Mombelli Dott.ssa Giuliana Germana
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Exploiting routine laboratory test to identify primary severe hypertriglyceridaemic patients in a large Italian hospital.
Eur J Prev Cardiol2024 Feb;():. doi: zwae056.
Pavanello Chiara, Pazzucconi Franco, Parolini Marina, Turri Marta, Mombelli Giuliana Germana, Castiglione Sofia, Alberti Antonia, De Maria Renata, Calabresi Laura
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Generation and validation of a classification model to diagnose familial hypercholesterolaemia in adults.
Atherosclerosis2023 Oct;383():117314. doi: 10.1016/j.atherosclerosis.2023.117314.
Albuquerque João, Medeiros Ana Margarida, Alves Ana Catarina, Jannes Cinthia Elim, Mancina Rosellina M, Pavanello Chiara, Chora Joana Rita, Mombelli Giuliana, Calabresi Laura, Pereira Alexandre da Costa, Krieger José Eduardo, Romeo Stefano, Bourbon Mafalda, Antunes Marília
Abstract
BACKGROUND AND AIMS:
The early diagnosis of familial hypercholesterolaemia is associated with a significant reduction in cardiovascular disease (CVD) risk. While the recent use of statistical and machine learning algorithms has shown promising results in comparison with traditional clinical criteria, when applied to screening of potential FH cases in large cohorts, most studies in this field are developed using a single cohort of patients, which may hamper the application of such algorithms to other populations. In the current study, a logistic regression (LR) based algorithm was developed combining observations from three different national FH cohorts, from Portugal, Brazil and Sweden. Independent samples from these cohorts were then used to test the model, as well as an external dataset from Italy.
METHODS:
The area under the receiver operating characteristics (AUROC) and precision-recall (AUPRC) curves was used to assess the discriminatory ability among the different samples. Comparisons between the LR model and Dutch Lipid Clinic Network (DLCN) clinical criteria were performed by means of McNemar tests, and by the calculation of several operating characteristics.
RESULTS:
AUROC and AUPRC values were generally higher for all testing sets when compared to the training set. Compared with DLCN criteria, a significantly higher number of correctly classified observations were identified for the Brazilian (p
CONCLUSIONS:
Compared to DLCN criteria, the LR model revealed improved ability to correctly classify observations, and was able to retain a similar number of FH cases, with less false positive retention. Generalization of the LR model was very good across all testing samples, suggesting it can be an effective screening tool if applied to different populations.
Copyright © 2023 Elsevier B.V. All rights reserved.
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Clinical Approach in the Management of Paediatric Patients with Familial Hypercholesterolemia: A National Survey Conducted by the LIPIGEN Paediatric Group.
Nutrients2023 Aug;15(15):. doi: 3468.
Pederiva Cristina, Gazzotti Marta, Arca Marcello, Averna Maurizio, Banderali Giuseppe, Biasucci Giacomo, Brambilla Marta, Buonuomo Paola Sabrina, Calabrò Paolo, Cipollone Francesco, Citroni Nadia, D'Addato Sergio, Del Ben Maria, Genovesi Simonetta, Guardamagna Ornella, Iannuzzo Gabriella, Iughetti Lorenzo, Mandraffino Giuseppe, Maroni Lorenzo, Mombelli Giuliana, Muntoni Sandro, Nascimbeni Fabio, Passaro Angelina, Pellegatta Fabio, Pirro Matteo, Pisciotta Livia, Pujia Roberta, Sarzani Riccardo, Scicali Roberto, Suppressa Patrizia, Zambon Sabina, Zenti Maria Grazia, Calandra Sebastiano, Catapano Alberico Luigi, Tarugi Patrizia, Galimberti Federica, Casula Manuela, Capra Maria Elena
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
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A subgroup analysis of the ODYSSEY APPRISE study: Safety and efficacy of alirocumab in the Italian cohort.
Nutr Metab Cardiovasc Dis2022 Nov;32(11):2638-2646. doi: 10.1016/j.numecd.2022.07.020.
Cefalù Angelo B, Garbelotto Raffaella, Mombelli Giuliana, Pirro Matteo, Rubba Paolo, Arca Marcello, Borghi Claudio, Bonomo Katia, Gonnelli Stefano, Massaroni Katia, Tirone Giampaolo, Averna Maurizio,
Abstract
BACKGROUND AND AIMS:
ODYSSEY APPRISE trial evaluated efficacy and safety of alirocumab in 994 patients with hypercholesterolemia and high CV risk in a real-life setting. The aim of the present report is to detail on the Italian cohort enrolled and treated in the trial.
METHODS AND RESULTS:
The methodology of the of the multinational, single-arm, Phase 3b open-label ODYSSEY APPRISE (Clinicaltrials.gov: NCT02476006) has been previously reported. 255 Italian patients were enrolled and treated according to the trial protocol. Overall mean exposure to alirocumab was 83.3 ± 27.7 weeks. At week 12, LDL-C decreased by 51.3 ± 23.1% and this reduction was overall maintained for the duration of the study. A similar reduction was observed in patients with and without heterozygous familial hypercholesterolemia (HeFH 50.7% ± 23.9 vs. non-FH, 53.6% ± 19.6). LDL-C was reduced below 1.8 mmol/L and/or by ? 50% reduction from baseline in 62% of patients overall (61% in HeFH and 67% in non-FH). Alirocumab was similarly well tolerated in the Italian cohort as in the entire study population and the more common treatment emergent adverse events (TEAEs) were influenza, myalgia and nasopharyngitis. The incidence LDL-C levels
CONCLUSION:
The efficacy and safety of alirocumab in a real-life setting, in the Italian subgroup of patients are consistent with findings in the entire study population and confirm that alirocumab is a beneficial approach to further reduce LDL-C levels in patients at high CV risk on maximally tolerated conventional lipid lowering treatment.
GOV IDENTIFIER:
NCT02476006.
Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
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Effects of PCSK9 inhibitors on HDL cholesterol efflux and serum cholesterol loading capacity in familial hypercholesterolemia subjects: a multi-lipid-center real-world evaluation.
Front Mol Biosci2022 ;9():925587. doi: 925587.
Palumbo Marcella, Giammanco Antonina, Purrello Francesco, Pavanello Chiara, Mombelli Giuliana, Di Pino Antonino, Piro Salvatore, Cefalù Angelo Baldassare, Calabresi Laura, Averna Maurizio, Bernini Franco, Zimetti Francesca, Adorni Maria Pia, Scicali Roberto
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond regulating LDL cholesterol (LDL-c) plasma levels, exerts several pleiotropic effects by modulating lipid metabolism in extrahepatic cells such as macrophages. Macrophage cholesterol homeostasis depends on serum lipoprotein functions, including the HDL capacity to promote cell cholesterol efflux (CEC) and the serum capacity to promote cell cholesterol loading (CLC). The aim of this observational study was to investigate the effect of PCSK9 inhibitors (PCSK9-i) treatment on HDL-CEC and serum CLC in patients with familial hypercholesterolemia (FH). 31 genetically confirmed FH patients were recruited. Blood was collected and serum isolated at baseline and after 6 months of PCSK9-i treatment. HDL-CEC was evaluated through the main pathways with a radioisotopic cell-based assay. Serum CLC was assessed fluorimetrically in human THP-1 monocyte-derived macrophages. After treatment with PCSK9-i, total cholesterol and LDL-c significantly decreased (-41.6%,
Copyright © 2022 Palumbo, Giammanco, Purrello, Pavanello, Mombelli, Di Pino, Piro, Cefalù, Calabresi, Averna, Bernini, Zimetti, Adorni and Scicali.
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Interactions of Oxysterols with Atherosclerosis Biomarkers in Subjects with Moderate Hypercholesterolemia and Effects of a Nutraceutical Combination ( BB536, Red Yeast Rice Extract) (Randomized, Double-Blind, Placebo-Controlled Study).
Nutrients2021 Jan;13(2):. doi: 427.
Cicolari Stefania, Pavanello Chiara, Olmastroni Elena, Puppo Marina Del, Bertolotti Marco, Mombelli Giuliana, Catapano Alberico L, Calabresi Laura, Magni Paolo
Abstract
BACKGROUND:
Oxysterol relationship with cardiovascular (CV) risk factors is poorly explored, especially in moderately hypercholesterolaemic subjects. Moreover, the impact of nutraceuticals controlling hypercholesterolaemia on plasma levels of 24-, 25- and 27-hydroxycholesterol (24-OHC, 25-OHC, 27-OHC) is unknown.
METHODS:
Subjects ( = 33; 18-70 years) with moderate hypercholesterolaemia (low-density lipoprotein cholesterol (LDL-C:): 130-200 mg/dL), in primary CV prevention as well as low CV risk were studied cross-sectionally. Moreover, they were evaluated after treatment with a nutraceutical combination ( BB536, red yeast rice extract (10 mg/dose monacolin K)), following a double-blind, randomized, placebo-controlled design. We evaluated 24-OHC, 25-OHC and 27-OHC levels by gas chromatography/mass spectrometry analysis.
RESULTS:
24-OHC and 25-OHC were significantly correlated, 24-OHC was correlated with apoB. 27-OHC and 27-OHC/total cholesterol (TC) were higher in men (median 209 ng/mL and 77 ng/mg, respectively) vs. women (median 168 ng/mL and 56 ng/mg, respectively); 27-OHC/TC was significantly correlated with abdominal circumference, visceral fat and, negatively, with high-density lipoprotein cholesterol (HDL-C). Triglycerides were significantly correlated with 24-OHC, 25-OHC and 27-OHC and with 24-OHC/TC and 25-OHC/TC. After intervention, 27-OHC levels were significantly reduced by 10.4% in the nutraceutical group Levels of 24-OHC, 24-OHC/TC, 25-OHC, 25-OHC/TC and 27-OHC/TC were unchanged.
CONCLUSIONS:
In this study, conducted in moderate hypercholesterolemic subjects, we observed novel relationships between 24-OHC, 25-OHC and 27-OHC and CV risk biomarkers. In addition, no adverse changes of OHC levels upon nutraceutical treatment were found.
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Correction to: Nutraceutical approach for the management of cardiovascular risk - a combination containing the probiotic Bifidobacterium longum BB536 and red yeast rice extract: results from a randomized, double-blind, placebo-controlled study.
Nutr J2019 Sep;18(1):54. doi: 54.
Ruscica Massimiliano, Pavanello Chiara, Gandini Sara, Macchi Chiara, Botta Margherita, Dall'Orto Daria, Del Puppo Marina, Bertolotti Marco, Bosisio Raffaella, Mombelli Giuliana, Sirtori Cesare R, Calabresi Laura, Magni Paolo
Abstract
Following publication of the original article [1], the authors reported an error in the affiliation of the third author, Sara Gandini. The correct affiliation should read: Division of Epidemiology and Biostatistics, IEO, European Institute of Oncology IRCCS, Milan, Italy.
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Nutraceutical approach for the management of cardiovascular risk - a combination containing the probiotic Bifidobacterium longum BB536 and red yeast rice extract: results from a randomized, double-blind, placebo-controlled study.
Nutr J2019 Feb;18(1):13. doi: 13.
Ruscica Massimiliano, Pavanello Chiara, Gandini Sara, Macchi Chiara, Botta Margherita, Dall'Orto Daria, Del Puppo Marina, Bertolotti Marco, Bosisio Raffaella, Mombelli Giuliana, Sirtori Cesare R, Calabresi Laura, Magni Paolo
Abstract
BACKGROUND:
Probiotics incorporated into dairy products have been shown to reduce total (TC) and LDL cholesterolemia (LDL-C) in subjects with moderate hypercholesterolemia. More specifically, probiotics with high biliary salt hydrolase activity, e.g. Bifidobacterium longum BB536, may decrease TC and LDL-C by lowering intestinal cholesterol reabsorption and, combined with other nutraceuticals, may be useful to manage hypercholesterolemia in subjects with low cardiovascular (CV) risk. This study was conducted to evaluate the efficacy and safety of a nutraceutical combination containing Bifidobacterium longum BB536, red yeast rice (RYR) extract (10?mg/day monacolin K), niacin, coenzyme Q10 (Lactoflorene Colesterolo®). The end-points were changes of lipid CV risk markers (LDL-C, TC, non-HDL-cholesterol (HDL-C), triglycerides (TG), apolipoprotein B (ApoB), HDL-C, apolipoprotein AI (ApoAI), lipoprotein(a) (Lp(a), proprotein convertase subtilisin/kexin type 9 (PCSK9)), and of markers of cholesterol synthesis/absorption.
METHODS:
A 12-week randomized, parallel, double-blind, placebo-controlled study. Thirty-three subjects (18-70?years) in primary CV prevention and low CV risk (SCORE: 0-1% in 24 and 2-4% in 9 subjects; LDL-C: 130-200?mg/dL) were randomly allocated to either nutraceutical (N?=?16) or placebo (N?=?17).
RESULTS:
Twelve-week treatment with the nutraceutical combination, compared to placebo, significantly reduced TC (-?16.7%), LDL-C (-?25.7%), non-HDL-C (-?24%) (all p?0.0001), apoB (-?17%, p?=?0.003). TG, HDL-C, apoAI, Lp(a), PCSK9 were unchanged. Lathosterol:TC ratio was significantly reduced by the nutraceutical combination, while campesterol:TC ratio and sitosterol:TC ratio did not change, suggesting reduction of synthesis without increased absorption of cholesterol. No adverse effects and a 97% compliance were observed.
CONCLUSIONS:
A 12-week treatment with a nutraceutical combination containing the probiotic Bifidobacterium longum BB536 and RYR extract significantly improved the atherogenic lipid profile and was well tolerated by low CV risk subjects.
TRIAL REGISTRATION:
NCT02689934 .
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Left main coronary wall thickness correlates with the carotid intima media thickness and may provide a new marker of cardiovascular risk.
Eur J Prev Cardiol2019 Jun;26(9):1001-1004. doi: 10.1177/2047487318806985.
Ruscica Massimiliano, Castelnuovo Samuela, Macchi Chiara, Gandini Sara, Mombelli Giuliana, Ferri Nicola, Labombarda Fabien, Sirtori Cesare R
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Systematic Lab Knowledge Integration for Management of Lipid Excess in High-Risk Patients: Rationale and Design of the SKIM LEAN Project.
Front Big Data2018 ;1():4. doi: 4.
Pavanello Chiara, Parolini Marina, Alberti Antonia, Carenini Michele, Maino Paolo, Mombelli Giuliana, Pazzucconi Franco, Origgi Gianni, Orsi Federica, Trivella Maria Giovanna, Calabresi Laura, De Maria Renata
Abstract
SKIM LEAN aims at exploiting Electronic Health Records (EHRs) to integrate knowledge derived from routine laboratory tests with background analysis of clinical databases, for the identification and early referral to specialist care, where appropriate, of patients with hypercholesterolemia, who may be inadequately controlled according to their cardiovascular (CV) risk level. SKIM LEAN addresses gaps in care that may occur through the lack of coordination between primary and specialist care, incomplete adherence to clinical guidelines, or poor patient's compliance to the physician's prescriptions because of comorbidities or drug side effects. Key project objectives include: (1) improved health professionals' competence and patient empowerment through a two-tiered educational website for general practitioners (GPs) and patients, and (2) implementation of a hospital-community shared care pathway to increase the proportion of patients at high/very-high CV risk (Familial Hypercholesterolemia, previous CV events) who achieve target LDL cholesterol (LDL-C) levels. Thanks to a close collaboration between clinical and information technology partners, SKIM LEAN will fully exploit the value of big data deriving from EHRs, and filter such knowledge using clinically-derived algorithms to risk-stratify patients. Alerts for GPs will be generated with interpreted test results. GPs will be able to refer patients with uncontrolled LDL-C within the shared pathway to the lipid or secondary prevention outpatient clinics of NIG hospital. Metrics to verify the project achievements include web-site visits, the number of alerts generated, numbers of patients referred by GPs, the proportion of secondary prevention patients who achieve LDL-C 50% decrease from baseline.
Copyright © 2018 Pavanello, Parolini, Alberti, Carenini, Maino, Mombelli, Pazzucconi, Origgi, Orsi, Trivella, Calabresi and De Maria.
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Influence of body variables in the development of metabolic syndrome-A long term follow-up study.
PLoS One2018 ;13(2):e0192751. doi: e0192751.
Pavanello Chiara, Zanaboni Anna Maria, Gaito Sabrina, Botta Margherita, Mombelli Giuliana, Sirtori Cesare R, Ruscica Massimiliano
Abstract
OBJECTIVES:
The body variable associated with the diagnosis of Metabolic Syndrome (MetS) is an elevated waist circumference (WC), although a number of other variables have been suggested. Among these, an elevated waist-to-height ratio (WHtR), ie a value higher than 0.5, that may identify abnormality, independently from height. An elevated WHtR provided the best correlation with MetS in a prior study in a large Italian population. In order to assess the validity of this conclusion, a long-term follow-up study re-examined this population, also in order to detect possible associations with cardiovascular (CV) risk.
METHODS AND RESULTS:
1,071 subjects with a complete follow-up of over 6 years were evaluated with a comparative assessment of the three anthropometric variables, namely WHtR, WC and body mass index (BMI). WHtR? 0.5 had the highest sensitivity for the identification of MetS, both in males and females (94.1% and 86.7% respectively). WHtR was of reduced specificity, occurring, yet less frequently (17.7% in males and 30% in females), in patients without MetS. By contrast, enlarged WC occurred with a lower frequency in male patients who developed MetS (30.2%) whereas in females, frequency was higher than in males (69.3%). Finally, a BMI? 25 kg/m2 had intermediate sensitivity and specificity regardless of gender. WC showed the highest odds ratio (2.62, 95%CI: 1.18-5.78) for the prediction of CV occurrence.
CONCLUSION:
The present study confirms WHtR as an excellent screening tool in identifying MetS carriers, but, different from reports in other countries, it shows a lower specificity in our population.
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Effect of a food supplement containing berberine, monacolin K, hydroxytyrosol and coenzyme Q on lipid levels: a randomized, double-blind, placebo controlled study.
Drug Des Devel Ther2017 ;11():1585-1592. doi: 10.2147/DDDT.S128623.
D'Addato Sergio, Scandiani Luciana, Mombelli Giuliana, Focanti Francesca, Pelacchi Federica, Salvatori Enrica, Di Loreto Giorgio, Comandini Alessandro, Maffioli Pamela, Derosa Giuseppe
Abstract
PURPOSE:
To evaluate the ability of the new food supplement, Body Lipid (BL), containing red yeast rice, berberine, coenzyme Q and hydroxytyrosol, to lower the LDL-C in patients with mild-to-moderate hypercholesterolemia and to assess the overall safety profile of the product.
METHODS:
In this multicenter, randomized, double-blind, placebo and active comparator (the marketed Armolipid Plus [AM]) controlled study, 158 hypercholesterolemic patients were randomized following a 4-week dietary run-in period. After 4 weeks of treatment with a daily oral dose of the new food supplement BL, AM or placebo, plus diet, the main outcome was the decrease of LDL-C, total cholesterol (TC), and triglyceride levels.
FINDINGS:
The absolute changes of LDL-C and TC levels from baseline, at week 4 were: -39.1 mg/dL ±17.76 and -45.9 mg/dL ±21.54, respectively in the BL group; 5.7 mg/dL ±14.98 and 2.4 mg/dL ±18.43, respectively in the placebo group. Results were statistically significant. In terms of mean percentage, BL was shown to be more effective in lowering LDL-C levels as compared to placebo and the active comparator (AM), with a reduction of -26.3%, +4.2%, -18.3%, respectively. Five adverse events (AEs) were reported by five patients after the initiation of the study treatment: two in the BL group (influence and insomnia), two in the AM group (ear pain and rash), and one in the placebo group (back pain). All AEs were mild in intensity, except for back pain (severe). The case of insomnia in the BL group and the case of rash in the AM group were judged as treatment related. The safety review of the laboratory (blood and urine) analyses, vital signs and physical findings did not show any clinical effect of the study products on any of the parameters.
IMPLICATIONS:
BL showed a good efficacy and safety profile and, for this reason, it can be considered an alternative to pharmacological treatment, for patients with mild-to-moderate hypercholesterolemia.
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Indicators of Cardiovascular Risk in Metabolic Syndrome: Long Term Follow-up in Italian Patients.
Curr Vasc Pharmacol2017 ;15(3):248-256. doi: 10.2174/1570161115666170126124149.
Mombelli Giuliana, Pavanello Chiara, Castelnuovo Samuela, Bosisio Raffaella, Simonelli Sara, Pazzucconi Franco, Sirtori Cesare Riccardo
Abstract
BACKGROUND:
Cardiovascular risk (CV) factors associated with the metabolic syndrome (MetS) may vary in different populations. In some, hypertension may be the major determinant, in others are low high-density lipoprotein cholesterol (HDL-C), high triglycerides, or another component.
SUBJECTS AND METHODS:
Subjects included in this analysis were identified in 2006, among those attending the Lipid Clinic of the Niguarda Hospital, and followed up through to 2013. Patient characteristics (including the occurrence of CV events) were obtained from electronic medical records. MetS was diagnosed according to the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) guidelines. The carotid intima media thickness (cIMT) was also followed in these patients over the years.
RESULTS:
After 7 years a total of 858 subjects had a complete follow-up; 271 of those had MetS. Patients developing a CV event showed elevated baseline cIMT (e.g. cIMTmax ? 2.4 mm in males and ? 2.2 mm in females); moreover the cIMT in MetS patients was higher at baseline and the rise over 7 years was larger compared with patients without MetS. By examining each body variable for MetS we found that a waist to height ratio (WHtR) ? 0.5 was present in nearly all subjects with a CV event.
CONCLUSION:
The follow-up data of a series of Italian patients with and without MetS, clearly indicates that the former have a raised cIMT and their arterial IMT progression is greater and the presence of a larger WHtR is apparently linked to a higher incidence of CV events.
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
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FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders.
Neurology2016 Nov;87(22):2290-2299.
Lehtonen Jenni M, Forsström Saara, Bottani Emanuela, Viscomi Carlo, Baris Olivier R, Isoniemi Helena, Höckerstedt Krister, Österlund Pia, Hurme Mikko, Jylhävä Juulia, Leppä Sirpa, Markkula Ritva, Heliö Tiina, Mombelli Giuliana, Uusimaa Johanna, Laaksonen Reijo, Laaksovirta Hannu, Auranen Mari, Zeviani Massimo, Smeitink Jan, Wiesner Rudolf J, Nakada Kazuto, Isohanni Pirjo, Suomalainen Anu
Abstract
OBJECTIVE:
To validate new mitochondrial myopathy serum biomarkers for diagnostic use.
METHODS:
We analyzed serum FGF21 (S-FGF21) and GDF15 from patients with (1) mitochondrial diseases and (2) nonmitochondrial disorders partially overlapping with mitochondrial disorder phenotypes. We (3) did a meta-analysis of S-FGF21 in mitochondrial disease and (4) analyzed S-Fgf21 and skeletal muscle Fgf21 expression in 6 mouse models with different muscle-manifesting mitochondrial dysfunctions.
RESULTS:
We report that S-FGF21 consistently increases in primary mitochondrial myopathy, especially in patients with mitochondrial translation defects or mitochondrial DNA (mtDNA) deletions (675 and 347 pg/mL, respectively; controls: 66 pg/mL, p
CONCLUSIONS:
S-FGF21 is a specific biomarker for muscle-manifesting defects of mitochondrial translation, including mitochondrial transfer-RNA mutations and primary and secondary mtDNA deletions, the most common causes of mitochondrial disease. However, normal S-FGF21 does not exclude structural respiratory chain complex or assembly factor defects, important to acknowledge in diagnostics.
CLASSIFICATION OF EVIDENCE:
This study provides Class III evidence that elevated S-FGF21 accurately distinguishes patients with mitochondrial myopathies from patients with other conditions, and FGF21 and GDF15 mitochondrial myopathy from other myopathies.
© 2016 American Academy of Neurology.
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Gender-related lipid and/or lipoprotein responses to statins in subjects in primary and secondary prevention.
J Clin Lipidol2015 ;9(2):226-33. doi: 10.1016/j.jacl.2014.12.003.
Mombelli Giuliana, Bosisio Raffaella, Calabresi Laura, Magni Paolo, Pavanello Chiara, Pazzucconi Franco, Sirtori Cesare R
Abstract
BACKGROUND:
Cardiovascular risk in men rises around the fourth decade of life, whereas women appear to be protected by sex hormones until menopause. This, in turn, tends to negatively affect the lipid profile. Since the 1980s, the incidence of cardiovascular diseases has been reported to progressively decline in men, but it has persisted almost unchanged in women. Major clinical trials on statins have been mostly conducted in men and have fostered the introduction of these agents into clinical practice worldwide. However, only few reports have examined a possible differential activity of statins in the 2 genders, providing in some cases opposite findings.
OBJECTIVE:
To evaluate gender-related differences in statin responses.
METHODS:
Variations of lipid profile after 1-year of treatment with different statins in 337 dyslipidemic patients (171 men and 166 women).
RESULTS:
In this series of patients, a significantly attenuated reduction of total cholesterol and low-density lipoprotein cholesterol in women vs men on drug treatment was noted after adjustment for dose and statin power (low-density lipoprotein cholesterol: -28.5 ± 11.8% in men vs -22.7 ± 11.8% in women; P
CONCLUSIONS:
The present study indicates that statin treatment has a reduced effectiveness in improving the plasma lipid profile in dyslipidemic women vs men. Whether such gender-related differences may have an impact on clinical outcomes remains to be elucidated.
Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.
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Nutraceutical approach to moderate cardiometabolic risk: results of a randomized, double-blind and crossover study with Armolipid Plus.
J Clin Lipidol2014 ;8(1):61-8. doi: 10.1016/j.jacl.2013.11.003.
Ruscica Massimiliano, Gomaraschi Monica, Mombelli Giuliana, Macchi Chiara, Bosisio Raffaella, Pazzucconi Franco, Pavanello Chiara, Calabresi Laura, Arnoldi Anna, Sirtori Cesare R, Magni Paolo
Abstract
BACKGROUND:
Primary cardiovascular prevention may be achieved by lifestyle/nutrition improvements and specific drugs, although a relevant role is now emerging for specific functional foods and nutraceuticals.
OBJECTIVES:
The aim of this study was to evaluate the usefulness of a nutraceutical multitarget approach in subjects with moderate cardiovascular risk and to compare it with pravastatin treatment.
SUBJECTS:
Thirty patients with moderate dyslipidemia and metabolic syndrome (according to the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults) were included in an 8-week randomized, double-blind crossover study and took either placebo or a nutraceutical combination that contained red yeast rice extract, berberine, policosanol, astaxanthin, coenzyme Q10, and folic acid (Armolipid Plus). Subsequently, they were subjected to another 8-week treatment with pravastatin 10 mg/d. This dosage was selected on the basis of its expected -20% efficacy in reducing low-density lipoprotein-cholesterol.
RESULTS:
Treatment with Armolipid Plus led to a significant reduction of total cholesterol (-12.8%) and low-density lipoprotein-cholesterol (-21.1%), similar to pravastatin (-16% and -22.6%, respectively), and an increase of high-density lipoprotein-cholesterol (4.8%). Armolipid Plus improved the leptin-to-adiponectin ratio, whereas adiponectin levels were unchanged.
CONCLUSIONS:
These results indicate that this nutraceutical approach shows a lipid-lowering activity comparable to pravastatin treatment. Hence, it may be a safe and useful option, especially in conditions of moderate cardiovascular risk, in which a pharmacologic intervention may not be appropriate.
Copyright © 2014 National Lipid Association. Published by Elsevier Inc. All rights reserved.
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Novel therapeutic strategies for the homozygous familial hypercholesterolemia.
Recent Pat Cardiovasc Drug Discov2013 Aug;8(2):143-50.
Mombelli Giuliana, Pavanello Chiara
Abstract
HoFH is an autosomal co-dominant disease with a prevalence of one in 1,000,000. Mutations of LDL-R gene are responsible for this disease. HoFH needs to be distinguished from autosomal recessive hypercholesterolemia protein (ARH) that causes a similar clinical phenotype. HoFH induces aggressive cardiovascular disease that can develop from birth. These patients possess high LDL-C levels, cutaneous and tendon xanthomas, and accelerated atherosclerosis shown in the first 2 decades of life. Current treatment modalities include life-style modifications, lipid-lowering therapy and LDL-apheresis. However, the treatment goal cannot be achieved only by statin therapy. New therapeutic strategies to lower LDL-C have been developed over recent years. These include monoclonal antibodies binding to PCSK9, inhibition of ApoB production and MTP-inhibitors. This review is focused on new treatments for HoFH and their patents. It is known to be an important contribution in this rare disease, which is difficult to manage.
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Severe high-density lipoprotein deficiency associated with autoantibodies against lecithin:cholesterol acyltransferase in non-Hodgkin lymphoma.
Arch Intern Med2012 Jan;172(2):179-81. doi: 10.1001/archinternmed.2011.661.
Simonelli Sara, Gianazza Elisabetta, Mombelli Giuliana, Bondioli Alighiero, Ferraro Giovanni, Penco Silvana, Sirtori Cesare R, Franceschini Guido, Calabresi Laura
Abstract
An antibody against the lecithin:cholesterol acyltransferase (LCAT) enzyme, which negates cholesterol esterification in plasma, causing severe high-density lipoprotein deficiency (HD), was identified in a woman with a large-cell non-Hodgkin lymphoma. Successful treatment of the lymphoma resulted in clearance of the antibody and complete correction of the defective cholesterol esterification and HD. To our knowledge, an acquired LCAT deficiency leading to severe HD has not been reported previously in association with a malignant disease, and this patient represents the first such documented case.
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Hypocholesterolaemic effects of lupin protein and pea protein/fibre combinations in moderately hypercholesterolaemic individuals.
Br J Nutr2012 Apr;107(8):1176-83. doi: 10.1017/S0007114511004120.
Sirtori Cesare R, Triolo Michela, Bosisio Raffaella, Bondioli Alighiero, Calabresi Laura, De Vergori Viviana, Gomaraschi Monica, Mombelli Giuliana, Pazzucconi Franco, Zacherl Christian, Arnoldi Anna
Abstract
The present study was aimed to evaluate the effect of plant proteins (lupin protein or pea protein) and their combinations with soluble fibres (oat fibre or apple pectin) on plasma total and LDL-cholesterol levels. A randomised, double-blind, parallel group design was followed: after a 4-week run-in period, participants were randomised into seven treatment groups, each consisting of twenty-five participants. Each group consumed two bars containing specific protein/fibre combinations: the reference group consumed casein+cellulose; the second and third groups consumed bars containing lupin or pea proteins+cellulose; the fourth and fifth groups consumed bars containing casein and oat fibre or apple pectin; the sixth group and seventh group received bars containing combinations of pea protein and oat fibre or apple pectin, respectively. Bars containing lupin protein+cellulose ( - 116 mg/l, - 4·2%), casein+apple pectin ( - 152 mg/l, - 5·3%), pea protein+oat fibre ( - 135 mg/l, - 4·7%) or pea protein+apple pectin ( - 168 mg/l, - 6·4%) resulted in significant reductions of total cholesterol levels (P
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Clinical response to statins: mechanism(s) of variable activity and adverse effects.
Ann Med2012 Aug;44(5):419-32. doi: 10.3109/07853890.2011.582135.
Sirtori Cesare R, Mombelli Giuliana, Triolo Michela, Laaksonen Reijo
Abstract
Statins represent a major advance in the treatment of hypercholesterolemia, a significant risk factor for atherosclerosis. There is, however, notable interindividual variation in the cholesterolemic response to statins, and the origin of this variability is poorly understood; pharmacogenetics has attempted to determine the role of genetic factors. Myopathy, further, has been reported in a considerable percentage of patients, but the mechanisms underlying muscle injury have yet to be fully characterized. Most statins are the substrates of several cytochrome P450s (CYP). CYP polymorphisms may be responsible for variations in hypolipidemic activity; inhibitors of CYPs, e.g. of CYP3A4, can significantly raise plasma concentrations of several statins, but consequences in terms of clinical efficacy are not uniform. Pravastatin and rosuvastatin are not susceptible to CYP inhibition but are substrates of the organic anion-transporting polypeptide (OATP) 1B1, encoded by the SLCO1B1 gene. Essentially all statins are, in fact, substrates of membrane transporters: SLCO1B1 polymorphisms can decrease the liver uptake, as well as the therapeutic potential of these agents, and may be linked to their muscular side-effects. A better understanding of the mechanisms of statin handling will help to minimize adverse effects and interactions, as well as to improve their lipid-lowering efficiency.
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Cholesteryl ester transfer protein antagonism by drugs--a poor choice.
Clin Chem2010 Oct;56(10):1550-3. doi: 10.1373/clinchem.2010.147389.
Sirtori Cesare R, Mombelli Giuliana
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Paradoxical decrease in high-density lipoprotein cholesterol with fenofibrate: a quite rare phenomenon indeed.
Cardiovasc Ther2010 Jun;28(3):153-60. doi: 10.1111/j.1755-5922.2009.00121.x.
Mombelli Giuliana, Pazzucconi Franco, Bondioli Alighiero, Zanaboni AnnaMaria, Gaito Sabrina, Calabresi Laura, Sirtori Cesare R
Abstract
Some recent clinical reports have suggested that paradoxical decreases in high-density lipoprotein cholesterol (HDL-C) levels after fenofibrate treatment may be quite common. These appear to occur mainly in patients with combined fibrate/statin therapy and possibly in those with low baseline HDL-C. Reports on HDL-C reductions after fenofibrate are possibly supported by the disappointing results in terms of HDL-C responses from the recent FIELD study. A survey on 581 patients treated for 1 year or longer was carried out in our Clinical Center. This indicated that paradoxical HDL-C reductions are a relatively uncommon phenomenon. Not more than 15.3% of the present series showed an HDL-C reduction, mostly of a modest degree. Further, reductions of HDL-C appear to occur mainly in individuals with significant HDL-C elevations (>50 mg/dL), almost never in patients with low HDL-C. Otherwise, there seems to be no impact of a previous diagnosis of diabetes or hypertension on the HDL-C changes. From a very recent pharmacogenomic study on the apo A1/C3/A4/A5 gene cluster, genetic influences appear only to reduce the positive impact of fenofibrate on HDL-C, but do not indicate any risk of occurrence of HDL-C reductions. Also based on our very long experience with this drug, it appears that fenofibrate raises HDL-C levels in the vast majority of treated patients, with a particularly dramatic effect in individuals with low HDL-C and hypertriglyceridemia.
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Waist-to-height ratio is a highly sensitive index for the metabolic syndrome in a Mediterranean population.
Metab Syndr Relat Disord2009 Oct;7(5):477-84. doi: 10.1089/met.2008.0101.
Mombelli Giuliana, Zanaboni Anna M, Gaito Sabrina, Sirtori Cesare R
Abstract
BACKGROUND:
The waist-to-height ratio (WHtR) is a potentially more reliable anthropometric index, particularly for populations of lower height. Performance of the WHtR versus body mass index (BMI) and enlarged waist circumference (WC) in the assessment of the metabolic syndrome was tested in nonobese males and females in a high-risk Italian population.
METHODS:
WHtR, BMI, and WC were determined in 552 males and 552 females, together with the evaluation of associated metabolic syndrome variables (hypertension, hyperglycemia, hypertriglyceridemia, and low high-density lipoprotein cholesterol [HDL-C]).
RESULTS:
WHtR > or = 0.5, the most frequently suggested threshold value, when added to any two nonanthropometric variables, gave a sensitivity for the identification of a metabolic syndrome of, respectively, 92.0% for males and 87.4% for females. Sensitivities for elevated WC (American Heart Association [AHA] criteria) and BMI > or = 25 proved lower. Areas under the receiver operating characteristic (ROC) curves for the different anthropometric indices confirmed that a WHtR > or = 0.5 provides a satisfactory balance between sensitivity and specificity.
CONCLUSIONS:
WHtR > or = 0.5 may be the most effective anthropometric index for screening high-risk patients in the diagnosis of metabolic syndrome, with the advantage of the opportunity of direct comparisons with other populations.
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Large waist circumference with normal BMI identifies a significant subset of Italian female patients with the metabolic syndrome--a high risk presentation?
Atherosclerosis2009 Oct;206(2):340-2. doi: 10.1016/j.atherosclerosis.2009.02.036.
Mombelli Giuliana, Zanaboni Anna M, Gaito Sabrina, Sirtori Cesare R
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Viability of developing CETP inhibitors.
Cardiovasc Ther2008 ;26(2):135-46. doi: 10.1111/j.1527-3466.2008.00049.x.
Sirtori Cesare R, Mombelli Giuliana
Abstract
The recent failure of a major inhibitor of the cholesterol ester transfer protein (CETP), in trials on high-risk coronary patients, indicated that potentially this therapeutic target might not be a viable one. This conclusion is, however, not surprising since evaluating prior knowledge, the rationale of this therapeutic approach appears to be extremely weak. Although raising high-density lipoprotein (HDL) by a variety of pharmaceutical approaches may still provide a desirable target, CETP inhibitory treatment has very little to offer. Analysis of the literature pertaining to the CETP approach, epidemiological data on individuals with CETP mutations, and finally and in-depth analyses of pharmacological interventions, all appear to indicate that CETP inhibitory treatment should not be pursued as a viable approach. In addition, some of the findings from the clinical studies, for example, in particular a dramatic rise of infectious complications, cast significant perplexity on the possibility of convincing health authorities on the clinical safety of CETP inhibitors. Potentially CETP stimulation, for example by probucol or derivatives may provide instead a more satisfactory approach to cardiovascular prevention.
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Persistently increased HDL-cholesterolemia and reduced triglyceridemia in a large lipid clinic population treated with fenofibrate for 15 years or longer.
Int J Cardiol2009 Apr;133(3):412-4. doi: 10.1016/j.ijcard.2007.11.090.
Mombelli Giuliana, Banfi Francesca, Falcioni Serena, Sirtori Cesare R
Abstract
BACKGROUND:
Fenofibrate, in the recent FIELD study in diabetics, induced a modest reduction of cardiovascular events, but unexpectedly there was an apparent loss of activity over time, thus, e.g., achieving only a 1.2% increase of HDL-cholesterolemia at study end.
METHOD:
Plasma lipid and lipoprotein changes were investigated in a large series of patients followed at 5-year intervals up to 15 years or longer at the Lipid Clinic of the University of Milano.
RESULTS:
The HDL-cholesterol raising properties (mean of +24.6% at 15 years) are well maintained over many years of treatment and tend to increase over time, particularly in diabetics. Fenofibrate also significantly reduced triglyceridemia and also LDL-cholesterolemia (-54.9 and -28.5%, respectively). There was a very low incidence of cardiovascular events.
CONCLUSIONS:
Long term fenofibrate treatment is associated with well maintained biochemical effects. The inadequate activity of fenofibrate over the 5 years of the FIELD study might be due to bioavailability problems previously noted with some slow release formulations.
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Apolipoprotein A-I breakdown is induced by thrombolysis in coronary patients.
Ann Med2007 ;39(4):306-11.
Eberini Ivano, Gianazza Elisabetta, Breghi Loranni, Klugmann Silvio, Calabresi Laura, Gomaraschi Monica, Mombelli Giuliana, Brusoni Bruno, Wait Robin, Sirtori Cesare R
Abstract
BACKGROUND:
The outcome of percutaneous coronary intervention (PCI) is apparently worse in patients receiving a prior thrombolytic therapy ('facilitated PCI'). Recombinant tissue-type plasminogen activator (rt-PA) can degrade circulating high-density lipoproteins (HDL) bound apolipoprotein A-I (apoA-I), thus possibly reducing the vascular protective activity. There have never been reports of the detection of apolipoprotein breakdown products in the circulation.
AIM:
We studied the potential interactions between the protein components of HDL and tenecteplase, infused as thrombolytic therapy.
METHODS:
Sera from a total of 40 patients with acute myocardial infarction (AMI), unstable angina (UA), and dilative cardiomyopathy (controls) were investigated. AMI patients underwent either immediate PCI or were treated with tenecteplase thrombolysis.
RESULTS:
Products of extensive proteolysis of apoA-I were found in many acute coronary patients treated with tenecteplase, and in some AMI patients before starting the treatment (time 0). These were not detected in controls, UA patients as well as AMI patients undergoing immediate PCI. Small pre-beta-HDLs were selectively degraded.
CONCLUSION:
Significant apoA-I degradation occurs in AMI patients after thrombolytic treatment. This finding may provide a potential mechanism for the apparent reduction of benefit of facilitated versus nonfacilitated PCI.
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Tolerability of statins is not linked to CYP450 polymorphisms, but reduced CYP2D6 metabolism improves cholesteraemic response to simvastatin and fluvastatin.
Pharmacol Res2007 Apr;55(4):310-7.
Zuccaro Piergiorgio, Mombelli Giuliana, Calabresi Laura, Baldassarre Damiano, Palmi Ilaria, Sirtori Cesare R
Abstract
Statin therapy, although generally well tolerated, leads not infrequently to significant subjective and at times objective adverse effects (AEs), mainly of a muscular nature. The genetic background of these AEs is not clear and possibly side effects and lipid lowering efficacy may be linked. Aim of the study was a detailed evaluation of CYP450 and apolipoprotein E gene polymorphisms in two large series of age-sex matched patients with and without muscular side effects to statins. In a Clinical Institution specialised in lipid-lipoprotein disorders, 50 statin treated patients were selected, with subjective or objective statin-associated myopathy, evaluated using standardized forms. These were sex and age matched with 50 statin-treated patients from the same Clinic, without any subjective or objective complaints. DNA samples for the evaluation of CYP450 genetic polymorphisms and apo E genotypes were collected in order to assess correlations with both genetic polymorphisms and AEs, as well as with therapeutic efficacy. None of the assessed CYP450 polymorphisms appeared to be related to an increased incidence of AEs. The CYP2D6 *1/*4 and *4/4* poor metabolizer (PM) status was associated to a higher efficacy of statins metabolized by this system and, in addition, the apo E2 genotype was, in this series, linked to increased HDL-C levels after therapy. Patients with statin associated myopathy are not characterized by significantly different genotypes for the CYP450s responsible for statin metabolism. On the other hand, CYP2D6 PM status is associated to an increased efficacy of statins metabolized by this system.
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