKT and ERK 1/2 activation. Our findings suggest that endocan promotes a more aggressive cancer cell phenotype in NSCLC.

Published
2023
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9. Arterial Stiffness and Adult Onset Vasculitis: A Systematic Review

Author

Alberto Lo Gullo, Clemente Giuffrida, Carmela Morace, Giovanni Squadrito, Paola Magnano San Lio, Luisa Ricciardi, Carlo Salvarani, and Giuseppe Mandraffino

Subjects
vasculitis, inflammation, atherosclerosis, arterial stiffness, Behcet disease, Takayasu arteritis, Medicine (General), R5-920
Abstract

Chronic inflammation represents the cornerstone of the raised cardiovascular (CV) risk in patients with inflammatory rheumatic diseases (IRD), including vasculitis. Standardized mortality ratios in these patients are higher as compared to the general population, and the excess of premature mortality is due to early atherosclerotic events. Thus, IRD patients need appropriate CV risk assessment and management according to this CV disease (CVD) burden. Adequate control of CV risk is still lacking in usual care, but early diagnosis of silent and subclinical CVD is crucial to improve the long-term prognosis of these patients. Increased arterial stiffness may provide a pathophysiological link between inflammation and increased cardiovascular risk. Several noninvasive methods are now available to estimate artery stiffness in the clinical setting, including pulse wave velocity assessment. The independent predictive value of arterial stiffness for cardiovascular events has been demonstrated in general as well as in selected populations, and reference values adjusted for age and blood pressure have been suggested. Thus, arterial stiffness is an interesting biomarker for cardiovascular risk stratification. This systematic review summarizes the additional value that PWV measurement can provide in the setting of vasculitis, with a focus in the different clinical stages and CV risk prevention. This systematic review is registered with registration number: Prospero CRD42021259603.

Published
2022
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10. Management of High Cardiovascular Risk in Diabetic Patients: Focus on Low Density Lipoprotein Cholesterol and Appropriate Drug Use in General Practice

Author

Michelangelo Rottura, Giulia Scondotto, Maria Antonietta Barbieri, Emanuela Elisa Sorbara, Chiara Nasso, Sebastiano Marino, Riccardo Scoglio, Giuseppe Mandraffino, Giovanni Pallio, Natasha Irrera, Egidio Imbalzano, Giovanni Squadrito, Francesco Squadrito, and Vincenzo Arcoraci

Subjects
cardiovascular risk, diabetes, lipid-lowering drugs, clinical practice, appropriateness, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

This study aimed to evaluate the management of high cardiovascular risk (CVr) in the patients with diabetes by exploring the prescribing behavior in a setting of general practitioners (GPs). A retrospective cohort study was carried out using the data recorded between 2018 and 2020 in the clinical database of 10 GPs. Diabetes was defined using the International Classification of Diseases (ICD-9-CM) coding (250*) or using the laboratory parameters (hyperglycemia condition: ≥126 mg/dL). A cohort was described stratifying by demographic, clinical and therapeutic characteristics, and laboratory tests. Both the CVr and statin prescriptions were evaluated; adherence to statin therapy (medication possession ratio, MPR ≥ 80) was calculated in accordance with the low-density lipoprotein cholesterol (LDL-C) target. The multivariate logistic regression models with adjusted odds ratios (ORs) and the corresponding 95% Confidence Intervals (CIs) were calculated to identify the predictors of lipid modifying agents use and achieved target therapy; moreover, glucose-lowering drugs use was evaluated. Out of 13,206 people screened, 1,851 (14.0%) patients were affected by diabetes mellitus (DM), and 1,373 were identified at high/very high CVr. Of them, 1,158 (84.3%) had at least one measurement of LDL-C, and 808 (58.8%) received a prescription with at least one lipid-lowering drug (LLD). The patients at high/very high CVr treated or not treated with LLD, reached the LDL-C target in 24.0 and 10.3%, respectively (p < 0.001). Furthermore, 34.6% of patients treated with high intensity LLDs and adherent to therapy showed the LDL-C values below the therapeutic target. Out of 1,373 patients at high/very high CVr, 958 (69.8%) had at least one prescription of glucose-lowering drugs. Of them, 52.0% (n = 498) were prescribed not in agreement with the current guidelines. More specifically, 392 patients (40.9%) were treated with metformin only, while the remaining 106 (11.1%) were treated with metformin together with hypoglycemic agents other than glucagon-like peptide-1 receptor agonists (GLP1-RA) or sodium-glucose-transporter 2 (SGLT2) inhibitors. Our results suggest the urgent need to improve the management of patients with diabetes at high and very high CVr in the real life, to reduce the burden of diabetes on the health system.

Published
2021
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11. Effects of Lipid Lowering Therapy Optimization by PCSK9 Inhibitors on Circulating CD34+ Cells and Pulse Wave Velocity in Familial Hypercholesterolemia Subjects without Atherosclerotic Cardiovascular Disease: Real-World Data from Two Lipid Units

Author

Roberto Scicali, Giuseppe Mandraffino, Michele Scuruchi, Alberto Lo Gullo, Antonino Di Pino, Viviana Ferrara, Carmela Morace, Caterina Oriana Aragona, Giovanni Squadrito, Francesco Purrello, and Salvatore Piro

Subjects
circulating CD34+ cells, familial hypercholesterolemia, PCSK9 inhibitors, pulse wave velocity, cardiovascular risk, Biology (General), QH301-705.5
Abstract

Background: Circulating CD34+ progenitor cells (CD34+CPCs) are characterized by pronounced tissue regeneration activity. Dyslipidemic subjects seemed to have reduced CD34+CPCs, and statin therapy appeared to restore their levels. We aimed to evaluate the effects of PCSK9 inhibitors (PCSK9-i) on CD34+CPCs and pulse wave velocity (PWV) in a cohort of heterozygous familial hypercholesterolemia (HeFH) subjects. Methods: We determined CD34+ cell count and its change after PCSK9-i in 30 selected HeFH subjects and 30 healthy controls. Lipid profile and PWV were evaluated at baseline (T0), 6 months after intensive lipid lowering strategy (statin plus ezetimibe, T1), and after 6 months of optimized therapy with PCSK9-i (T2); CD34+ cell count was reported at T1 and T2. Results: At T1, the median value of CD34+ cells was not significantly different between HeFH subjects and controls, and the same result was obtained at T2. PWV was significantly reduced at T1 (ΔPWV − 14.8%, p < 0.001 vs. T0) and T2 (ΔPWV − 10.96%, p < 0.001 vs. T1). Dividing HeFH subjects into two groups of high- and low-CD34+ cell count, CD34+CPCs appeared to be polarized with a significant difference between the two groups (1.2 (0.46) vs. 4.74 (1.92), p < 0.001), also with respect to controls (both p < 0.001). This polarization was no longer observed at T2, and neither with respect to controls. ΔCD34+ was +67.4% in the low-CD34+ group and −39.24% in the high-CD34+ group (p < 0.001). Lastly, we found a significant correlation between ΔCD34+ cell number and ΔPWV in HeFH subjects (rho = −0.365, p < 0.05), particularly in the low-CD34+ group (rho = −0.681, p < 0.001). Conclusion: PCSK9-i exhibited favorable effects on CD34 + CPCs as was on PWV values in a cohort of FH subjects. Our preliminary findings suggest a possible positive role of this novel lipid-lowering strategy on vascular homeostasis.

Published
2022
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12. Fatty Liver as Potential Biomarker of Atherosclerotic Damage in Familial Combined Hyperlipidemia

Author

Giuseppe Mandraffino, Carmela Morace, Maria Stella Franzè, Veronica Nassisi, Davide Sinicropi, Maria Cinquegrani, Carlo Saitta, Riccardo Scoglio, Sebastiano Marino, Alessandra Belvedere, Valentina Cairo, Alberto Lo Gullo, Michele Scuruchi, Giovanni Raimondo, and Giovanni Squadrito

Subjects
NAFLD, FCH, carotid atherosclerosis, noninvasive diagnosis, liver ultrasound, liver fibrosis, Biology (General), QH301-705.5
Abstract

Familial combined hyperlipidemia (FCH) is a very common inherited lipid disorder, characterized by a high risk of developing cardiovascular (CV) disease and metabolic complications, including insulin resistance (IR) and type 2 diabetes mellitus (T2DM). The prevalence of non-alcoholic fatty liver disease (NAFLD) is increased in FCH patients, especially in those with IR or T2DM. However, it is unknown how precociously metabolic and cardiovascular complications appear in FCH patients. We aimed to evaluate the prevalence of NAFLD and to assess CV risk in newly diagnosed insulin-sensitive FCH patients. From a database including 16,504 patients, 110 insulin-sensitive FCH patients were selected by general practitioners and referred to the Lipid Center. Lipid profile, fasting plasma glucose and insulin were determined by standard methods. Based on the results of the hospital screening, 96 patients were finally included (mean age 52.2 ± 9.8 years; 44 males, 52 females). All participants underwent carotid ultrasound to assess carotid intima media thickness (cIMT), presence or absence of plaque, and pulse wave velocity (PWV). Liver steatosis was assessed by both hepatic steatosis index (HSI) and abdomen ultrasound (US). Liver fibrosis was non-invasively assessed by transient elastography (TE) and by fibrosis 4 score (FIB-4) index. Carotid plaque was found in 44 out of 96 (45.8%) patients, liver steatosis was found in 68 out of 96 (70.8%) and in 41 out of 96 (42.7%) patients by US examination and HSI, respectively. Overall, 72 subjects (75%) were diagnosed with steatosis by either ultrasound or HSI, while 24 (25%) had steatosis excluded (steatosis excluded by both US and HSI). Patients with liver steatosis had a significantly higher body mass index (BMI) compared to those without (p < 0.05). Steatosis correlated with fasting insulin (p < 0.05), liver stiffness (p < 0.05), BMI (p < 0.001), and inversely with high-density lipoprotein cholesterol (p < 0.05). Fibrosis assessed by TE was significantly associated with BMI (p < 0.001) and cIMT (p < 0.05); fibrosis assessed by FIB-4 was significantly associated with sex (p < 0.05), cIMT (p < 0.05), and atherosclerotic plaque (p < 0.05). The presence of any grade of liver fibrosis was significantly associated with atherosclerotic plaque in the multivariable model, independent of alcohol habit, sex, HSI score, and liver stiffness by TE (OR 6.863, p < 0.001). In our cohort of newly diagnosed, untreated, insulin-sensitive FCH patients we found a high prevalence of liver steatosis. Indeed, the risk of atherosclerotic plaque was significantly increased in patients with liver fibrosis, suggesting a possible connection between liver disease and CV damage in dyslipidemic patients beyond the insulin resistance hypothesis.

Published
2022
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14. Role of Vitamin K in Chronic Kidney Disease: A Focus on Bone and Cardiovascular Health

Author

Federica Bellone, Maria Cinquegrani, Ramona Nicotera, Nazareno Carullo, Alessandro Casarella, Pierangela Presta, Michele Andreucci, Giovanni Squadrito, Giuseppe Mandraffino, Marcello Prunestì, Cristina Vocca, Giovambattista De Sarro, Davide Bolignano, and Giuseppe Coppolino

Subjects
kidney, vitamin K, phylloquinone, menaquinone, cardiovascular disease, calcification, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Chronic kidney disease (CKD) is commonly associated with vitamin K deficiency. Some of the serious complications of CKD are represented by cardiovascular disease (CVD) and skeletal fragility with an increased risk of morbidity and mortality. A complex pathogenetic link between hormonal and ionic disturbances, bone tissue and metabolism alterations, and vascular calcification (VC) exists and has been defined as chronic kidney disease–mineral and bone disorder (CKD-MBD). Poor vitamin K status seems to have a key role in the progression of CKD, but also in the onset and advance of both bone and cardiovascular complications. Three forms of vitamin K are currently known: vitamin K1 (phylloquinone), vitamin K2 (menaquinone), and vitamin K3 (menadione). Vitamin K plays different roles, including in activating vitamin K-dependent proteins (VKDPs) and in modulating bone metabolism and contributing to the inhibition of VC. This review focuses on the biochemical and functional characteristics of vitamin K vitamers, suggesting this nutrient as a possible marker of kidney, CV, and bone damage in the CKD population and exploring its potential use for promoting health in this clinical setting. Treatment strategies for CKD-associated osteoporosis and CV disease should include vitamin K supplementation. However, further randomized clinical studies are needed to assess the safety and the adequate dosage to prevent these CKD complications.

Published
2022
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15. PCSK9 Plasma Levels Are Associated with Mechanical Vascular Impairment in Familial Hypercholesterolemia Subjects without a History of Atherosclerotic Cardiovascular Disease: Results of Six-Month Add-On PCSK9 Inhibitor Therapy

Author

Arianna Toscano, Maria Cinquegrani, Michele Scuruchi, Antonino Di Pino, Salvatore Piro, Viviana Ferrara, Carmela Morace, Alberto Lo Gullo, Egidio Imbalzano, Francesco Purrello, Giovanni Squadrito, Roberto Scicali, and Giuseppe Mandraffino

Subjects
PCSK9, familial hypercholesterolemia, atherosclerotic injury, Microbiology, QR1-502
Abstract

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a key regulator of low-density lipoprotein (LDL) metabolism involved in the degradation of the low-density lipoprotein receptor (LDLR) through complex mechanisms. The PCSK9 plasma levels change according to lipid lowering therapy (LLT). Few data exist regarding the role of PCSK9 in vascular damage. We aimed to evaluate the impact of PCSK9 plasma levels on pulse wave velocity (PWV) and the effect of PCSK9 inhibitors (PCSK9-i) on circulating PCSK9 and PWV in a cohort of heterozygous familial hypercholesterolemia (HeFH) subjects. In a previous step, HeFH patients were enrolled and LLT was prescribed according to guidelines. Biochemical analyses and PWV assessment were performed at baseline (T0), after 6 months of high-efficacy statin plus ezetimibe (T1) and after 6 months of PCSK9-i (T2). The PCSK9 levels were evaluated in 26 selected HeFH subjects at the three time points and 26 healthy subjects served as controls for the reference value for PCSK9 plasma levels. The PWV values decreased at each time point in HeFH subjects after LLT starting (8.61 ± 2.4 m/s, −8.7%; p < 0.001 vs. baseline at T1, and 7.9 ± 2.1 m/s, −9.3%; p < 0.001 vs. both T1 and baseline) and it was correlated to PCSK9 (r = 0.411, p = 0.03). The PCSK9 levels increased on statin/EZE therapy (+42.8% at T1) while it decreased after PCSK9-i was started (−34.4% at T2). We noted a significant relationship between PCSK9 levels and PWV changes at T1 and T2. In conclusion, PCSK9 levels were associated with baseline PWV values in HeFH subjects; moreover, we found that PCSK9 level variations seemed to be correlated with PWV changes on LLT. A longer observation time and wider sample size are needed to assess the potential role of PCSK9 plasma levels on the vascular function and remodelling, and to clarify the effects of PCSK9-i in these pathways.

Published
2022
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16. Expression and Change of miRs 145, 221 and 222 in Hypertensive Subjects Treated with Enalapril, Losartan or Olmesartan

Author

Giuseppe Mandraffino, Alberto Lo Gullo, Maria Cinquegrani, Angela D’Ascola, Davide Sinicropi, Egidio Imbalzano, Giuseppe Blando, Giuseppe Maurizio Campo, Carmela Morace, Clemente Giuffrida, Salvatore Campo, Giovanni Squadrito, and Michele Scuruchi

Subjects
microRNA, atherosclerosis, arterial hypertension, arterial stiffness, cell programming, Biology (General), QH301-705.5
Abstract

miR profile could be associated to CV risk, and also to prognosis/outcome in response to therapeutic approach. We aimed to evaluate if anti-hypertensive drugs enalapril, losartan or olmesartan have effects on monocyte miR profile in essential hypertensives without target organ involvement. For this purpose, 82 hypertensives and 49 controls were included; we evaluated SBP/DBP, lipid profile, glucose, CRP, fibrinogen, arterial stiffness indices (PWV; AIx), and cIMT at baseline (T0) and after 24 weeks of treatment (T1). Subjects with LDL-C ≥ 160 mg/dL, TG ≥ 200 mg/dL, BMI ≥ 30, and other additional CV risk factors were excluded. Patients who were prescribed to receive once-a-day enalapril 20 mg, losartan 100 mg or olmesartan 20 mg were eligible for the study. At T1, we found a significant improvement of SBP (−18.5%), DBP (−18%), HDL-C and LDL-C (+3% and −5.42%), glucose (−2.15%), BMI (−3.23%), fibrinogen (−11%), CRP (−17.5%,), AIx (−49.1%) PWV (−32.2%), and monocyte miR expression (miR-221: −28.4%; miR-222: −36%; miR-145: +41.7%) with respect to baseline. miR profile was compared to control subjects at baseline and at T1. We found some little difference in the behaviour of the three treatments on some variables: olmesartan was the most effective in reducing fibrinogen, DBP, CRP, and AIx (−13.1%, −19.3%, −21.4%, and −56.8%, respectively). Enalapril was the drug more significantly increasing the expression of miR-145. In conclusion, enalapril, losartan and olmesartan are effective in improving mechanical and humoral factors associated to AS and atherogenesis. These drugs appear to be able to modify miRs 221/222 and miR-145 expression in drug-naïve hypertensives, making it closer to that of control subjects; additionally, this provides a good blood pressure compensation, contributing to slow the progression of vascular damage.

Published
2021
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17. Endocan and Circulating Progenitor Cells in Women with Systemic Sclerosis: Association with Inflammation and Pulmonary Hypertension

Author

Alberto Lo Gullo, Giuseppe Mandraffino, Javier Rodríguez-Carrio, Michele Scuruchi, Davide Sinicropi, Maria Postorino, Carmela Morace, Clemente Giuffrida, Davide Sciortino, Romina Gallizzi, Saverio Loddo, Concetta Zito, and Giovanni Squadrito

Subjects
endocan, circulating progenitor cells, pulmonary hypertension, systemic sclerosis, Biology (General), QH301-705.5
Abstract

Background: Systemic sclerosis (SSc) is characterized by early vasculopathy and fibrosis in the skin, lungs, and other tissues. Vascular manifestations of SSc include Raynaud’s phenomenon, digital ulcers, and pulmonary artery hypertension (PAH). PAH is the second most common cause of mortality in SSc. Circulating CD34+ cells associated with cardiovascular health status in several conditions, including chronic immune-inflammatory disease. CD34+ cell numbers have been found inconstantly reduced in SSc. Endocan, a proteoglycan expressed by endothelial cells, was recently suggested as a marker of vascular stress. We tested the relationships among CD34+ cells, endocan, inflammatory markers, vitamin D levels, and clinical parameters in SSc patients with PAH. METHODS: Standard echocardiography was performed. Vitamin D levels, CD34+ cells, inflammatory markers, endocan plasma levels were determined in 36 female SSc patients (24 diffuse/12 limited) and 36 matched controls (HC). RESULTS: We found no difference in CD34+ and vitamin D levels in SSc as compared to controls; ESR, CRP, fibrinogen, endocan, sPAP were higher in SSc with respect to controls. We found a correlation between endocan and: CD34+ cells (r: −0.540, p = 0.002), pulmonary arterial pressure (sPAP) (r: 0.565, p < 0.001), tricuspid annular plane excursion (TAPSE) (r: −0.311, p < 0.01), and E/A ratio (r: −0.487, p < 0.001), but not with ejection fraction (r: −0.057, p = 0.785) in SSc. CD34+ cells correlate with fibrinogen (r: −0.619, p < 0.001), sPAP (r: −0.404, p = 0.011), E/A (r: 0.470, p < 0.005 in SSc. CONCLUSION: CD34+ cell number was significantly correlated with endocan levels and with sPAP in SSc; endocan and CD34+ progenitor cells might be suggested as a potential marker of disease status.

Published
2021
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18. Adverse Drug Reactions in Hospitalized Patients: Results of the FORWARD (Facilitation of Reporting in Hospital Ward) Study

Author

Claudia Giardina, Paola M. Cutroneo, Eleonora Mocciaro, Giuseppina T. Russo, Giuseppe Mandraffino, Giorgio Basile, Franco Rapisarda, Rosarita Ferrara, Edoardo Spina, and Vincenzo Arcoraci

Subjects
adverse drug reactions, pharmacovigilance, preventability, hospital admission, elderly, internal medicine, Therapeutics. Pharmacology, RM1-950
Abstract

Background: Adverse drug reactions (ADRs) are an important public health problem, representing a major cause of morbidity and mortality. However, several countries have no recent studies available. Since 2014, a prospective active pharmacovigilance project, aimed to improve ADRs monitoring in hospital wards (FORWARD) was performed in Sicily. This study, as part of FORWARD project, was aimed to describe ADRs occurred during the hospital stay in Internal Medicine wards. ADRs related to hospital admission, characteristics and preventability of ADRs were also evaluated.Methods: Demographic, clinical, and pharmacological data on patients admitted to six wards of Internal Medicine, from 2014 to 2015, were collected by trained, qualified monitors, who screened all medical records. The rate of ADRs occurred during hospital stay and those leading to hospitalization were analyzed. A descriptive analysis of the reactions, suspected drugs, and associated factors was performed according to the setting analyzed.Results: During the study period, 4,802 admissions were recorded; in 3.2% of them ADRs occurred during hospital stay while in 6.2%, admission was due to ADRs. The duration of hospital stay was longer in patients who experienced ADRs during hospitalization, compared to patients without ADRs [median days 12 (Q1–Q3: 8–17) vs. 9 (6–13)]; p < 0.001). Females [OR1.39 (95% CI 1.03–1.93)] and patients taking ≥ 4 drugs [OR1.46 (95% CI 1.06–2.03)] were more likely to experience ADRs during hospital stay, as well as to be admitted because of ADRs [female: OR1.75 (95% CI 1.37–2.24); ≥ 4 drugs: OR2.14 (95% CI 1.67–2.74)]. The most frequent ADRs occurred during hospital stay were cutaneous (26.8%), general (13.4%), vascular (13.4%), and cardiac (11.5%) disorders and the drug classes mainly involved were anti-bacterials (38.2%) and antithrombotic agents (21.7%). ADRs were serious in 44.6% and probably preventable in 69.4%. Gastrointestinal (27.7%), hematological (26.5%), metabolic (18.1%), and nervous (16.1%) disorders were the main ADRs cause of hospitalization, primarily due to antithrombotic agents (39.0%) RAS-inhibitors (13.9%), NSAIDs (11.9%), and diuretics (9.0%). Only 12.9% of them was not preventable.Conclusion: Adverse drug reactions occurred during hospitalization or contributing to admission to Internal Medicine wards were considerable and most of them were preventable. Females and patients taking many medications were more likely to present ADRs both during hospital stay or as cause of admission.

Published
2018
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19. Circulating progenitor cells in hypertensive subjects: Effectiveness of a treatment with olmesartan in improving cell number and miR profile in addition to expected pharmacological effects.

Author

Giuseppe Mandraffino, Caterina Oriana Aragona, Valentina Cairo, Michele Scuruchi, Alberto Lo Gullo, Angela D'Ascola, Angela Alibrandi, Saverio Loddo, Sebastiano Quartuccio, Carmela Morace, Enricomaria Mormina, Giorgio Basile, Antonino Saitta, and Egidio Imbalzano

Subjects
Medicine, Science
Abstract

CD34+ circulating progenitor cells (CD34+CPCs) are a population of multipotent cells which can delay the development of atherosclerosis and cardiovascular disease (CVD) in conditions of increased CV risk. MicroRNAs (miRs) 221 and 222 modulate different genes regulating angiogenesis and inflammation; moreover, miR221/22 have beenshown to participate in differentiation and proliferation of CD34+CPCs, inhibiting cell migration and homing. miR221/222 in CD34+CPCs from hypertensive subjects are also increased and associated with CD34+cell number and reactive oxygen species (ROS). We evaluated CD34+CPC number, intracellular miR221/222 and ROS levels, arterial stiffness (AS)and echocardiography indices at baseline (T0).Then, after a six-month treatment with olmesartan, 20 mg/day (T1), in 57 hypertensive patients with left ventricular hypertrophy (LVH) and with no additional risk factor for CVD, and in 29 healthy controls (baseline),fibrinogen, C-reactive protein (CRP), glucose and lipid profiles were also evaluated.At T1, blood pressure values, CRP and fibrinogen levels, ROS and miR221/222 were significantly decreased (all p

Published
2017
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20. Endothelial Progenitor Cells for Diagnosis and Prognosis in Cardiovascular Disease

Author

Caterina Oriana Aragona, Egidio Imbalzano, Federica Mamone, Valentina Cairo, Alberto Lo Gullo, Angela D’Ascola, Maria Adriana Sardo, Michele Scuruchi, Giorgio Basile, Antonino Saitta, and Giuseppe Mandraffino

Subjects
Internal medicine, RC31-1245
Abstract

Objective. To identify, evaluate, and synthesize evidence on the predictive power of circulating endothelial progenitor cells (EPCs) in cardiovascular disease, through a systematic review of quantitative studies. Data Sources. MEDLINE was searched using keywords related to “endothelial progenitor cells” and “endothelium” and, for the different categories, respectively, “smoking”; “blood pressure”; “diabetes mellitus” or “insulin resistance”; “dyslipidemia”; “aging” or “elderly”; “angina pectoris” or “myocardial infarction”; “stroke” or “cerebrovascular disease”; “homocysteine”; “C-reactive protein”; “vitamin D”. Study Selection. Database hits were evaluated against explicit inclusion criteria. From 927 database hits, 43 quantitative studies were included. Data Syntheses. EPC count has been suggested for cardiovascular risk estimation in the clinical practice, since it is currently accepted that EPCs can work as proangiogenic support cells, maintaining their importance as regenerative/reparative potential, and also as prognostic markers. Conclusions. EPCs showed an important role in identifying cardiovascular risk conditions, and to suggest their evaluation as predictor of outcomes appears to be reasonable in different defined clinical settings. Due to their capability of proliferation, circulation, and the development of functional progeny, great interest has been directed to therapeutic use of progenitor cells in atherosclerotic diseases. This trial is registered with registration number: Prospero CRD42015023717.

Published
2016
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21. Vitamin D Status in Rheumatoid Arthritis: Inflammation, Arterial Stiffness and Circulating Progenitor Cell Number.

Author

Alberto Lo Gullo, Giuseppe Mandraffino, Gianluca Bagnato, Caterina Oriana Aragona, Egidio Imbalzano, Angela D'Ascola, Francesco Rotondo, Antonella Cinquegrani, Enricomaria Mormina, Carlo Saitta, Antonio Giovanni Versace, Maria Adriana Sardo, Renato Lo Gullo, Saverio Loddo, and Antonino Saitta

Subjects
Medicine, Science
Abstract

Suboptimal vitamin D status was recently acknowledged as an independent predictor of cardiovascular diseases and all-cause mortality in several clinical settings, and its serum levels are commonly reduced in Rheumatoid Arthritis (RA). Patients affected by RA present accelerated atherosclerosis and increased cardiovascular morbidity and mortality with respect to the general population. In RA, it has been reported an impairment of the number and the activity of circulating proangiogenic haematopoietic cells (PHCs), including CD34+, that may play a role in endothelial homeostasis. The purpose of the study is to investigate the association between vitamin D levels and PHCs, inflammatory markers, and arterial stiffening in patients with RA.CD34+ cells were isolated from 27 RA patients and 41 controls. Vitamin D levels, C-reactive protein (CRP), fibrinogen, pulse wave velocity (PWV), and carotid intima-media thickness (cIMT) were also evaluated. CD34+ count and vitamin D levels were lower in RA patients as compared to controls, while fibrinogen, CRP, PWV and cIMT were higher in RA patients. CD34+ cell number appeared to be associated with vitamin D levels, and negatively correlated to fibrinogen and early atherosclerosis markers (PWV and cIMT); vitamin D levels appear also to be inversely associated to fibrinogen.RA patients with moderate disease activity presented with low vitamin D levels, low CD34+ cell count, increased PWV and cIMT; we found that vitamin D deficiency is associated to CD34+ cell reduction in peripheral blood, and with fibrinogen levels. This suggests that vitamin D might contribute to endothelial homeostasis in patients with RA.

Published
2015
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23. Classifying Cardiac Anomalies in Right and Left Isomerism: Concordant and Discordant Patterns

Author

Lilia Oreto, Giuseppe Mandraffino, Paolo Ciliberti, Teresa P. Santangelo, Placido Romeo, Antonio Celona, Placido Gitto, Lorenzo Galletti, Fiore S. Iorio, Alfredo Di Pino, Aurelio Secinaro, Paolo Guccione, Robert H. Anderson, and Salvatore Agati

Subjects
Pediatrics, Perinatology and Child Health, Radiology, Nuclear Medicine and imaging, Surgery, General Medicine, Cardiology and Cardiovascular Medicine
Published
2023

24. Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia

Author

Olmastroni, Elena, Gazzotti, Marta, Averna, Maurizio, Arca, Marcello, Tarugi, Patrizia, Calandra, Sebastiano, Bertolini, Stefano, Catapano, Alberico L, Casula, Manuela, Laura D'Erasmo, Angelo Baldassare Cefalu, Andrea Bartuli, Paola Sabrina Buonuomo, Andrea Benso, Guglielmo Beccuti, Giacomo Biasucci, Maria Elena Capra, Gianni Biolo, Pierandrea Vinci, Luca Bonanni, Claudio Borghi, Sergio D'Addato, Antonio Carlo Bossi, Giancarla Meregalli, Adriana Branchi, Paolo Calabrò, Francesca Carubbi, Fabio Nascimbeni, Francesco Cipollone, Marco Bucci, Nadia Citroni, Maria Del Ben, Francesco Baratta, Massimo Federici, Martina Montagna, Claudio Ferri, Serena Notargiacomo, Anna Maria Fiorenza, Emanuela Colombo, Giuliana Fortunato, Maria Donata Di Taranto, Andrea Giaccari, Simona Moffa, Francesco Giorgino, Sergio Di Molfetta, Ornella Guardamagna, Luisa De Sanctis, Arcangelo Iannuzzi, Raimondo Cavallaro, Gabriella Iannuzzo, Marco Gentile, Lorenzo Iughetti, Patrizia Bruzzi, Salvatore Lia, Alessandro Lupi, Giuseppe Mandraffino, Arianna Toscano, Rossella Marcucci, Martina Berteotti, Lorenzo Maroni, Fabiana Locatelli, Tiziana Montalcini, Giuliana Mombelli, Sandro Muntoni, Davide Baldera, Gianfranco Parati, Angelina Passaro, Valerio Pecchioli, Cristina Pederiva, Giuseppe Banderali, Antonio Pipolo, Debora D'Elia, Matteo Pirro, Vanessa Bianconi, Livia Pisciotta, Elena Formisano, Francesco Purrello, Roberto Scicali, Elena Repetti, Elena Cantino, Elisabetta Rinaldi, Elena Sani, Riccardo Sarzani, Francesco Spannella, Francesco Sbrana, Beatrice Dal Pino, Patrizia Suppressa, Veronica Cocco, Chiara Trenti, Emanuele Alberto Negri, Josè Pablo Werba, Alessandra Romandini, Sabina Zambon, Alberto Zambon, Maria Grazia Zenti, Giulia Fainelli, Fabio Pellegatta, Liliana Grigore, Katia Bonomo, Eleonora Capatti, Ada Cutolo, Fabio Fimiani, Simonetta Genovesi, Sandro Inchiostro, Chiara Pavanello, Roberta Pujia, Alon Schaffer, Olmastroni, Elena, Gazzotti, Marta, Averna, Maurizio, Arca, Marcello, Tarugi, Patrizia, Calandra, Sebastiano, Bertolini, Stefano, Catapano, Alberico L, Casula, Manuela, and Laura D'Erasmo, Angelo Baldassare Cefalu, Andrea Bartuli, Paola Sabrina Buonuomo, Andrea Benso, Guglielmo Beccuti, Giacomo Biasucci, Maria Elena Capra, Gianni Biolo, Pierandrea Vinci, Luca Bonanni, Claudio Borghi, Sergio D'Addato, Antonio Carlo Bossi, Giancarla Meregalli, Adriana Branchi, Paolo Calabrò, Francesca Carubbi, Fabio Nascimbeni, Francesco Cipollone, Marco Bucci, Nadia Citroni, Maria Del Ben, Francesco Baratta, Massimo Federici, Martina Montagna, Claudio Ferri, Serena Notargiacomo, Anna Maria Fiorenza, Emanuela Colombo, Giuliana Fortunato, Maria Donata Di Taranto, Andrea Giaccari, Simona Moffa, Francesco Giorgino, Sergio Di Molfetta, Ornella Guardamagna, Luisa De Sanctis, Arcangelo Iannuzzi, Raimondo Cavallaro, Gabriella Iannuzzo, Marco Gentile, Lorenzo Iughetti, Patrizia Bruzzi, Salvatore Lia, Alessandro Lupi, Giuseppe Mandraffino, Arianna Toscano, Rossella Marcucci, Martina Berteotti, Lorenzo Maroni, Fabiana Locatelli, Tiziana Montalcini, Giuliana Mombelli, Sandro Muntoni, Davide Baldera, Gianfranco Parati, Angelina Passaro, Valerio Pecchioli, Cristina Pederiva, Giuseppe Banderali, Antonio Pipolo, Debora D'Elia, Matteo Pirro, Vanessa Bianconi, Livia Pisciotta, Elena Formisano, Francesco Purrello, Roberto Scicali, Elena Repetti, Elena Cantino, Elisabetta Rinaldi, Elena Sani, Riccardo Sarzani, Francesco Spannella, Francesco Sbrana, Beatrice Dal Pino, Patrizia Suppressa, Veronica Cocco, Chiara Trenti, Emanuele Alberto Negri, Josè Pablo Werba, Alessandra Romandini, Sabina Zambon, Alberto Zambon, Maria Grazia Zenti, Giulia Fainelli, Fabio Pellegatta, Liliana Grigore, Katia Bonomo, Eleonora Capatti, Ada Cutolo, Fabio Fimiani, Simonetta Genovesi, Sandro Inchiostro, Chiara Pavanello, Roberta Pujia, Alon Schaffer

Subjects
cardiovascular risk, lipoprotein(a), familial hypercholesterolemia
Abstract

Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and Results An lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M- and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score ≥1). Subjects with FH/M- also had lower mean levels of pretreatment low-density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M- and FH/M+ groups

Published
2023

26. Evaluation of lipoprotein(a) in the prevention and management of atherosclerotic cardiovascular disease: A survey among the Lipid Clinics Network

Author

Catapano, Alberico L, Tokgözoğlu, Lale, Banach, Maciej, Gazzotti, Marta, Olmastroni, Elena, Casula, Manuela, Ray, Kausik K, the Lipid Clinics Network, Alaa ABDELRAZIK (University Hospital of North Midland, United Kingdom), Alberto MELLO E SILVA (Sociedade Portuguesa de Aterosclerose, Portugal), Alexander VONBANK (VIVIT Institute, Austria), Alexandros, D TSELEPIS (Dept of Chemistry, Atherothrombosis Research Center, University of Ioannina, Greece), Alper SONMEZ (Department of Endocrinology and Metabolism, Ankara Guven Hospital, Turkey), Angelina PASSARO (Department of Translational Medicine, University of Ferrara &amp, Center for the Study and Treatment of Metabolic Diseases, Atherosclerosis, and Clinical Nutrition, University Hospital of Ferrara Arcispedale Sant’Anna, Italy), Anja VOGT (Medizinische Klinik und Poliklinik IV, Klinikum der Universit¨at München, Germany), Ann MERTENS (Clinical and Experimental Endocrinology, Leuven, Ku, Leuven, Belgium), Ann VERHAEGEN (Antwerp University Hospital, Belgium), Arman, S POSTADZHIYAN (Medical University of Sofia, Saint Anna University Hospital, Departement of Cardiology, Bulgaria), BAHADIR KIRILMAZ (Canakkale Onsekiz Mart University, Medical Faculty Cardiology Dept, Baris GUNGOR (University of Health Sciences Dr. Siyami Ersek Hospital, Turkey), Berit S HEDEGAARD (Aalborg University, Denmark), Bertrand CARIOU (Nantes Universit´e, Chu, Nantes, Cnrs, Inserm, l’institut du thorax, Nantes, France), Britta OTTE (Universit¨atsklinikum Münster, Lipidambulanz, Germany), Bu˘gra ¨OZKAN (Mersin University, Turkey), of cardiology, Christ BERGE (Dept., Unversity Hopsital, Haukeland., Norway), F EBENBICHLER (Department for Internal Medicine I, Christoph, Medical University Innsbruck, Austria), Christoph J BINDER (Medical University of Vienna, Austria), Christoph OLIVIER (Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Conrad AZZOPARDI (Mater Dei Hospital, Malta), Cristina SOLER (Lipid Unit, Hospital de Sta Caterina, Spain), Dan GAITA (Universitatea de Medicina si Farmacie Victor Babes din Timisoara &amp, Clinica de Cardiologie, Institutul de Boli Cardiovasculare Timisoara, Romania), Daniel WEGHUBER (Department of Pediatrics, Paracelsus Medical University, Dilek URAL (Koç University School of Medicine Department of Cardiology, Turkey), Diogo CRUZ (Hospital de Cascais - Dr. Jos´e de Almeida, Portugal), Dragos VINEREANU (University of Medicine and Pharmacy, University and Emergency Hospital, Bucharest, Romania), Elena D PENCU (Grand Hˆopital de Charleroi GHDC, Belgium), Emil HAGSTR¨OM (Dept of medical sciences, Uppsala, University, Sweden), Erik B SCHMIDT (Aalborg University, Denmark), Erik, S STROES (Dept of vascular medicine, Amsterdamumc, The, Netherlands), Evangelos LIBEROPOULOS (1st Department of Propedeutic Medicine, School of Medicine, National and Kapodistrian University of Athens, General Hospital of Athens Laiko, Fabian DEMEURE (CHU UCL Namur - Site Godinne, Belgium), Fabio FIMIANI (Azienda Ospedaliera di Rilievo Nazionale AORN Dei Colli, Monaldi', 'V., Unit of Inherited and Rare Cardiovascular Diseases, Italy, ), Fabio PELLEGATTA (Center for the Study of Atherosclerosis. Bassini Hospital. Cinisello Balsamo, Italy), Fahri BAYRAM (Erciyes University, Turkey), Finn L HENRIKSEN (Department of Cardiology Odense University Hospital, Denmark), Florian H¨OLLERL (1st Medical Department, Landstrasse, Clinic, Vienna Health Association, Francesco CIPOLLONE (Clinica Medica Institute of, Department of Medicine and Aging Sciences, d’Annunzio' University, 'G., Francisco ARAÚJO (Hospital Lusíadas, Portugal), Franck BOCCARA (Sorbonne Universit´e, Groupe de Recherche Clinique number 22, C2MV—Complications Cardiovasculaires et M´etaboliques chez les Patients Vivant avec le Virus de l’Immunod´eficience Humaine, Institut National de la Sant´e et de la Recherche M´edicale Unit´e Mixte de Recherche, S 938, Centre de Recherche Saint-Antoine, Institut Hospital Universitaire de Cardiom ´etabolisme et Nutrition Cardiologie, Hˆopital Saint Antoine Assistance Publique–Hˆopitaux de Paris, Paris, France), François PAILLARD (Cardiologie et Centre Clinico-Biologique des Lipides et Ath´eroscl´erose, Chu, Rennes, France), Imre University Teaching Hospital, Gabor SIMONYI (DBC St., Metabolic, Center, Lipid, Center, Hungary), Gabriella IANNUZZO (Department of Clinical Medicine and Surgery. University of Naples Federico II, Italy), Giuseppe MANDRAFFINO (Department of Clinical and Experimental Medicine, - Lipid Center, University of Messina, Graham BAYLY (Dept Clinical Biochemistry, University Hospitals Bristol, United, Kingdom), Gustavs LATKOVSKIS (Institute of Cardiology and Regenerative Medicine, University of Latvia &amp, Latvian Center of Cardiology, Pauls Stradins Clinical University Hospital &amp, University of Latvia, Latvia), Gy¨orgy PARAGH (Division of Metabolic Disorders, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary), Hana ROSOLOVA (Charles University Prague Medical Hospital in Pilsen, Czech Republic), Handrean SORAN (Central Manchester University Hospital NHS Foundation Trust, United Kingdom), Helle KANSTRUP (Department of cardiology, Aarhus University hospital, Denmark), Hermann TOPLAK (Department of Medicine, Division of Endocrinology and Diabetology, Medical University Graz, Hülya ÇIÇEKÇIO ˘GLU (ankara bilkent city hospital, Turkey), Inanc ARTAC (Department of Cardiology, Kafkas University Hospital, Ioanna GOUNI-BERTHOLD (Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Irfan, V DUZEN (Gaziantep University, Cardiology, Department, Isabel M PALMA (CHUPORTO - Centro Hospitalar Universit ´ario do Porto, Portugal), Istvan REIBER (Szent Gyorgy University Teaching Hospital of Fejer County, Hungary), Iveta DZIVITE-KRISANE (Children’s University Hospital, Latvia), Jeanine, E ROETERS VAN LENNEP (Department of Internal medicine, Erasmus MC University Medical Center, Jean-Luc, J BALLIGAND (Institut de Recherche Exp´erimentale et Clinique, Universite catholique de Louvain, Bruxelles), Joao C PORTO (CHUC, Portugal), Jo˜ao, S DUARTE (Hospital Egas Moniz, Lisboa, Portugal), Johan DE SUTTER (AZ Maria Middelares Hospital Gent, Belgium), Jos´e L´OPEZ-MIRANDA (Lipid and Arteriosclerosis Unit. Department of Internal Medicine. Hospital Universitario Reina Sofia. IMIBIC. University of Cordoba. CiberOBN, Spain), Jose M MOSTAZA (Hospital La Paz-Carlos III, Spain), Jurgita PLISIENE (Lithuanian University of Health sciences, Lithuania), Kadir, U MERT (Eskis ¸ehir Osmangazi University, Department of Cardiology, Kirsten, B HOLVEN (Department of Nutrition, University of Oslo and National Advisory unit on FH, Oslo University Hospital, Kjetil RETTERSTØL (The Lipid Clinic, Oslo University Hospital and Department of Nutrition, University of Oslo, Kristian, K THOMSEN (University Hospital of South Denmark, Esbjerg, Denmark), Lale TOKGOZOGLU (Hacettepe University, Turkey), Laszlo BAJNOK (1st Department of Medicine, Medical, School, University of Pecs, Lia E BANG (Copenhagen University Hospital, Denmark), Liliana GRIGORE (IRCCS Multimedica, Italy), Lluís MASANA (Hospital Universitari Sant Joan. Universitat Rovira i Virgili. CIBERDEM. Reus, Spain), Loukianos S RALLIDIS (University General Hospital Attikon, Greece), Maciej BANACH (Department of Preventive Cardiology and Lipidology, Medical University of Lodz, Poland), Małgorzata WALU´S-MIARKA (Jagiellonian University Medical College, Of Metabolic Diseases and Diabetology, Dept., Manuel CASTRO CABEZAS (Franciscus Gasthuis &amp, Vlietland Rotterdam, The Netherlands), Marcello ARCA (Sapienza University of Rome, Italy), Margus VIIGIMAA (North Estonia Medical Centre, Tallinn University of Technology, Estonia), Martin, P BOGSRUD (Unit for Cardiac and Cardiovascular Genetics, Matej MLINARIˇC (Department of Endocrinology, Diabetes and Metabolism, University Children’s Hospital, University Medical Centre Ljubljana, Slovenia), Matteo PIRRO (Section of Internal Medicine, Angiology and Arteriosclerosis Diseases, Maurizio AVERNA (Department PROMISE-University of Palermo &amp, Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Palermo, Italy), Meral KAYIKCIOGLU (Ege University Medical School Department of Cardiology, Turkey), Merete HEITMANN (Bispebjerg-Frederiksberg University Hospital, Denmark), Mette MOURIDSEN (Department of Cardiology, Herlev and Gentofte Hospital, University of Copenhagen, Michal VRABLIK (3rd Department of Internal Medicine, General University Hospital and 1st Medical Faculty, Charles, University, Prague, Czech, Republic), Michel FARNIER (PEC2, University of Bourgogne Franche-Comt´e, Laboratory Medicine, Michel R LANGLOIS (Dept., Jan Hospital, AZ St., Belgium), Milad KHEDR (Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Muge ILDIZLI DEMIRBAS (Kartal Kosuyolu Research and Training Hospital, Turkey), Myra TILNEY (Lipid Clinic, Mater Dei Hospital &amp, Dept of Medicine, University of Malta Medical School, Malta), Nadia CITRONI (Internal Medicine, APSS Trento Hospital, Of Internal Medicine, Niels P RIKSEN (Dept., Radboud university medical center, Nikolay M RUNEV (UMHAT Alexandrovska, Bulgaria), Nora KUPSTYTEKRISTAPONE (Hospital of Lithuanian University of Health Sciences Kaunas Clinics, Lithuania), Olena MITCHENKO (NSC, Clinical and Regenerative Medicine of the NAMS of Ukraine, Ukraine), Oliver WEING¨ARTNER (Universit¨atsklinikum Jena, Department of Internal Medicine, I, Oner OZDOGAN (University of Health Sciences, Izmir Faculty of Medicine, Tepecik Training and Research Hospital, Ovidio MU˜NIZGRIJALVO (Hospital Virgen del Rocío, Spain), Ozcan BASARAN (Mugla Sitki Kocman University, Pankaj GUPTA (University Hospitals of Leicester, United Kingdom), Paolo PARINI (Cardio Metabolic Unit, Karolinska, Institutet, and Theme Inflammation and Ageing, Karolinska University Hospital Huddinge, Patrizia SUPPRESSA (Department of Internal Medicine and rare disease Centre, Bari, Italy), Paul DOWNIE (Salisbury NHS Foundation trust, United Kingdom), Pavel JESINA (Metabolic Center General University Hospital, Czech Republic), of Internal Medicine, Pavel KRAML (Dept., Third Faculty of Medicine, Charles University and Kr´alovsk´e Vinohrady University Hospital Prague, Pawel BURCHARDT (Department of Cardiology, Cardiovascular, Unit, Hospital, J. Stru´s., Pozna´n, &amp, Department of Hypertension, Angiology and Internal Medicine, Poznan University of Medical Sciences, Pozna´n, Poland), Pedro VALDIVIELSO (Hospital VIRGEN DE LA VICTORIA, Spain), Pedro VON HAFE (Instituto Cuf, Portugal), Dept, Peter FASCHING (5th Med., Clinic, Ottakring, Philippe MOULIN (Hospices civils de Lyon/INSERM/Universit ´e Lyon1, Hˆopital Louis Pradel, F´ed´eration, D’Endocrinologie, Quit´eria RATO (Sociedade Portuguesa de Aterosclerose, Portugal), Reinhold INNERHOFER (Medical University Vienna, Austria), Renata C´IFKOV´A (Center for Cardiovascular Prevention, Charles University in Prague, First Faculty of Medicine and Thomayer University Hospital, Rene VALERO (Aix Marseille Univ, Aphm, Inserm, Inrae, C2vn, University Hospital La Conception, Department of Nutrition, Metabolic Diseases and Endocrinology, Scicali, Roberto, Robin URB´ANEK (Internal medicine, Obezita-Ormiga, s. r. o., Roma KAVALIAUSKIENE (Klaip˙ eda Seamen’s Hospital, Lituania), Roman CIBULKA (Department of paramedic science, medical diagnostics studies and public health, Faculty of Health Care Studies, University of West Bohemia, Sabina ZAMBON (Department of Medicine, - DIMED, University of Padova, Sergio D’ADDATO (University of Bologna. IRCCS S. Orsola Bologna, Italy), Stanislav ZEMEK (Lipidova ambulance, Czech Republic), Stefano ROMEO (Gothenburg University, Sweden), Stephanie K¨ONEMANN (Department of Internal Medicine, B, University Medicine Greifswald, DZHK (German Centre for Cardiovascular Research), Susanne GREBER-PLATZER (Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Thomas STULNIG (Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University Vienna &amp, Third Medical Department and Karl Landsteiner Institute for Metabolic Diseases and Nephrology, Clinic, Hietzing, Vienna, Austria), Thomas MUHR (Dept of Cardiology, Link¨oping University Hospital, Tina, Z KHAN (Consultant Cardiologist, Royal Brompton and Harefield Hospitals Part of Guy’s and St Thomas’ NHS Foundation Trust, Tomas FREIBERGER (Centre of Cardiovascular Surgery and Transplantation, Brno &amp, Medical, Faculty, Masaryk, University, Brno, Tom´aˇs ˇS´ALEK (Metabolic Clinic, Tomas Bata Hospital, Zlín, Tomas VASYLIUS (Republican Panevezys hospital, Of Cardiology, Dep., Lithuania), Ulrich LAUFS (Klinik und Poliklinik für Kardiologie, Universit ¨atsklinikum Leipzig, Ulrike SCHATZ (University Hospital Carl Gustav Carus Dresden at the Technical University Dresden, Department of Internal Medicine III, Urh GROSELJ (UMC, - University Children’s Hospital Ljubljana, University of Ljubljana, Victoria MARCO-BENEDI (Hospital Universitario Miguel Servet, Iisa, Cibercv, Vincent MAHER (Advanced Lipid Management and Research ALMAR centre, Tallaght University Hospital, Ireland), Vladimír BLAHA (University Hospital Hradec Kr´alov´e and Charles University, Faculty of Medicine in Hradec Kr´alov´e, 3rd Department of Internal Medicine, - Metabolism and Gerontology, Vladimir SOSKA (Department of Clinical Biochemistry, St. Anne’s University Hospital Brno, 2nd Clinic of Internal Medicine, Masaryk University Brno, Volker JJ SCHETTLER (Centre of Nephrology G¨ottingen, Germany), Wolfgang REINHARDT (SUS Malmoe, Sweden), Xavier PINT´O (Hospital Universitari de Bellvitge-Idibell-UB-CiberObn, Spain), Yoto YOTOV (Second Cardiology Clinic, Marina, University Hospital Sv., Medical University of Varna, Zaneta PETRULIONIENE (Vilnius University Medical Faculty, Vilnius University Hospital Santaros klinikos, Lithuania), ˇZeljko REINER (Department for Metabolic Diseases, University Hospital Center Zagreb, and Croatia, ).

Subjects
Clinicians, Clinical evaluation, Cardiology and Cardiovascular Medicine, Cardiovascular risk, Lipoprotein(a)
Published
2023

27. 444 PULSE WAVE VELOCITY TO GLOBAL WORK EFFICIENCY RATIO IN HYPERTENSION: A NEW WAY TO EXPLORE VENTRICULAR-ARTERIAL COUPLING

Author

Giancarlo Trimarchi, Francesca Lofrumento, Giuseppe Mandraffino, Maurizio Cusmà-piccione, Federico Spanò, Giuseppe Certo, Roberta Manganaro, Scipione Carerj, Gianluca Di Bella, and Concetta Zito

Subjects
Cardiology and Cardiovascular Medicine
Abstract

Introduction Ventricular–arterial coupling (VAC) is considered as the cornerstone of the functional interaction between ventricles and the arterial system. VAC is commonly assessed as arterial elastance (Ea) to ventricular end-systolic elastance (Ees) ratio and it has independent prognostic value in hypertension, so it may be used to refine risk stratification and monitor therapeutic interventions in hypertensive patients. Therefore, VAC may be better characterized by the measurement of each component of this ratio through novel and more sensitive markers of myocardial function (e.g. global longitudinal strain and myocardial work parameters) and arterial function (e.g. pulse wave velocity). In this context, we aim to investigate whether new coupling indices may be able to identify left ventricular (LV) performance changes induced by blood pressure (BP) overload earlier than conventional ones. Methods 50 young individuals were prospectively enrolled, distinguishing between newly diagnosed untreated hypertensives (n= 25; 40±8 years) and controls (n=25; 39±9 years), matched for age and gender. All patients underwent at the same time carotid-femoral pulse wave velocity (PWV) measurement through an applanation tonometer (SphygmoCor® XCEL) and a transthoracic echocardiogram to calculate Ea/Ees ratio, assessed as end-systolic volume to stroke volume ratio (ESV/SV), global longitudinal strain (GLS) and myocardial work efficiency (GWE). Two new indices of VAC were derived: PWV/GLS, previously validated and PWV/GWE, still unknown. Results Ea/Ees ratio was lower in hypertensives (0,48±0,17) than in controls (0,57±0,14) but without any significant difference (p=0.18), whereas PWV/GLS was significantly higher in hypertensives than in controls (0,45±0,19 vs 0,35 ± 0,09 m/sec%; p= 0,02). PWV/GLS ratio correlated to Ea/Ees (r= 0,52; p < 0,01), diastolic dysfunction degree (r=-0,59; p Conclusions Innovative indices of ventricular-arterial coupling could be more sensitive to investigate the impact of hypertension on LV performance.

Published
2022

28. 783 RELATIONSHIP BETWEEN PULSE WAVE VELOCITY AND MYOCARDIAL WORK IN UNTREATED HYPERTENSIVE PATIENTS WITH PRESERVED LVEF

Author

Francesca Lofrumento, Giuseppe Mandraffino, Giancarlo Trimarchi, Anna Mancinelli, Davide Restelli, Rosalba De Sarro, Maurizio Cusmà-piccione, Roberta Manganaro, Gianluca Di Bella, Antonio Micari, Scipione Carerj, and Concetta Zito

Subjects
Cardiology and Cardiovascular Medicine
Abstract

Introduction Hemodynamic interaction between left ventricular (LV) and arterial system is a key determinant of cardiovascular performance. The non-invasive carotid-femoral Pulse Wave Velocity (PWV), obtained with applanation tonometry, is considered the most precise way of estimating arterial stiffness. The LV myocardial work (MW), based on non-invasive LV pressure-strain loop (PSL), is a new promising tool to assess LV function. Aims The aim of the study was to evaluate the correlation between PWV and MW parameters in a population of non-hypertensive and newly diagnosed untreated hypertensive people. Materials and methods 80 people (M=48), divided in hypertensive (group 1 n=40, 45±10 years) and non-hypertensive (group 2 n=40, 40±12 years), were prospectively enrolled. All underwent conventional transthoracic echocardiogram and at the same day carotid femoral PWV was calculated with applanation tonometry (SphygmoCor® XCEL). MW parameters were obtained using 2D Speckle-tracking technique. Results Comparing the two groups, PWV and Global Work Wasted (GWW) were significantly higher in the hypertensives group (9,73±2,4 vs 7,79±1,1; p=0,001 and 146±50 vs 85±27, p=0,001), as shown in Figure 1, whereas Global Work Efficiency (GWE) and Global Work Constructive (GWC) were significantly lower (93,6±2,5 vs 95,6±1,2, p=0,001 and 2410±122 vs 2167±65, p=0,002). We found a linear and positive correlation of PWV with GWW (r=0,271, p=0,016), as seen in Figure 2, and a linear and negative correlation of PWV with GWE (r=-0,282, p=0,012). Conclusion This study highlights the role of PWV and MW evaluation in hypertensives. Higher PWV and GWW could be considered as red flags of myocardial damage suggesting the need of an early appropriate antihypertensive therapy.

Published
2022

29. Serum endocan as a predictive biomarker of cardiovascular risk in obese pediatric patients

Author

Carmela Morace, Selenia Lorenza Curatola, Giuseppe Mandraffino, Michele Scuruchi, Angela Elvira Serranò, Angelo Tropeano, Fortunato Lombardo, Giuseppina Salzano, Giovanni Squadrito, Antonio Giovanni Versace, and Mariella Valenzise

Abstract

Background: Endocan is a soluble dermatan sulfate PG (50kDa), expressed and secreted by endothelial cells of the dermal microvasculature, the coronary, the pulmonary arteries and the capillaries from adipose tissue. It plays an important role in the pathogenesis of vascular disorders, inflammation, endothelium dysfunction and neoangiogenesis. The biosynthesis of endocan is upregulated by inflammatory cytokines like TNF-α, IL-1, TGF-β1 and by proangiogenic and growth factors like VEGF, EGF and FGF-2; conversely, it is downregulated by INF-γ and insulin level, but this event in obese patients is attenuated by insulin resistance. Methods: The study included 19 patients with obesity (10 males and 9 females), aged between 2-18 years, screened at the pediatric Endocrinology Clinic of our Department in Messina (Italy). Results: The results, compared with the healthy controlled group, have shown upraised endocan serum levels in children with BMI higher than normal (30,044 ±0,984), demonstrating a positive correlation trend between endocan and BMI (rho 0.356, p = 0.13). Furthermore endocan serum levels were significantly correlated to the insulin levels (rho 0.474, p = 0.047) and HOMA-IR (rho 0.434, p = 0.072). These findings confirm the correlation between endothelial damage and insulin resistance in obese children. Instead we did not found any association between Endocan and lipid serum levels, nor with the fasting blood glucose value (rho 0.024, p = 0.926). An elevated correlation was also revealed with steatosis, and with the ultrasound grade of liver steatosis (rho 0.514, p = 0.087 and rho 0.512, p = 0.088, respectively), despite not raising statistically significant results, given the small sample size, indeed only 12 children of the study underwent ultrasound. Conclusions: We can assume that endocan could be used also in children with obesity as a biomarker and that could be a valid predictor in order to stratify the future cardiovascular risk in adulthood. Retrospectively registered

Published
2022

30. The Role of Registers in Increasing Knowledge and Improving Management of Children and Adolescents Affected by Familial Hypercholesterolemia: the LIPIGEN Pediatric Group

Author

Gazzotti, Marta, Casula, Manuela, Bertolini, Stefano, Capra, Maria Elena, Olmastroni, Elena, Catapano, Alberico Luigi, Pederiva, Cristina, and the LIPIGEN Pediatric Group: Massimiliano Allevi, Internal Medicine and Geriatrics, Department of Clinical and Molecular Sciences, University 'Politecnica delle Marche' and IRCCS-INRCA, Ancona, Italy, Marcello, Arca, Dipartimento di Medicina Traslazionale, e di Precisione, O Policlinico Umberto I, Sapienza Università di Roma—A. U., Rome, Italy, Renata, Auricchio, Dipartimento di Scienze Mediche Traslazionali, AOU Policlinico Federico II, Naples, Italy, Averna, Maurizio, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna, e Specialistica di Eccellenza, Università degli Studi di Palermo, Palermo, Italy, Davide, Baldera, Dipartimento di Scienze Biomediche, Università degli Studi di Cagliari and Centro per le Malattie Dismetaboliche, e l’Arteriosclerosi, Onlus Cagliari, Associazione ME. DI. CO., Cagliari, Italy, Giuseppe, Banderali, Clinica Pediatrica, U. O., Servizio Clinico Dislipidemie per lo Studio, e la Prevenzione dell’Aterosclerosi in età Pediatrica, ASSTSanti Paolo, e Carlo, Milan, Italy, Andrea, Bartuli, UOC Malattie Rare, e Genetica Medica, Ospedale Pediatrico Bambino Gesù, Irccs, Rome, Italy, Stefano, Bertolini, Department of Internal Medicine, University of Genova, Genova, Italy, Giacomo, Biasucci, Centro Dislipidemie in Età Evolutiva, Pediatria e Neonatologia, U. O., Ospedale Guglielmo da Saliceto, Piacenza, Italy, Claudio, Borghi, di Medicina Interna Cardiovascolare, U. O., Centro, Aterosclerosi, Ambulatorio, Dislipidemie, Orsola-Malpighi, IRCCS S. Orsola Ospedale Policlinico S., Bologna, Italy, Patrizia, Bruzzi, Pediatria, U. O. C., Azienda Ospedaliero Universitaria di Modena, Modena, Italy, Raffaele, Buganza, Paediatric, Endocrinology, Department of Public Health and Paediatric Sciences, Turin, University, Turin, Italy, Paola Sabrina Buonuomo, Paolo, Calabrò, U. O. C. Cardiologia Clinica a Direzione Universitaria e U. T. I. C., 'Sant’Anna e San Sebastiano', A. O. R. N., Italy and Dipartimento di Scienze Mediche Traslazionali, Università degli Studi della Campania, Sebastiano, Calandra, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Maria Elena Capra, Francesca, Carubbi, Medicina interna metabolica, U. O., Centro dislipidemie, e malattie metaboliche rare, Ospedale Civile Baggiovara, AOU di Modena, Manuela, Casula, Dipartimento di Scienze Farmacologiche, e Biomolecolari, Università degli Studi di Milano, and IRCCS MultiMedica, Sesto San Giovanni (Milan), Alberico Luigi Catapano, Arturo, Cesaro, Università degli Studi della Campania 'Luigi Vanvitelli', Francesco, Cipollone, Clinica, Medica, Centro di riferimento regionale per le Dislipidemie, Annunziata, Ospedale Policlinico S. S., Chieti, Italy, Nadia, Citroni, Centro Dislipidemie, e Aterosclerosi, UOC Medicina Interna, Ospedale di Trento, Trento, Italy, Giuseppe, Covetti, Medicina Interna 2, U. O., Centro per le malattie da arteriosclerosi, Aorn, Cardarelli, Annalaura, Cremonini, IRCCS Ospedale policlinico San Martino UOSD Dietetica, e Nutrizione Clinica and Dipartimento di Medicina Interna, Università di Genova, Sergio, D’Addato, Maria Del Ben, Dipartimento Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari, - Sapienza Università, Policlinico Umberto I, A. O., Maria Donata Di Taranto, Dipartimento di Medicina Molecolare, e Biotecnologie Mediche, Università degli studi di Napoli Federico II and CEINGE Biotecnologie Avanzate, s. c. a. r. l., Giuliana, Fortunato, Roberto, Franceschi, Uoc, Pediatria, Federica, Galimberti, Irccs, Multimedica, Marta, Gazzotti, Fondazione SISA (Società Italiana per lo Studio dell’Aterosclerosi), Simonetta, Genovesi, IRCCS Istituto Auxologico Italiano and Dipartimento di Medicina, e Chirurgia, Università di Milano- Bicocca, Antonina, Giammanco, Liliana, Grigore, Centro per lo Studio dell’Aterosclerosi, Italy and Centro per lo Studio dell’Aterosclerosi, Bassini, Ospedale E., Cinisello, Balsamo, Ornella, Guardamagna, Arcangelo, Iannuzzi, Gabriella, Iannuzzo, Dipartimento di Medicina Clinica, e Chirurgia, Centro Coordinamento regionale per le Iperlipidemie, Lidia Lascala, AOU Mater Domini, Fabiana, Locatelli, Ambulatorio ipertensione dislipidemie rischio cardiovascolare, ASST Valle Olona, Ospedale di Gallarate, Gallarate, Italy, Ospedale di Busto Arsizio, Busto, Arsizio, Lorenzo, Iughetti, Sara, Madaghiele, Frugoni' and Centro di Assistenza e Ricerca Malattie Rare, U. O. di Medicina Interna e Geriatria 'C., Universitaria Policlinico Consorziale, A. O., Università degli Studi di Bari 'Aldo Moro', Bari, Italy, Giuseppe, Mandraffino, Martino, Department of Clinical and Experimental Medicine—Lipid Center—University Hospital G., Messina, Italy, Massimo Raffaele Mannarino, Internal, Medicine, University of Perugia, Angiology and Arteriosclerosis Diseases. Department of Medicine and Surgery., Perugia, Italy, Bucci, Marco, Lorenzo, Maroni, Ilenia, Minicocci, Giuliana, Mombelli, Centro Dislipidemie ASST Grande Ospedale Metropolitano Niguarda, Sandro, Muntoni, Fabio, Nascimbeni, Elena, Olmastroni, Servizio di Epidemiologia, e Farmacologia Preventiva (SEFAP), Dipartimento di Science Farmacologiche, e Biomolecolari, Gianfranco, Parati, Università di Milano-Bicocca, Angelina, Passaro, Department of Translational Medicine, University of Ferrara, Italy and Research and Innovation Section, University Hospital of Ferrara Arcispedale Sant’Anna, Chiara, Pavanello, Milan, Italy and Centro Grossi Paoletti, Milano, Italy, Cristina, Pederiva, ASST-Santi Paolo, e Carlo, Fabio, Pellegatta, Francesco Massimo Perla, Dipartimento Materno Infantile, e Scienze Urologiche—Sapienza Università, Medicina, Generale, Ospedale di Trecenta, Trecenta, Rovigo, Matteo, Pirro, Livia, Pisciotta, Arturo, Pujia, Mater Domini, A. O. U., UOC di Nutrizione Clinica, Purrello, Francesco, Department of Clinical and Experimental Medicine, University of Catania, Ospedale, Garibaldi, Catania, Italy, Elisabetta, Rinaldi, Endocrinologia, U. O., Diabetologia, e Malattie del Metabolismo, Universitaria Integrata di Verona, Centro regionale specializzato per la diagnosi e terapia delle dislipidemie e aferesi terapeutica and A. O., Verona, Italy, Riccardo, Sarzani, Scicali, Roberto, Patrizia, Suppressa, Patrizia, Tarugi, Department of Life Sciences, Sabrina, Verachtert, Giovanni Battista Vigna, Josè Pablo Werba, Ambulatorio Prevenzione Aterosclerosi, U. O., IRCCS Centro Cardiologico Monzino, Alberto, Zambon, Dipartimento di Medicina, Università di Padova, Padua, Italy, Sabina, Zambon, Maria Grazia Zenti, Servizio di Diabetologia, e Malattie Metaboliche, Pederzoli, Ospedale P., Peschiera del Garda, and Verona, Italy.

Subjects
genetic diagnosis, clinical diagnosis, familial hypercholesterolemia, cardiovascular genetics, pathology register, pediatric cohort, Settore BIO/14 - Farmacologia, Genetics, Molecular Medicine, Genetics (clinical)
Abstract

Pathology registers can be a useful tool to overcome obstacles in the identification and management of familial hypercholesterolemia since childhood. In 2018, the LIPIGEN pediatric group was constituted within the Italian LIPIGEN study to focus on FH subjects under 18 years. This work aimed at discussing its recent progress and early outcomes. Demographic, biochemical, and genetic baseline characteristics were collected, with an in-depth analysis of the genetic defects. The analysis was carried out on 1,602 children and adolescents (mean age at baseline 9.9 ± 4.0 years), and almost the whole cohort underwent the genetic test (93.3%). Overall, the untreated mean value of LDL-C was 220.0 ± 97.2 mg/dl, with an increasing gradient from subjects with a negative (N = 317; mean untreated LDL-C = 159.9 ± 47.7 mg/dl), inconclusive (N = 125; mean untreated LDL-C = 166.4 ± 56.5 mg/dl), or positive (N = 1,053; mean untreated LDL-C = 246.5 ± 102.1 mg/dl) genetic diagnosis of FH. In the latter group, the LDL-C values presented a great variability based on the number and the biological impact of involved causative variants. The LIPIGEN pediatric group represents one of the largest cohorts of children with FH, allowing the deepening of the characterization of their baseline and genetic features, providing the basis for further longitudinal investigations for complete details.

Published
2022
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31. Endocan, a novel inflammatory marker, is upregulated in human chondrocytes stimulated with IL-1 beta

Author

Angela D'Ascola, Giuseppe Mandraffino, Salvatore Campo, Michele Scuruchi, Giuseppe M. Campo, and Angela Avenoso

Subjects
0301 basic medicine, Cell type, Angiogenesis, Interleukin-1beta, Clinical Biochemistry, Context (language use), Inflammation, Proinflammatory cytokine, 03 medical and health sciences, Chondrocytes, 0302 clinical medicine, Downregulation and upregulation, Cell Movement, Human chondrocytes, medicine, Humans, Endocan, NF-kB, Molecular Biology, Neovascularization, Pathologic, biology, Interleukin-6, Tumor Necrosis Factor-alpha, Chemistry, Transcription Factor RelA, NF-kappa B p50 Subunit, Cell Biology, General Medicine, Recombinant Proteins, In vitro, Neoplasm Proteins, Up-Regulation, Cartilage, 030104 developmental biology, Proteoglycan, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Proteoglycans, medicine.symptom
Abstract

Endocan is a circulating proteoglycan, involved in immunity, inflammation, and endothelial function. It has been recently suggested as a biomarker of inflammation, increased angiogenesis, and cancer. In vitro studies have shown that endocan expression could be upregulated by inflammatory cytokines and proangiogenic molecules. High endocan levels were also shown in arthritic joint tissues and particularly in sites characterized by severe inflammation. This study was performed to evaluate endocan expression in chondrocytes stimulated with IL-ß. mRNA and related protein production were measured for endocan, TNF-α, and IL-6. NF-kB activity was also evaluated. IL-1ß treatment induced a significant upregulation of both endocan and the inflammatory parameters as well as NF-kB activity. The treatment of chondrocytes with the specific NF-kB inhibitor before IL-1ß stimulation was able to reduce endocan and the inflammatory markers over-expression. The results of our study indicated that endocan is also expressed in human chondrocytes; furthermore, consistent with previous results in other cell types and tissues, IL-1ß-induced inflammatory response involves the expression of endocan through NF-kB activation. In this context, endocan seems to be an important inflammatory marker associated with the activation of NF-kB pathway.

Published
2021

32. Abnormal left ventricular global strain during exercise-test in young healthy smokers

Author

Scipione Carerj, Clemente Giuffrida, Lilia Oreto, Giuseppe Mandraffino, Giovanni Squadrito, Carmela Morace, M. Cinquegrani, Alberto Lo Gullo, Concetta Zito, F. Savarino, and Egidio Imbalzano

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Longitudinal strain, Adolescent, Heart Ventricles, Cardiology, lcsh:Medicine, Diseases, 030204 cardiovascular system & hematology, Fibrinogen, Article, 03 medical and health sciences, Ventricular Dysfunction, Left, Young Adult, 0302 clinical medicine, Medical research, Internal medicine, medicine, Humans, Wall motion, lcsh:Science, Multidisciplinary, Ejection fraction, business.industry, Smoking, lcsh:R, Health care, Strain imaging, Stroke Volume, Global strain, Intensity (physics), 030104 developmental biology, Echocardiography, Baseline characteristics, Case-Control Studies, Exercise Test, Female, lcsh:Q, business, Biomarkers, medicine.drug
Abstract

Background. It is unknown how much precociously the cigarette smoking (CS) may compromise the integrity of the cardiovascular (CV) system. Myocardial function can be routinely assessed by conventional echocardiography, but abnormalities are only detected when somewhat a remodelling has already occurred. These limitations could be overcome by strain imaging. Methods. We evaluated whether young smokers with normal left ventricular (LV) geometry, wall motion and ejection fraction may present abnormalities in myocardial deformation, both at rest and during physical effort. We selected 50 young smokers with no additional CV risk factors, and 60 non-smokers to undergo a standardized exercise-test. Consistently, we evaluated the CV adaptation to exercise by both conventional echocardiography and speckle-tracking analysis (2D-STE). Results. We found no difference between smokers and controls regarding baseline characteristics; as expected, smokers presented with lower HDL-cholesterol (p

Published
2020

33. Lipoprotein(a) and family history for cardiovascular disease in paediatric patients: A new frontier in cardiovascular risk stratification. Data from the LIPIGEN paediatric group

Author

Cristina Pederiva, Maria Elena Capra, Giacomo Biasucci, Giuseppe Banderali, Enrico Fabrizi, Marta Gazzotti, Manuela Casula, Alberico L. Catapano, Marcello Arca, Maurizio Averna, Stefano Bertolini, Sebastiano Calandra, Alberico Luigi Catapano, Patrizia Tarugi, Fabio Pellegatta, Andrea Bartuli, Claudio Borghi, Paolo Calabrò, Francesca Carubbi, Francesco Cipollone, Nadia Citroni, Maria Del Ben, Giuliana Fortunato, Ornella Guardamagna, Arcangelo Iannuzzi, Gabriella Iannuzzo, Lorenzo Iughetti, Giuseppe Mandraffino, Lorenzo Maroni, Giuliana Mombelli, Sandro Muntoni, Gianfranco Parati, Angelina Passaro, Livia Pisciotta, Arturo Pujia, Francesco Purrello, Anna Rita Roscini, Riccardo Sarzani, Patrizia Suppressa, Josè Pablo Werba, Sabina Zambon, Maria Grazia Zenti, Massimiliano Allevi, Renata Auricchio, Davide Baldera, Patrizia Bruzzi, Marco Bucci, Paola Sabrina Buonuomo, Angelo Baldassarre Cefalù, Giuseppe Covetti, Sergio D'Addato, Maria Donata Di Taranto, Roberto Franceschi, Fabio Fimiani, Simonetta Genovesi, Liliana Grigore, Graziana Lupattelli, Sara Madaghiele, Giulia Massini, Ilenia Minicocci, Tiziana Montalcini, Fabio Nascimbeni, Chiara Pavanello, Francesco Massimo Perla, Gaia Peroni, Elena Sani, Roberto Scicali, Arianna Toscano, Giovanni Battista Vigna, Alberto Zambon, Federica Galimberti, Elena Olmastroni, and Veronica Zampoleri

Subjects
Male, Adolescent, Family history, High cardiovascular risk, Paediatric FH, Lp(a), Children/adolescents, Premature CVD, Cholesterol, LDL, Hyperlipoproteinemia Type II, Cardiovascular Diseases, Heart Disease Risk Factors, Risk Factors, Humans, Female, Cardiology and Cardiovascular Medicine, Child, Lipoprotein(a)
Abstract

Little is known about the role of Lp(a) in the assessment of cardiovascular risk in the paediatric population. Trying to clarify the clinical relevance of Lp(a) in risk stratification, the aim of the study is to evaluate the association between Lp(a) plasma levels in children with familial hypercholesterolaemia (FH) and positive family history for premature cardiovascular disease (pCVD) in first- and second-degree relatives.653 Caucasian children and adolescents (334 females and 319 males), aged 2-17 years, with diagnosis of FH from a paediatric cohort included in the LIPIGEN Network, were selected. We compared family history of pCVD, lipid and genetic profile in two groups based on Lp(a) levels below or above 30 mg/dL. To determine the independent predictors of pCVD, a multivariate logistic regression was used, with all clinical characteristics and blood measurements as predictors.Subjects with Lp(a) 30 mg/dl more frequently reported positive family history of pCVD compared to subjects with Lp(a)≤30 mg/dl (69.90% vs 36.66%, p 0.0001), while did not show differences in terms of median [interquartile range] LDL-cholesterol level (153.00 [88.00 vs 164.50 [90.25] mg/dL, p = 0.3105). In the regression analysis, Lp(a) 30 mg/dl was an independent predictor of family history of pCVD. Comparing subjects with or without family history of pCVD, we reported significant differences for Lp(a) 30 mg/dl (46.25% vs 17.65%, p 0.0001), FH genetic mutation (50.48% vs 40.75%, p = 0,0157), as well as for LDL-cholesterol (p = 0.0013) and total cholesterol (p = 0.0101).Children/adolescents with FH and Lp(a) 30 mg/dl where more likely to have a positive family history of pCVD. Lp(a) screening in children and adolescents with FH may enhance risk assessment and help identify those subjects, children and relatives, at increased pCVD risk.

Published
2021

34. Expression and Change of miRs 145, 221 and 222 in Hypertensive Subjects Treated with Enalapril, Losartan or Olmesartan

Author

Salvatore Campo, Carmela Morace, Angela D'Ascola, Davide Sinicropi, Michele Scuruchi, Clemente Giuffrida, Giuseppe M. Campo, Giovanni Squadrito, Giuseppe Mandraffino, Giuseppe Blando, Alberto Lo Gullo, M. Cinquegrani, and Egidio Imbalzano

Subjects
0301 basic medicine, medicine.medical_specialty, arterial hypertension, QH301-705.5, Urology, cell programming, Medicine (miscellaneous), 030204 cardiovascular system & hematology, Fibrinogen, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Medicine, Enalapril, Biology (General), medicine.diagnostic_test, microRNA, business.industry, Control subjects, medicine.disease, 030104 developmental biology, Blood pressure, Losartan, arterial stiffness, Arterial stiffness, atherosclerosis, business, Lipid profile, Olmesartan, medicine.drug, circulatory and respiratory physiology
Abstract

miR profile could be associated to CV risk, and also to prognosis/outcome in response to therapeutic approach. We aimed to evaluate if anti-hypertensive drugs enalapril, losartan or olmesartan have effects on monocyte miR profile in essential hypertensives without target organ involvement. For this purpose, 82 hypertensives and 49 controls were included, we evaluated SBP/DBP, lipid profile, glucose, CRP, fibrinogen, arterial stiffness indices (PWV, AIx), and cIMT at baseline (T0) and after 24 weeks of treatment (T1). Subjects with LDL-C ≥ 160 mg/dL, TG ≥ 200 mg/dL, BMI ≥ 30, and other additional CV risk factors were excluded. Patients who were prescribed to receive once-a-day enalapril 20 mg, losartan 100 mg or olmesartan 20 mg were eligible for the study. At T1, we found a significant improvement of SBP (−18.5%), DBP (−18%), HDL-C and LDL-C (+3% and −5.42%), glucose (−2.15%), BMI (−3.23%), fibrinogen (−11%), CRP (−17.5%,), AIx (−49.1%) PWV (−32.2%), and monocyte miR expression (miR-221: −28.4%, miR-222: −36%, miR-145: +41.7%) with respect to baseline. miR profile was compared to control subjects at baseline and at T1. We found some little difference in the behaviour of the three treatments on some variables: olmesartan was the most effective in reducing fibrinogen, DBP, CRP, and AIx (−13.1%, −19.3%, −21.4%, and −56.8%, respectively). Enalapril was the drug more significantly increasing the expression of miR-145. In conclusion, enalapril, losartan and olmesartan are effective in improving mechanical and humoral factors associated to AS and atherogenesis. These drugs appear to be able to modify miRs 221/222 and miR-145 expression in drug-naïve hypertensives, making it closer to that of control subjects, additionally, this provides a good blood pressure compensation, contributing to slow the progression of vascular damage.

Published
2021
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35. Prevalence of Pulmonary Hypertension in an Unselected Community-Based Population: A Retrospective Echocardiographic Study—RES-PH Study

Author

Giuseppe Mandraffino, Marco Vatrano, Vincenzo Antonio Ciconte, Luana Orlando, Giovanni Squadrito, Alberto Lo Gullo, Clemente Giuffrida, Antonio Giovanni Versace, Pierpaolo Di Micco, Egidio Imbalzano, Vincenzo Russo, Alberto Mazza, Imbalzano, E., Vatrano, M., Lo Gullo, A., Orlando, L., Mazza, A., Antonio Ciconte, V., Russo, V., Giuffrida, C., Micco, P. D., Versace, A. G., Mandraffino, G., and Squadrito, G.

Subjects
medicine.medical_specialty, Population, Medicine (miscellaneous), 030204 cardiovascular system & hematology, Article, 03 medical and health sciences, 0302 clinical medicine, pulmonary artery systolic pressure, Internal medicine, medicine.artery, Epidemiology, pulmonary hypertension, medicine, echocardiography, education, unselected population, COPD, education.field_of_study, Ejection fraction, business.industry, medicine.disease, Pulmonary hypertension, Blood pressure, 030228 respiratory system, Pulmonary artery, Cardiology, Population study, Medicine, business, Echocardiography, Pulmonary artery systolic pressure, Unselected population
Abstract

Introduction. The actual prevalence of pulmonary hypertension (PH) in Italy is unknown. Echocardiography is useful in the screening of patients with suspected PH by estimation of the pulmonary artery systolic pressure (PASP) from the regurgitant tricuspid flow velocity evaluation, according to the simplified Bernoulli equation. Objectives. We aimed to evaluate the frequency of suspected PH among unselected patients. Methods. We conducted a retrospective cross-sectional database search of 7005 patients, who underwent echocardiography, to estimate the prevalence of PH, between January 2013 and December 2014. Medical and echocardiographic data were collected from a stratified etiological group of PH, using criteria of the European Society of Cardiology classifications. Results. The mean age of the study population was 57.1 ± 20.5 years, of which 55.3% were male. The prevalence of intermediate probability of PH was 8.6%, with nearly equal distribution between men and women (51.3 vs. 48.7%, p = 0.873). The prevalence of high probability of PH was 4.3%, with slightly but not significant higher prevalence in female patients (43.2 vs. 56.8%, p = 0.671). PH is predominant in patients with chronic obstructive pulmonary disease (COPD) or left ventricle (LV) systolic dysfunction and related with age. PASP was significantly linked with left atrial increase and left ventricular ejection fraction. In addition, an increased PASP was related to an enlargement of the right heart chamber. Conclusions. PH has a frequency of 4.3% in our unselected population, but the prevalence may be more relevant in specific subgroups. A larger epidemiological registry could be an adequate strategy to increase quality control and identify weak points in the evaluation and treatment of these patients.

Published
2021

36. miR9 inhibits 6-mer HA-induced cytokine production and apoptosis in human chondrocytes by reducing NF-kB activation

Author

Michele Scuruchi, Angela D'Ascola, Angela Avenoso, Annie Zappone, Giuseppe Mandraffino, Salvatore Campo, and Giuseppe M. Campo

Subjects
Inflammation, Toll-Like Receptor 4, MicroRNAs, Chondrocytes, Biophysics, NF-kappa B, Cytokines, Humans, Apoptosis, Hyaluronic Acid, Molecular Biology, Biochemistry, Cells, Cultured
Abstract

The present study aimed to investigate the expression of miR9 and its correlation with cytokines, proteolytic enzymes and apoptosis in an experimental model of 6-mer HA induced inflammation in human chondrocytes. Human articular chondrocytes, transfected with a miR-9 mimic and miR-9 inhibitor, were stimulated with 6-mer HA in presence/absence of a specific NF-kB inhibitor. 6-mer HA induced a significant increase of TLR-4, CD44, IL-8, IL-18, MMP-9, ADAMTS-5, BAX and BCL-2 mRNAs expression and the related proteins, as well as NF-kB activation, associated with a significant up regulation of miR-9. In chondrocytes transfected with the miR-9 mimic before 6-mer HA treatment we found a decrease of such inflammatory cytokines, metalloproteases and pro-apoptotic molecules, while we found them increased in chondrocytes transfected with the miR9 inhibitor before 6-mer HA stimulation. The activities of TLR-4 and CD44, up regulated by 6-mer HA, were not modified by miR9 mimic/inhibitor, while the NF-kB activation was significantly affected. We suggested that the up regulation of miR9, induced by 6-mer HA, could be a cellular attempt to limit cell damage during inflammation.

Published
2021

37. Impact of high neutrophil-to-lymphocyte ratio on the cardiovascular benefit of PCSK9 inhibitors in familial hypercholesterolemia subjects with atherosclerotic cardiovascular disease: Real-world data from two lipid units

Author

Francesco Purrello, Giovanni Squadrito, Roberto Scicali, Antonino Di Pino, Salvatore Piro, Viviana Ferrara, Giuseppe Mandraffino, and Michele Scuruchi

Subjects
medicine.medical_specialty, Apolipoprotein B, Neutrophils, Endocrinology, Diabetes and Metabolism, Familial hypercholesterolemia, Medicine (miscellaneous), Pulse Wave Analysis, Hyperlipoproteinemia Type II, Ezetimibe, Internal medicine, medicine, Humans, Lymphocytes, Neutrophil to lymphocyte ratio, Pulse wave velocity, Neutrophil-to-lymphocyte ratio, Nutrition and Dietetics, biology, business.industry, PCSK9, Anticholesteremic Agents, fungi, PCSK9 Inhibitors, medicine.disease, Cardiovascular risk, Atherosclerosis, Inflammatory profile, Treatment Outcome, PCSK9 inhibitors, Cardiology, biology.protein, Population study, Observational study, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract

BACKGROUND AND AIMS Neutrophil-to-lymphocyte ratio (NLR) is a novel inflammatory biomarker strongly associated with atherosclerotic cardiovascular disease (ASCVD). Our aim was to evaluate the role of NLR on pulse wave velocity (PWV) after adding-on proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9-i) in familial hypercholesterolemia (FH) subjects with ASCVD. METHODS AND RESULTS In this prospective observational study, we evaluated 45 FH subjects with ASCVD on high-intensity statins plus ezetimibe and with an off-target LDL-C. Study population was divided into two groups according to the mean value of NLR. All patients received PCSK9-i therapy and obtained biochemical analysis as well as PWV evaluation at baseline and after six months of PCSK9-i. After six months of add-on PCSK9-i therapy, a significant reduction of TC, LDL-C, Non-HDL-C, Lp(a) and ApoB plasma levels was observed in the two groups; while low-NLR group exhibited a significant PWV reduction after six-month therapy with PCSK9-i (Δ -16.2%, p

Published
2021

38. Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)

Author

Jie Lin, Snejana Tisheva, Ishwar C. Verma, Francesco Cipollone, Liam R. Brunham, Florentina Predica, Perla A.C. Gonzalez, Jocelyne Inamo, André R. Miserez, Belma Pojskic, Michel Farnier, Avishay Ellis, Katia Bonomo, Ibrahim Al-Zakwani, Maria Grazia Zenti, Humberto A. Lopez, Khairul Shafiq Ibrahim, Erkin M. Mirrakhimov, Alexey Meshkov, Jose P. de Moura, Muthukkaruppan Annamalai, Raul D. Santos, F. Paillard, Maria Del Ben, Jan Lacko, Miguel T. Rico, Ximena Reyes, Laura E.G. de Leon, Noor Shafina Mohd Nor, Ulrich Julius, Mohammed A. Batais, Dieter Böhm, Ta-Chen Su, Takuya Kobayashi, Magdalena Chmara, Marco Gebauer, Marcos M. Lima-Martínez, Ravshanbek D. Kurbanov, Daisaku Masuda, Amro El-Hadidy, Melanie Schüler, Francisco Fuentes, Florian J. Mayer, Helena Vaverkova, F. Ulrich Beil, Juraj Bujdak, Mario Stoll, Isabelle Ruel, Elena Dorn, Thomas M. Stulnig, Abubaker Elfatih, Rano B. Alieva, Jiri Vesely, Valérie Carreau, Cristina M. Sibaja, Sophie Béliard, Olivier Ziegler, Adriana Branchi, Daniel Schurr, G.B. John Mancini, Tai E. Shyong, Eric L.T. Siang, Mafalda Bourbon, Zerrin Yigit, Meral Kayıkçıoğlu, Jacques Genest, Wei Yu, Michal Vrablík, Shavkat U. Hoshimov, Dan Gaita, Antonio Pipolo, Ashraf H.A. AlQudaimi, Walter Speidl, Gianfranco Parati, Zaliha Ismail, Victoria M. Zubieta, René Valéro, Tomas Salek, Hana Halamkova, Gustavs Latkovskis, Nicole Allendorf-Ostwald, Agnes Perrin, Vladimir Soska, Anastasia Garoufi, Francisco Araujo, Nacu C. Portilla, Thomas Segiet, Charalambos Koumaras, Hila Knobler, Fatih Sivri, Hani Altaradi, Ivan Pećin, Long Jiang, Alexander Dressel, Marlena Woś, Jana Franekova, D. Agapakis, Quitéria Rato, Dirk J. Blom, Marcin A. Bartlomiejczyk, Krzysztof Dyrbuś, Maurizio Averna, Phivos Symeonides, Yung A. Chua, Asim Rana, András Nagy, Juan C.G. Cuellar, Alexander Jäkel, Maya Safarova, Neama Luqman, Amalia-Despoina Koutsogianni, Patrick Tounian, Jose A. Alvarez, Ada Cuevas, Corinna Richter, Sybil Charrieres, Vitaliy Zafiraki, Michalis Doumas, Angela Lux, Thanh Huong Truong, Elaine Chow, José Luis Díaz-Díaz, Jesus R.H. Almada, Sabine Füllgraf-Horst, Gustavo G. Retana, Claudio Borghi, Gianni Biolo, Ivajlo Tzvetkov, Patrícia Pais, Mehmet Akbulut, Kumiko Nagahama, Oner Ozdogan, Frank Leistikow, Jianxun He, Alexander R.M. Lyons, Poranee Ganokroj, Luis E.S. Mendia, Ann-Cathrin Koschker, Gabriela A.G. Ramirez, Dainus Gilis, Karin Balinth, José Ramiro Cruz, Paolo Calabrò, Alberico L. Catapano, Emmanouil Skalidis, Hamida Al-Barwani, Genovefa Kolovou, Carolyn S.P. Lam, Yoto Yotov, Yaacov Henkin, Gabriella Iannuzzo, Aimi Z. Razman, Alma B.M. Rodriguez, Hans Dieplinger, Darlington E. Obaseki, Ursulo J. Herrera, Arcangelo Iannuzzi, Christoph Säly, Elena Olmastroni, Francisco G. Padilla, S.A. Nazli, Ioanna Gouni-Berthold, Miriam Kozárová, Urh Groselj, Igor Shaposhnik, Lorenzo Iughetti, Nawal Rwaili, Cinthia E. Jannes, Andrea Bartuli, Mikhail Voevoda, Marat V. Ezhov, Yanyu Duan, Alper Sonmez, Mustafa Yenercag, Ariane Sultan, Natasza Gilis-Malinowska, Tavintharan Subramaniam, Mohamed Ashraf, Jing Pang, Kota Matsuki, Tao Jiang, Gerald Klose, Eduardo A.R. Rodriguez, Lucie Solcova, Riccardo Sarzani, Mahmoud Traina, Alejandra Vázquez Cárdenas, Gordon A. Francis, Adolat V. Ziyaeva, Ronen Durst, Maciej Banach, Francisco Silva, Heribert Schunkert, Børge G. Nordestgaard, Ziyou Liu, Ahmad Bakhtiar Md Radzi, Hana Rosolova, Andrea Bäßler, Abdulhalim Jamal Kinsara, Noël Peretti, Victor Gurevich, Margarita T. Tamayo, Abdullah Tuncez, Florian Höllerl, Ljubica Stosic, Jianguang Qi, Anja Kirschbaum, Jitendra P.S. Sawhney, Michael Scholl, Kausik K. Ray, Mohamed Bendary, Hapizah Nawawi, Adrienne Tarr, Barbora Nussbaumerova, B.C. Brice, Kurt Huber, Noor Alicezah Mohd Kasim, A. Rahman A. Jamal, Vaclava Palanova, Giacomo Biasucci, Pucong Ye, Eva Cubova, Roopa Mehta, Rüdiger Schweizer, Veronica Zampoleri, Jacek Jóźwiak, Alyaa Al-Khateeb, Jing Hong, Katarina Raslova, Kirsten B. Holven, Tatiana Rozkova, Reinhold Busch, Alexander Klabnik, Konrad Hein, Eloy A.Z. Carrillo, Robin Urbanek, Livia Pisciotta, Fatma Y. Coskun, Jose J.G. Garcia, Valerio Pecchioli, Azra D. Nalbantic, Weerapan Khovidhunkit, Jernej Kovac, Michaela Kadurova, Mohammed Al-Jarallah, Vita Saripo, Christos V. Rizos, Jie Peng, Ang L. Chua, Dorothee Deiss, Nor A.A. Murad, Aneta Stróżyk, See Kwok, Gökhan Alici, Gillian J. Pilcher, John J.P. Kastelein, Dmitry Duplyakov, Calin Lengher, Milena Budikova, C. Azzopardi, Christina Antza, Luis E.V. Arroyo, Khalid Al-Jumaily, Ahmad Al-Sarraf, Carlos A. Aguilar-Salinas, Erkayim Bektasheva, Arta Upena-RozeMicena, Qian Wang, Xumin Wang, Leah Leavit, Radzi Rahmat, Selim Topcu, Željko Reiner, Lorenzo Maroni, Matija Cevc, Elizabeth R. Cooremans, Masatsune Ogura, Tevfik Sabuncu, Ruy D Arjona Villicaña, Andrea Giaccari, Xuesong Fan, Auryan Szalat, Sanjaya Dissanayake, Etienne Khoury, Anja Vogt, Hermann Toplak, Alexis Baass, Isabel Palma, Gaelle Sablon, Dana A. Hay, Ya Yang, Margus Viigimaa, Erik S.G. Stroes, Dror Harats, Konstantin Krychtiuk, Zesen Liu, Aleksandra Parczewska, Yves Cottin, Yichen Qu, Mathilde Di-Fillipo, Agnieszka Konopka, Lamija Pojskic, Guadalupe J. Dominguez, Ahmet Temizhan, Roberto C. Chacon, Ibrahim E. Dural, Qiang Yong, G. Kees Hovingh, Kang Meng, Sandra Kutkiene, Julie Lemale, Reinhold Innerhofer, Alexandros D. Tselepis, Handrean Soran, Wolfgang König, Bassam Atallah, Olena Mitchenko, Jana Cepova, Eduardo M. Rodriguez, Ulrich Laufs, Norhidayah Rosman, Alena Lubasova, V. Durlach, Frederick J. Raal, Elyor Khodzhiboboev, Cristina Pederiva, Hui Yuan, Ashraf Reda, Fahad Alnouri, Konstantinos Tziomalos, Thanh T. Le, Jana Sirotiakova, Régis Hankard, Hector E.A. Cazares, Betsabel Rodriguez, Lenka Pavlickova, Assen Goudev, Julius Katzmann, Diana Boger, Wael Almahmeed, Katarina T. Podkrajsek, Sabina Zambon, Fahri Bayram, Nadia Citroni, Samir Rafla, Vincent Rigalleau, Aleksandr B. Shek, Hani Sabbour, Berenice G. Guzman, Shoshi Shpitzen, Eric Tarantino, Ahmed Bendary, Fedya Nikolov, Jean Bergeron, Stefan Kopf, Iva Rasulic, Gerald F. Watts, Muhammad I.A. Hafidz, Mehmet B. Yilmaz, Kathrin Biolik, Ira A. Haack, Robert A. Hegele, Sonia Dulong, Bartosz Wasąg, Osama Sanad, Susana Correia, Zhenjia Wang, Dana Biedermann, Christel König, Helena Podzimkova, Ihab Daoud, Mohammad Alghamdi, Dražen Perica, László Márk, Iosif Koutagiar, Volkan Dogan, Vladimir Blaha, Chandrashekhar K. Ponde, Katerina Valoskova, Amer A. Jabbar, Azhari Rosman, Sazzli Kasim, Mesut Demir, Ulugbek I. Nizamov, Aldo Ferreira-Hermosillo, Dilek Yesilbursa, Atef Elbahry, Arshad Abdulrasheed, Omer A. Elamin, Vasileios Athyros, Joanna Lewek, Gergely Nagy, Ursula Kassner, Jian Jiao, Klaus G. Parhofer, Charlotte Nzeyimana, Marcin Pajkowski, Stanislav Zemek, Jose J.C. Macías, Cornelius Müller, G. Sfikas, Leopoldo Pérez de Isla, Yulia Ragino, Fahad Al-Zadjali, Abdul Rais Sanusi, Anna Rita Roscini, Jean Ferrières, Selim Jambart, Jean Pierre Rabes, Laura Schreier, Hofit Cohen, Olivier S. Descamps, N. Lalic, Christine Stumpp, Antonio J. Vallejo-Vaz, Jutta Christmann, Manuela Casula, Mariko Harada-Shiba, Olga Lunegova, Ewa Starostecka, Nicolas D. Oca, Alain Carrié, Achilleas Attilakos, Savas Ozer, Andreea Dumitrescu, Jürgen Merke, Urte Aliosaitiene, Evangelos Liberopoulos, Manuel O. De los Rios Ibarra, Maria J. Virtuoso, Alessandro Lupi, Panagiotis Anagnostis, Ruth Agar, Dorota Ferrieres, George Liamis, José Eduardo Krieger, Mariann Harangi, Fouzia Sadiq, Francois Schiele, Saif Kamal, Mária Audikovszky, Peter Baumgartner, Marta Gazzotti, Daniel Gaudet, Ashanty F. Ortega, Marcin Gruchała, Philippe Moulin, Ljiljana Popovic, Luca Bonanni, E. Kiouri, Mika Hori, Chiara Trenti, Elena Repetti, Carlo Sabbà, Sophie Bernard, Alejandro R. Zazueta, Mirac Vural, Jesus R. Gonzalez, C. Stevens, Francesca Carubbi, Wenhui Wen, Sabri Demircan, Kanika I. Dharmayat, Anne Tybjærg-Hansen, Elizabete Terauda, Claudia Zemmrich, Alphonsus Isara, Fabiola L. Sobrevilla, Anell Hernandez Garcia, Ibrahim Sisic, Justin T. I-Shing, Yvonne Winhofer-Stöckl, Luya Wang, Manfred Mayer, Mohanad Al-ageedi, Judith Wiener, Mohammed Al-Kindi, Anis Safura Ramli, Yan Chen, Denis Angoulvant, Aytekin Oguz, K.H. Wolmarans, Claudio Ferri, Tomáš Freiberger, Lubomira Cermakova, Julieta D.M. Portano, Pierre Henri Ducluzeau, Katerina Vonaskova, Levent H. Can, Mario H.F. Andrade, György Paragh, C. Ebenbichler, Karina J.A. Rivera, Alia Khudari, Elisabeth Steinhagen-Thiessen, Ana C. Alves, Victoria Korneva, Sandra Singh, Georgia Anastasiou, Nur S. Hamzan, Massimo Federici, Lale Tokgozoglu, Hector G. Alcala, Oana Moldovan, Giuseppe Mandraffino, Swarup A.V. Shah, Lukas Burda, Ersel Onrat, Manuel de los Reyes Barrera Bustillo, Mirjana Radovic, Arman Postadzhiyan, Nien-Tzu Chang, Aylin Yildirir, Martin Mäser, Bruno Fink, Svetlana Mosteoru, Ulrike Schatz, Luis A.V. Talavera, Magdalena Dusejovska, Richard Ceska, Faisal A. Al-Allaf, T.F. Ashavaid, Gereon Böll, Sona Machacova, Gonzalo C. Vargas, Antonio Gallo, Elina Pantchechnikova, Lukas Tichy, Gersina Rega-Kaun, Moses Elisaf, Branislav Vohnout, Antonio Bossi, Suad Al-Mukhaini, Natasa Rajkovic, Ursa Sustar, Merih Kutlu, Mohamed Sobhy, Britta Otte, Ana M. Medeiros, Borut Jug, Patrick Couture, Rodrigo Alonso, Wolfgang Seeger, Guzal J. Abdullaeva, Ahmet Celik, Nasreen Al-Sayed, Béla Benczúr, Petra E. Khoury, Rafezah Razali, Ma L.R. Osorio, Ruiying Zhang, Monica M.N. Usme, Humberto Garcia Aguilar, Ceyhun Ceyhan, Antje Spens, Christoph J. Binder, Volker Schrader, Terrance C.S. Jin, Neftali E.A. Villa, Aleksandra Michalska-Grzonkowska, Francesco Purrello, Marshima M. Rosli, Vincent Maher, Dilshad Rasul, Ines Colaço, Ornella Guardamagna, Giuliana Mombelli, Khalid F. AlHabib, Fahmi Alkaf, Marianne Benn, Youmna Ghaleb, Arsenio V. Vazquez, Lakshmi L. Reddy, Salih Kilic, Siti Hamimah Sheikh Abdul Kadir, E. Bilianou, Rossella Marcucci, Sandro Muntoni, Kurt Widhalm, Evangelos A. Zacharis, Kuznetsova T. Yu, Eric Bruckert, Antonia Sonntag, Katerina Rehouskova, Josè Pablo Werba, Leobardo Sauque-Reyna, Myra Tilney, Dov Gavishv, A.M. Fiorenza, Zdenka Krejsova, Hong A. Le, Andrey V. Susekov, Isabel Klein, Mai N.T. Nguyen, Andrejs Erglis, Muge Ildizli, Diane Brisson, Salmi Razali, Winfried März, Ovidio Muñiz-Grijalvo, Justyna Borowiec-Wolna, Ingrid Buganova, Ngoc T. Kim, Yue Wu, István Reiber, Jose C.A. Martinez, Pavel Malina, Sandy Elbitar, Stephan Matthias, Ali F. Abdalsahib, Zlatko Fras, Wilson E Sadoh, Lucas Kleemann, Tayfun Sahin, Martin P. Bogsrud, Fabio Pellegatta, Mohamed A. Shafy, Yuntao Li, Martine Paquette, Zuhier Awan, Arturo Pujia, Xiantao Song, Renata Cifkova, Alexandre C. Pereira, Ioannis Skoumas, Roman Cibulka, Tadej Battelino, Mariusz Gąsior, Ghada Kazamel, Lahore S.U. Shah, Eran Leitersdorf, Niki Katsiki, Daniel Elías-López, Khalid Al-Rasadi, Grete Talviste, Sarka Mala, Rocio M. Alvarado, Pavel Kraml, Gerret Paulsen, Angelina Passaro, Zsolt Karányi, Carine Ayoub, Vera Adamkova, Ivo Petrov, Turky H. Almigbal, Rohana Abdul Ghani, Franck Boccara, Brian W. McCrindle, François Martin, Jamshed J. Dalal, Shitong Cheng, Khalid Al-Waili, Chaoyi Zhang, Ramon M. Prado, Lubica Cibickova, Lubomira Fabryova, Tobias Wiesner, Thuhairah Hasrah Abdul Rahman, Tan J. Le, Marcello Arca, Sabine Scholl-Bürgi, Juan R. Saucedo, Georgijs Nesterovics, Carla V.M. Valencia, Alexander Stadelmann, Vasileios Kotsis, Lina Badimon, Shizuya Yamashita, Jose C.M. Oyervides, Lay K. Teh, Susanne Greber-Platzer, Marianne Abifadel, Ruta Meiere, Wibke Reinhard, Pablo Corral, Nina Schmidt, Alain Pradignac, A. David Marais, Marta Jordanova, Marzena Romanowska-Kocejko, Johannes Scholl, Brian Tomlinson, Laura G.G. Herrera, Loukianos S. Rallidis, Pedro Mata, Sameh Emil, Matej Mlinaric, Emile Ferrari, Suraya Abdul Razak, Alexandra Ershova, Andrie G. Panayiotou, Alinna Y.R. Garcia, Kairat Davletov, Katarina Lalic, Doan L. Do, Krzysztof Chlebus, Ricardo A. Carrera, Daniel I.P. Vazquez, Nikolaos Sakkas, Liyuan Xu, Mays Altaey, Aysa Hacioglu, Alexandro J. Martagon, Marta Żarczyńska-Buchowiecka, Michael Schömig, Jürgen Homberger, Andrea Benso, Bertrand Cariou, Ardon Rubinstein, Omer Gedikli, Emre Durakoglugil, Mei Chong, Bahadir Kirilmaz, Suhaila Abd Muid, Jose M. Salgado, Berenice P. Aparicio, Mutaz Alkhnifsawi, Bruno Vergès, Cécile Yelnik, Goreti Lobarinhas, Zaneta Petrulioniene, Sylvia Asenjo, Aytul B. Yildirim, László Bajnok, Vallejo-Vaz A.J., Stevens C.A.T., Lyons A.R.M., Dharmayat K.I., Freiberger T., Hovingh G.K., Mata P., Raal F.J., Santos R.D., Soran H., Watts G.F., Abifadel M., Aguilar-Salinas C.A., Alhabib K.F., Alkhnifsawi M., Almahmeed W., Alnouri F., Alonso R., Al-Rasadi K., Al-Sarraf A., Al-Sayed N., Araujo F., Ashavaid T.F., Banach M., Beliard S., Benn M., Binder C.J., Bogsrud M.P., Bourbon M., Chlebus K., Corral P., Davletov K., Descamps O.S., Durst R., Ezhov M., Gaita D., Genest J., Groselj U., Harada-Shiba M., Holven K.B., Kayikcioglu M., Khovidhunkit W., Lalic K., Latkovskis G., Laufs U., Liberopoulos E., Lima-Martinez M.M., Lin J., Maher V., Marais A.D., Marz W., Mirrakhimov E., Miserez A.R., Mitchenko O., Nawawi H., Nordestgaard B.G., Panayiotou A.G., Paragh G., Petrulioniene Z., Pojskic B., Postadzhiyan A., Raslova K., Reda A., Reiner, Sadiq F., Sadoh W.E., Schunkert H., Shek A.B., Stoll M., Stroes E., Su T.-C., Subramaniam T., Susekov A.V., Tilney M., Tomlinson 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Jiao J., Wu Y., Wen W., Xu L., Zhang R., Qu Y., He J., Fan X., Wang Z., Chow E., Pecin I., Perica D., Symeonides P., Vrablik M., Ceska R., Soska V., Tichy L., Adamkova V., Franekova J., Cifkova R., Kraml P., Vonaskova K., Cepova J., Dusejovska M., Pavlickova L., Blaha V., Rosolova H., Nussbaumerova B., Cibulka R., Vaverkova H., Cibickova L., Krejsova Z., Rehouskova K., Malina P., Budikova M., Palanova V., Solcova L., Lubasova A., Podzimkova H., Bujdak J., Vesely J., Jordanova M., Salek T., Urbanek R., Zemek S., Lacko J., Halamkova H., Machacova S., Mala S., Cubova E., Valoskova K., Burda L., Bendary A., Daoud I., Emil S., Elbahry A., Rafla S., Sanad O., Kazamel G., Ashraf M., Sobhy M., El-Hadidy A., Shafy M.A., Kamal S., Bendary M., Talviste G., Angoulvant D., Boccara F., Cariou B., Carreau V., Carrie A., Charrieres S., Cottin Y., Di-Fillipo M., Ducluzeau P.H., Dulong S., Durlach V., Farnier M., Ferrari E., Ferrieres D., Ferrieres J., Gallo A., hankard R., Inamo J., Lemale J., Moulin P., Paillard F., Peretti N., Perrin A., Pradignac A., Rabes J.P., Rigalleau V., Sultan A., Schiele F., Tounian P., Valero R., Verges B., Yelnik C., Ziegler O., Haack I.A., Schmidt N., Dressel A., Klein I., Christmann J., Sonntag A., Stumpp C., Boger D., Biedermann D., Usme M.M.N., Beil F.U., Klose G., Konig C., Gouni-Berthold I., Otte B., Boll G., Kirschbaum A., Merke J., Scholl J., Segiet T., Gebauer M., Predica F., Mayer M., Leistikow F., Fullgraf-Horst S., Muller C., Schuler M., Wiener J., Hein K., Baumgartner P., Kopf S., Busch R., Schomig M., Matthias S., Allendorf-Ostwald N., Fink B., Bohm D., Jakel A., Koschker A.-C., Schweizer R., Vogt A., Parhofer K., Konig W., Reinhard W., Bassler A., Stadelmann A., Schrader V., Katzmann J., Tarr A., Steinhagen-Thiessen E., Kassner U., Paulsen G., Homberger J., Zemmrich C., Seeger W., Biolik K., Deiss D., Richter C., Pantchechnikova E., Dorn E., Schatz U., Julius U., Spens A., Wiesner T., Scholl M., Rizos C.V., Sakkas N., Elisaf M., Skoumas I., Tziomalos K., Rallidis L., Kotsis V., Doumas M., Athyros V., Skalidis E., Kolovou G., Garoufi A., Bilianou E., Koutagiar I., Agapakis D., Kiouri E., Antza C., Katsiki N., Zacharis E., Attilakos A., Sfikas G., Koumaras C., Anagnostis P., Anastasiou G., Liamis G., Koutsogianni A.-D., Karanyi Z., Harangi M., Bajnok L., Audikovszky M., Mark L., Benczur B., Reiber I., Nagy G., Nagy A., Reddy L.L., Shah S.A.V., Ponde C.K., Dalal J.J., Sawhney J.P.S., Verma I.C., Altaey M., Al-Jumaily K., Rasul D., Abdalsahib A.F., Jabbar A.A., Al-ageedi M., Agar R., Cohen H., Ellis A., Gavishv D., Harats D., Henkin Y., Knobler H., Leavit L., Leitersdorf E., Rubinstein A., Schurr D., Shpitzen S., Szalat A., Casula M., Zampoleri V., Gazzotti M., Olmastroni E., Sarzani R., Ferri C., Repetti E., Sabba C., Bossi A.C., Borghi C., Muntoni S., Cipollone F., Purrello F., Pujia A., Passaro A., Marcucci R., Pecchioli V., Pisciotta L., Mandraffino G., Pellegatta F., Mombelli G., Branchi A., Fiorenza A.M., Pederiva C., Werba J.P., Parati G., Carubbi F., Iughetti L., Iannuzzi A., Iannuzzo G., Calabro P., Averna M, Biasucci G., Zambon S., Roscini A.R., Trenti C., Arca M., Federici M., Del Ben M., Bartuli A., Giaccari A., Pipolo A., Citroni N., Guardamagna O., Bonomo K., Benso A., Biolo G., Maroni L., Lupi A., Bonanni L., Zenti M.G., Matsuki K., Hori M., Ogura M., Masuda D., Kobayashi T., Nagahama K., Al-Jarallah M., Radovic M., Lunegova O., Bektasheva E., Khodzhiboboev E., Erglis A., Gilis D., Nesterovics G., Saripo V., Meiere R., Upena-RozeMicena A., Terauda E., Jambart S., Khoury P.E., Elbitar S., Ayoub C., Ghaleb Y., Aliosaitiene U., Kutkiene S., Kasim N.A.M., Nor N.S.M., Ramli A.S., Razak S.A., Al-Khateeb A., Kadir S.H.S.A., Muid S.A., Rahman T.A., Kasim S.S., Radzi A.B.M., Ibrahim K.S., Razali S., Ismail Z., Ghani R.A., Hafidz M.I.A., Chua A.L., Rosli M.M., Annamalai M., Teh L.K., Razali R., Chua Y.A., Rosman A., Sanusi A.R., Murad N.A.A., Jamal A.R.A., Nazli S.A., Razman A.Z., Rosman N., Rahmat R., Hamzan N.S., Azzopardi C., Mehta R., Martagon A.J., Ramirez G.A.G., Villa N.E.A., Vazquez A.V., Elias-Lopez D., Retana G.G., Rodriguez B., Macias J.J.C., Zazueta A.R., Alvarado R.M., Portano J.D.M., Lopez H.A., Sauque-Reyna L., Herrera L.G.G., Mendia L.E.S., Aguilar H.G., Cooremans E.R., Aparicio B.P., Zubieta V.M., Gonzalez P.A.C., Ferreira-Hermosillo A., Portilla N.C., Dominguez G.J., Garcia A.Y.R., Cazares H.E.A., Gonzalez J.R., Valencia C.V.M., Padilla F.G., Prado R.M., De los Rios Ibarra M.O., Villicana R.D.A., Rivera K.J.A., Carrera R.A., Alvarez J.A., Martinez J.C.A., de los Reyes Barrera Bustillo M., Vargas G.C., Chacon R.C., Andrade M.H.F., Ortega A.F., Alcala H.G., de Leon L.E.G., Guzman B.G., Garcia J.J.G., Cuellar J.C.G., Cruz J.R.G., Garcia A.H., Almada J.R.H., Herrera U.J., Sobrevilla F.L., Rodriguez E.M., Sibaja C.M., Rodriguez A.B.M., Oyervides J.C.M., Vazquez D.I.P., Rodriguez E.A.R., Osorio M.L.R., Saucedo J.R., Tamayo M.T., Talavera L.A.V., Arroyo L.E.V., Carrillo E.A.Z., Isara A., Obaseki D.E., Al-Waili K., Al-Zadjali F., Al-Zakwani I., Al-Kindi M., Al-Mukhaini S., Al-Barwani H., Rana A., Shah L.S.U., Starostecka E., Konopka A., Lewek J., Bartlomiejczyk M., Gasior M., Dyrbus K., Jozwiak J., Gruchala M., Pajkowski M., Romanowska-Kocejko M., Zarczynska-Buchowiecka M., Chmara M., Wasag B., Parczewska A., Gilis-Malinowska N., Borowiec-Wolna J., Strozyk A., Wos M., Michalska-Grzonkowska A., Medeiros A.M., Alves A.C., Silva F., Lobarinhas G., Palma I., de Moura J.P., Rico M.T., Rato Q., Pais P., Correia S., Moldovan O., Virtuoso M.J., Salgado J.M., Colaco I., Dumitrescu A., Lengher C., Mosteoru S., Meshkov A., Ershova A., Rozkova T., Korneva V., Yu K.T., Zafiraki V., Voevoda M., Gurevich V., Duplyakov D., Ragino Y., Safarova M., Shaposhnik I., Alkaf F., Khudari A., Rwaili N., Al-Allaf F., Alghamdi M., Batais M.A., Almigbal T.H., Kinsara A., AlQudaimi A.H.A., Awan Z., Elamin O.A., Altaradi H., Rajkovic N., Popovic L., Singh S., Stosic L., Rasulic I., Lalic N.M., Lam C., Le T.J., Siang E.L.T., Dissanayake S., I-Shing J.T., Shyong T.E., Jin T.C.S., Balinth K., Buganova I., Fabryova L., Kadurova M., Klabnik A., Kozarova M., Sirotiakova J., Battelino T., Kovac J., Mlinaric M., Sustar U., Podkrajsek K.T., Fras Z., Jug B., Cevc M., Pilcher G.J., Blom D.J., Wolmarans K.H., Brice B.C., Muniz-Grijalvo O., Diaz-Diaz J.L., de Isla L.P., Fuentes F., Badimon L., Martin F., Lux A., Chang N.-T., Ganokroj P., Akbulut M., Alici G., Bayram F., Can L.H., Celik A., Ceyhan C., Coskun F.Y., Demir M., Demircan S., Dogan V., Durakoglugil E., Dural I.E., Gedikli O., Hacioglu A., Ildizli M., Kilic S., Kirilmaz B., Kutlu M., Oguz A., Ozdogan O., Onrat E., Ozer S., Sabuncu T., Sahin T., Sivri F., Sonmez A., Temizhan A., Topcu S., Tuncez A., Vural M., Yenercag M., Yesilbursa D., Yigit Z., Yildirim A.B., Yildirir A., Yilmaz M.B., Atallah B., Traina M., Sabbour H., Hay D.A., Luqman N., Elfatih A., Abdulrasheed A., Kwok S., Oca N.D., Reyes X., Alieva 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B., Stoll, M., Stroes, E., Su, T. -C., Subramaniam, T., Susekov, A. V., Tilney, M., Tomlinson, B., Truong, T. H., Tselepis, A. D., Tybjaerg-Hansen, A., Vazquez Cardenas, A., Viigimaa, M., Wang, L., Yamashita, S., Kastelein, J. J. P., Bruckert, E., Vohnout, B., Schreier, L., Pang, J., Ebenbichler, C., Dieplinger, H., Innerhofer, R., Winhofer-Stockl, Y., Greber-Platzer, S., Krychtiuk, K., Speidl, W., Toplak, H., Widhalm, K., Stulnig, T., Huber, K., Hollerl, F., Rega-Kaun, G., Kleemann, L., Maser, M., Scholl-Burgi, S., Saly, C., Mayer, F. J., Sablon, G., Tarantino, E., Nzeyimana, C., Pojskic, L., Sisic, I., Nalbantic, A. D., Jannes, C. E., Pereira, A. C., Krieger, J. E., Petrov, I., Goudev, A., Nikolov, F., Tisheva, S., Yotov, Y., Tzvetkov, I., Baass, A., Bergeron, J., Bernard, S., Brisson, D., Brunham, L. R., Cermakova, L., Couture, P., Francis, G. A., Gaudet, D., Hegele, R. A., Khoury, E., Mancini, G. B. J., Mccrindle, B. W., Paquette, M., Ruel, I., Cuevas, A., Asenjo, S., Wang, X., Meng, K., Song, X., Yong, Q., Jiang, T., Liu, Z., Duan, Y., Hong, J., Ye, P., Chen, Y., Qi, J., Li, Y., Zhang, C., Peng, J., Yang, Y., Yu, W., Wang, Q., Yuan, H., Cheng, S., Jiang, L., Chong, M., Jiao, J., Wu, Y., Wen, W., Xu, L., Zhang, R., Qu, Y., He, J., Fan, X., Wang, Z., Chow, E., Pecin, I., Perica, D., Symeonides, P., Vrablik, M., Ceska, R., Soska, V., Tichy, L., Adamkova, V., Franekova, J., Cifkova, R., Kraml, P., Vonaskova, K., Cepova, J., Dusejovska, M., Pavlickova, L., Blaha, V., Rosolova, H., Nussbaumerova, B., Cibulka, R., Vaverkova, H., Cibickova, L., Krejsova, Z., Rehouskova, K., Malina, P., Budikova, M., Palanova, V., Solcova, L., Lubasova, A., Podzimkova, H., Bujdak, J., Vesely, J., Jordanova, M., Salek, T., Urbanek, R., Zemek, S., Lacko, J., Halamkova, H., Machacova, S., Mala, S., Cubova, E., Valoskova, K., Burda, L., Bendary, A., Daoud, I., Emil, S., Elbahry, A., Rafla, S., Sanad, O., Kazamel, G., Ashraf, M., Sobhy, M., El-Hadidy, A., Shafy, M. 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U., Klose, G., Konig, C., Gouni-Berthold, I., Otte, B., Boll, G., Kirschbaum, A., Merke, J., Scholl, J., Segiet, T., Gebauer, M., Predica, F., Mayer, M., Leistikow, F., Fullgraf-Horst, S., Muller, C., Schuler, M., Wiener, J., Hein, K., Baumgartner, P., Kopf, S., Busch, R., Schomig, M., Matthias, S., Allendorf-Ostwald, N., Fink, B., Bohm, D., Jakel, A., Koschker, A. -C., Schweizer, R., Vogt, A., Parhofer, K., Konig, W., Reinhard, W., Bassler, A., Stadelmann, A., Schrader, V., Katzmann, J., Tarr, A., Steinhagen-Thiessen, E., Kassner, U., Paulsen, G., Homberger, J., Zemmrich, C., Seeger, W., Biolik, K., Deiss, D., Richter, C., Pantchechnikova, E., Dorn, E., Schatz, U., Julius, U., Spens, A., Wiesner, T., Scholl, M., Rizos, C. V., Sakkas, N., Elisaf, M., Skoumas, I., Tziomalos, K., Rallidis, L., Kotsis, V., Doumas, M., Athyros, V., Skalidis, E., Kolovou, G., Garoufi, A., Bilianou, E., Koutagiar, I., Agapakis, D., Kiouri, E., Antza, C., Katsiki, N., Zacharis, E., Attilakos, A., Sfikas, G., Koumaras, C., Anagnostis, P., Anastasiou, G., Liamis, G., Koutsogianni, A. -D., Karanyi, Z., Harangi, M., Bajnok, L., Audikovszky, M., Mark, L., Benczur, B., Reiber, I., Nagy, G., Nagy, A., Reddy, L. L., Shah, S. A. V., Ponde, C. K., Dalal, J. J., Sawhney, J. P. S., Verma, I. C., Altaey, M., Al-Jumaily, K., Rasul, D., Abdalsahib, A. F., Jabbar, A. A., Al-ageedi, M., Agar, R., Cohen, H., Ellis, A., Gavishv, D., Harats, D., Henkin, Y., Knobler, H., Leavit, L., Leitersdorf, E., Rubinstein, A., Schurr, D., Shpitzen, S., Szalat, A., Casula, M., Zampoleri, V., Gazzotti, M., Olmastroni, E., Sarzani, R., Ferri, C., Repetti, E., Sabba, C., Bossi, A. C., Borghi, C., Muntoni, S., Cipollone, F., Purrello, F., Pujia, A., Passaro, A., Marcucci, R., Pecchioli, V., Pisciotta, L., Mandraffino, G., Pellegatta, F., Mombelli, G., Branchi, A., Fiorenza, A. M., Pederiva, C., Werba, J. P., Parati, G., Carubbi, F., Iughetti, L., Iannuzzi, A., Iannuzzo, G., Calabro, P., Averna, M., Biasucci, G., Zambon, S., Roscini, A. R., Trenti, C., Arca, M., Federici, M., Del Ben, M., Bartuli, A., Giaccari, A., Pipolo, A., Citroni, N., Guardamagna, O., Bonomo, K., Benso, A., Biolo, G., Maroni, L., Lupi, A., Bonanni, L., Zenti, M. G., Matsuki, K., Hori, M., Ogura, M., Masuda, D., Kobayashi, T., Nagahama, K., Al-Jarallah, M., Radovic, M., Lunegova, O., Bektasheva, E., Khodzhiboboev, E., Erglis, A., Gilis, D., Nesterovics, G., Saripo, V., Meiere, R., Upena-RozeMicena, A., Terauda, E., Jambart, S., Khoury, P. E., Elbitar, S., Ayoub, C., Ghaleb, Y., Aliosaitiene, U., Kutkiene, S., Kasim, N. A. M., Nor, N. S. M., Ramli, A. S., Razak, S. A., Al-Khateeb, A., Kadir, S. H. S. A., Muid, S. A., Rahman, T. A., Kasim, S. S., Radzi, A. B. M., Ibrahim, K. S., Razali, S., Ismail, Z., Ghani, R. A., Hafidz, M. I. A., Chua, A. L., Rosli, M. M., Annamalai, M., Teh, L. K., Razali, R., Chua, Y. A., Rosman, A., Sanusi, A. R., Murad, N. A. A., Jamal, A. R. A., Nazli, S. A., Razman, A. Z., Rosman, N., Rahmat, R., Hamzan, N. S., Azzopardi, C., Mehta, R., Martagon, A. J., Ramirez, G. A. G., Villa, N. E. A., Vazquez, A. V., Elias-Lopez, D., Retana, G. G., Rodriguez, B., Macias, J. J. C., Zazueta, A. R., Alvarado, R. M., Portano, J. D. M., Lopez, H. A., Sauque-Reyna, L., Herrera, L. G. G., Mendia, L. E. S., Aguilar, H. G., Cooremans, E. R., Aparicio, B. P., Zubieta, V. M., Gonzalez, P. A. C., Ferreira-Hermosillo, A., Portilla, N. C., Dominguez, G. J., Garcia, A. Y. R., Cazares, H. E. A., Gonzalez, J. R., Valencia, C. V. M., Padilla, F. G., Prado, R. M., De los Rios Ibarra, M. O., Villicana, R. D. A., Rivera, K. J. A., Carrera, R. A., Alvarez, J. A., Martinez, J. C. A., de los Reyes Barrera Bustillo, M., Vargas, G. C., Chacon, R. C., Andrade, M. H. F., Ortega, A. F., Alcala, H. G., de Leon, L. E. G., Guzman, B. G., Garcia, J. J. G., Cuellar, J. C. G., Cruz, J. R. G., Garcia, A. H., Almada, J. R. H., Herrera, U. J., Sobrevilla, F. L., Rodriguez, E. M., Sibaja, C. M., Rodriguez, A. B. M., Oyervides, J. C. M., Vazquez, D. I. P., Rodriguez, E. A. R., Osorio, M. L. R., Saucedo, J. R., Tamayo, M. T., Talavera, L. A. V., Arroyo, L. E. V., Carrillo, E. A. Z., Isara, A., Obaseki, D. E., Al-Waili, K., Al-Zadjali, F., Al-Zakwani, I., Al-Kindi, M., Al-Mukhaini, S., Al-Barwani, H., Rana, A., Shah, L. S. U., Starostecka, E., Konopka, A., Lewek, J., Bartlomiejczyk, M., Gasior, M., Dyrbus, K., Jozwiak, J., Gruchala, M., Pajkowski, M., Romanowska-Kocejko, M., Zarczynska-Buchowiecka, M., Chmara, M., Wasag, B., Parczewska, A., Gilis-Malinowska, N., Borowiec-Wolna, J., Strozyk, A., Wos, M., Michalska-Grzonkowska, A., Medeiros, A. M., Alves, A. C., Silva, F., Lobarinhas, G., Palma, I., de Moura, J. P., Rico, M. T., Rato, Q., Pais, P., Correia, S., Moldovan, O., Virtuoso, M. J., Salgado, J. M., Colaco, I., Dumitrescu, A., Lengher, C., Mosteoru, S., Meshkov, A., Ershova, A., Rozkova, T., Korneva, V., Yu, K. T., Zafiraki, V., Voevoda, M., Gurevich, V., Duplyakov, D., Ragino, Y., Safarova, M., Shaposhnik, I., Alkaf, F., Khudari, A., Rwaili, N., Al-Allaf, F., Alghamdi, M., Batais, M. A., Almigbal, T. H., Kinsara, A., Alqudaimi, A. H. A., Awan, Z., Elamin, O. A., Altaradi, H., Rajkovic, N., Popovic, L., Singh, S., Stosic, L., Rasulic, I., Lalic, N. M., Lam, C., Le, T. J., Siang, E. L. T., Dissanayake, S., I-Shing, J. T., Shyong, T. E., Jin, T. C. S., Balinth, K., Buganova, I., Fabryova, L., Kadurova, M., Klabnik, A., Kozarova, M., Sirotiakova, J., Battelino, T., Kovac, J., Mlinaric, M., Sustar, U., Podkrajsek, K. T., Fras, Z., Jug, B., Cevc, M., Pilcher, G. J., Blom, D. J., Wolmarans, K. H., Brice, B. C., Muniz-Grijalvo, O., Diaz-Diaz, J. L., de Isla, L. P., Fuentes, F., Badimon, L., Martin, F., Lux, A., Chang, N. -T., Ganokroj, P., Akbulut, M., Alici, G., Bayram, F., Can, L. H., Celik, A., Ceyhan, C., Coskun, F. Y., Demir, M., Demircan, S., Dogan, V., Durakoglugil, E., Dural, I. E., Gedikli, O., Hacioglu, A., Ildizli, M., Kilic, S., Kirilmaz, B., Kutlu, M., Oguz, A., Ozdogan, O., Onrat, E., Ozer, S., Sabuncu, T., Sahin, T., Sivri, F., Sonmez, A., Temizhan, A., Topcu, S., Tuncez, A., Vural, M., Yenercag, M., Yesilbursa, D., Yigit, Z., Yildirim, A. B., Yildirir, A., Yilmaz, M. B., Atallah, B., Traina, M., Sabbour, H., Hay, D. A., Luqman, N., Elfatih, A., Abdulrasheed, A., Kwok, S., Oca, N. D., Reyes, X., Alieva, R. B., Kurbanov, R. D., Hoshimov, S. U., Nizamov, U. I., Ziyaeva, A. V., Abdullaeva, G. J., Do, D. L., Nguyen, M. N. T., Kim, N. T., Le, T. T., Le, H. A., Tokgozoglu, L., Catapano, A. L., Ray, K. K., and EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC), Borghi C

Subjects
Male, Settore MED/09 - Medicina Interna, Arterial disease, Cross-sectional study, Adult population, Coronary Disease, Disease, Global Health, Medical and Health Sciences, Doenças Cardio e Cérebro-vasculares, Anticholesteremic Agent, Monoclonal, Prevalence, Registries, Familial Hypercholesterolemia, Humanized, Stroke, 11 Medical and Health Sciences, LS2_9, Studies Collaboration, Anticholesteremic Agents, General Medicine, Heart Disease Risk Factor, Middle Aged, FHSC global registry data, Europe, Treatment Outcome, Lower prevalence, Guidance, lipids (amino acids, peptides, and proteins), Female, Proprotein Convertase 9, Familial hypercholesterolaemia, Life Sciences & Biomedicine, Human, Adult, medicine.medical_specialty, Combination therapy, FHSC global registry, heterozygous familial hypercholesterolaemia, Cardiovascular risk factors, Antibodies, Monoclonal, Humanized, Insights, Antibodies, NO, Hyperlipoproteinemia Type II, Clinician, Medicine, General & Internal, Internal medicine, General & Internal Medicine, Health Sciences, medicine, Humans, EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC), Cross-Sectional Studie, Science & Technology, Global Perspective, business.industry, Cholesterol, LDL, medicine.disease, Cross-Sectional Studies, Heart Disease Risk Factors, Hydroxymethylglutaryl-CoA Reductase Inhibitor, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business
Abstract

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53.6%] women) from 56 countries were included in the study. Of these, 31 798 (75.4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84.2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46.2 years (IQR 34.3-58.0); median age at diagnosis of familial hypercholesterolaemia was 44.4 years (32.5-56.5), with 40.2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17.4% (2.1% for stroke and 5.2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81.1%) were receiving statins and 3691 (21.2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5.43 mmol/L (IQR 4.32-6.72) among patients not taking lipid-lowering medications and 4.23 mmol/L (3.20-5.66) among those taking them. Among patients taking lipid-lowering medications, 2.7% had LDL cholesterol lower than 1.8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin-kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1.8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p, Pfizer Independent Grant for Learning Change [16157823]; Amgen; Merck Sharp Dohme; Sanofi-Aventis; Daiichi Sankyo; Regeneron; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK; NIHR; Czech Ministry of Health [NU20-02-00261]; Canadian Institutes of Health Research; Austrian Heart Foundation; Tyrolean Regional Government; Gulf Heart Association, The EAS FHSC is an academic initiative that has received funding from a Pfizer Independent Grant for Learning & Change 2014 (16157823) and from investigator-initiated research grants to the European Atherosclerosis Society-Imperial College London from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron. KKR acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK. KID acknowledges support from a PhD Studentship from NIHR under the Applied Health Research programme for Northwest London, UK (the views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health). TF was supported by a grant from the Czech Ministry of Health (NU20-02-00261). JG receives support from the Canadian Institutes of Health Research. The Austrian Familial Hypercholesterolaemia registry has been supported by funds from the Austrian Heart Foundation and the Tyrolean Regional Government. The Gulf Familial Hypercholesterolaemia registry was done under the auspices of the Gulf Heart Association.

Published
2021

39. Hyaluronan oligosaccharides modulate inflammatory response, NIS and thyreoglobulin expression in human thyrocytes

Author

Michele Scuruchi, Salvatore Campo, Angela D'Ascola, Rosaria Maddalena Ruggeri, Teresa Manuela Vicchio, Angela Avenoso, Giuseppe M. Campo, and Giuseppe Mandraffino

Subjects
0301 basic medicine, Cell type, medicine.medical_treatment, Biophysics, Oligosaccharides, Inflammation, Cytokines, Hyaluronan fragments, NIS, Thyreoglobulin, Thyroid cells, Biochemistry, Thyroglobulin, Thyroiditis, 03 medical and health sciences, Gene expression, Blocking antibody, medicine, Humans, Hyaluronic Acid, Molecular Biology, Cells, Cultured, 030102 biochemistry & molecular biology, biology, Symporters, Chemistry, CD44, Thyroid, NF-kappa B p50 Subunit, medicine.disease, Toll-Like Receptor 2, Cell biology, Toll-Like Receptor 4, 030104 developmental biology, medicine.anatomical_structure, Cytokine, Hyaluronan Receptors, Thyroid Epithelial Cells, biology.protein, medicine.symptom
Abstract

Autoimmune thyroid diseases, such as Hashimoto's thyroiditis, are characterized by lymphocytic infiltration and altered function of the thyroid. During inflammation, it has been reported a decreased expression in Tg and NIS, accompanied by an increase in HA production that accumulates in the gland. HA fragments produced in different pathological states can modulate gene expression in a variety of cell types and may prime inflammatory response by interacting with the TLR-2, TLR-4 and CD44 that, in turn, induce NF-kB activation finally responsible of inflammatory mediator transcription, such as IL-1β, TNF-α and IL-6. The aim of this study was to investigate the potential inflammatory effect and the biochemical pathways activated by 6-mer HA oligosaccharides in cultured human thyrocytes. 6-mer HA treatment induced up-regulation of TLR-2, TLR-4, CD44 mRNA and related protein levels, increased HA production and NF-kB activation, that in turn increased IL-1β and IL-6 concentrations. Instead, we found evidence of an opposite effect on thyroid specific-gene Tg and NIS, that were decreased after 6-mer HA addition. Thyrocytes exposition to specific blocking antibodies for TLR-2, TLR-4 and CD44 abolished up-regulation of NF-κB activation and the consequent pro-inflammatory cytokine production, while restored Tg and NIS levels. A further goal of this study was demonstrate that also other LMW HA have pro inflammatory proprieties. These data suggest that HA fragments, through the involvement of TLR-2, TLR-4 and CD44 signaling cascade, contribute to prime the inflammatory response in thyrocytes and, by reducing the expression of thyroid-specific genes, could promote the loss of function of gland such as in Hashimoto's thyroiditis.

Published
2020

40. Hyaluronan fragmentation during inflammatory pathologies: A signal that empowers tissue damage

Author

Michele Scuruchi, Giuseppe Bruschetta, Giuseppe M. Campo, Salvatore Campo, Angela Avenoso, Giuseppe Mandraffino, Antonino Saitta, and Angela D Ascola

Subjects
Chemokine, Cellular homeostasis, Context (language use), Inflammation, Cytokines, Extracellular matrix, Hyaluronan fragments, Toll-like receptors, Transcription factors, Animals, Extracellular Matrix, Humans, Hyaluronic Acid, Toll-Like Receptors, 03 medical and health sciences, 0302 clinical medicine, Drug Discovery, medicine, Fragmentation (cell biology), Receptor, Transcription factor, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, Chemistry, General Medicine, Cell biology, 030220 oncology & carcinogenesis, biology.protein, medicine.symptom
Abstract

The mechanisms that modulate the response to tissue injury are not fully understood. Abnormalities in the repair response are associated with a variety of chronic disease states characterized by inflammation, followed subsequently by excessive ECM deposition. As cell-matrix interactions are able to regulate cellular homeostasis, modification of ECM integrity appears to be an unspecific factor in promoting the onset and progression of inflammatory diseases. Evidence is emerging to show that endogenous ECM molecules supply signals to damage tissues and cells in order to promote further ECM degradation and inflammation progression. Several investigations have been confirmed that HA fragments of different molecular sizes exhibit different biological effects and responses. In fact, the increased deposition of HA into the ECM is a strong hallmark of inflammation processes. In the context of inflammatory pathologies, highly polymerized HA is broken down into small components, which are able to exacerbate the inflammatory response by inducing the release of various detrimental mediators such as reactive oxygen species, cytokines, chemokines and destructive enzymes and by facilitating the recruitment of leukocytes. However, strategies involving the modulation of the HA fragment with specific receptors on cell surface could represent different promising effects for therapeutic scope. : This review will focus on the inflammation action of small HA fragments in recent years obtained by in vivo reports.

Published
2020

41. Biglycan and atherosclerosis: Lessons from high cardiovascular risk conditions

Author

Giuseppe Mandraffino, Francesco Potì, Javier Rodríguez-Carrio, Michele Scuruchi, and Giuseppe M. Campo

Subjects
0301 basic medicine, medicine.medical_specialty, Lipoproteins, Inflammation, 030204 cardiovascular system & hematology, Dermatan sulfate, Cigarette Smoking, Extracellular matrix, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Internal medicine, Diabetes mellitus, Biglycan, Diabetes Mellitus, Prevalence, medicine, Animals, Humans, Chondroitin sulfate, Renal Insufficiency, Chronic, Molecular Biology, Cardiovascular risk factors, Dyslipidemias, biology, business.industry, Cell Biology, Atherosclerosis, medicine.disease, Disease Models, Animal, 030104 developmental biology, Endocrinology, chemistry, Proteoglycan, Hypertension, Disease Progression, biology.protein, Proteoglycans, medicine.symptom, business, Dyslipidemia
Abstract

Atherosclerosis (ATH) is a chronic, dynamic, evolutive process involving morphological and structural subversion of artery walls, leading to the formation of atherosclerotic plaques. ATH generally initiates during the childhood, occurring as a result of a number of changes in the intima tunica and in the media of arteries. A key event occurring during the pathobiology of ATH is the accumulation of lipoproteins in the sub-intimal spaces mediated by extracellular matrix (ECM) molecules, especially by the chondroitin sulfate/dermatan sulfate (CS/DS) -containing proteoglycans (CS/DSPGs). Among them, the proteoglycan biglycan (BGN) is critically involved in the onset and progression of ATH and evidences show that BGN represents the missing link between the pro-atherogenic status induced by both traditional and non-traditional cardiovascular risk factors and the development and progression of vascular damage. In the light of these findings, the role of BGN in dyslipidemia, hypertension, cigarette smoking, diabetes, chronic kidney disease and inflammatory status is briefly analyzed and discussed in order to shed new light on the underlying mechanisms governing the association between BGN and ATH.

Published
2020

42. Speckle tracking echocardiography as a new diagnostic tool for an assessment of cardiovascular disease in rheumatic patients

Author

Giovanni Squadrito, Javier Rodríguez-Carrio, Alberto Lo Gullo, Giuseppe Mandraffino, Egidio Imbalzano, and Romina Gallizzi

Subjects
medicine.medical_specialty, Population, Speckle tracking echocardiography, Disease, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Risk Factors, Internal medicine, Rheumatic Diseases, Medicine, Humans, 030212 general & internal medicine, education, Subclinical infection, Ankylosing spondylitis, education.field_of_study, Ejection fraction, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, Gold standard (test), medicine.disease, Prognosis, Early Diagnosis, Cardiovascular Diseases, Echocardiography, Cardiology, Cardiology and Cardiovascular Medicine, business
Abstract

Chronic inflammation represents the cornerstone of the raised cardiovascular (CV) risk in patients with inflammatory rheumatic diseases (IRD). Standardized mortality ratios are increased in these patients compared to the general population, which can be explained by premature mortality associated with early atherosclerotic events. Thus, IRD patients need appropriate CV risk management in view of this CV disease (CVD) burden. Currently, optimal CV risk management is still lacking in usual care, and early diagnosis of silent and subclinical CVD involvement is mandatory to improve the long-term prognosis of those patients. Although CV involvement in such patients is highly heterogeneous and may affect various structures of the heart, it can now be diagnosed earlier and promptly treated. CV imaging provides valuable information as a reliable diagnostic tool. Currently, different techniques are employed to evaluate CV risk, including transthoracic or trans-esophageal echocardiography, magnetic resonance imaging, or computed tomography, to investigate valve abnormalities, pericardial disease, and ventricular wall motion defects. All the above methods are reliable in investigating CV involvement, but more recently, Speckle Tracking Echocardiography (STE) has been suggested to be diagnostically more accurate. In recent years, the role of left ventricular ejection fraction (LVEF) as the gold standard parameter for the evaluation of systolic function has been debated, and many efforts have been focused on the clinical validation of new non-invasive tools for the study of myocardial contractility as well as to characterize the subclinical alterations of the myocardial function. Improvement in the accuracy of STE has resulted in a large amount of research showing the ability of STE to overcome LVEF limitations in the majority of primary and secondary heart diseases. This review summarizes the additional value that STE measurement can provide in the setting of IRD, with a focus in the different clinical stages.

Published
2020

43. Arterial stiffness improvement after adding on PCSK9 inhibitors or ezetimibe to high-intensity statins in patients with familial hypercholesterolemia: A Two–Lipid Center Real-World Experience

Author

F. Mamone, Roberto Scicali, Egidio Imbalzano, Antonino Di Pino, Francesco Purrello, Agata Maria Rabuazzo, F. Savarino, Antonino Saitta, Salvatore Piro, M. Cinquegrani, Giuseppe Mandraffino, Giovanni Squadrito, Michele Scuruchi, and Javier Rodríguez-Carrio

Subjects
medicine.medical_specialty, Statin, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Familial hypercholesterolemia, Urology, 030204 cardiovascular system & hematology, Ezetimibe, LDL cholesterol, PCSK9 inhibitors, Pulse wave velocity, 03 medical and health sciences, 0302 clinical medicine, Internal Medicine, medicine, 030212 general & internal medicine, Nutrition and Dietetics, medicine.diagnostic_test, business.industry, PCSK9, medicine.disease, Arterial stiffness, lipids (amino acids, peptides, and proteins), Observational study, Cardiology and Cardiovascular Medicine, Lipid profile, business, medicine.drug
Abstract

Background Familial hypercholesterolemia (FH) is characterized by increased cardiovascular risk; despite-high intensity statins, only few patients with FH achieve the recommended low-density lipoprotein cholesterol (LDL-C) targets. Objective We aimed to evaluate the effectiveness of six-month add-on therapy with proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-i) or ezetimibe on lipid profile and pulse wave velocity (PWV) in patients with FH. Methods In this observational study, we evaluated 98 genetically confirmed patients with FH with an LDL-C off-target despite high-intensity statins with or without ezetimibe; of these, 53 patients (statin plus ezetimibe) added PCSK9-i (PCSK9-i group) and 45 (statin only) added ezetimibe (EZE group) per applicable guidelines and reimbursement rules. All patients obtained biochemical analysis and PWV evaluation at baseline and after six months of optimized treatment. Results After 6 months of add-on therapy, most patients achieving LDL-C targets were in the PCSK9-i group (77.3% PCSK9-i group vs 37.8% EZE group, P Conclusions Lipid and PWV profiles in patients with FH significantly improved after addition of PCSK9-i or ezetimibe to high-intensity statin therapy; moreover, ΔPWV was associated with ΔLDL. Our results are consistent with a beneficial role of these novel therapies in FH subjects.

Published
2020

44. Serglycin is involved in inflammatory response in articular mouse chondrocytes

Author

Giuseppe M. Campo, Giuseppe Bruschetta, Angela D'Ascola, Giuseppe Mandraffino, Salvatore Campo, Michele Scuruchi, and Angela Avenoso

Subjects
Cartilage, Articular, 0301 basic medicine, Small interfering RNA, Lipopolysaccharide, Interleukin-1beta, Vesicular Transport Proteins, Biophysics, Nitric Oxide Synthase Type II, Inflammation, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Chondrocytes, 0302 clinical medicine, medicine, Animals, Serglycin, RNA, Messenger, RNA, Small Interfering, CD44, Cytokines, NF-kB, Receptor, Molecular Biology, Gene knockdown, Messenger RNA, biology, Interleukin-6, Tumor Necrosis Factor-alpha, NF-kappa B, Cell Biology, Cell biology, Mice, Inbred C57BL, Hyaluronan Receptors, 030104 developmental biology, Gene Expression Regulation, Matrix Metalloproteinase 9, Proteoglycan, chemistry, 030220 oncology & carcinogenesis, biology.protein, Proteoglycans, medicine.symptom
Abstract

Serglycin is expressed by a variety of cell types and mediates different functions in both normal and pathological conditions by interacting with different biological molecules, such as the CD44 receptor. Many studies suggest that serglycin has a crucial role in inflammatory response, but there are limited data on the functions of this proteoglycan in chondrocytes. In this study we investigated the effect of serglycin knockdown induced by a specific serglycin small interfering RNA (SRGN siRNA) in normal mouse chondrocytes stimulated with lipopolysaccharide (LPS). LPS administration in normal chondrocytes increased the expression of serglycin mRNA and related protein and the production of the pro-inflammatory mediators TNF-alpha, IL-1beta, IL-6, iNOS and MMP-9, through NF-kB activation. In addition, a marked increased expression of CD44 after LPS stimulation was observed. Notably, the CD44 expression and the inflammatory response were significantly reduced by SRGN siRNA treatment in LPS treated chondrocytes. Similar results were obtained in normal mouse chondrocytes exposed to LPS, using a specific blocking antibody against CD44. These results indicate that serglycin produced in LPS-induced inflammation in normal mouse chondrocytes is able to modulate inflammation by interacting with CD44 receptor, suggesting a possible key role in the cartilage inflammation.

Published
2018

45. Atrial septal defect morphology and stenting in hypoplastic left heart syndrome after hybrid palliation

Author

Lilia Oreto, Lucia Manuri, Fiore S. Iorio, Scipione Carerj, Michele B. Saitta, Paolo Guccione, Giuseppe Mandraffino, Salvatore Agati, and Concetta Zito

Subjects
Male, Cardiac Catheterization, medicine.medical_specialty, medicine.medical_treatment, Foramen secundum, 030204 cardiovascular system & hematology, Heart Septal Defects, Atrial, Hypoplastic left heart syndrome, Pulmonary artery banding, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Hypoplastic Left Heart Syndrome, medicine, Humans, Effective treatment, Abnormalities, Multiple, Postoperative Period, Cardiac Surgical Procedures, Retrospective Studies, business.industry, Palliative Care, Significant difference, Angiography, Infant, Newborn, Stent, General Medicine, medicine.disease, Pulmonary hypertension, Echocardiography, Doppler, Color, 030228 respiratory system, Pediatrics, Perinatology and Child Health, Balloon dilation, Cardiology, Restrictive atrial septal defect, hybrid palliation, hypoplastic left heart syndrome, malalignement atrial septal defect, stenting, Female, Stents, Cardiology and Cardiovascular Medicine, business, Follow-Up Studies
Abstract

AimsThe aim of this study was to describe atrial septal defect morphology in hypoplastic left heart syndrome, to report the incidence of restrictiveness and its relationship with defect morphology, to correlate restriction with midterm outcome, and to describe our interventional approach to restrictive defect.Methods and resultsFrom 2011 to 2015, 31 neonates with hypoplastic left heart syndrome underwent hybrid procedure with pulmonary artery banding and ductal stenting at our Institution. Restrictive physiology of the atrial septal defect was based on Doppler gradient >6 mmHg through the defect and on clinical signs of pulmonary hypertension. The mean gradient was then measured invasively. Restrictive defect occurred in 11/27 patients (40%). The restrictive group showed three ostium secundum defects (27%) and eight complex morphologies (73%). Conversely, in the non-restrictive group, we observed 11 ostium secundum defects (69%) and five complex morphologies (31%). Early balloon atrioseptostomy was required in three cases. Late restriction occurred in eight patients and was dealt with balloon dilation, stenting, or atrioseptectomy. There was no significant difference between restrictive and non-restrictive groups in terms of early or 12-month survival.ConclusionsComplex morphologies were more frequently related to restrictiveness. Stenting technique has a crucial role, as the procedure carries a significant risk for stent migration. Effective treatment of restrictive atrial septal defect is related to a better outcome, as it leads to equalisation of survival between patients with and those without restrictive atrial septal defect.

Published
2017

46. Biglycan expression, earlier vascular damage and pro-atherogenic profile improvement after smoke cessation in young people

Author

Enricomaria Mormina, Lilia Oreto, Carmela Morace, Angela D'Ascola, C.O. Aragona, Egidio Imbalzano, Giuseppe Mandraffino, F. Mamone, Maurizio Cinquegrani, Carlo Saitta, Scipione Carerj, Angela Alibrandi, Michele Scuruchi, and Antonino Saitta

Subjects
Male, 0301 basic medicine, Time Factors, medicine.medical_treatment, Smoke cessation, Blood Pressure, Smoking Prevention, 030204 cardiovascular system & hematology, Fibrinogen, 0302 clinical medicine, Risk Factors, Biglycan, Pulse wave velocity, Vascular inflammation, media_common, Smoking, Age Factors, Arterial stiffness, Cardiology, Proteoglycans, Female, Inflammation Mediators, Cardiology and Cardiovascular Medicine, medicine.drug, Adult, medicine.medical_specialty, Adolescent, media_common.quotation_subject, Down-Regulation, Pulse Wave Analysis, Young Adult, 03 medical and health sciences, Arterial stiffness, Vascular inflammation, Atherosclerosis, Proteoglycans, Biglycan, Smoking, Smoke cessation, Internal medicine, medicine, Humans, Risk factor, Inflammation, business.industry, Cholesterol, HDL, Recovery of Function, Abstinence, Atherosclerosis, medicine.disease, Surgery, 030104 developmental biology, Blood pressure, Smoking cessation, Smoking Cessation, Endothelium, Vascular, business, Biomarkers
Abstract

Background and aims Young cigarette smokers may already present with early signs of vascular inflammation and damage; biglycan (BGN) has been shown to play a critical role in the initiation and progression of vascular lesions, also in young smokers. We investigated whether after smoke cessation, monocyte BGN expression is reduced; moreover, we evaluated any improvement of pro-atherogenic profile and arterial stiffness (AS), and their relationship with BGN in abstinent smokers. Methods Two-hundred-fifty-one young people who had decided to quit smoking were enrolled; of these, 71 had completed the 12-month observation period maintaining smoking abstinence. At enrollment and 12 months later, we evaluated anthropometrics, laboratory profile, carotid-femoral pulse wave velocity (cf-PWV), carotid intima-media thickness (cIMT), BGN expression. Results After 12-month smoke abstinence, we found a significant decrease in inflammatory markers (Hs-CRP: −23.3%; fibrinogen: −11.8%; IL-6: −9.2%), and increased HDL-C levels (+9.3%); blood pressure values were also slightly reduced. cf-PWV (−8.9%) appeared to be improved; cIMT remained unchanged. BGN expression appeared to be reduced (−42.8% relative reduction). BGN reduction appeared to be associated with fibrinogen reduction, and smoking burden. Reduced cf-PWV appeared to be dependent on change in fibrinogen, SBP, IL-6, and BGN by multiple regression analysis. Conclusions After the first year of smoke abstinence, the levels of IL-6, CRP, fibrinogen, HDL-C, and BGN expression, as well cf-PWV, are significantly improved as compared to baseline. This is the first evidence that removing exposure to a well-known cardiovascular risk factor, such as cigarette smoking, leads to significant reduction of BGN expression.

Published
2017

47. Frailty modifications and prognostic impact in older patients admitted in acute care

Author

Daniela Brischetto, Giorgio Basile, Giuliana Ciancio, Giuseppe Maltese, Giuseppe Mandraffino, Angela Alibrandi, Matteo Cesari, Nunziata Morabito, Antonino Lasco, and Antonino Catalano

Subjects
Male, medicine.medical_specialty, Aging, Frail Elderly, Frailty Index, 03 medical and health sciences, 0302 clinical medicine, Elderly, Older patients, Acute care, Internal medicine, Hospital discharge, medicine, Humans, 030212 general & internal medicine, Hospital Mortality, Mortality, Elderly, Frailty, Hospitalization, Length of stay, Mortality, Aged, Aged 80 and over, Female, Frail Elderly, Frailty, Geriatric Assessment, Hospital Mortality, Hospitalization, Humans, Length of Stay, Male, Prognosis, Aging, Geriatrics and Gerontology, Geriatric Assessment, Aged, Geriatrics, Aged, 80 and over, Frailty, business.industry, Significant difference, Length of Stay, Prognosis, Frailty assessment, Hospitalization, Aged 80 and over, Hospital admission, Female, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract

Frailty is a predictor of adverse outcomes in older subjects. The aims of this study are to (1) measure the frailty status and its changes occurring during the hospital stay, (2) determine the relationships among frailty and adverse outcomes. Frailty was assessed using a 46-item Frailty Index (FI) in 156 patients admitted to an Acute Geriatric Medicine Unit. The FI was calculated within 24 h from the hospital admission (aFI) and at his/her discharge (dFI). Patients were followed up to 12 months after the hospital discharge. A statistically significant difference was reported between the aFI (0.31, IQR 0.19–0.44) and the dFI (0.29, IQR 0.19–0.40; p = 0.04). The aFI was directly associated with the risk of in-hospital death (OR = 5.9; 95% CI 2.0–17.5; p = 0.001), 1 year mortality (OR = 5.5, 95% CI 2.4–12.7, p

Published
2019

48. Serglycin as part of IL-1β induced inflammation in human chondrocytes

Author

Giuseppe M. Campo, Angela Avenoso, Giuseppe Mandraffino G, Angela D'Ascola, Michele Scuruchi, and Salvatore Campo S

Subjects
0301 basic medicine, Cell type, Interleukin-1beta, Vesicular Transport Proteins, Biophysics, Arthritis, Inflammation, Biochemistry, 03 medical and health sciences, Chondrocytes, Matrix Metalloproteinase 13, medicine, Humans, Serglycin, RNA, Messenger, Receptor, Molecular Biology, Hyaluronan Receptors, Interleukin-6, NF-kappa B p50 Subunit, Proteoglycans, Transcription Factor RelA, Tumor Necrosis Factor-alpha, 030102 biochemistry & molecular biology, biology, Chemistry, CD44, medicine.disease, Cell biology, 030104 developmental biology, Proteoglycan, biology.protein, medicine.symptom, Intracellular
Abstract

Serglycin (SRGN) is an intracellular proteoglycan produced and secreted by several cell types. The increased expression of SRGN was associated with greater aggressiveness in cancer and inflammation. In this study, we demonstrated that SRGN is increased in human chondrocytes after IL-β stimulation. Furthermore, we found that secreted SRGN was able to bind the CD44 receptor thus participating in the extension of the inflammatory response. Using SRGN knockdown cells we observed a significantly decrease in specific inflammatory markers and NF-kB activation. Similar results were observed by blocking the CD44 receptor. These data provide further evidences for a direct involvement of SRGN in the mechanisms regulating the non-infectious chondrocytes damage, and the consequent joint inflammation and cartilage destruction in arthritis.

Published
2019

49. Endocan and Circulating Progenitor Cells in Women with Systemic Sclerosis: Association with Inflammation and Pulmonary Hypertension

Author

Michele Scuruchi, Giuseppe Mandraffino, Clemente Giuffrida, Davide Sciortino, Javier Rodríguez-Carrio, Giovanni Squadrito, Maria Concetta Postorino, Saverio Loddo, Concetta Zito, Carmela Morace, Davide Sinicropi, Romina Gallizzi, and Alberto Lo Gullo

Subjects
medicine.medical_specialty, QH301-705.5, systemic sclerosis, CD34, Medicine (miscellaneous), Inflammation, 030204 cardiovascular system & hematology, Fibrinogen, circulating progenitor cells, Gastroenterology, Article, General Biochemistry, Genetics and Molecular Biology, Circulating progenitor cells, Endocan, Pulmonary hypertension, Systemic sclerosis, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Internal medicine, pulmonary hypertension, medicine, Vitamin D and neurology, Biology (General), Progenitor cell, skin and connective tissue diseases, 030203 arthritis & rheumatology, endocan, Ejection fraction, integumentary system, business.industry, medicine.disease, medicine.symptom, business, medicine.drug
Abstract

Background: Systemic sclerosis (SSc) is characterized by early vasculopathy and fibrosis in the skin, lungs, and other tissues. Vascular manifestations of SSc include Raynaud’s phenomenon, digital ulcers, and pulmonary artery hypertension (PAH). PAH is the second most common cause of mortality in SSc. Circulating CD34+ cells associated with cardiovascular health status in several conditions, including chronic immune-inflammatory disease. CD34+ cell numbers have been found inconstantly reduced in SSc. Endocan, a proteoglycan expressed by endothelial cells, was recently suggested as a marker of vascular stress. We tested the relationships among CD34+ cells, endocan, inflammatory markers, vitamin D levels, and clinical parameters in SSc patients with PAH. METHODS: Standard echocardiography was performed. Vitamin D levels, CD34+ cells, inflammatory markers, endocan plasma levels were determined in 36 female SSc patients (24 diffuse/12 limited) and 36 matched controls (HC). RESULTS: We found no difference in CD34+ and vitamin D levels in SSc as compared to controls, ESR, CRP, fibrinogen, endocan, sPAP were higher in SSc with respect to controls. We found a correlation between endocan and: CD34+ cells (r: −0.540, p = 0.002), pulmonary arterial pressure (sPAP) (r: 0.565, p &lt, 0.001), tricuspid annular plane excursion (TAPSE) (r: −0.311, p &lt, 0.01), and E/A ratio (r: −0.487, p &lt, 0.001), but not with ejection fraction (r: −0.057, p = 0.785) in SSc. CD34+ cells correlate with fibrinogen (r: −0.619, p &lt, 0.001), sPAP (r: −0.404, p = 0.011), E/A (r: 0.470, p &lt, 0.005 in SSc. CONCLUSION: CD34+ cell number was significantly correlated with endocan levels and with sPAP in SSc, endocan and CD34+ progenitor cells might be suggested as a potential marker of disease status.

Published
2021

50. Quantitative polymerase Chain reaction profiling of microRNAs in peripheral lymph-monocytes from MGUS subjects

Author

Caterina Musolino, Alessandro Allegra, Giuseppe Mandraffino, Manuela Mania, Vanessa Innao, Salvatore Campo, Angela Avenoso, Andrea Gaetano Allegra, Michele Scuruchi, and Angela D'Ascola

Subjects
Male, 0301 basic medicine, Apoptosis, Monoclonal Gammopathy of Undetermined Significance, Polymerase Chain Reaction, Monocytes, Lymph-monocytes, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Multiple myeloma, Lymphocyte homeostasis, microRNA, Gene expression, Humans, Medicine, Gene Regulatory Networks, Lymphocytes, Cell proliferation, Aged, biology, business.industry, Gene Expression Profiling, Cell Biology, Middle Aged, medicine.disease, MicroRNAs, 030104 developmental biology, Real-time polymerase chain reaction, Case-Control Studies, 030220 oncology & carcinogenesis, Monoclonal, MGUS, biology.protein, Cancer research, Female, Antibody, Transcriptome, business, Monoclonal gammopathy of undetermined significance
Abstract

Monoclonal gammopathy of undetermined significance (MGUS) is a pre-malignant abnormality of plasma cells, with increased serum levels of immunoglobulins. Patients with MGUS may evolve to multiple myeloma through a multistep process including deregulated gene expression. microRNAs are small non-coding RNA molecules involved in post-transcriptional regulation of crucial biological processes, such as morphogenesis, cell differentiation, apoptosis, and cancer. This study aimed to evaluate microRNA expression on peripheral lymph-monocytes from MGUS subjects compared with healthy controls using qPCR arrays. Blood samples were collected by venipuncture from fifteen, newly diagnosed MGUS patients and fifteen healthy subjects. A further group (validation group) of six newly diagnosed MGUS patients and five healthy control were enrolled for the validation of miRNAs and their mRNAs target. The study was conducted performing miProfile miRNA qPCR arrays, followed by validation of miRNAs and related mRNA targets through RT-qPCR. The functional interaction between microRNAs and target gene were obtained by Ingenuity Pathways Analysis (IPA). IPA network analysis identified only molecules and relationships experimentally observed in peripheral lymphomonocytes. The following miRNAs :133a-3p, 16−5p, 291−3p, 23a-3p, 205−5p, 17−5p, 7a-5p, 221−3p, 30c-5p, 126a-3p,155−5p, let-7a-5p and 26a-5p, involved in the regulation of genes with a role in lymphocyte homeostasis, cell proliferation, apoptosis, and multiple myeloma (MM) progression, were differently expressed in MGUS with respect to healthy subjects. This miRNA signature and its relative targets could be considered for the formulation of new therapeutic strategies in the prophylaxis or treatment of monoclonal gammopathies.

Published
2021

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