Publications by authors named "Cesare R Sirtori"

136 Publications

Long-term fasting improves lipoprotein-associated atherogenic risk in humans.

Eur J Nutr 2021 May 7. Epub 2021 May 7.

Buchinger Wilhelmi Clinic, Wilhelm-Beck-Straße 27, 88662, Überlingen, Germany.

Purpose: Dyslipidemia is a major health concern associated with an increased risk of cardiovascular mortality. Long-term fasting (LF) has been shown to improve plasma lipid profile. We performed an in-depth investigation of lipoprotein composition.

Methods: This observational study included 40 volunteers (50% men, aged 32-65 years), who underwent a medically supervised fast of 14 days (250 kcal/day). Changes in lipid and lipoprotein levels, as well as in lipoprotein subclasses and particles, were measured by ultracentrifugation and nuclear magnetic resonance (NMR) at baseline, and after 7 and 14 fasting days.

Results: The largest changes were found after 14 fasting days. There were significant reductions in triglycerides (TG, - 0.35 ± 0.1 mmol/L), very low-density lipoprotein (VLDL)-TG (- 0.46 ± 0.08 mmol/L), VLDL-cholesterol (VLDL-C, - 0.16 ± 0.03 mmol/L) and low-density lipoprotein (LDL)-C (- 0.72 ± 0.14 mmol/L). Analysis of LDL subclasses showed a significant decrease in LDL1-C (- 0.16 ± 0.05 mmol/L), LDL2-C (- 0.30 ± 0.06 mmol/L) and LDL3-C (- 0.27 ± 0.05 mmol/L). NMR spectroscopy showed a significant reduction in large VLDL particles (- 5.18 ± 1.26 nmol/L), as well as large (- 244.13 ± 39.45 nmol/L) and small LDL particles (- 38.45 ± 44.04 nmol/L). A significant decrease in high-density lipoprotein (HDL)-C (- 0.16 ± 0.04 mmol/L) was observed. By contrast, the concentration in large HDL particles was significantly raised. Apolipoprotein A1 decreased significantly whereas apolipoprotein B, lipoprotein(a), fibrinogen and high-sensitivity C-reactive protein were unchanged.

Conclusion: Our results suggest that LF improves lipoprotein levels and lipoprotein subclasses and ameliorates the lipoprotein-associated atherogenic risk profile, suggesting a reduction in the cardiovascular risk linked to dyslipidemia.

Trial Registration: Study registration number: DRKS-ID: DRKS00010111 Date of registration: 03/06/2016 "retrospectively registered".
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http://dx.doi.org/10.1007/s00394-021-02578-0DOI Listing
May 2021

The effect of transgender hormonal treatment on high density lipoprotein cholesterol efflux capacity.

Atherosclerosis 2021 Apr 13;323:44-53. Epub 2021 Mar 13.

Department of Pharmacology and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy.

Background And Aims: A decrease in high-density lipoprotein (HDL)-cholesterol concentrations during transgender hormone therapy has been shown. However, the ability of HDL to remove cholesterol from arterial wall macrophages, termed cholesterol efflux capacity (CEC), has proven to be a better predictor of cardiovascular disease (CVD) largely independently of HDL-concentrations. In addition, the serum capacity to load macrophages with cholesterol (cholesterol loading capacity, CLC) represents an index of pro-atherogenic potential. As transgender individuals are exposed to lifelong exogenous hormone therapy (HT), it becomes of interest to study whether HDL-CEC and serum CLC are affected by HT. HDL-CEC and serum CLC have been evaluated in 15 trans men treated with testosterone and in 15 trans women treated with estradiol and cyproterone acetate at baseline and after 12 months of HT.

Methods: Total HDL-CEC from macrophages and its major contributors, the ATP-binding cassette transporters (ABC) A1 and ABCG1 HDL-CEC and HDL-CEC by aqueous diffusion were determined by a radioisotopic assay. CLC was evaluated in human THP-1 macrophages.

Results: In trans women, total HDL-CEC decreased by 10.8% (95%CI: -14.3;-7.3; p < 0.001), ABCA1 HDL-CEC by 23.8% (-34.7; -12.9; p < 0.001) and aqueous diffusion HDL-CEC by 4.8% (-8.4;-1.1; p < 0.01). In trans men, only aqueous diffusion HDL-CEC decreased significantly, -9.8% (-15.7;-3.9; p < 0.01). ABCG1 HDL-CEC did not change in either group. Serum CLC and HDL subclass distribution were not modified by HT in both groups.

Conclusions: Total HDL-CEC decreased during HT in trans women, with a specific reduction in ABCA1 CEC. This finding might contribute to a higher CVD risk.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.03.008DOI Listing
April 2021

Lipid Lowering Drugs: Present Status and Future Developments.

Curr Atheroscler Rep 2021 Mar 10;23(5):17. Epub 2021 Mar 10.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.

Purpose Of Review: Based on the recent data of the DA VINCI study, it is clear that, besides utilization of statins, there is a need to increase non-statin lipid lowering approaches to reduce the cardiovascular burden in patients at highest risk.

Recent Findings: For hypercholesterolemia, the small synthetic molecule bempedoic acid has the added benefit of selective liver activation, whereas inclisiran, a hepatic inhibitor of the PCSK9 synthesis, has comparable effects with PCSK9 monoclonal antibodies. For hypertriglyceridemia, cardiovascular benefit has been achieved by the use of icosapent ethyl, whereas results with pemafibrate, a selective agonist of PPAR-α, are eagerly awaited. In the era of RNA-based therapies, new options are offered to dramatically reduce levels of lipoprotein(a) (APO(a)L) and of triglycerides (ANGPTL3L and APOCIII-L). Despite the demonstrated benefits of statins, a large number of patients still remain at significant risk because of inadequate LDL-C reduction or elevated blood triglyceride-rich lipoproteins or lipoprotein(a). The area of lipid modulating agents is still ripe with ideas and major novelties are to be awaited in the next few years.
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http://dx.doi.org/10.1007/s11883-021-00918-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946696PMC
March 2021

Cardiovascular risk and testosterone - from subclinical atherosclerosis to lipoprotein function to heart failure.

Rev Endocr Metab Disord 2021 Jun 22;22(2):257-274. Epub 2021 Feb 22.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.

The cardiovascular (CV) benefit and safety of treating low testosterone conditions is a matter of debate. Although testosterone deficiency has been linked to a rise in major adverse CV events, most of the studies on testosterone replacement therapy were not designed to assess CV risk and thus excluded men with advanced heart failure or recent history of myocardial infarction or stroke. Besides considering observational, interventional and prospective studies, this review article evaluates the impact of testosterone on atherosclerosis process, including lipoprotein functionality, progression of carotid intima media thickness, inflammation, coagulation and thromboembolism, quantification of plaque volume and vascular calcification. Until adequately powered studies evaluating testosterone effects in hypogonadal men at increased CV risk are available (TRAVERSE trial), clinicians should ponder the use of testosterone in men with atherosclerotic cardiovascular disease and discuss benefit and harms with the patients.
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http://dx.doi.org/10.1007/s11154-021-09628-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087565PMC
June 2021

Nonalcoholic fatty liver disease or metabolic dysfunction-associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches.

Eur J Clin Invest 2021 Feb 14:e13519. Epub 2021 Feb 14.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.

Background: A consensus of experts has proposed to replace the term nonalcoholic fatty liver disease (NAFLD), whose global prevalence is 25%, with metabolic dysfunction-associated fatty liver disease (MAFLD), to describe more appropriately the liver disease related to metabolic derangements. MAFLD is closely intertwined with type 2 diabetes, obesity, dyslipidaemia, all linked to a rise in the risk of cardiovascular disease (CVDs). Since controversy still stands on whether or not NAFLD/MAFLD raises the odds of CVD, the present review aims to evaluate the impact of NAFLD/MAFLD aetiologies on CV health and the potential correction by dietary and drug approaches.

Results: Epidemiological studies indicate that NAFLD raises risk of fatal or non-fatal CVD events. NAFLD patients have a higher prevalence of arterial plaques and stiffness, coronary calcification, and endothelial dysfunction. Although genetic and environmental factors strongly contribute to NAFLD pathogenesis, a Mendelian randomization analysis indicated that the PNPLA3 genetic variant leading to NAFLD may not be causally associated with CVD risk. Among other genetic variants related to NAFLD, TM6SF2 appears to be protective, whereas MBOAT7 may favour venous thromboembolism.

Conclusions: NAFLD is correlated to a higher CVD risk which may be ameliorated by dietary interventions. This is not surprising, since new criteria defining MAFLD include other metabolic risk abnormalities fuelling development of serious adverse extrahepatic outcomes, for example CVD. The present lack of a targeted pharmacological approach makes the identification of patients with liver disease at higher CVD risk (eg diabetes, hypertension, obesity or high levels of C-reactive protein) of major clinical interest.
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http://dx.doi.org/10.1111/eci.13519DOI Listing
February 2021

Evaluation of Transthoracic Echocardiography in the Assessment of Atherosclerosis of the Left Main Coronary Artery: Comparison with Optical Frequency Domain Imaging (a Pilot Study).

J Clin Med 2021 Jan 12;10(2). Epub 2021 Jan 12.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy.

Background: Risk stratification using non-invasive imaging of the coronary vessels is emerging as an optimal standard of care for patients with dyslipidemias. Of particular interest is the evaluation of the left main coronary artery (LMCA), where calcium deposition appears to be a predictor of cardiovascular events.

Methods: In coronary patients, we evaluated wall thickness and internal diameter of the LMCA examined by transthoracic echocardiography (TTE) and compared these with findings obtained by optical frequency domain imaging (OFDI), this latter also used to evaluate calcium deposition.

Results: A significant positive correlation between TTE and OFDI for the anterior wall thickness (r = 0.41, = 0.043) and internal diameter (r = 0.36, = 0.048) of the LMCA was detected. Echocardiographic wall measurements were higher in patients with fibro-calcific plaques. The receiver operating characteristic (ROC) curve showed that an anterior wall thickness of LMCA ≥ 1.4 mm was predictive of fibro-calcific plaque (area under the curve = 0.815 and = 0.006), sensitivity and specificity being 76.9% and 80%, respectively (Youden's Index = 0.56).

Conclusions: Measurement of anterior wall thickness of the LMCA by TTE and OFDI appears to be closely correlated and may predict the presence of coronary calcification.
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http://dx.doi.org/10.3390/jcm10020256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827741PMC
January 2021

Gender difference in lipoprotein(a) concentration as a predictor of coronary revascularization in patients with known coronary artery disease.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 Mar 15;1866(3):158869. Epub 2020 Dec 15.

U.O. Lipoapheresis and Center for Inherited Dyslipidaemias, Fondazione Toscana Gabriele Monasterio, Pisa, Italy. Electronic address:

Background And Aims: Whether there is a gender difference in the impact of elevated plasma Lp(a) levels on recurrent coronary events remains unclear. We, therefore, evaluated the association between Lp(a) levels and the occurrence of major adverse coronary events in a large series of coronary patients (32% women).

Methods: This single-center prospective cohort study investigated 3034 consecutive patients admitted to the Coronary Care Unit with a diagnosis of coronary ischemia. According to the inclusion criteria, 2374 patients completed the follow-up (mean of 2 years). The end-points were non-fatal myocardial infarction (MI), revascularization and coronary deaths.

Results: Elevated Lp(a) levels were significantly associated with rate of revascularization, but not with non-fatal MI and cardiac death. According to Lp(a) stratification (≤30 mg/dl, >30-50 mg/dl and ≥50 mg/dl), there was a significant rise of revascularization events in the whole sample of participants, with a trend in hazard ratio (HR) of 1.23 (95% CI 1.04-1.46) and a 6% rise for every 10 mg/dl increment in Lp(a) levels. This effect was mainly driven by women (HR 2.04, 95%CI 1.33-3.12) who showed a 14% incremental risk for every 10 mg/dl rise in Lp(a) levels.

Conclusions: In patients with coronary artery disease, elevated plasma Lp(a) levels were found to be a potentially useful predictor of the need for coronary revascularizations, especially in women.
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http://dx.doi.org/10.1016/j.bbalip.2020.158869DOI Listing
March 2021

Carotid IMT and atherosclerosis: "Calling things by name".

Authors:
Cesare R Sirtori

Atherosclerosis 2021 01 24;317:67. Epub 2020 Nov 24.

Università Degli Studi di Milano, Dipartimento di Scienze Farmacologiche e Bimolecolari, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.atherosclerosis.2020.11.024DOI Listing
January 2021

Lipoprotein(a) Lowering-From Lipoprotein Apheresis to Antisense Oligonucleotide Approach.

J Clin Med 2020 Jul 3;9(7). Epub 2020 Jul 3.

Dipartimento di Science Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy.

It is well-known that elevated lipoprotein(a)-Lp(a)-levels are associated with a higher risk of cardiovascular (CV) mortality and all-cause mortality, although a standard pharmacotherapeutic approach is still undefined for patients with high CV risk dependent on hyperlipoproteinemia(a). Combined with high Lp(a) levels, familial hypercholesterolemia (FH) leads to a greater CVD risk. In suspected FH patients, the proportion of cases explained by a rise of Lp(a) levels ranges between 5% and 20%. In the absence of a specific pharmacological approach able to lower Lp(a) to the extent required to achieve CV benefits, the most effective strategy today is lipoprotein apheresis (LA). Although limited, a clear effect on Lp(a) is exerted by PCSK9 antagonists, with apparently different mechanisms when given with statins (raised catabolism) or as monotherapy (reduced production). In the era of RNA-based therapies, a new dawn is represented by the use of antisense oligonucleotides APO(a)L, able to reduce Lp(a) from 35% to over 80%, with generally modest injection site reactions. The improved knowledge of Lp(a) atherogenicity and possible prevention will be of benefit for patients with residual CV risk remaining after the most effective available lipid-lowering agents.
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http://dx.doi.org/10.3390/jcm9072103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408876PMC
July 2020

Inherited atherogenic dyslipidemias: are they correctly reported?

Eur J Prev Cardiol 2020 Jun 12:2047487320930308. Epub 2020 Jun 12.

Institute of Clinical Physiology, National Research Council, Italy.

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http://dx.doi.org/10.1177/2047487320930308DOI Listing
June 2020

Unravelling the health effects of fasting: a long road from obesity treatment to healthy life span increase and improved cognition.

Ann Med 2020 08 10;52(5):147-161. Epub 2020 Jun 10.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.

In recent years a revival of interest has emerged in the health benefits of intermittent fasting and long-term fasting, as well as of other related nutritional strategies. In addition to meal size and composition a new focus on time and frequency of meals has gained attention. The present review will investigate the effects of the main forms of fasting, activating the metabolic switch from glucose to fat and ketones (G-to-K), starting 12-16 h after cessation or strong reduction of food intake. During fasting the deactivation of mTOR regulated nutrient signalling pathways and activation of the AMP protein kinase trigger cell repair and inhibit anabolic processes. Clinical and animal studies have clearly indicated that modulating diet and meal frequency, as well as application of fasting patterns, intermittent fasting, periodic fasting, or long-term fasting are part of a new lifestyle approach leading to increased life and health span, enhanced intrinsic defences against oxidative and metabolic stresses, improved cognition, as well as a decrease in cardiovascular risk in both obese and non-obese subjects. Finally, in order to better understand the mechanisms beyond fasting-related changes, human studies as well as non-human models closer to human physiology may offer useful clues.KEY-MESSAGESBiochemical changes during fasting are characterised by a glucose to ketone switch, leading to a rise of ketones, advantageously used for brain energy, with consequent improved cognition.Ketones reduce appetite and help maintain effective fasting.Application of fasting patterns increases healthy life span and defences against oxidative and metabolic stresses.Today's strategies for the use of therapeutic fasting are based on different protocols, generally relying on intermittent fasting, of different duration and calorie intake.Long-term fasting, with durations between 5 and 21 days can be successfully repeated in the course of a year.
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http://dx.doi.org/10.1080/07853890.2020.1770849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877980PMC
August 2020

Clinical approach to the inflammatory etiology of cardiovascular diseases.

Pharmacol Res 2020 09 20;159:104916. Epub 2020 May 20.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.

Inflammation is an obligatory marker of arterial disease, both stemming from the inflammatory activity of cholesterol itself and from well-established molecular mechanisms. Raised progenitor cell recruitment after major events and clonal hematopoiesis related mechanisms have provided an improved understanding of factors regulating inflammatory phenomena. Trials with inflammation antagonists have led to an extensive evaluation of biomarkers such as the high sensitivity C reactive protein (hsCRP), not exerting a causative role, but frequently indicative of the individual cardiovascular (CV) risk. Aim of this review is to provide indication on the anti-inflammatory profile of agents of general use in CV prevention, i.e. affecting lipids, blood pressure, diabetes as well nutraceuticals such as n-3 fatty acids. A crucial issue in the evaluation of the benefit of the anti-inflammatory activity is the frequent discordance between a beneficial activity on a major risk factor and associated changes of hsCRP, as in the case of statins vs PCSK9 antagonists. In hypertension, angiotensin converting enzyme inhibitors exert an optimal anti-inflammatory activity, vs the case of sartans. The remarkable preventive activity of SLGT-2 inhibitors in heart failure is not associated with a clear anti-inflammatory mechanism. Finally, icosapent ethyl has been shown to reduce the CV risk in hypertriglyceridemia, with a 27 % reduction of hsCRP. The inflammation-based approach to arterial disease has considerably gained from an improved understanding of the clinical diagnostic strategy and from a better knowledge on the mode of action of numerous agents, including nutraceuticals.
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http://dx.doi.org/10.1016/j.phrs.2020.104916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238995PMC
September 2020

Pharmacological aspects of ANGPTL3 and ANGPTL4 inhibitors: New therapeutic approaches for the treatment of atherogenic dyslipidemia.

Pharmacol Res 2020 03 10;153:104653. Epub 2020 Jan 10.

Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Padua, Italy.

Among the determinants of atherosclerotic cardiovascular disease (ASCVD), genetic and experimental evidence has provided data on a major role of angiopoietin-like proteins 3 and 4 (ANGPTL3 and ANGPTL4) in regulating the activity of lipoprotein lipase (LPL), antagonizing the hydrolysis of triglycerides (TG). Indeed, beyond low-density lipoprotein cholesterol (LDL-C), ASCVD risk is also dependent on a cluster of metabolic abnormalities characterized by elevated fasting and post-prandial levels of TG-rich lipoproteins and their remnants. In a head-to-head comparison between murine models for ANGPTL3 and ANGPTL4, the former was found to be a better pharmacological target for the treatment of hypertriglyceridemia. In humans, loss-of-function mutations of ANGPTL3 are associated with a marked reduction of plasma levels of VLDL, low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Carriers of loss-of-function mutations of ANGPTL4 show instead lower TG-rich lipoproteins and a modest but significant increase of HDL. The relevance of ANGPTL3 and ANGPTL4 as new therapeutic targets is proven by the development of monoclonal antibodies or antisense oligonucleotides. Studies in animal models, including non-human primates, have demonstrated that short-term treatment with monoclonal antibodies against ANGPTL3 and ANGPTL4 induces activation of LPL and a marked reduction of plasma TG-rich-lipoproteins, apparently without any major side effects. Inhibition of both targets also partially reduces LDL-C, independent of the LDL receptor. Similar evidence has been observed with the antisense oligonucleotide ANGPTL3-L. The genetic studies have paved the way for the development of new ANGPTL3 and 4 antagonists for the treatment of atherogenic dyslipidemias. Conclusive data of phase 2 and 3 clinical trials are still needed in order to define their safety and efficacy profile.
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http://dx.doi.org/10.1016/j.phrs.2020.104653DOI Listing
March 2020

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 J 2019 Sep 9;18(1):54. Epub 2019 Sep 9.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.

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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http://dx.doi.org/10.1186/s12937-019-0483-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734387PMC
September 2019

Impact of PPAR-Alpha Polymorphisms-The Case of Metabolic Disorders and Atherosclerosis.

Int J Mol Sci 2019 Sep 6;20(18). Epub 2019 Sep 6.

Centro Dislipidemie, A.S.S.T. Grande Ospedale Metropolitano Niguarda, 20122 Milan, Italy.

Peroxisome proliferator activated receptor α (PPARα) has the most relevant biological functions among PPARs. Activation by drugs and dietary components lead to major metabolic changes, from reduced triglyceridemia to improvement in the metabolic syndrome. Polymorphisms of PPARα are of interest in order to improve our understanding of metabolic disorders associated with a raised or reduced risk of diseases. PPARα polymorphisms are mainly characterized by two sequence changes, L162V and V227A, with the latter occurring only in Eastern nations, and by numerous SNPs (Single nucleotide polymorphisms) with a less clear biological role. The minor allele of L162V associates with raised total cholesterol, LDL-C (low-density lipoprotein cholesterol), and triglycerides, reduced HDL-C (high-density lipoprotein metabolism), and elevated lipoprotein (a). An increased cardiovascular risk is not clear, whereas a raised risk of diabetes or of liver steatosis are not well supported. The minor allele of the V227A polymorphism is instead linked to a reduction of steatosis and raised γ-glutamyltranspeptidase levels in non-drinking Orientals, the latter being reduced in drinkers. Lastly, the minor allele of rs4353747 is associated with a raised high-altitude appetite loss. These and other associations indicate the predictive potential of PPARα polymorphisms for an improved understanding of human disease, which also explain variability in the clinical response to specific drug treatments or dietary approaches.
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http://dx.doi.org/10.3390/ijms20184378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770475PMC
September 2019

Differential effects of red yeast rice, Berberis aristata and Morus alba extracts on PCSK9 and LDL uptake.

Nutr Metab Cardiovasc Dis 2019 11 14;29(11):1245-1253. Epub 2019 Jun 14.

Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Padua, Italy.

Background And Aims: The novel nutraceutical combination containing red yeast rice (monacolin K 3.3 mg), Berberis aristata cortex extract (Berberine 531.25 mg) and Morus alba leaves extract (1-deoxynojirimycin 4 mg) is effective in the management of elevated plasma low-density lipoprotein cholesterol (LDL-C) levels. The aim of the present study was to investigate the effects of the three components on proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of LDL receptor (LDLR) expression, in hepatocyte cell lines and to compare their effects on LDL cellular uptake.

Methods And Results: HepG2 and Huh7 cells were incubated with B. aristata cortex extract (BCE), red yeast rice (RYR) and M. alba leaves extract (MLE) alone or in combination for 24 h. RYR (50 μg/mL) increased PCSK9 protein expression (Western blot analysis and ELISA), PCSK9 mRNA (qPCR) and its promoter activity (luciferase reporter assay). BCE (40 μg/mL) reduced instead PCSK9 expression, mRNA levels and promoter activity. MLE determined a concentration-dependent reduction of PCSK9 at the mRNA and protein levels, with a maximal reduction at 1 mg/mL, without significant changes of PCSK9 promoter activity. MLE also downregulated the expression of 3-hydroxy-3-methyl-3-glutaryl coenzyme A reductase and fatty acid synthase mRNA levels. The combination of RYR, BCE and MLE reduced the PCSK9 mRNA and protein levels, as well as the promoter activity. Finally, the single components and their combination induced LDL receptor and LDL uptake by the hepatocytes.

Conclusion: The positive effect of MLE on PCSK9 supports the rationale of using the nutraceutical combination of RYR, BCE and MLE to control hyperlipidemic conditions.
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http://dx.doi.org/10.1016/j.numecd.2019.06.001DOI Listing
November 2019

PCSK9 inhibition and inflammation: A narrative review.

Atherosclerosis 2019 09 17;288:146-155. Epub 2019 Jul 17.

Centro Dislipidemie, A.S.S.T. Grande Ospedale Metropolitano Niguarda, Milan, Italy.

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality despite excellent pharmacological and revascularization approaches. Low-density lipoproteins (LDL) are undoubtedly the most significant biochemical variables associated with atheroma, however, compelling data identify inflammation as critical for the maintenance of the atherosclerotic process, underlying some of the most feared vascular complications. Although its causal role is questionable, high-sensitivity C-reactive protein (hs-CRP) represents a major biomarker of inflammation and associated risk in CVD. While statin-associated reduced risk may be related to the lowering of both LDL-C and hs-CRP, PCSK9 inhibitors leading to dramatic LDL-C reductions do no alter hs-CRP levels. On the other hand, hs-CRP levels identify groups of patients with a high risk of CV disease achieving better ASCVD prevention in response to PCSK9 inhibition. In the FOURIER study, even in patients with extremely low levels of LDL-C, there was a stepwise risk increment according to the values of hs-CRP: +9% (<1 mg/L), +10.8% (1-3 mg/L) and +13.1% (>3 mg/L). Likewise, in the SPIRE-1 and -2 studies, bococizumab patients with hs-CRP> 3 mg/L had a 60% greater risk of future CV events. Most of the patients enrolled in the PCSK9 trials were on maximally tolerated statin therapy at baseline, and an elevated hs-CRP may reflect residual inflammatory risk after standard LDL-C lowering therapy. Moreover, data on changes in inflammation markers in carriers of PCSK9 loss-of-function mutations are scanty and not conclusive, thus, evidence from the effects of anti-inflammatory molecules on PCSK9 levels might help unravel this hitherto complex tangle.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.07.015DOI Listing
September 2019

Methotrexate for Cardiovascular Risk Reduction: The Right Choice?

Angiology 2020 02 11;71(2):105-107. Epub 2019 Jun 11.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

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http://dx.doi.org/10.1177/0003319719855165DOI Listing
February 2020

Can we further optimize statin therapy to increase tolerability?

Expert Opin Drug Discov 2019 09 17;14(9):843-847. Epub 2019 May 17.

c Centro Dislipidemie, A.S.S.T. Grande Ospedale Metropolitano Niguarda , Milan , Italy.

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http://dx.doi.org/10.1080/17460441.2019.1615436DOI Listing
September 2019

Recent advances in synthetic pharmacotherapies for dyslipidaemias.

Eur J Prev Cardiol 2020 10 6;27(15):1576-1596. Epub 2019 May 6.

Department of Pharmacological and Bimolecular Sciences, Università degli Studi di Milano, Milan, Italy.

Despite the demonstrated benefits of statins and injectable biologics, there is a need for new and safe oral agents for addressing classical lipid targets, low-density lipoprotein cholesterol (LDL-C), triglycerides and high-density lipoprotein cholesterol (HDL-C). LDL-C is unquestionably causal in the development of atherogenesis and atherosclerotic cardiovascular disease, but new options are required to address triglyceride-rich lipoproteins and lipoprotein(a). For hypercholesterolaemia, pitavastatin provides a very low dose and potent statin that does not adversely affect glucose metabolism; bempedoic acid acts at a biochemical step preceding hydroxymethylglutaryl-CoA reductase and is not associated with muscular side effects. For hypertriglyceridaemia, pemafibrate displays a unique and selective agonist activity on peroxisomal proliferator activated receptor-α that does not elevate homocysteine or creatinine. Although omega-3 fatty acids supplementation is not effective in secondary prevention, high dose eicosapentaenoic ethyl ester can lead to a remarkable fall in first and recurrent events in high risk patients with hypertriglyceridaemia/low HDL-C. Gemcabene, a dicarboxylic acid regulating apolipoprotein B-100, is effective in reducing both cholesterol and triglycerides. Among cholesteryl ester transfer protein antagonists that elevate HDL-C, only anacetrapib reduces cardiovascular events. Probucol stimulates reverse cholesteryl ester transport, lowers LDL-C stabilizing plaques and may lower incidence of cardiovascular events. These agents, which act through novel mechanisms, afford good and potentially safe treatment choices that may increase adherence and the attainment of therapeutic targets.
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http://dx.doi.org/10.1177/2047487319845314DOI Listing
October 2020

PCSK9 in HIV infection: New opportunity or red herring?

Atherosclerosis 2019 05 9;284:216-217. Epub 2019 Mar 9.

Centro Dislipidemie, A.S.S.T. Grande Ospedale Metropolitano Niguarda, Milan, Italy.

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http://dx.doi.org/10.1016/j.atherosclerosis.2019.03.002DOI Listing
May 2019

PCSK9 monoclonal antibodies and lipoprotein apheresis for lowering lipoprotein(a): making choices in an era of RNA-based therapies.

Eur J Prev Cardiol 2019 Jun 7;26(9):998-1000. Epub 2019 Mar 7.

5 Centro Dislipidemie, ASST Grande Ospedale Metropolitano Niguarda, Italy.

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http://dx.doi.org/10.1177/2047487319833504DOI Listing
June 2019

High-Density Lipoprotein Function Is Reduced in Patients Affected by Genetic or Idiopathic Hypogonadism.

J Clin Endocrinol Metab 2019 08;104(8):3097-3107

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.

Context: Low testosterone levels are associated with an increased incidence of cardiovascular (CV) events, but the underlying biochemical mechanisms are not fully understood. The clinical condition of hypogonadism offers a unique model to unravel the possible role of lipoprotein-associated abnormalities in CV risk. In particular, the assessment of the functional capacities of high-density lipoproteins (HDLs) may provide insights besides traditional risk factors.

Design: To determine whether reduced testosterone levels correlate with lipoprotein function, HDL cholesterol (HDL-C) efflux capacity (CEC) and serum cholesterol loading capacity (CLC).

Participants: Genetic and idiopathic hypogonadal patients (n = 20) and control subjects (n = 17).

Results: Primary and secondary hypogonadal patients presented with lower HDL ATP-binding cassette transporter A1 (ABCA1)-, ATP-binding cassette transporter G1 (ABCG1)-, and aqueous diffusion-mediated CEC (-19.6%, -40.9%, and -12.9%, respectively), with a 16.2% decrement of total CEC. In the whole series, positive correlations between testosterone levels and both total HDL CEC (r2 = 0.359, P = 0.0001) and ABCG1 HDL CEC (r2 = 0.367, P = 0.0001) were observed. Conversely, serum CLC was markedly raised (+43%) in hypogonadals, increased, to a higher extent, in primary vs secondary hypogonadism (18.45 ± 2.78 vs 15.15 ± 2.10 µg cholesterol/mg protein) and inversely correlated with testosterone levels (r2 = 0.270, P = 0.001). HDL-C concentrations did not correlate with either testosterone levels, HDL CEC (total, ABCG1, and ABCA1) or serum CLC.

Conclusions: In hypogonadal patients, proatherogenic lipoprotein-associated changes are associated with lower cholesterol efflux and increased influx, thus offering an explanation for a potentially increased CV risk.
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http://dx.doi.org/10.1210/jc.2018-02027DOI Listing
August 2019

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 J 2019 02 22;18(1):13. Epub 2019 Feb 22.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.

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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http://dx.doi.org/10.1186/s12937-019-0438-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387491PMC
February 2019

Long-term exposure to air pollution raises circulating levels of proprotein convertase subtilisin/kexin type 9 in obese individuals.

Eur J Prev Cardiol 2019 04 26;26(6):578-588. Epub 2018 Nov 26.

1 Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy.

Aims: Exposure to airborne particulate matter has been consistently associated with early death and increased morbidity, particularly raising the risk of cardiovascular disease. Obesity, one of the leading cardiovascular disease risk factors, increases susceptibility to the adverse effects of particulate matter exposure. Proprotein convertase subtilisin/kexin type 9 has been related to a large number of cardiovascular risk factors, e.g. atherogenic lipoproteins, arterial stiffness and platelet activation. Thus, the present study was aimed at evaluating, in a series of obese individuals, the effects of particulate matter less than 10 µm in diameter (PM) on proprotein convertase subtilisin/kexin type 9 circulating levels.

Methods And Results: In 500 obese subjects, participating in the cross-sectional Susceptibility to Particle Health Effects, miRNAs and Exosomes (SPHERE) study, we evaluated the effects of long- and short-term PM exposure on circulating proprotein convertase subtilisin/kexin type 9 levels. In the studied individuals (body mass index: 33.3 ± 5.2 kg/m) with an annual average PM exposure of 40.12 ± 4.71 µg/m, proprotein convertase subtilisin/kexin type 9 levels were 248.7 ± 78.6 ng/mL. In univariate analysis, PM exposure (annual average) was associated with proprotein convertase subtilisin/kexin type 9 levels (β=1.83, standard error = 0.75, p = 0.014). Interestingly, in a multivariable linear regression model, this association was observed only for carriers of lower concentrations of interferon-γ, whereas it was lost in the presence of higher interferon-γ levels. Proprotein convertase subtilisin/kexin type 9 levels were positively associated with the Framingham Risk Score, which was raised by 15.8% for each 100 ng/ml rise of proprotein convertase subtilisin/kexin type 9.

Conclusions: In obese individuals, more sensitive to the damaging effects of environmental air pollution, PM exposure positively associates with proprotein convertase subtilisin/kexin type 9 plasma levels especially in those with low levels of interferon-γ.
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http://dx.doi.org/10.1177/2047487318815320DOI Listing
April 2019

Left main coronary wall thickness correlates with the carotid intima media thickness and may provide a new marker of cardiovascular risk.

Eur J Prev Cardiol 2019 Jun 22;26(9):1001-1004. Epub 2018 Oct 22.

2 Centro Dislipidemie, Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Italy.

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http://dx.doi.org/10.1177/2047487318806985DOI Listing
June 2019

Cholesteryl ester transfer protein: An enigmatic pharmacology - Antagonists and agonists.

Atherosclerosis 2018 11 1;278:286-298. Epub 2018 Oct 1.

Centro Dislipidemie, A.S.S.T. Grande Ospedale Metropolitano Niguarda, Milan, Italy.

The cholesteryl ester transfer protein (CETP) system moves cholesteryl esters (CE) from high density lipoproteins (HDL) to lower density lipoproteins, i.e. very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) in exchange for triglycerides (TGs). This shuttle process will ultimately form complexes facilitating a bidirectional exchange of CE and TGs, the end process being CE delivery to catabolic sites. The CETP system is generally characteristic of higher animal species; lower species, not provided with this system, have higher and enlarged HDL enriched with apo E, suitable for tissue receptor interaction. Discovery of the CETP system has led to the development of agents interfering with CETP, thus elevating HDL-C and potentially preventing cardiovascular (CV) disease. Activation of CETP leads instead to reduced HDL-C levels, but also to an enhanced removal of CE from tissues. CETP antagonists are mainly small molecules (torcetrapib, anacetrapib, evacetrapib, dalcetrapib) and have provided convincing evidence of a HDL-C raising activity, but disappointing results in trials of CV prevention. In contrast, the CETP agonist probucol leads to HDL-C lowering followed by an increment of tissue cholesterol removal (reduction of xanthomas, xanthelasmas) and positive findings in secondary prevention trials. The drug has an impressive anti-inflammatory profile (markedly reduced interleukin-1β expression). Newer agents, some of natural origin, have additional valuable pharmacodynamic properties. The pharmacological approach to the CETP system remains enigmatic, although the failure of CETP antagonists has dampened enthusiasm. Studies on the system, a crossroad for any investigation on cholesterol metabolism, have however provided crucial contributions and will still be confronting any scientist working on CV prevention.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.09.035DOI Listing
November 2018

The effect of statin therapy on endoplasmic reticulum stress.

Pharmacol Res 2018 11 9;137:150-158. Epub 2018 Oct 9.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

The endoplasmic reticulum (ER) is critical in protein processing and particularly in ensuring that proteins undergo their correct folding to exert their functionality. What is becoming increasingly clear is that the ER may undergo increasing stress brought about by nutrient deprivation, hypoxia, oxidized lipids, point mutations in secreted proteins, cellular differentiation or significant deviation from metabolic set points, and loss of Ca homeostasis, with detrimental effects on ER-resident calcium-dependent chaperones, alone or in combination. This results in the unfolded protein response (UPR) that is a repair mechanism to limit the formation of newly damaged proteins until ER homeostasis is restored, though may result in increased cell death. ER stress has been shown to be implicated in a variety of diseases. Statins are well-known cholesterol-lowering drugs and have been extensively reported to possess beneficial cholesterol-independent effects in a variety of human diseases. This review focuses on the concept of ER stress, the underlying molecular mechanisms and their relationship to the pathophysiology and, finally, the role of statins in moderating ER stress and UPR.
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http://dx.doi.org/10.1016/j.phrs.2018.10.006DOI Listing
November 2018