PMID- 31100618 OWN - NLM STAT- Publisher LR - 20190603 IS - 1879-1484 (Electronic) IS - 0021-9150 (Linking) VI - 286 DP - 2019 May 4 TI - Potential utility of the SAFEHEART risk equation for rationalising the use of PCSK9 monoclonal antibodies in adults with heterozygous familial hypercholesterolemia. PG - 40-45 LID - S0021-9150(19)30408-3 [pii] LID - 10.1016/j.atherosclerosis.2019.05.003 [doi] AB - BACKGROUND AND AIMS: Patients with familial hypercholesterolaemia (FH) may require proprotein convertase subtilisin/kexin-type 9 (PCSK9) mAb as add-on therapy to achieve LDL-cholesterol (LDL-C) goals. However, the current cost of these therapies means that choosing suitable patients is based on consensus or clinical judgement rather than a quantitative risk assessment. We used the SAFEHEART Risk Equation (RE) to estimate the number needed to treat (NNT) at different risk thresholds and baseline LDL-C to identify those FH patients more likely to derive the greatest benefit from PCSK9 mAb. METHODS: Five-year event rates were calculated using the SAFEHEART-RE for every patient, overall and across LDL-C strata. A 60% reduction of LDL-C after theoretical treatment with PCSK9 mAb was assumed. Individual absolute risk simulating the effects of PCSK9 inhibition was calculated using the SAFEHEART-RE and, in a similar way, by using the Cholesterol Treatment Trialists' (CTT) Collaboration criteria. Absolute risk reduction and NNTs were calculated. RESULTS: Of the total SAFEHEART population, 2,153 were FH cases aged 18 years or older, on maximum tolerated lipid lowering treatment. NNTs were dependent of both baseline predicted risk and baseline LDL-C level ranging from 44 to 17 for those with 5-year risk of >/=1 to >/=5. The smallest NNT (12) was observed among those with 5-year risk of >/=5% and LDL-C >/=160mg/dl. Using the CTT criteria produced similar results. CONCLUSIONS: The SAFEHEART-RE may provide a useful quantitative tool for rationalising the selection of FH patients who might derive greater absolute benefits from PCSK9 mAb. CI - Copyright (c) 2019. Published by Elsevier B.V. FAU - Perez de Isla, Leopoldo AU - Perez de Isla L AD - Cardiology Department, Hospital Clinico San Carlos, IDISSC, Universidad Complutense, Madrid, Spain; Fundacion Hipercolesterolemia Familiar, Madrid, Spain. Electronic address: leopisla@hotmail.com. FAU - Ray, Kausik K AU - Ray KK AD - Imperial Centre for Cardiovascular Disease Prevention, Department of primary Care and Public Health, Imperial College London, London, UK. FAU - Watts, Gerald F AU - Watts GF AD - School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia; Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Perth, Australia. FAU - Santos, Raul D AU - Santos RD AD - Heart Institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil; Hospital Israelita Albert Einstein, Sao Paulo, Brazil. FAU - Alonso, Rodrigo AU - Alonso R AD - Clinica las Condes, Santiago de Chile, Chile. FAU - Muniz-Grijalvo, Ovidio AU - Muniz-Grijalvo O AD - Department of Internal Medicine, Hospital Virgen del Rocio, Sevilla, Spain. FAU - Diaz-Diaz, Jose Luis AU - Diaz-Diaz JL AD - Department of Internal Medicine, Hospital Abente y Lago, A Coruna, Spain. FAU - Badimon, Lina AU - Badimon L AD - Cardiovascular program-ICCC, IR-Hospital de la Santa Creu i Sant Pau, CiberCV, Barcelona, Spain. FAU - Catapano, Alberico L AU - Catapano AL AD - Department of Pharmacological and Biomolecular Sciences, University of Milan and MultiMedica IRCCS, Milano, Italy. FAU - Mata, Pedro AU - Mata P AD - Fundacion Hipercolesterolemia Familiar, Madrid, Spain. Electronic address: pmata@colesterolfamiliar.org. LA - eng PT - Journal Article DEP - 20190504 PL - Ireland TA - Atherosclerosis JT - Atherosclerosis JID - 0242543 OTO - NOTNLM OT - CTT OT - Cardiovascular risk assessment OT - Familial hypercholesterolemia OT - NNT OT - PCSK9 mAb OT - SAFEHEART EDAT- 2019/05/18 06:00 MHDA- 2019/05/18 06:00 CRDT- 2019/05/18 06:00 PHST- 2019/04/07 00:00 [received] PHST- 2019/04/25 00:00 [revised] PHST- 2019/05/03 00:00 [accepted] PHST- 2019/05/18 06:00 [pubmed] PHST- 2019/05/18 06:00 [medline] PHST- 2019/05/18 06:00 [entrez] AID - S0021-9150(19)30408-3 [pii] AID - 10.1016/j.atherosclerosis.2019.05.003 [doi] PST - aheadofprint SO - Atherosclerosis. 2019 May 4;286:40-45. doi: 10.1016/j.atherosclerosis.2019.05.003. PMID- 30926528 OWN - NLM STAT- In-Data-Review LR - 20190420 IS - 1096-1186 (Electronic) IS - 1043-6618 (Linking) VI - 143 DP - 2019 May TI - Cardiovascular events with PCSK9 inhibitors: an updated meta-analysis of randomised controlled trials. PG - 143-150 LID - S1043-6618(18)31849-8 [pii] LID - 10.1016/j.phrs.2019.03.021 [doi] AB - The therapy with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors efficiently reduces plasma cholesterol levels, which has been recently associated with improvement in cardiovascular outcomes. This meta-analysis aimed at investigating the safety and efficacy of treatment with the clinically available anti-PCSK9 monoclonal antibodies (mAbs) in all published randomized clinical trials (RCTs), updating the available results with the recently published ODYSSEY OUTCOMES trial. Data search was carried out using PubMed/MEDLINE and EMBASE (inception - January 2019). Inclusion criteria were: (1) phase 2 or 3 RCTs; (2) comparing anti-PCSK9 mAbs (specifically evolocumab and alirocumab) with placebo; (3) with effects on outcomes reported; (4) with treatment duration longer than 8 weeks. Odds ratios (ORs) with 95% CIs were used as summary statistics. We pooled the estimates by using both the DerSimonian & Laird method (random-effects model). Between-study heterogeneity was tested by Cochrane's Q test and measured with the I2 statistics. Twenty-eight RCTs comprising 62,281 participants (33,204 in the mAb arm, 29,077 in the placebo arm) were included in the meta-analysis. The treatment follow-up ranged from 8 weeks up to 208 weeks. Overall, no significant difference in all-cause mortality was observed between the two groups (OR 0.93 [95% CI, 0.85-1.03]). The treatment with an anti-PCSK9 mAb was associated with a significant reduction of CV events compared with placebo (OR 0.83 [95% CI, 0.78-0.87]), being the FOURIER and ODYSSEY OUTCOMES studies the major contributors. Both myocardial infarction and stroke were significantly reduced following the treatment with an anti-PCSK9 mAb. No significant difference was observed in cardiovascular mortality (OR 0.94 [95% CI, 0.83-1.07]). The incidence of serious adverse events was similar in the two groups (OR: 0.95, [95% CI, 0.91-0.99]). Thus, the pharmacological approach with anti-PCSK9 mAbs significantly and safely improves cardiovascular outcomes. Despite that, the pooled analysis failed to show a significant cardiovascular mortality benefit with anti-PCSK9 mAb treatment, suggesting that specific longer-term studies are warranted to address this issue. We suggest that the observed delay between the rapid effect on plasma cholesterol levels and the emergence of the clinical benefit, observed both in FOURIER and ODYSSEY OUTCOMES trials, might explain this finding. CI - Copyright (c) 2019. Published by Elsevier Ltd. FAU - Casula, Manuela AU - Casula M AD - Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy. FAU - Olmastroni, Elena AU - Olmastroni E AD - Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy. FAU - Boccalari, Mezio T AU - Boccalari MT AD - Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy. FAU - Tragni, Elena AU - Tragni E AD - Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy. FAU - Pirillo, Angela AU - Pirillo A AD - Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy; IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy. FAU - Catapano, Alberico L AU - Catapano AL AD - Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy. Electronic address: alberico.catapano@unimi.it. LA - eng PT - Journal Article DEP - 20190326 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 OTO - NOTNLM OT - Cardiovascular events OT - Cardiovascular mortality OT - Monoclonal antibodies OT - PCSK9 EDAT- 2019/03/31 06:00 MHDA- 2019/03/31 06:00 CRDT- 2019/03/31 06:00 PHST- 2018/11/23 00:00 [received] PHST- 2019/02/15 00:00 [revised] PHST- 2019/03/25 00:00 [accepted] PHST- 2019/03/31 06:00 [pubmed] PHST- 2019/03/31 06:00 [medline] PHST- 2019/03/31 06:00 [entrez] AID - S1043-6618(18)31849-8 [pii] AID - 10.1016/j.phrs.2019.03.021 [doi] PST - ppublish SO - Pharmacol Res. 2019 May;143:143-150. doi: 10.1016/j.phrs.2019.03.021. Epub 2019 Mar 26. PMID- 31029825 OWN - NLM STAT- Publisher LR - 20190511 IS - 1879-260X (Electronic) IS - 0925-4439 (Linking) DP - 2019 Apr 26 TI - Cholesterol metabolism, pancreatic beta-cell function and diabetes. LID - S0925-4439(19)30123-1 [pii] LID - 10.1016/j.bbadis.2019.04.012 [doi] AB - Cholesterol plays an essential role in determining cell membrane physico-chemical characteristics and functions. A proper membrane structure is critical in pancreatic beta-cells for glucose-mediated insulin secretion, and alterations in cellular cholesterol content may negatively affect this process, leading to beta-cell dysfunction. The low density lipoprotein receptor (LDL-R) appears to play a relevant role in ss-cell dysfunction due to cholesterol accumulation. This observation raised the question of whether hypocholesterolemic drugs which increase LDL-R expression might bear diabetogenic properties, thus increasing the risk of new-onset diabetes or worsen glycaemic parameters in diabetic patients. Being at higher cardiovascular risk, diabetic patients are usually treated with hypolipidemic drugs to correct the atherogenic dyslipidemia characteristic of this pathological condition. Statin therapy has been associated with an increased incidence of new-onset diabetes (NOD), being the diabetogenic effect depending on the type and dose of statin. However, it is worth noting that the benefits on cardiovascular mortality largely exceed the increased risk associated with the development of diabetes. Although genetic variants associated with lower levels of LDL-C are also associated with an increased NOD risk, clinical trials with lipid-lowering drugs other than statins, namely ezetimibe or monoclonal antibodies against PCSK9, did not observe an increase of developing diabetes. In summary, molecular evidence clearly points to a key role for cholesterol homeostasis in pancreatic beta-cell function which, in humans, is negatively affected by statins. Available data exclude that this could be the case for other hypocholesterolemic approaches, but long-term studies are warranted to explore this critical aspect. CI - Copyright (c) 2019 Elsevier B.V. All rights reserved. FAU - Perego, Carla AU - Perego C AD - Department of Excellence of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Da Dalt, Lorenzo AU - Da Dalt L AD - Department of Excellence of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Pirillo, Angela AU - Pirillo A AD - SISA Centre, Bassini Hospital, Cinisello Balsamo, Milan, Italy. FAU - Galli, Alessandra AU - Galli A AD - Department of Excellence of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Catapano, Alberico L AU - Catapano AL AD - Department of Excellence of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy; IRCSS Multimedica, Milan, Italy. Electronic address: alberico.catapano@unimi.it. FAU - Norata, Giuseppe D AU - Norata GD AD - Department of Excellence of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy; SISA Centre, Bassini Hospital, Cinisello Balsamo, Milan, Italy. Electronic address: danilo.norata@unimi.it. LA - eng PT - Journal Article PT - Review DEP - 20190426 PL - Netherlands TA - Biochim Biophys Acta Mol Basis Dis JT - Biochimica et biophysica acta. Molecular basis of disease JID - 101731730 OTO - NOTNLM OT - Cholesterol OT - Diabetes OT - Hypocholesterolemic drugs OT - Insulin OT - beta-cell EDAT- 2019/04/29 06:00 MHDA- 2019/04/29 06:00 CRDT- 2019/04/29 06:00 PHST- 2018/02/23 00:00 [received] PHST- 2018/12/20 00:00 [revised] PHST- 2019/01/06 00:00 [accepted] PHST- 2019/04/29 06:00 [pubmed] PHST- 2019/04/29 06:00 [medline] PHST- 2019/04/29 06:00 [entrez] AID - S0925-4439(19)30123-1 [pii] AID - 10.1016/j.bbadis.2019.04.012 [doi] PST - aheadofprint SO - Biochim Biophys Acta Mol Basis Dis. 2019 Apr 26. pii: S0925-4439(19)30123-1. doi: 10.1016/j.bbadis.2019.04.012. PMID- 30972066 OWN - NLM STAT- In-Data-Review LR - 20190414 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 10 DP - 2019 TI - Identification of AnnexinA1 as an Endogenous Regulator of RhoA, and Its Role in the Pathophysiology and Experimental Therapy of Type-2 Diabetes. PG - 571 LID - 10.3389/fimmu.2019.00571 [doi] AB - Annexin A1 (ANXA1) is an endogenously produced anti-inflammatory protein, which plays an important role in the pathophysiology of diseases associated with chronic inflammation. We demonstrate that patients with type-2 diabetes have increased plasma levels of ANXA1 when compared to normoglycemic subjects. Plasma ANXA1 positively correlated with fatty liver index and elevated plasma cholesterol in patients with type-2 diabetes, suggesting a link between aberrant lipid handling, and ANXA1. Using a murine model of high fat diet (HFD)-induced insulin resistance, we then investigated (a) the role of endogenous ANXA1 in the pathophysiology of HFD-induced insulin resistance using ANXA1(-/-) mice, and (b) the potential use of hrANXA1 as a new therapeutic approach for experimental diabetes and its microvascular complications. We demonstrate that: (1) ANXA1(-/-) mice fed a HFD have a more severe diabetic phenotype (e.g., more severe dyslipidemia, insulin resistance, hepatosteatosis, and proteinuria) compared to WT mice fed a HFD; (2) treatment of WT-mice fed a HFD with hrANXA1 attenuated the development of insulin resistance, hepatosteatosis and proteinuria. We demonstrate here for the first time that ANXA1(-/-) mice have constitutively activated RhoA. Interestingly, diabetic mice, which have reduced tissue expression of ANXA1, also have activated RhoA. Treatment of HFD-mice with hrANXA1 restored tissue levels of ANXA1 and inhibited RhoA activity, which, in turn, resulted in restoration of the activities of Akt, GSK-3beta and endothelial nitric oxide synthase (eNOS) secondary to re-sensitization of IRS-1 signaling. We further demonstrate in human hepatocytes that ANXA1 protects against excessive mitochondrial proton leak by activating FPR2 under hyperglycaemic conditions. In summary, our data suggest that (a) ANXA1 is a key regulator of RhoA activity, which restores IRS-1 signal transduction and (b) recombinant human ANXA1 may represent a novel candidate for the treatment of T2D and/or its complications. FAU - Purvis, Gareth S D AU - Purvis GSD AD - Department of Translational Medicine and Therapeutics, Bart's and The London School of Medicine and Dentistry, The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. FAU - Collino, Massimo AU - Collino M AD - Department of Drug Science and Technology, University of Turin, Turin, Italy. FAU - Loiola, Rodrigo A AU - Loiola RA AD - Department of Translational Medicine and Therapeutics, Bart's and The London School of Medicine and Dentistry, The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. FAU - Baragetti, Andrea AU - Baragetti A AD - Department of Pharmacological and Biomolecular Sciences, Universita Degli Studi di Milano, Milan, Italy. FAU - Chiazza, Fausto AU - Chiazza F AD - Department of Drug Science and Technology, University of Turin, Turin, Italy. FAU - Brovelli, Martina AU - Brovelli M AD - Department of Translational Medicine and Therapeutics, Bart's and The London School of Medicine and Dentistry, The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. AD - Department of Pharmacological and Biomolecular Sciences, Universita Degli Studi di Milano, Milan, Italy. AD - Centro SISA per lo studio del'Aterosclerosi, Bassini Hospital, Lombardy, Italy. FAU - Sheikh, Madeeha H AU - Sheikh MH AD - Department of Translational Medicine and Therapeutics, Bart's and The London School of Medicine and Dentistry, The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. FAU - Collotta, Debora AU - Collotta D AD - Department of Drug Science and Technology, University of Turin, Turin, Italy. FAU - Cento, Alessia AU - Cento A AD - Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. FAU - Mastrocola, Raffaella AU - Mastrocola R AD - Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. FAU - Aragno, Manuela AU - Aragno M AD - Department of Molecular Biotechnology and Sciences for the Health, University of Turin, Turin, Italy. FAU - Cutrin, Juan C AU - Cutrin JC AD - Department of Molecular Biotechnology and Sciences for the Health, University of Turin, Turin, Italy. FAU - Reutelingsperger, Chris AU - Reutelingsperger C AD - Department of Biochemistry, Cardiovascular Research Institute, Maastricht University, Maastricht, Netherlands. FAU - Grigore, Liliana AU - Grigore L AD - Centro SISA per lo studio del'Aterosclerosi, Bassini Hospital, Lombardy, Italy. AD - IRCCS Multimedica, Lombardy, Italy. FAU - Catapano, Alberico L AU - Catapano AL AD - Department of Pharmacological and Biomolecular Sciences, Universita Degli Studi di Milano, Milan, Italy. FAU - Yaqoob, Magdi M AU - Yaqoob MM AD - Department of Translational Medicine and Therapeutics, Bart's and The London School of Medicine and Dentistry, The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. FAU - Norata, Giuseppe Danilo AU - Norata GD AD - Department of Pharmacological and Biomolecular Sciences, Universita Degli Studi di Milano, Milan, Italy. AD - Centro SISA per lo studio del'Aterosclerosi, Bassini Hospital, Lombardy, Italy. FAU - Solito, Egle AU - Solito E AD - Department of Translational Medicine and Therapeutics, Bart's and The London School of Medicine and Dentistry, The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. AD - Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita Degli Studi di Napoli "Federico II", Naples, Italy. FAU - Thiemermann, Christoph AU - Thiemermann C AD - Department of Translational Medicine and Therapeutics, Bart's and The London School of Medicine and Dentistry, The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. LA - eng PT - Journal Article DEP - 20190327 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 PMC - PMC6446914 OTO - NOTNLM OT - Annexin A1 OT - Rho A OT - hepatosteatosis OT - metabolism OT - nephropathy OT - type-2 diabetes EDAT- 2019/04/12 06:00 MHDA- 2019/04/12 06:00 CRDT- 2019/04/12 06:00 PHST- 2019/01/11 00:00 [received] PHST- 2019/03/04 00:00 [accepted] PHST- 2019/04/12 06:00 [entrez] PHST- 2019/04/12 06:00 [pubmed] PHST- 2019/04/12 06:00 [medline] AID - 10.3389/fimmu.2019.00571 [doi] PST - epublish SO - Front Immunol. 2019 Mar 27;10:571. doi: 10.3389/fimmu.2019.00571. eCollection 2019. PMID- 30888513 OWN - NLM STAT- In-Data-Review LR - 20190510 IS - 1539-0829 (Electronic) IS - 1534-4827 (Linking) VI - 19 IP - 5 DP - 2019 Mar 19 TI - The Interconnection Between Immuno-Metabolism, Diabetes, and CKD. PG - 21 LID - 10.1007/s11892-019-1143-4 [doi] AB - PURPOSE OF REVIEW: Metabolic reprogramming is increasingly recognized as an essential trait of functional activation of immune cells. Here, we describe the link between immuno-metabolism, diabetes, and diabetic nephropathy. RECENT FINDINGS: Crosstalk between cellular metabolic functions and immune activation occurs when plasma levels of glucose, triglycerides, and free fatty acids increase, thus promoting systemic low-grade inflammation that further boosts the development of metabolic complications. In the long run, this settles an "apparent paradox," where, despite excessive inflammation, the immune system is suppressed, further promoting progression to end-stage renal disease (ESRD) and predisposing to premature deaths from infections and cardiovascular diseases. Reviewing the effects of diabetes treatments on immuno-inflammatory responses suggests that the benefit of these drugs might extend beyond the simple control of glucose homeostasis. Hyperglycemia and dyslipidemia correlate with enhancement of the immuno-inflammatory response that can promote and worsen metabolic diseases and support the progression toward ESRD. The identification of cellular checkpoints that modulate the immuno-metabolic machinery of immune cells opens new venues for metabolic drugs. FAU - Bonacina, Fabrizia AU - Bonacina F AD - Department of Excellence of Pharmacological and Biomolecular Sciences (DisFeB), Universita Degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy. FAU - Baragetti, Andrea AU - Baragetti A AD - Department of Excellence of Pharmacological and Biomolecular Sciences (DisFeB), Universita Degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy. AD - SISA Centre, Bassini Hospital, 20092, Cinisello Balsamo, Italy. FAU - Catapano, Alberico Luigi AU - Catapano AL AD - Department of Excellence of Pharmacological and Biomolecular Sciences (DisFeB), Universita Degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy. AD - IRCSS Multimedica, 20138, Milan, Italy. FAU - Norata, Giuseppe Danilo AU - Norata GD AD - Department of Excellence of Pharmacological and Biomolecular Sciences (DisFeB), Universita Degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy. danilo.norata@unimi.it. AD - SISA Centre, Bassini Hospital, 20092, Cinisello Balsamo, Italy. danilo.norata@unimi.it. LA - eng PT - Journal Article PT - Review DEP - 20190319 PL - United States TA - Curr Diab Rep JT - Current diabetes reports JID - 101093791 OTO - NOTNLM OT - Diabetes OT - Immune response OT - Kidney disease OT - Metabolism EDAT- 2019/03/20 06:00 MHDA- 2019/03/20 06:00 CRDT- 2019/03/20 06:00 PHST- 2019/03/20 06:00 [entrez] PHST- 2019/03/20 06:00 [pubmed] PHST- 2019/03/20 06:00 [medline] AID - 10.1007/s11892-019-1143-4 [doi] AID - 10.1007/s11892-019-1143-4 [pii] PST - epublish SO - Curr Diab Rep. 2019 Mar 19;19(5):21. doi: 10.1007/s11892-019-1143-4. PMID- 30865797 OWN - NLM STAT- MEDLINE DCOM- 20190325 LR - 20190325 IS - 1533-4406 (Electronic) IS - 0028-4793 (Linking) VI - 380 IP - 11 DP - 2019 Mar 14 TI - Mendelian Randomization Study of ACLY and Cardiovascular Disease. PG - 1033-1042 LID - 10.1056/NEJMoa1806747 [doi] AB - BACKGROUND: ATP citrate lyase is an enzyme in the cholesterol-biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the target of statins. Whether the genetic inhibition of ATP citrate lyase is associated with deleterious outcomes and whether it has the same effect, per unit decrease in the low-density lipoprotein (LDL) cholesterol level, as the genetic inhibition of HMGCR is unclear. METHODS: We constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase (ACLY) and HMGCR to create instruments that mimic the effect of ATP citrate lyase inhibitors and HMGCR inhibitors (statins), respectively. We then compared the associations of these genetic scores with plasma lipid levels, lipoprotein levels, and the risk of cardiovascular events and cancer. RESULTS: A total of 654,783 participants, including 105,429 participants who had major cardiovascular events, were included in the study. The ACLY and HMGCR scores were associated with similar patterns of changes in plasma lipid and lipoprotein levels and with similar effects on the risk of cardiovascular events per decrease of 10 mg per deciliter in the LDL cholesterol level: odds ratio for cardiovascular events, 0.823 (95% confidence interval [CI], 0.78 to 0.87; P = 4.0x10(-14)) for the ACLY score and 0.836 (95% CI, 0.81 to 0.87; P = 3.9x10(-19)) for the HMGCR score. Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer. CONCLUSIONS: Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level. (Funded by Esperion Therapeutics and others.). CI - Copyright (c) 2019 Massachusetts Medical Society. FAU - Ference, Brian A AU - Ference BA AD - From the Centre for Naturally Randomized Trials (B.A.F., T.B.F.), Medical Research Council, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (B.A.F., S.B., C.O.-W., A.M.W., A.S.B., E.D.A., J.D.), Medical Research Council Biostatistics Unit (S.B.), and NIHR Blood and Transplant Research Unit in Donor Health and Genomics (A.S.B., E.D.A., J.D.), University of Cambridge, Cambridge, and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London (K.K.R.) - all in the United Kingdom; the Department of Pharmacologic and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milan (A.L.C.); Michigan State University, East Lansing (D.R.N.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); and Monash University, Clayton, VIC, Australia (S.J.N.). FAU - Ray, Kausik K AU - Ray KK AD - From the Centre for Naturally Randomized Trials (B.A.F., T.B.F.), Medical Research Council, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (B.A.F., S.B., C.O.-W., A.M.W., A.S.B., E.D.A., J.D.), Medical Research Council Biostatistics Unit (S.B.), and NIHR Blood and Transplant Research Unit in Donor Health and Genomics (A.S.B., E.D.A., J.D.), University of Cambridge, Cambridge, and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London (K.K.R.) - all in the United Kingdom; the Department of Pharmacologic and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milan (A.L.C.); Michigan State University, East Lansing (D.R.N.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); and Monash University, Clayton, VIC, Australia (S.J.N.). FAU - Catapano, Alberico L AU - Catapano AL AD - From the Centre for Naturally Randomized Trials (B.A.F., T.B.F.), Medical Research Council, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (B.A.F., S.B., C.O.-W., A.M.W., A.S.B., E.D.A., J.D.), Medical Research Council Biostatistics Unit (S.B.), and NIHR Blood and Transplant Research Unit in Donor Health and Genomics (A.S.B., E.D.A., J.D.), University of Cambridge, Cambridge, and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London (K.K.R.) - all in the United Kingdom; the Department of Pharmacologic and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milan (A.L.C.); Michigan State University, East Lansing (D.R.N.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); and Monash University, Clayton, VIC, Australia (S.J.N.). FAU - Ference, Thatcher B AU - Ference TB AD - From the Centre for Naturally Randomized Trials (B.A.F., T.B.F.), Medical Research Council, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (B.A.F., S.B., C.O.-W., A.M.W., A.S.B., E.D.A., J.D.), Medical Research Council Biostatistics Unit (S.B.), and NIHR Blood and Transplant Research Unit in Donor Health and Genomics (A.S.B., E.D.A., J.D.), University of Cambridge, Cambridge, and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London (K.K.R.) - all in the United Kingdom; the Department of Pharmacologic and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milan (A.L.C.); Michigan State University, East Lansing (D.R.N.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); and Monash University, Clayton, VIC, Australia (S.J.N.). FAU - Burgess, Stephen AU - Burgess S AD - From the Centre for Naturally Randomized Trials (B.A.F., T.B.F.), Medical Research Council, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (B.A.F., S.B., C.O.-W., A.M.W., A.S.B., E.D.A., J.D.), Medical Research Council Biostatistics Unit (S.B.), and NIHR Blood and Transplant Research Unit in Donor Health and Genomics (A.S.B., E.D.A., J.D.), University of Cambridge, Cambridge, and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London (K.K.R.) - all in the United Kingdom; the Department of Pharmacologic and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milan (A.L.C.); Michigan State University, East Lansing (D.R.N.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); and Monash University, Clayton, VIC, Australia (S.J.N.). FAU - Neff, David R AU - Neff DR AD - From the Centre for Naturally Randomized Trials (B.A.F., T.B.F.), Medical Research Council, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (B.A.F., S.B., C.O.-W., A.M.W., A.S.B., E.D.A., J.D.), Medical Research Council Biostatistics Unit (S.B.), and NIHR Blood and Transplant Research Unit in Donor Health and Genomics (A.S.B., E.D.A., J.D.), University of Cambridge, Cambridge, and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London (K.K.R.) - all in the United Kingdom; the Department of Pharmacologic and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milan (A.L.C.); Michigan State University, East Lansing (D.R.N.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); and Monash University, Clayton, VIC, Australia (S.J.N.). FAU - Oliver-Williams, Clare AU - Oliver-Williams C AD - From the Centre for Naturally Randomized Trials (B.A.F., T.B.F.), Medical Research Council, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (B.A.F., S.B., C.O.-W., A.M.W., A.S.B., E.D.A., J.D.), Medical Research Council Biostatistics Unit (S.B.), and NIHR Blood and Transplant Research Unit in Donor Health and Genomics (A.S.B., E.D.A., J.D.), University of Cambridge, Cambridge, and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London (K.K.R.) - all in the United Kingdom; the Department of Pharmacologic and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milan (A.L.C.); Michigan State University, East Lansing (D.R.N.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); and Monash University, Clayton, VIC, Australia (S.J.N.). FAU - Wood, Angela M AU - Wood AM AD - From the Centre for Naturally Randomized Trials (B.A.F., T.B.F.), Medical Research Council, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (B.A.F., S.B., C.O.-W., A.M.W., A.S.B., E.D.A., J.D.), Medical Research Council Biostatistics Unit (S.B.), and NIHR Blood and Transplant Research Unit in Donor Health and Genomics (A.S.B., E.D.A., J.D.), University of Cambridge, Cambridge, and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London (K.K.R.) - all in the United Kingdom; the Department of Pharmacologic and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milan (A.L.C.); Michigan State University, East Lansing (D.R.N.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); and Monash University, Clayton, VIC, Australia (S.J.N.). FAU - Butterworth, Adam S AU - Butterworth AS AD - From the Centre for Naturally Randomized Trials (B.A.F., T.B.F.), Medical Research Council, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (B.A.F., S.B., C.O.-W., A.M.W., A.S.B., E.D.A., J.D.), Medical Research Council Biostatistics Unit (S.B.), and NIHR Blood and Transplant Research Unit in Donor Health and Genomics (A.S.B., E.D.A., J.D.), University of Cambridge, Cambridge, and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London (K.K.R.) - all in the United Kingdom; the Department of Pharmacologic and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milan (A.L.C.); Michigan State University, East Lansing (D.R.N.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); and Monash University, Clayton, VIC, Australia (S.J.N.). FAU - Di Angelantonio, Emanuele AU - Di Angelantonio E AD - From the Centre for Naturally Randomized Trials (B.A.F., T.B.F.), Medical Research Council, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (B.A.F., S.B., C.O.-W., A.M.W., A.S.B., E.D.A., J.D.), Medical Research Council Biostatistics Unit (S.B.), and NIHR Blood and Transplant Research Unit in Donor Health and Genomics (A.S.B., E.D.A., J.D.), University of Cambridge, Cambridge, and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London (K.K.R.) - all in the United Kingdom; the Department of Pharmacologic and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milan (A.L.C.); Michigan State University, East Lansing (D.R.N.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); and Monash University, Clayton, VIC, Australia (S.J.N.). FAU - Danesh, John AU - Danesh J AD - From the Centre for Naturally Randomized Trials (B.A.F., T.B.F.), Medical Research Council, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (B.A.F., S.B., C.O.-W., A.M.W., A.S.B., E.D.A., J.D.), Medical Research Council Biostatistics Unit (S.B.), and NIHR Blood and Transplant Research Unit in Donor Health and Genomics (A.S.B., E.D.A., J.D.), University of Cambridge, Cambridge, and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London (K.K.R.) - all in the United Kingdom; the Department of Pharmacologic and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milan (A.L.C.); Michigan State University, East Lansing (D.R.N.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); and Monash University, Clayton, VIC, Australia (S.J.N.). FAU - Kastelein, John J P AU - Kastelein JJP AD - From the Centre for Naturally Randomized Trials (B.A.F., T.B.F.), Medical Research Council, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (B.A.F., S.B., C.O.-W., A.M.W., A.S.B., E.D.A., J.D.), Medical Research Council Biostatistics Unit (S.B.), and NIHR Blood and Transplant Research Unit in Donor Health and Genomics (A.S.B., E.D.A., J.D.), University of Cambridge, Cambridge, and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London (K.K.R.) - all in the United Kingdom; the Department of Pharmacologic and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milan (A.L.C.); Michigan State University, East Lansing (D.R.N.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); and Monash University, Clayton, VIC, Australia (S.J.N.). FAU - Nicholls, Stephen J AU - Nicholls SJ AD - From the Centre for Naturally Randomized Trials (B.A.F., T.B.F.), Medical Research Council, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (B.A.F., S.B., C.O.-W., A.M.W., A.S.B., E.D.A., J.D.), Medical Research Council Biostatistics Unit (S.B.), and NIHR Blood and Transplant Research Unit in Donor Health and Genomics (A.S.B., E.D.A., J.D.), University of Cambridge, Cambridge, and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London (K.K.R.) - all in the United Kingdom; the Department of Pharmacologic and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milan (A.L.C.); Michigan State University, East Lansing (D.R.N.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); and Monash University, Clayton, VIC, Australia (S.J.N.). LA - eng GR - Investigator Initiated Grant Award/NIHR Cambridge Biomedical Research Centre/International PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - N Engl J Med JT - The New England journal of medicine JID - 0255562 RN - 0 (Cholesterol, LDL) RN - 0 (Dicarboxylic Acids) RN - 0 (Fatty Acids) RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 0 (Hypolipidemic Agents) RN - 0 (Lipoproteins) RN - 0 (Membrane Proteins) RN - 0 (NPC1L1 protein, human) RN - 0 (Triglycerides) RN - 1EJ6Z6Q368 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) RN - EC 1.1.1.- (HMGCR protein, human) RN - EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases) RN - EC 2.3.3.8 (ATP Citrate (pro-S)-Lyase) SB - AIM SB - IM MH - ATP Citrate (pro-S)-Lyase/antagonists & inhibitors/*genetics MH - Cardiovascular Diseases/*genetics MH - Cholesterol, LDL/*blood MH - Diabetes Mellitus/genetics MH - Dicarboxylic Acids/pharmacology/therapeutic use MH - Fatty Acids/pharmacology/therapeutic use MH - Female MH - *Genetic Predisposition to Disease MH - Humans MH - Hydroxymethylglutaryl CoA Reductases/*genetics MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology/therapeutic use MH - Hypercholesterolemia/drug therapy MH - Hypolipidemic Agents/pharmacology/therapeutic use MH - Lipoproteins/blood MH - Male MH - Membrane Proteins/genetics MH - *Mendelian Randomization Analysis MH - Middle Aged MH - Neoplasms/genetics MH - Odds Ratio MH - Risk MH - Triglycerides/blood EDAT- 2019/03/14 06:00 MHDA- 2019/03/26 06:00 CRDT- 2019/03/14 06:00 PHST- 2019/03/14 06:00 [entrez] PHST- 2019/03/14 06:00 [pubmed] PHST- 2019/03/26 06:00 [medline] AID - 10.1056/NEJMoa1806747 [doi] PST - ppublish SO - N Engl J Med. 2019 Mar 14;380(11):1033-1042. doi: 10.1056/NEJMoa1806747. PMID- 30865796 OWN - NLM STAT- MEDLINE DCOM- 20190325 LR - 20190325 IS - 1533-4406 (Electronic) IS - 0028-4793 (Linking) VI - 380 IP - 11 DP - 2019 Mar 14 TI - Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. PG - 1022-1032 LID - 10.1056/NEJMoa1803917 [doi] AB - BACKGROUND: Short-term studies have shown that bempedoic acid, an inhibitor of ATP citrate lyase, reduces levels of low-density lipoprotein (LDL) cholesterol. Data are limited regarding the safety and efficacy of bempedoic acid treatment in long-term studies involving patients with hypercholesterolemia who are receiving guideline-recommended statin therapy. METHODS: We conducted a randomized, controlled trial involving patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. Patients had to have an LDL cholesterol level of at least 70 mg per deciliter while they were receiving maximally tolerated statin therapy with or without additional lipid-lowering therapy. (Maximally tolerated statin therapy was defined as the highest intensity statin regimen that a patient was able to maintain, as determined by the investigator.) Patients were randomly assigned in a 2:1 ratio to receive bempedoic acid or placebo. The primary end point was safety, and the principal secondary end point (principal efficacy end point) was the percentage change in the LDL cholesterol level at week 12 of 52 weeks. RESULTS: The trial involved 2230 patients, of whom 1488 were assigned to receive bempedoic acid and 742 to receive placebo. The mean (+/-SD) LDL cholesterol level at baseline was 103.2+/-29.4 mg per deciliter. The incidence of adverse events (1167 of 1487 patients [78.5%] in the bempedoic acid group and 584 of 742 [78.7%] in the placebo group) and serious adverse events (216 patients [14.5%] and 104 [14.0%], respectively) did not differ substantially between the two groups during the intervention period, but the incidence of adverse events leading to discontinuation of the regimen was higher in the bempedoic acid group than in the placebo group (162 patients [10.9%] vs. 53 [7.1%]), as was the incidence of gout (18 patients [1.2%] vs. 2 [0.3%]). At week 12, bempedoic acid reduced the mean LDL cholesterol level by 19.2 mg per deciliter, representing a change of -16.5% from baseline (difference vs. placebo in change from baseline, -18.1 percentage points; 95% confidence interval, -20.0 to -16.1; P<0.001). Safety and efficacy findings were consistent, regardless of the intensity of background statin therapy. CONCLUSIONS: In this 52-week trial, bempedoic acid added to maximally tolerated statin therapy did not lead to a higher incidence of overall adverse events than placebo and led to significantly lower LDL cholesterol levels. (Funded by Esperion Therapeutics; CLEAR Harmony ClinicalTrials.gov number, NCT02666664.). CI - Copyright (c) 2019 Massachusetts Medical Society. FAU - Ray, Kausik K AU - Ray KK AD - From the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London (K.K.R.); the Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY (H.E.B.); the University of Milan and Multimedica IRCCS, Milan (A.L.C.); Esperion Therapeutics, Ann Arbor, MI (N.D.L., L.T.B., L.R.S., P.L.R.); and Baylor College of Medicine, Houston (C.M.B.). FAU - Bays, Harold E AU - Bays HE AD - From the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London (K.K.R.); the Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY (H.E.B.); the University of Milan and Multimedica IRCCS, Milan (A.L.C.); Esperion Therapeutics, Ann Arbor, MI (N.D.L., L.T.B., L.R.S., P.L.R.); and Baylor College of Medicine, Houston (C.M.B.). FAU - Catapano, Alberico L AU - Catapano AL AD - From the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London (K.K.R.); the Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY (H.E.B.); the University of Milan and Multimedica IRCCS, Milan (A.L.C.); Esperion Therapeutics, Ann Arbor, MI (N.D.L., L.T.B., L.R.S., P.L.R.); and Baylor College of Medicine, Houston (C.M.B.). FAU - Lalwani, Narendra D AU - Lalwani ND AD - From the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London (K.K.R.); the Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY (H.E.B.); the University of Milan and Multimedica IRCCS, Milan (A.L.C.); Esperion Therapeutics, Ann Arbor, MI (N.D.L., L.T.B., L.R.S., P.L.R.); and Baylor College of Medicine, Houston (C.M.B.). FAU - Bloedon, LeAnne T AU - Bloedon LT AD - From the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London (K.K.R.); the Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY (H.E.B.); the University of Milan and Multimedica IRCCS, Milan (A.L.C.); Esperion Therapeutics, Ann Arbor, MI (N.D.L., L.T.B., L.R.S., P.L.R.); and Baylor College of Medicine, Houston (C.M.B.). FAU - Sterling, Lulu R AU - Sterling LR AD - From the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London (K.K.R.); the Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY (H.E.B.); the University of Milan and Multimedica IRCCS, Milan (A.L.C.); Esperion Therapeutics, Ann Arbor, MI (N.D.L., L.T.B., L.R.S., P.L.R.); and Baylor College of Medicine, Houston (C.M.B.). FAU - Robinson, Paula L AU - Robinson PL AD - From the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London (K.K.R.); the Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY (H.E.B.); the University of Milan and Multimedica IRCCS, Milan (A.L.C.); Esperion Therapeutics, Ann Arbor, MI (N.D.L., L.T.B., L.R.S., P.L.R.); and Baylor College of Medicine, Houston (C.M.B.). FAU - Ballantyne, Christie M AU - Ballantyne CM AD - From the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London (K.K.R.); the Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY (H.E.B.); the University of Milan and Multimedica IRCCS, Milan (A.L.C.); Esperion Therapeutics, Ann Arbor, MI (N.D.L., L.T.B., L.R.S., P.L.R.); and Baylor College of Medicine, Houston (C.M.B.). CN - CLEAR Harmony Trial LA - eng SI - ClinicalTrials.gov/NCT02666664 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - N Engl J Med JT - The New England journal of medicine JID - 0255562 RN - 0 (Apolipoproteins B) RN - 0 (Cholesterol, LDL) RN - 0 (Dicarboxylic Acids) RN - 0 (Fatty Acids) RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Peptide Fragments) RN - 0 (apolipoprotein B (3304-3317)) RN - 1EJ6Z6Q368 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) RN - 9007-41-4 (C-Reactive Protein) RN - 97C5T2UQ7J (Cholesterol) RN - EC 2.3.3.8 (ATP Citrate (pro-S)-Lyase) SB - AIM SB - IM CIN - N Engl J Med. 2019 Mar 14;380(11):1076-1079. PMID: 30865805 MH - ATP Citrate (pro-S)-Lyase/antagonists & inhibitors MH - Aged MH - Apolipoproteins B/blood MH - C-Reactive Protein/analysis MH - Cholesterol/blood MH - Cholesterol, LDL/*blood MH - Dicarboxylic Acids/adverse effects/*therapeutic use MH - Drug Therapy, Combination MH - Fatty Acids/adverse effects/*therapeutic use MH - Female MH - Humans MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use MH - Hypercholesterolemia/blood/*drug therapy MH - Hypoglycemic Agents/adverse effects/*therapeutic use MH - Male MH - Middle Aged MH - Peptide Fragments/blood MH - Treatment Outcome IR - Aazami H FIR - Aazami, Hessam IR - Akhtar A FIR - Akhtar, Asif IR - Ballantyne CM FIR - Ballantyne, Christie Mitchell IR - Baum S FIR - Baum, Seth IR - Bays HE FIR - Bays, Harold E IR - Bertolet B FIR - Bertolet, Barry IR - Bloom SA FIR - Bloom, Stephen A IR - Boffetti PF FIR - Boffetti, Paul F IR - Brown A FIR - Brown, Alan IR - Butman SM FIR - Butman, Samuel M IR - Cannon KD FIR - Cannon, Kevin D IR - Case C FIR - Case, Christopher IR - Claxton E Jr FIR - Claxton, Edmund Jr IR - Collins JF FIR - Collins, John F IR - Dahl CF FIR - Dahl, Charles F IR - Desai PV FIR - Desai, Pratik V IR - Doyle TP FIR - Doyle, Timothy P IR - Eilerman BS FIR - Eilerman, Bradley S IR - Erickson BR FIR - Erickson, Bernard R IR - Gessler CJ Jr FIR - Gessler, Carl J Jr IR - Halpern SW FIR - Halpern, Stephen W IR - Henderson DA FIR - Henderson, David A IR - Karim AH FIR - Karim, Amin Haji IR - Lederman SN FIR - Lederman, Samuel N IR - Lieber IH FIR - Lieber, Ira H IR - Lillo JL FIR - Lillo, Joseph Leonard IR - Mahal SS FIR - Mahal, Sharan S IR - Malhotra V FIR - Malhotra, Vinay IR - Malik AZ FIR - Malik, Amir Z IR - Maniscalco B FIR - Maniscalco, Benedict IR - McGuinn WP 2nd FIR - McGuinn, William P 2nd IR - McKenney JM FIR - McKenney, James M IR - Melvin EJ FIR - Melvin, Eric J IR - Prasad Potu R FIR - Prasad Potu, Ranganatha IR - Prasada S FIR - Prasada, Sudhir IR - Pritchard JC FIR - Pritchard, James C IR - Reyna J FIR - Reyna, Javier IR - Rizk MM FIR - Rizk, Maged M IR - Robinson JG FIR - Robinson, Jennifer G IR - Rozeman P FIR - Rozeman, Phillip IR - Rubino J FIR - Rubino, John IR - Sampognaro GC FIR - Sampognaro, Gregory C IR - Suneja R FIR - Suneja, Randeep IR - Thompson PD FIR - Thompson, Paul D IR - Weinstein DL FIR - Weinstein, Debra L IR - Woolf K FIR - Woolf, Kevin IR - Zarate JC FIR - Zarate, Juan C IR - Zhang W FIR - Zhang, Wenwu IR - Bakbak A FIR - Bakbak, Asaad IR - Cha J FIR - Cha, James IR - Cheema A FIR - Cheema, Asim IR - Constance C FIR - Constance, Christian IR - Deslongchamps F FIR - Deslongchamps, Francois IR - Gaudet D FIR - Gaudet, Daniel IR - Hartleib MC FIR - Hartleib, Michael C IR - Kouz S FIR - Kouz, Simon IR - Ricci JA FIR - Ricci, Joseph A IR - Robinson S FIR - Robinson, Simon IR - Savard D FIR - Savard, Daniel IR - St-Amour E FIR - St-Amour, Eric IR - Tardif JC FIR - Tardif, Jean-Claude IR - Banach M FIR - Banach, Maciej IR - Blach E FIR - Blach, Elzbieta IR - Bryniarski L FIR - Bryniarski, Leszek IR - Cesarz M FIR - Cesarz, Marek IR - Chmielak Z FIR - Chmielak, Zbigniew IR - Czernecka E FIR - Czernecka, Ewa IR - Konieczny M FIR - Konieczny, Marek IR - Krzykowska J FIR - Krzykowska, Jolanta IR - Krzyzagorska E FIR - Krzyzagorska, Ewa IR - Leksycka A FIR - Leksycka, Agata IR - Lysek R FIR - Lysek, Roman IR - Mordaka R FIR - Mordaka, Robert IR - Rozpondek P FIR - Rozpondek, Piotr IR - Sidorowicz-Bialynicka A FIR - Sidorowicz-Bialynicka, Anna IR - Wojewoda P FIR - Wojewoda, Pawel IR - Woznicka-Leskiewicz L FIR - Woznicka-Leskiewicz, Lucyna IR - Ross H FIR - Ross, Holly IR - Blagden MD FIR - Blagden, Mark D IR - Huong Y FIR - Huong, Yieng IR - Fiore G FIR - Fiore, Gieseppe IR - Ivan P FIR - Ivan, Paul IR - Kondagunta VH FIR - Kondagunta, Venkata H IR - Poterajilo A FIR - Poterajilo, Anton IR - Rayman G FIR - Rayman, Gerry IR - Sathyapalan T FIR - Sathyapalan, Thozhukat IR - Sharma R FIR - Sharma, Rajiv IR - Thomas H FIR - Thomas, Hawys IR - Wong YK FIR - Wong, Yuk-Ki IR - Wright AT FIR - Wright, Anthony T IR - Amoroso G FIR - Amoroso, Giovanni IR - Bartels GL FIR - Bartels, Gerard L IR - Hermans WR FIR - Hermans, Walter R IR - Karalis I FIR - Karalis, Ioannis IR - Nawaz A FIR - Nawaz, Aneqqa IR - Rojas Lingan GM FIR - Rojas Lingan, Gloria M IR - Smits PC FIR - Smits, Peter C IR - Stroes E FIR - Stroes, Erik IR - Troquay RP FIR - Troquay, Roel P IR - van Bemmel BM FIR - van Bemmel, Bastiaan M IR - van Kempen WW FIR - van Kempen, Willem W IR - van Kesteren HAM FIR - van Kesteren, Henricus Arnoldus M IR - Axthelm C FIR - Axthelm, Christoph IR - Becker B FIR - Becker, Bernd IR - Birkenfeld AL FIR - Birkenfeld, Andreas L IR - Contzen C FIR - Contzen, Christel IR - Hartard M FIR - Hartard, Manfred IR - Konig HJ FIR - Konig, Hans-Joachim IR - Rinke A FIR - Rinke, Andrea IR - Schiefke I FIR - Schiefke, Ingolf IR - Sigal H FIR - Sigal, Helena IR - Taeschner H FIR - Taeschner, Heidrun IR - Vismane L FIR - Vismane, Liana EDAT- 2019/03/14 06:00 MHDA- 2019/03/26 06:00 CRDT- 2019/03/14 06:00 PHST- 2019/03/14 06:00 [entrez] PHST- 2019/03/14 06:00 [pubmed] PHST- 2019/03/26 06:00 [medline] AID - 10.1056/NEJMoa1803917 [doi] PST - ppublish SO - N Engl J Med. 2019 Mar 14;380(11):1022-1032. doi: 10.1056/NEJMoa1803917. PMID- 30859179 OWN - NLM STAT- Publisher LR - 20190312 IS - 1755-3245 (Electronic) IS - 0008-6363 (Linking) DP - 2019 Mar 12 TI - Pentraxin 3 deficiency protects from the metabolic inflammation associated to diet-induced obesity. LID - cvz068 [pii] LID - 10.1093/cvr/cvz068 [doi] AB - AIM: Low-grade chronic inflammation characterizes obesity and metabolic syndrome. Here we aim at investigating the impact of the acute-phase protein long pentraxin 3 (PTX3) on the immune-inflammatory response occurring during diet-induced obesity. METHODS AND RESULTS: PTX3 deficiency in mice fed a high fat diet for 20 weeks protects from weight gain and adipose tissue deposition in visceral and subcutaneous depots. This effect is not related to changes in glucose homeostasis and lipid metabolism but is associated with the improved immune cell phenotype in the adipose tissue of Ptx3 deficient animals which is characterized by M2-macrophages polarization and increased angiogenesis. These findings are recapitulated in humans where carriers of a PTX3 haplotype (PTX3 h2/h2 haplotype), resulting in lower PTX3 plasma levels, presented with a reduced prevalence of obesity and decreased abdominal adiposity compared to non-carriers. CONCLUSIONS: Our results support a critical role for PTX3 in the onset of obesity by promoting inflammation and limiting adipose tissue vascularization and delineate PTX3 targeting as a valuable strategy for the treatment of adipose tissue-associated inflammatory response. CI - Published on behalf of the European Society of Cardiology. All rights reserved. (c) The Author(s) 2019. For permissions please email: journals.permissions@oup.com. FAU - Bonacina, F AU - Bonacina F AD - Department of Excellence of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Moregola, A AU - Moregola A AD - Department of Excellence of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Porte, R AU - Porte R AD - IRCC Humanitas Clinical and Research Center, Rozzano, Italy. FAU - Baragetti, A AU - Baragetti A AD - Department of Excellence of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. AD - Centro SISA per lo Studio dell'Aterosclerosi, Ospedale Bassini, Cinisello Balsamo, Italy. FAU - Bonavita, E AU - Bonavita E AD - Cancer Inflammation and Immunity Group, CRUK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK. FAU - Salatin, A AU - Salatin A AD - Department of Excellence of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Grigore, L AU - Grigore L AD - Centro SISA per lo Studio dell'Aterosclerosi, Ospedale Bassini, Cinisello Balsamo, Italy. AD - IRCSS Multimedica, Milan, Italy. FAU - Pellegatta, F AU - Pellegatta F AD - Centro SISA per lo Studio dell'Aterosclerosi, Ospedale Bassini, Cinisello Balsamo, Italy. AD - IRCSS Multimedica, Milan, Italy. FAU - Molgora, M AU - Molgora M AD - IRCC Humanitas Clinical and Research Center, Rozzano, Italy. FAU - Sironi, M AU - Sironi M AD - IRCC Humanitas Clinical and Research Center, Rozzano, Italy. FAU - Barbati, E AU - Barbati E AD - IRCC Humanitas Clinical and Research Center, Rozzano, Italy. FAU - Mantovani, A AU - Mantovani A AD - IRCC Humanitas Clinical and Research Center, Rozzano, Italy. AD - Humanitas University Rozzano, Italy. FAU - Bottazzi, B AU - Bottazzi B AD - IRCC Humanitas Clinical and Research Center, Rozzano, Italy. FAU - Catapano, A L AU - Catapano AL AD - Department of Excellence of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. AD - IRCSS Multimedica, Milan, Italy. FAU - Garlanda, C AU - Garlanda C AD - IRCC Humanitas Clinical and Research Center, Rozzano, Italy. AD - Humanitas University Rozzano, Italy. FAU - Norata, G D AU - Norata GD AD - Department of Excellence of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. AD - Centro SISA per lo Studio dell'Aterosclerosi, Ospedale Bassini, Cinisello Balsamo, Italy. LA - eng PT - Journal Article DEP - 20190312 PL - England TA - Cardiovasc Res JT - Cardiovascular research JID - 0077427 EDAT- 2019/03/13 06:00 MHDA- 2019/03/13 06:00 CRDT- 2019/03/13 06:00 PHST- 2018/08/01 00:00 [received] PHST- 2019/02/25 00:00 [revised] PHST- 2019/01/23 00:00 [revised] PHST- 2019/03/04 00:00 [accepted] PHST- 2019/03/13 06:00 [entrez] PHST- 2019/03/13 06:00 [pubmed] PHST- 2019/03/13 06:00 [medline] AID - 5374872 [pii] AID - 10.1093/cvr/cvz068 [doi] PST - aheadofprint SO - Cardiovasc Res. 2019 Mar 12. pii: 5374872. doi: 10.1093/cvr/cvz068. PMID- 30629143 OWN - NLM STAT- In-Data-Review LR - 20190226 IS - 1755-3245 (Electronic) IS - 0008-6363 (Linking) VI - 115 IP - 3 DP - 2019 Mar 1 TI - Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies. PG - 510-518 LID - 10.1093/cvr/cvz003 [doi] AB - Since the discovery of the role of proprotein convertase subtilisin kexin 9 (PCSK9) in the regulation of low-density lipoprotein cholesterol (LDL-C) in 2003, a paradigm shift in the treatment of hypercholesterolaemia has occurred. The PCSK9 secreted into the circulation is a major downregulator of the low-density lipoprotein receptor (LDLR) protein, as it chaperones it to endosomes/lysosomes for degradation. Humans with loss-of-function of PCSK9 exhibit exceedingly low levels of LDL-C and are protected from atherosclerosis. As a consequence, innovative strategies to modulate the levels of PCSK9 have been developed. Since 2015 inhibitory monoclonal antibodies (evolocumab and alirocumab) are commercially available. When subcutaneously injected every 2-4 weeks, they trigger a approximately 60% LDL-C lowering and a 15% reduction in the risk of cardiovascular events. Another promising approach consists of a liver-targetable specific PCSK9 siRNA which results in approximately 50-60% LDL-C lowering that lasts up to 6 months (Phases II-III clinical trials). Other strategies under consideration include: (i) antibodies targeting the C-terminal domain of PCSK9, thereby inhibiting the trafficking of PCSK9-LDLR to lysosomes; (ii) small molecules that either prevent PCSK9 binding to the LDLR, its trafficking to lysosomes or its secretion from cells; (iii) complete silencing of PCSK9 by CRISPR-Cas9 strategies; (iv) PCSK9 vaccines that inhibit the activity of circulating PCSK9. Time will tell whether other strategies can be as potent and safe as monoclonal antibodies to lower LDL-C levels. CI - Published on behalf of the European Society of Cardiology. All rights reserved. (c) The Author(s) 2019. For permissions, please email: journals.permissions@oup.com. FAU - Seidah, Nabil G AU - Seidah NG AD - Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM; Affiliated to the University of Montreal), Montreal, QC H2W1R7, Canada. FAU - Prat, Annik AU - Prat A AD - Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM; Affiliated to the University of Montreal), Montreal, QC H2W1R7, Canada. FAU - Pirillo, Angela AU - Pirillo A AD - Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy. AD - IRCCS MultiMedica, Milan, Italy. FAU - Catapano, Alberico Luigi AU - Catapano AL AD - IRCCS MultiMedica, Milan, Italy. AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Norata, Giuseppe Danilo AU - Norata GD AD - Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy. AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. LA - eng PT - Journal Article PL - England TA - Cardiovasc Res JT - Cardiovascular research JID - 0077427 PMC - PMC6383053 OTO - NOTNLM OT - Gene silencing OT - LDL-C OT - Monoclonal antibodies OT - PCSK9 EDAT- 2019/01/11 06:00 MHDA- 2019/01/11 06:00 CRDT- 2019/01/11 06:00 PMCR- 2020/03/01 00:00 PHST- 2018/10/31 00:00 [received] PHST- 2018/12/06 00:00 [revised] PHST- 2019/01/05 00:00 [accepted] PHST- 2020/03/01 00:00 [pmc-release] PHST- 2019/01/11 06:00 [pubmed] PHST- 2019/01/11 06:00 [medline] PHST- 2019/01/11 06:00 [entrez] AID - 5284912 [pii] AID - 10.1093/cvr/cvz003 [doi] PST - ppublish SO - Cardiovasc Res. 2019 Mar 1;115(3):510-518. doi: 10.1093/cvr/cvz003. PMID- 30545250 OWN - NLM STAT- In-Data-Review LR - 20190318 IS - 2047-4881 (Electronic) IS - 2047-4873 (Linking) VI - 26 IP - 5 DP - 2019 Mar TI - Increasing high-density lipoprotein cholesterol levels for cardiovascular benefit: The end of a dream? PG - 531-532 LID - 10.1177/2047487318820976 [doi] FAU - Pirillo, Angela AU - Pirillo A AD - 1 Center for the Study of Atherosclerosis, E. Bassini Hospital, Italy. AD - 2 IRCCS MultiMedica, Italy. FAU - Catapano, Alberico Luigi AU - Catapano AL AD - 2 IRCCS MultiMedica, Italy. AD - 3 Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy. LA - eng PT - Journal Article DEP - 20181213 PL - England TA - Eur J Prev Cardiol JT - European journal of preventive cardiology JID - 101564430 EDAT- 2018/12/14 06:00 MHDA- 2018/12/14 06:00 CRDT- 2018/12/15 06:00 PHST- 2018/12/14 06:00 [pubmed] PHST- 2018/12/14 06:00 [medline] PHST- 2018/12/15 06:00 [entrez] AID - 10.1177/2047487318820976 [doi] PST - ppublish SO - Eur J Prev Cardiol. 2019 Mar;26(5):531-532. doi: 10.1177/2047487318820976. Epub 2018 Dec 13. PMID- 30520012 OWN - NLM STAT- In-Data-Review LR - 20190131 IS - 1532-6535 (Electronic) IS - 0009-9236 (Linking) VI - 105 IP - 2 DP - 2019 Feb TI - Lipid Lowering and Incidence of Cataract, a Role for Fibrates. PG - 318-319 LID - 10.1002/cpt.1269 [doi] FAU - Casula, Manuela AU - Casula M AD - Epidemiology and Preventive Pharmacology Centre, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy. FAU - Pirillo, Angela AU - Pirillo A AD - Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy. AD - IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy. FAU - Catapano, Alberico L AU - Catapano AL AUID- ORCID: http://orcid.org/0000-0002-7593-2094 AD - Epidemiology and Preventive Pharmacology Centre, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy. AD - IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy. LA - eng GR - 2015-0524/Fondazione Cariplo GR - 2015-0564/Fondazione Cariplo GR - PHC-03-2015/667837-2/H2020 REPROGRAM PT - Journal Article DEP - 20181205 PL - United States TA - Clin Pharmacol Ther JT - Clinical pharmacology and therapeutics JID - 0372741 EDAT- 2018/12/07 06:00 MHDA- 2018/12/07 06:00 CRDT- 2018/12/07 06:00 PHST- 2018/10/12 00:00 [received] PHST- 2018/10/13 00:00 [accepted] PHST- 2018/12/07 06:00 [pubmed] PHST- 2018/12/07 06:00 [medline] PHST- 2018/12/07 06:00 [entrez] AID - 10.1002/cpt.1269 [doi] PST - ppublish SO - Clin Pharmacol Ther. 2019 Feb;105(2):318-319. doi: 10.1002/cpt.1269. Epub 2018 Dec 5. PMID- 30694319 OWN - NLM STAT- MEDLINE DCOM- 20190219 LR - 20190426 IS - 1538-3598 (Electronic) IS - 0098-7484 (Linking) VI - 321 IP - 4 DP - 2019 Jan 29 TI - Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. PG - 364-373 LID - 10.1001/jama.2018.20045 [doi] AB - Importance: Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels. Objective: To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C-lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB. Design, Setting, and Participants: Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C-lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017. Exposures: Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores. Main Outcomes and Measures: Odds ratio (OR) for coronary heart disease (CHD)-defined as coronary death, myocardial infarction, or coronary revascularization-per 10-mg/dL lower concentration of ApoB-containing lipoproteins. Results: A total of 654783 participants, including 91129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 x 10-1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 x 10-465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802], P = 3.9 x 10-38 and OR, 0.773 [95% CI, 0.747-0.801], P = 1.1 x 10-46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065], P = .19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055], P = .19; ApoB: OR, 0.761 [95% CI, 0.723-0.798], P = 7.51 x 10-20). Conclusions and Relevance: Triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB. FAU - Ference, Brian A AU - Ference BA AD - Centre for Naturally Randomized Trials, University of Cambridge, Cambridge, United Kingdom. AD - Institute for Advanced Studies, University of Bristol, Bristol, United Kingdom. AD - MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. FAU - Kastelein, John J P AU - Kastelein JJP AD - Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. FAU - Ray, Kausik K AU - Ray KK AD - Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom. FAU - Ginsberg, Henry N AU - Ginsberg HN AD - Irving Institute for Clinical and Translational Research, Columbia University Vagelos College of Physicians and Surgeons, New York, New York. FAU - Chapman, M John AU - Chapman MJ AD - National Institute for Health and Medical Research (INSERM), Pitie-Salpetriere University Hospital, Paris, France. FAU - Packard, Chris J AU - Packard CJ AD - Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom. FAU - Laufs, Ulrich AU - Laufs U AD - Department of Cardiology, University of Leipzig, Leipzig, Germany. FAU - Oliver-Williams, Clare AU - Oliver-Williams C AD - MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. FAU - Wood, Angela M AU - Wood AM AD - MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. FAU - Butterworth, Adam S AU - Butterworth AS AD - MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. FAU - Di Angelantonio, Emanuele AU - Di Angelantonio E AD - MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. FAU - Danesh, John AU - Danesh J AD - MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. FAU - Nicholls, Stephen J AU - Nicholls SJ AD - Monash Cardiovascular Research Centre, University, Melbourne, Australia. FAU - Bhatt, Deepak L AU - Bhatt DL AD - Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. FAU - Sabatine, Marc S AU - Sabatine MS AD - Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. FAU - Catapano, Alberico L AU - Catapano AL AD - Department of Pharmacological and Biomolecular Sciences, University of Milan, Multimedica IRCCS, Milano, Italy. LA - eng GR - Medical Research Council/United Kingdom GR - European Research Council/International GR - British Heart Foundation/United Kingdom PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - JAMA JT - JAMA JID - 7501160 RN - 0 (Apolipoproteins B) RN - 0 (Cholesterol, LDL) RN - 0 (Receptors, LDL) RN - 0 (Triglycerides) RN - EC 3.1.1.34 (Lipoprotein Lipase) SB - AIM SB - IM CIN - JAMA. 2019 Jan 29;321(4):347-349. PMID: 30694301 MH - Apolipoproteins B/*blood MH - Case-Control Studies MH - Cholesterol, LDL/*blood MH - Coronary Disease/blood/*genetics MH - Female MH - *Genetic Predisposition to Disease MH - *Genetic Variation MH - Humans MH - Lipoprotein Lipase/*genetics/metabolism MH - Loss of Function Mutation MH - Male MH - Mendelian Randomization Analysis MH - Metabolic Networks and Pathways MH - Middle Aged MH - Prospective Studies MH - Receptors, LDL/*genetics MH - Risk Factors MH - Triglycerides/*blood PMC - PMC6439767 EDAT- 2019/01/30 06:00 MHDA- 2019/03/21 06:00 CRDT- 2019/01/30 06:00 PMCR- 2019/07/29 00:00 PHST- 2019/07/29 00:00 [pmc-release] PHST- 2019/01/30 06:00 [entrez] PHST- 2019/01/30 06:00 [pubmed] PHST- 2019/03/21 06:00 [medline] AID - 2722770 [pii] AID - 10.1001/jama.2018.20045 [doi] PST - ppublish SO - JAMA. 2019 Jan 29;321(4):364-373. doi: 10.1001/jama.2018.20045. PMID- 29982592 OWN - NLM STAT- In-Data-Review LR - 20190122 IS - 1522-9645 (Electronic) IS - 0195-668X (Linking) VI - 40 IP - 4 DP - 2019 Jan 21 TI - PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor. PG - 357-368 LID - 10.1093/eurheartj/ehy357 [doi] AB - Aims: PCSK9 loss of function genetic variants are associated with lower low-density lipoprotein cholesterol but also with higher plasma glucose levels and increased risk of Type 2 diabetes mellitus. Here, we investigated the molecular mechanisms underlying this association. Methods and results: Pcsk9 KO, WT, Pcsk9/Ldlr double KO (DKO), Ldlr KO, albumin AlbCre+/Pcsk9LoxP/LoxP (liver-selective Pcsk9 knock-out mice), and AlbCre-/Pcsk9LoxP/LoxP mice were used. GTT, ITT, insulin and C-peptide plasma levels, pancreas morphology, and cholesterol accumulation in pancreatic islets were studied in the different animal models. Glucose clearance was significantly impaired in Pcsk9 KO mice fed with a standard or a high-fat diet for 20 weeks compared with WT animals; insulin sensitivity, however, was not affected. A detailed analysis of pancreas morphology of Pcsk9 KO mice vs. controls revealed larger islets with increased accumulation of cholesteryl esters, paralleled by increased insulin intracellular levels and decreased plasma insulin, and C-peptide levels. This phenotype was completely reverted in Pcsk9/Ldlr DKO mice implying the low-density lipoprotein receptor (LDLR) as the proprotein convertase subtilisin/kexin Type 9 (PCSK9) target responsible for the phenotype observed. Further studies in albumin AlbCre+/Pcsk9LoxP/LoxP mice, which lack detectable circulating PCSK9, also showed a complete recovery of the phenotype, thus indicating that circulating, liver-derived PCSK9, the principal target of monoclonal antibodies, does not impact beta-cell function and insulin secretion. Conclusion: PCSK9 critically controls LDLR expression in pancreas perhaps contributing to the maintenance of a proper physiological balance to limit cholesterol overload in beta cells. This effect is independent of circulating PCSK9 and is probably related to locally produced PCSK9. FAU - Da Dalt, Lorenzo AU - Da Dalt L AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via balzaretti,9, Milan, Italy. FAU - Ruscica, Massimiliano AU - Ruscica M AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via balzaretti,9, Milan, Italy. FAU - Bonacina, Fabrizia AU - Bonacina F AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via balzaretti,9, Milan, Italy. FAU - Balzarotti, Gloria AU - Balzarotti G AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via balzaretti,9, Milan, Italy. FAU - Dhyani, Ashish AU - Dhyani A AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via balzaretti,9, Milan, Italy. FAU - Di Cairano, Eliana AU - Di Cairano E AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via balzaretti,9, Milan, Italy. FAU - Baragetti, Andrea AU - Baragetti A AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via balzaretti,9, Milan, Italy. AD - Centro SISA per lo studio dell'Aterosclerosi, Ospedale Bassini, Via Massimo Gorki, 50, Cinisello Balsamo, Italy. FAU - Arnaboldi, Lorenzo AU - Arnaboldi L AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via balzaretti,9, Milan, Italy. FAU - De Metrio, Simona AU - De Metrio S AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via balzaretti,9, Milan, Italy. FAU - Pellegatta, Fabio AU - Pellegatta F AD - Centro SISA per lo studio dell'Aterosclerosi, Ospedale Bassini, Via Massimo Gorki, 50, Cinisello Balsamo, Italy. FAU - Grigore, Liliana AU - Grigore L AD - Centro SISA per lo studio dell'Aterosclerosi, Ospedale Bassini, Via Massimo Gorki, 50, Cinisello Balsamo, Italy. AD - IRCCS Multimedica Hospital, Via Milanese, 300, Sesto San Giovanni, Italy. FAU - Botta, Margherita AU - Botta M AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via balzaretti,9, Milan, Italy. FAU - Macchi, Chiara AU - Macchi C AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via balzaretti,9, Milan, Italy. FAU - Uboldi, Patrizia AU - Uboldi P AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via balzaretti,9, Milan, Italy. FAU - Perego, Carla AU - Perego C AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via balzaretti,9, Milan, Italy. FAU - Catapano, Alberico Luigi AU - Catapano AL AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via balzaretti,9, Milan, Italy. AD - IRCCS Multimedica Hospital, Via Milanese, 300, Sesto San Giovanni, Italy. FAU - Norata, Giuseppe Danilo AU - Norata GD AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via balzaretti,9, Milan, Italy. AD - School of Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Science, Curtin University, Kent Street, Bentley, Perth 6102, Western Australia, Australia. LA - eng PT - Journal Article PL - England TA - Eur Heart J JT - European heart journal JID - 8006263 EDAT- 2018/07/10 06:00 MHDA- 2018/07/10 06:00 CRDT- 2018/07/09 06:00 PHST- 2017/09/13 00:00 [received] PHST- 2018/06/04 00:00 [accepted] PHST- 2018/07/10 06:00 [pubmed] PHST- 2018/07/10 06:00 [medline] PHST- 2018/07/09 06:00 [entrez] AID - 5047864 [pii] AID - 10.1093/eurheartj/ehy357 [doi] PST - ppublish SO - Eur Heart J. 2019 Jan 21;40(4):357-368. doi: 10.1093/eurheartj/ehy357. PMID- 30500603 OWN - NLM STAT- In-Data-Review LR - 20190127 IS - 1879-1484 (Electronic) IS - 0021-9150 (Linking) VI - 280 DP - 2019 Jan TI - Safety and efficacy of mipomersen in patients with heterozygous familial hypercholesterolemia. PG - 109-117 LID - S0021-9150(18)31472-2 [pii] LID - 10.1016/j.atherosclerosis.2018.11.017 [doi] AB - BACKGROUND AND AIMS: Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased cardiovascular disease risk. Despite multiple LDL-C-lowering therapies, many HeFH patients do not reach LDL-C targets. Mipomersen, an antisense oligonucleotide against apolipoprotein B (apoB), might further lower LDL-C in HeFH patients. We assessed the efficacy and safety of two mipomersen dosing regimens in HeFH patients and explored whether thrice-weekly dosing improves the benefit-risk profile. METHODS: In this double-blind trial, HeFH patients (LDL-C >160mg/dL) on maximal tolerated LDL-lowering therapy were randomized to mipomersen 200mg once weekly (n=104), mipomersen 70mg thrice weekly (n=102), or placebo in matching frequency (n=103) for 60 weeks. Main outcomes were LDL-C, apoB, and lipoprotein(a) levels after 60 weeks of treatment. RESULTS: Mipomersen 200mg once weekly and mipomersen 70mg thrice weekly significantly lowered LDL-C compared with placebo by 21.0% and 18.8%, respectively, and apoB by 22.1% and 21.7% (all p<0.001). Lipoprotein(a) was significantly lowered by 27.7% (p<0.001) with thrice-weekly dosing. Injection-site reactions and flu-like symptoms led to discontinuation in 21.2% (200mg), 17.6% (70mg), and 5.8% (placebo) of participants. Alanine transaminase was elevated (>/=3x upper limit of normal at least once) in 21.2%, 21.6%, and 1.0% of subjects, respectively. CONCLUSIONS: Mipomersen 200mg once weekly and 70mg thrice weekly are effective in lowering apoB-containing lipoproteins in HeFH patients. This is counterbalanced by limited tolerability and increased hepatic transaminase levels in about 21% of patients. The thrice-weekly dosing regimen was associated with lower frequency of flu-like symptoms, which might help avert discontinuation in some patients, but otherwise had no major benefits. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved. FAU - Reeskamp, Laurens F AU - Reeskamp LF AD - Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address: l.f.reeskamp@amc.uva.nl. FAU - Kastelein, John J P AU - Kastelein JJP AD - Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. FAU - Moriarty, Patrick M AU - Moriarty PM AD - Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA. FAU - Duell, P Barton AU - Duell PB AD - Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA. FAU - Catapano, Alberico L AU - Catapano AL AD - Dipartimento Dieccellenza Scienze Farmacologiche e Biomolecolari, Milano, Italy; IRCCS Multimedica, Milano, Italy. FAU - Santos, Raul D AU - Santos RD AD - Lipid Clinic Heart Institute (InCor), University of Sao Paulo Medical School, University of Sao Paulo, Sao Paulo, Brazil; Hospital Israelita Albert Einstein, Sao Paulo, Brazil. FAU - Ballantyne, Christie M AU - Ballantyne CM AD - Sections of Cardiology and Cardiovascular Research, Baylor College of Medicine, Houston, TX, USA. LA - eng PT - Journal Article DEP - 20181110 PL - Ireland TA - Atherosclerosis JT - Atherosclerosis JID - 0242543 OTO - NOTNLM OT - Antisense oligonucleotide OT - Heterozygous familial hypercholesterolemia OT - Lipoproteins OT - Mipomersen OT - Randomized controlled trial OT - apoB EDAT- 2018/12/01 06:00 MHDA- 2018/12/01 06:00 CRDT- 2018/12/01 06:00 PHST- 2018/09/20 00:00 [received] PHST- 2018/10/22 00:00 [revised] PHST- 2018/11/08 00:00 [accepted] PHST- 2018/12/01 06:00 [pubmed] PHST- 2018/12/01 06:00 [medline] PHST- 2018/12/01 06:00 [entrez] AID - S0021-9150(18)31472-2 [pii] AID - 10.1016/j.atherosclerosis.2018.11.017 [doi] PST - ppublish SO - Atherosclerosis. 2019 Jan;280:109-117. doi: 10.1016/j.atherosclerosis.2018.11.017. Epub 2018 Nov 10. PMID- 30340914 OWN - NLM STAT- In-Data-Review LR - 20181121 IS - 1879-260X (Electronic) IS - 0925-4439 (Linking) VI - 1865 IP - 1 DP - 2019 Jan TI - Corrigendum to "Vascular pentraxin 3 controls arterial thrombosis by targeting collagen and fibrinogen induced platelets aggregation" [Biochim. Biophys. Acta, 1862 (2016) 1182-1190]. PG - 262 LID - S0925-4439(18)30352-1 [pii] LID - 10.1016/j.bbadis.2018.09.017 [doi] FAU - Bonacina, F AU - Bonacina F AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Barbieri, S S AU - Barbieri SS AD - IRCCS, Centro Cardiologico Monzino, Milan, Italy. FAU - Cutuli, L AU - Cutuli L AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Amadi, P AU - Amadi P AD - IRCCS, Centro Cardiologico Monzino, Milan, Italy. FAU - Don, A AU - Don A AD - IRCCS, Humanitas Research Foundation, Bruzzano, Milan, Italy. FAU - Sironi, M AU - Sironi M AD - IRCCS, Humanitas Research Foundation, Bruzzano, Milan, Italy. FAU - Tartari, S AU - Tartari S AD - IRCCS, Humanitas Research Foundation, Bruzzano, Milan, Italy. FAU - Mantovani, A AU - Mantovani A AD - IRCCS, Humanitas Research Foundation, Bruzzano, Milan, Italy. FAU - Bottazzi, B AU - Bottazzi B AD - IRCCS, Humanitas Research Foundation, Bruzzano, Milan, Italy. FAU - Garlanda, C AU - Garlanda C AD - IRCCS, Humanitas Research Foundation, Bruzzano, Milan, Italy. FAU - Tremoli, E AU - Tremoli E AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy; IRCCS, Centro Cardiologico Monzino, Milan, Italy. FAU - Catapano, A L AU - Catapano AL AD - IRCCS Multimedica, Milan, Italy. Electronic address: alberico.catapano@unimi.it. FAU - Norata, G D AU - Norata GD AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy; SISA Centre for the Study of Atherosclerosis, Bassini Hospital, Cinisello B, Milan, Italy; William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University, London, UK. Electronic address: danilo.norata@unimi.it. LA - eng PT - Published Erratum DEP - 20181016 PL - Netherlands TA - Biochim Biophys Acta Mol Basis Dis JT - Biochimica et biophysica acta. Molecular basis of disease JID - 101731730 EFR - Biochem Biophys Res Commun. 2018 Sep 26;504(1):270-276. PMID: 30172372 EDAT- 2018/10/21 06:00 MHDA- 2018/10/21 06:00 CRDT- 2018/10/21 06:00 PHST- 2018/10/21 06:00 [pubmed] PHST- 2018/10/21 06:00 [medline] PHST- 2018/10/21 06:00 [entrez] AID - S0925-4439(18)30352-1 [pii] AID - 10.1016/j.bbadis.2018.09.017 [doi] PST - ppublish SO - Biochim Biophys Acta Mol Basis Dis. 2019 Jan;1865(1):262. doi: 10.1016/j.bbadis.2018.09.017. Epub 2018 Oct 16. PMID- 30295742 OWN - NLM STAT- In-Data-Review LR - 20181221 IS - 1755-3245 (Electronic) IS - 0008-6363 (Linking) VI - 115 IP - 1 DP - 2019 Jan 1 TI - High-density lipoprotein cholesterol levels, cardiovascular disease risk, and cancer: a relation which does not apply to all? PG - 6-7 LID - 10.1093/cvr/cvy247 [doi] FAU - Catapano, Alberico Luigi AU - Catapano AL AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via Balzaretti, 9 - Milan, Italy. AD - IRCCS MultiMedica, Milan, Italy. FAU - Pirillo, Angela AU - Pirillo A AD - IRCCS MultiMedica, Milan, Italy. AD - Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy. FAU - Norata, Giuseppe Danilo AU - Norata GD AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via Balzaretti, 9 - Milan, Italy. AD - Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy. LA - eng PT - Journal Article PL - England TA - Cardiovasc Res JT - Cardiovascular research JID - 0077427 EDAT- 2018/10/09 06:00 MHDA- 2018/10/09 06:00 CRDT- 2018/10/09 06:00 PHST- 2018/10/09 06:00 [pubmed] PHST- 2018/10/09 06:00 [medline] PHST- 2018/10/09 06:00 [entrez] AID - 5115992 [pii] AID - 10.1093/cvr/cvy247 [doi] PST - ppublish SO - Cardiovasc Res. 2019 Jan 1;115(1):6-7. doi: 10.1093/cvr/cvy247. PMID- 29848265 OWN - NLM STAT- In-Process LR - 20190531 IS - 1875-533X (Electronic) IS - 0929-8673 (Linking) VI - 26 IP - 9 DP - 2019 TI - Biological Consequences of Dysfunctional HDL. PG - 1644-1664 LID - 10.2174/0929867325666180530110543 [doi] AB - Epidemiological studies have suggested an inverse correlation between high-density lipoprotein (HDL) cholesterol levels and the risk of cardiovascular disease. HDLs promote reverse cholesterol transport (RCT) and possess several putative atheroprotective functions, associated to the anti-inflammatory, anti-thrombotic and anti-oxidant properties as well as to the ability to support endothelial physiology. The assumption that increasing HDL-C levels would be beneficial on cardiovascular disease (CVD), however, has been questioned as, in most clinical trials, HDL-C-raising therapies did not result in improved cardiovascular outcomes. These findings, together with the observations from Mendelian randomization studies showing that polymorphisms mainly or solely associated with increased HDL-C levels did not decrease the risk of myocardial infarction, shift the focus from HDL-C levels toward HDL functional properties. Indeed, HDL from atherosclerotic patients not only exhibit impaired atheroprotective functions but also acquire pro-atherogenic properties and are referred to as "dysfunctional" HDL; this occurs even in the presence of normal or elevated HDL-C levels. Pharmacological approaches aimed at restoring HDL functions may therefore impact more significantly on CVD outcome than drugs used so far to increase HDL-C levels. The aim of this review is to discuss the pathological conditions leading to the formation of dysfunctional HDL and their role in atherosclerosis and beyond. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Pirillo, Angela AU - Pirillo A AD - Center for the Study of Atherosclerosis, Bassini Hospital, Cinisello Balsamo, Italy. AD - IRCCS Multimedica, Milan, Italy. FAU - Catapano, Alberico Luigi AU - Catapano AL AD - IRCCS Multimedica, Milan, Italy. AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Norata, Giuseppe Danilo AU - Norata GD AD - Center for the Study of Atherosclerosis, Bassini Hospital, Cinisello Balsamo, Italy. AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. AD - School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia. LA - eng PT - Journal Article PL - United Arab Emirates TA - Curr Med Chem JT - Current medicinal chemistry JID - 9440157 OTO - NOTNLM OT - HDL quality OT - HDL subfractions OT - High density lipoprotein OT - apolipoprotein-A OT - atherosclerosis OT - cardiovascular disease OT - dysfunctional HDL OT - epidemiological studies. EDAT- 2018/06/01 06:00 MHDA- 2018/06/01 06:00 CRDT- 2018/06/01 06:00 PHST- 2017/10/02 00:00 [received] PHST- 2017/12/25 00:00 [revised] PHST- 2017/12/27 00:00 [accepted] PHST- 2018/06/01 06:00 [pubmed] PHST- 2018/06/01 06:00 [medline] PHST- 2018/06/01 06:00 [entrez] AID - CMC-EPUB-90786 [pii] AID - 10.2174/0929867325666180530110543 [doi] PST - ppublish SO - Curr Med Chem. 2019;26(9):1644-1664. doi: 10.2174/0929867325666180530110543.