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1.
Angiology ; 70(9): 819-829, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31185726

RESUMO

The association between lipoprotein (a) (Lp(a)) and 10-year first fatal/nonfatal cardiovascular disease (CVD) risk in apparently healthy men and women was evaluated. The ATTICA prospective study was conducted during 2001-2012 and included n = 1514 men and n = 1528 women (age >18 years) from the greater Athens area, Greece. Follow-up CVD assessment (2011-2012) was achieved in n = 2020 participants (n = 317 cases); baseline Lp(a) was measured in n = 1890 participants. The recommended threshold of 50 mg/dL was used to define abnormal Lp(a) status. Ten-year CVD-event rate was 14% and 24% in participants with Lp(a) <50 and Lp(a) ≥50 mg/dL, respectively. Multivariate analysis revealed that participants with Lp(a) ≥50 mg/dL versus Lp(a) <50 mg/dL had about 2 times higher CVD risk (hazard ratio (HR) = 2.18, 95% confidence interval (CI) 1.11, 4.28). The sex-based analysis revealed that the independent Lp(a) effect was retained only in men (HR = 2.00, 95% CI 1.19, 2.56); in women, significance was lost after adjusting for lipid markers. Sensitivity analyses revealed that Lp(a) increased CVD risk only in case of abnormal high-density lipoprotein cholesterol, apolipoprotein A1, and triglycerides as well as low adherence to Mediterranean diet. Certain patient characteristics may be relevant when considering Lp(a) as a therapeutic or risk-prediction target.


Assuntos
Biomarcadores/metabolismo , Doenças Cardiovasculares/epidemiologia , Lipoproteína(a)/metabolismo , Fatores Sexuais , Adulto , Idoso , Sistema Cardiovascular/fisiopatologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos
3.
Drugs ; 79(7): 751-766, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30989634

RESUMO

AIM: Our aim was to assess the efficacy and safety of mipomersen through a systematic review of the literature and a meta-analysis of the available clinical studies. METHODS: A systematic literature search in SCOPUS, PubMed Medline, ISI Web of Science and Google Scholar databases was conducted up to January 20, 2019, in order to identify clinical trials assessing the effect of mipomersen on lipoproteins, and the safety profile of mipomersen. Effect sizes for lipid changes were expressed as weighted mean differences (WMD) and 95% confidence intervals (CI). For safety analysis, odd ratios (OR) and 95% CI were calculated using the Mantel-Haenszel method. Data were pooled from 13 clinical studies comprising 49 arms, which included 1053 subjects overall, with 729 in the active-treated arm and 324 in the control arm. RESULTS: Meta-analysis of data suggested that mipomersen significantly reduced low-density lipoprotein cholesterol (WMD - 1.52, 95% CI - 1.85 to - 1.19; p < 0.001), total cholesterol (WMD - 1.55, 95% CI - 1.97 to - 1.13; p < 0.001), non-high-density lipoprotein cholesterol (non-HDL-C) (WMD - 1.66, 95% CI - 2.06 to - 1.27; p < 0.001), lipoprotein(a) (WMD - 0.99, 95% CI - 1.37 to - 0.62; p < 0.001), apolipoprotein B (WMD - 1.66, 95% CI - 2.04 to - 1.27; p < 0.001), triglycerides (WMD -0.61, 95% CI - 0.76 to - 0.46, p < 0.001), very-low-density lipoprotein cholesterol (WMD - 0.58, 95% CI - 0.73 to - 0.43; p < 0.001) and apolipoprotein A-I (WMD - 0.25, 95% CI - 0.51 to - 0.001; p = 0.049) without affecting HDL-C levels (WMD 0.11, 95% CI - 0.03 to 0.26; p = 0.124). However, treatment with mipomersen was positively associated with an increased risk of discontinuation of treatment (OR 3.02, 95% CI 1.96-4.65; p < 0.001), injection-site reaction (OR 11.41, 95% CI 7.88-16.52; p < 0.001), hepatic steatosis (OR 4.96, 95% CI 1.99-12.39; p = 0.001), hepatic enzymes elevation (OR 3.61, 95% CI 2.09-6.24; p < 0.001) and flu-like symptoms (OR 2.02, 95% CI 1.45-2.81; p < 0.001). CONCLUSION: Despite favourable effects on the lipid profile, some concerns are reinforced from the safety profile. As a matter of fact, mipomersen therapy is more likely discontinued and associated with increased risk of injection-site reactions, hepatic steatosis, hepatic enzyme elevation, and flu-like symptoms.


Assuntos
Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/farmacologia , Adolescente , Adulto , Idoso , Apolipoproteína A-I/metabolismo , LDL-Colesterol/metabolismo , Fígado Gorduroso/tratamento farmacológico , Feminino , Humanos , Lipídeos , Lipoproteína(a)/metabolismo , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Triglicerídeos/metabolismo
4.
Eur J Clin Invest ; 49(7): e13117, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30937890

RESUMO

BACKGROUND: Minimal lipoprotein(a) [Lp(a)] target values are advocated for high-risk cardiovascular patients. We investigated the prognostic value of Lp(a) in the acute setting of patients with acute coronary syndromes (ACS). MATERIALS AND METHODS: Plasma levels of Lp(a) were collected at time of angiography from 1711 patients hospitalized for ACS in a multicentre Swiss prospective cohort. Associations between elevated Lp(a) ≥30 mg/dL (cut-off corresponding to the 75th percentile of the assay) or Lp(a) tertiles at baseline, and major adverse cardiovascular events (MACE) at 1 year, defined as a composite of cardiac death, myocardial infarction or stroke, were assessed using hazard ratios (HR) and 95% confidence intervals (CI) adjusting for traditional cardiovascular risk factors (age, sex, smoking, diabetes, hypertension, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C] and triglycerides. RESULTS: Lp(a) levels range between 2.5 and 132 mg/dL with a median value of 6 mg/dL and a mean value of 14.2 mg/dL. A total of 276 patients (23.0%) had Lp(a) plasma levels ≥30 mg/dL. Patients with elevated Lp(a) were more likely to be of female gender and to have higher levels of total cholesterol, LDL-C, HDL-C and triglycerides. Higher Lp(a) was associated with failure to reach the LDL-C target <1.8 mmol/L at 1 year (HR 1.71, 95% CI 1.13-2.58, P = 0.01). No association was found between elevated Lp(a) and MACE at 1 year (HR 1.05, 95% CI 0.64-1.73), nor for Lp(a) tertiles (HR 0.82, 95% CI 0.52-1.28, P > 0.20) or standardized continuous variables (0.98, 95% CI 0.82-1.19 for each increase of standard deviation). CONCLUSIONS: Our real-world data suggest high Lp(a) levels at time of angiography are not predictive for cardiovascular outcomes in patients otherwise medically well controlled, but might be useful to identify patients who would not be on LDL-C targets 1 year after ACS.


Assuntos
Síndrome Coronariana Aguda/sangue , Lipoproteína(a)/metabolismo , Biomarcadores/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Morte Súbita Cardíaca/etiologia , Feminino , Humanos , Hiperlipoproteinemia Tipo II , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Prognóstico , Estudos Prospectivos , Acidente Vascular Cerebral/etiologia , Triglicerídeos/metabolismo
5.
Biomolecules ; 9(4)2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934954

RESUMO

We sought to investigate whether levels of matrix metalloproteinases (MMPs) and their inhibitors predict coronary atherosclerotic plaque instability, as assessed by intravascular ultrasound (IVUS) virtual histology during coronary angiography. Blood samples were collected before angiography in 32 subjects (mean age 56 ± 8 years) with stable coronary heart disease (CHD) and elevated lipoprotein(a) (Lp(a), 94 ± 35 mg/dL). Levels of high-sensitivity C-reactive protein (hsCRP), apolipoprotein B100 (apoB100), MMP-7, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2 were determined using commercially available enzyme-linked immunosorbent assay kits. Results. The morphology of a total of sixty coronary lesions was assessed by virtual histology IVUS imaging. Eleven (18%) plaques in nine (28%) patients were classified as plaques with an unstable phenotype or a thin-cap fibroatheroma. Age, low-density lipoprotein cholesterol, apoB100, MMP-7, and MMP-9 levels were positively associated with necrotic core volume. Conversely, there was a negative relationship between MMP-7 and -9 levels and fibrous and fibro-fatty tissue volume. Multivariate regression analysis revealed that MMP-9 is a strong independent predictor of atherosclerotic plaque instability in stable CHD patients. In stable CHD patients with elevated Lp(a), MMP-9 levels are positively associated with the size of the necrotic core of coronary atherosclerotic plaques.


Assuntos
Angiografia Coronária , Doença das Coronárias/enzimologia , Lipoproteína(a)/sangue , Metaloproteinase 9 da Matriz/sangue , Placa Aterosclerótica/enzimologia , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Doença das Coronárias/sangue , Doença das Coronárias/metabolismo , Feminino , Humanos , Lipoproteína(a)/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Placa Aterosclerótica/sangue , Placa Aterosclerótica/metabolismo , Software
6.
Clin Biochem ; 66: 44-48, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30772277

RESUMO

BACKGROUND AND AIMS: Several clinical and genetic factors have been shown to modulate the cardiovascular risk in subjects affected by familial hypercholesterolemia (FH). Genome wide association studies (GWAS) in the general population have identified several single nucleotide polymorphisms (SNPs) significantly associated with the risk of cardiovascular disease (CVD). This include the rs2048327 variant in the SLC22A3 gene. However, the effect of this SNP in FH subjects is unknown. The objectives of this study are to investigate the association between rs2048327 and the prevalence of CVD as well as with the concentration of lipoprotein (a) (Lp (a)), in a cohort of genetically-confirmed heterozygous FH patients. METHODS: An enzyme-linked immunoassay kit was used to assess the Lp (a) concentration, whereas an exome chip genotyping method was used to impute the rs2048327 genotype. RESULTS: The cohort comprised 287 non-carriers (TT), 305 heterozygous carriers (TC) and 76 homozygous carriers of the rs2048327 variant. In a model corrected for traditional cardiovascular risk factors, rs2048327 was significantly associated with Lp (a) level (median value of 12, 16 and 29 mg/dL in TT, TC and CC carriers, respectively, p < .0001). In a model corrected for cardiovascular risk factors and Lp(a) value, carrying the C allele was associated with a 2-fold increased risk of CVD (OR 1.96, 95%CI 1.21-3.19, p = .007). CONCLUSIONS: In this study, we demonstrated that the rs2048327 SNP of the SLC22A3 gene was significantly associated with Lp(a) as well as with CVD events in FH subjects. Further studies are required in order to investigate the mechanisms behind these associations.


Assuntos
Doenças Cardiovasculares/genética , Hiperlipoproteinemia Tipo II/genética , Lipoproteína(a)/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lipoproteína(a)/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco
7.
Pathology ; 51(2): 155-164, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30595508

RESUMO

Lipoprotein(a) [Lp(a)] is an apolipoprotein B (apoB)-containing plasma lipoprotein similar in structure to low-density lipoprotein (LDL). Lp(a) is more complex than LDL due to the presence of apolipoprotein(a) [apo(a)], a large glycoprotein sharing extensive homology with plasminogen, which confers some unique properties onto Lp(a) particles. ApoB and apo(a) are essential for the assembly and catabolism of Lp(a); however, other proteins associated with the particle may modify its metabolism. Lp(a) specifically carries a cargo of oxidised phospholipids (OxPL) bound to apo(a) which stimulates many proinflammatory pathways in cells of the arterial wall, a key property underlying its pathogenicity and association with cardiovascular disease (CVD). While the liver and kidney are the major tissues implicated in Lp(a) clearance, the pathways for Lp(a) uptake appear to be complex and are still under investigation. Biochemical studies have revealed an exceptional array of receptors that associate with Lp(a) either via its apoB, apo(a), or OxPL components. These receptors fall into five main categories, namely 'classical' lipoprotein receptors, toll-like and scavenger receptors, lectins, and plasminogen receptors. The roles of these receptors have largely been dissected by genetic manipulation in cells or mice, although their relative physiological importance for removal of Lp(a) from the circulation remains unclear. The LPA gene encoding apo(a) has an overwhelming effect on Lp(a) levels which precludes any clear associations between potential Lp(a) receptor genes and Lp(a) levels in population studies. Targeted approaches and the selection of unique Lp(a) phenotypes within populations has nevertheless allowed for some associations to be made. Few of the proposed Lp(a) receptors can specifically be manipulated with current drugs and, as such, it is not currently clear whether any of these receptors could provide relevant targets for therapeutic manipulation of Lp(a) levels. This review summarises the current status of knowledge about receptor-mediated pathways for Lp(a) catabolism.


Assuntos
Apolipoproteínas A/metabolismo , Doenças Cardiovasculares/metabolismo , Lipoproteína(a)/metabolismo , Receptores de Lipoproteínas/metabolismo , Receptores Depuradores/metabolismo , Animais , Apolipoproteínas A/genética , Estudo de Associação Genômica Ampla , Humanos , Rim/metabolismo , Lectinas/metabolismo , Lipoproteína(a)/genética , Fígado/metabolismo , Camundongos , Oxirredução , Fosfolipídeos/metabolismo , Plasminogênio/metabolismo , Receptores de Lipoproteínas/genética
8.
Nat Rev Cardiol ; 16(5): 305-318, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30675027

RESUMO

Epidemiological and clinical studies over the past decade have firmly established that elevated plasma concentrations of lipoprotein(a) (Lp(a)) are an important, independent and probably causal risk factor for the development of cardiovascular diseases. Whereas a link between Lp(a) levels and atherosclerotic cardiovascular disease (ASCVD) has been appreciated for decades, the role of Lp(a) in calcific aortic valve disease (CAVD) and aortic stenosis has come into focus only in the past 5 years. ASCVD and CAVD are aetiologically distinct but have several risk factors in common and similar pathological processes at the cellular and molecular levels. Oxidized phospholipids, which modify Lp(a) primarily by covalent binding to its unique apolipoprotein(a) (apo(a)) component, might hold the key to Lp(a) pathogenicity and provide a mechanistic link between ASCVD and CAVD. Oxidized phospholipids colocalize with apo(a)-Lp(a) in arterial and aortic valve lesions and directly participate in the pathogenesis of these disorders by promoting endothelial dysfunction, lipid deposition, inflammation and osteogenic differentiation, leading to calcification. The advent of potent Lp(a)-lowering therapies provides the opportunity to address directly the causality of Lp(a) in ASCVD and CAVD and, more importantly, to provide both a novel approach to reduce the residual risk of ASCVD and a long-sought medical treatment for CAVD.


Assuntos
Estenose da Valva Aórtica , Valva Aórtica/patologia , Calcinose , Doença da Artéria Coronariana , Lipoproteína(a)/metabolismo , Fosfolipídeos/metabolismo , Calcificação Vascular/metabolismo , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/prevenção & controle , Calcinose/metabolismo , Calcinose/prevenção & controle , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/prevenção & controle , Descoberta de Drogas , Humanos , Oxirredução
9.
Eur J Clin Invest ; 49(2): e13053, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30447089

RESUMO

BACKGROUND: Lipoprotein apheresis effectively lowers lipoprotein(a) [Lp(a)] and low-density lipoprotein (LDL) by approximately 60%-70%. The rebound of LDL and Lp(a) particle concentrations following lipoprotein apheresis allows the determination of fractional catabolic rate (FCR) and hence production rate (PR) during non-steady state conditions. We aimed to investigate the kinetics of Lp(a) and LDL apolipoprotein B-100 (apoB) particles in patients with elevated Lp(a) and coronary artery disease undergoing regular apheresis. PATIENTS AND METHODS: A cross-sectional study was carried out in 13 patients with elevated Lp(a) concentration (>500 mg/L) and coronary artery disease. Lp(a) and LDL-apoB metabolic parameters, including FCR and PR were derived by the fit of a compartment model to the Lp(a) and LDL-apoB concentration data following lipoprotein apheresis. RESULTS: The FCR of Lp(a) was significantly lower than that of LDL-apoB (0.39 [0.31, 0.49] vs 0.57 [0.46, 0.71] pools/day, P = 0.03) with no significant differences in the corresponding PR (14.80 [11.34, 19.32] vs 15.73 [11.93, 20.75] mg/kg/day, P = 0.80). No significant associations were observed between the FCR and PR of Lp(a) and LDL-apoB. CONCLUSIONS: In patients with elevated Lp(a), the fractional catabolism of Lp(a) is slower than that of LDL-apoB particles, implying that different metabolic pathways are involved in the catabolism of these lipoproteins. These findings have implications for new therapies for lowering apolipoprotein(a) and apoB to prevent atherosclerotic cardiovascular disease.


Assuntos
Apolipoproteínas B/metabolismo , Remoção de Componentes Sanguíneos , Doença da Artéria Coronariana/terapia , Lipoproteína(a)/metabolismo , Lipoproteínas LDL/metabolismo , Adolescente , Adulto , Idoso , Anticolesterolemiantes/uso terapêutico , Aspirina/uso terapêutico , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/complicações , Estudos Transversais , Ezetimiba/uso terapêutico , Feminino , Óleos de Peixe/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/uso terapêutico , Adulto Jovem
10.
J Clin Lipidol ; 12(6): 1335-1345, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30527801

RESUMO

Lipoprotein(a), or Lp(a), is a major risk factor for atherothrombotic events along with low-density lipoprotein cholesterol and, inversely, high-density lipoprotein cholesterol. Lp(a) also contributes to the progression of calcific aortic stenosis and to the rare occurrence of arterial thrombotic strokes without atherosclerosis in children and younger women. Much has been learned about the inheritance of Lp(a) levels and the relationship between apolipoprotein(a) structure and function. Recent work suggests an intriguing interaction between oxidized phospholipids on Lp(a) and inflammatory interleukin-1 genotypes. New pharmaceutical approaches with antisense and RNA interference technology may achieve up to 90% lowering of Lp(a). This Roundtable includes practical considerations for clinically measuring and responding to Lp(a) levels.


Assuntos
Aterosclerose/metabolismo , Lipoproteína(a)/metabolismo , Aterosclerose/epidemiologia , Humanos , Lipoproteína(a)/química , Fatores de Risco
11.
Kardiologiia ; 58(6): 70-78, 2018 06.
Artigo em Russo | MEDLINE | ID: mdl-30362439

RESUMO

Lipoprotein(a) [Lp(a)] consists of an LDL-like particle in which the apolipoprotein B100 is covalently bound to apolipoprotein(a) by a single disulfide bond. Lp(a) is synthesized in the liver and its plasma concentration varies from 0 to 400 mg/dl. Increased level of Lp(a) is considered to be an independent risk factor of cardiovascular diseases and coronary heart disease. Data about the significance of hyperlipoproteinemia(a) in the development of atherosclerosis of peripheral (lower limbs) and carotid arteries remain controversial. This review is devoted to Lp(a), its relationship with atherosclerosis of different vascular beds, as well as modern possibilities of hyperlipoproteinemia(a) correction.


Assuntos
Aterosclerose/etiologia , Doenças das Artérias Carótidas/etiologia , Lipoproteína(a)/metabolismo , Apolipoproteína B-100/metabolismo , Aterosclerose/metabolismo , Doenças Cardiovasculares , Doenças das Artérias Carótidas/metabolismo , Humanos , Fatores de Risco
12.
Curr Pharm Des ; 24(31): 3634-3637, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30360706

RESUMO

BACKGROUND: A combination therapy with PCSK9-inhibitors (PCSK9-I) and lipoprotein-apheresis (LA) may have synergistic effects on circulating lipid and lipoprotein levels, in particular in Homozygous Familial Hypercholesterolaemic (HoFH) subjects. The relationships between the above mentioned novel therapeutic approaches as highly effective treatment option for Dyslipidemia in Heterozygous Familial Hypercholesterolaemic (HeFH) patients deserve further investigation in larger datasets. OBJECTIVE: This review aims to present the role of lipoprotein apheresis in the management of familial hypercholesterolaemia and discuss the potential advantages and disadvantages of its combination with PCSK9 inhibitors. METHODS: A comprehensive literature search regarding lipoprotein apheresis in patients with familial hypercholesterolaemia and its combination with PCSK9 inhibitors has been performed. RESULTS: LA is also a potent therapeutic player having impact on inflammation and related mediators. A large body of evidence on this is available. On the contrary, only few observations are available on PCSK9-I effects on inflammation. CONCLUSIONS: It is quite clear that further investigation on possible direct and/or indirect pleiotropic effects of PCSK9-I on inflammatory molecules is necessary and to be expected. Evidence on both arguments with regard to HoFH and HeFH, are reported in short.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aterosclerose/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Mediadores da Inflamação/antagonistas & inibidores , Lipoproteína(a)/antagonistas & inibidores , Pró-Proteína Convertase 9/antagonistas & inibidores , Aterosclerose/metabolismo , Humanos , Hiperlipoproteinemia Tipo II/metabolismo , Lipoproteína(a)/metabolismo , Pró-Proteína Convertase 9/metabolismo
13.
Curr Pharm Des ; 24(31): 3665-3671, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30317988

RESUMO

BACKGROUND: Familial hypercholesterolaemia (FH) is a genetically determined lipid disorder, affecting 1 per 200-500 individuals in the general population. It is significantly and independently associated with an increased risk of Cardiovascular Disease (CVD), although it remains still an underrecognized and undertreated disease. Lipoprotein (a) [Lp(a)] is a low-density-lipoprotein (LDL)-like molecule, containing an additional protein, apolipoprotein (a). OBJECTIVE: This review aims to present and discuss available data on the role of Lp(a) in patients with FH, in terms of its potential augmentation of CVD risk. METHODS: A comprehensive search of the literature was performed to identify studies evaluating the CV effects of Lp(a) in patients with FH. RESULTS: Lp(a) has been recognised as an independent risk factor for CVD, mainly coronary artery disease (CAD). Most, but not all, studies show increased Lp(a) concentrations in adults and children with FH. There is also evidence of an independent association between Lp(a) and CVD (mainly CAD) risk in these patients. CONCLUSION: Some therapeutic modalities, such as niacin, oestrogens, tibolone and proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors may effectively reduce Lp(a) concentrations by 25-30%, although their clinical benefit of this effect remains to be established.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Lipoproteína(a)/antagonistas & inibidores , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Humanos , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/metabolismo , Lipoproteína(a)/genética , Lipoproteína(a)/metabolismo , Medição de Risco
14.
J Clin Lipidol ; 12(5): 1313-1323, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30100157

RESUMO

BACKGROUND: Lipoprotein(a) [Lp(a)] is reported as Lp(a) particle mass (mg/dL) or molar concentration of apolipoprotein(a) [apo(a)] (nmol/L), which is considered the gold standard. Values are often converted from one measurement to the other but the validity of this is unknown. OBJECTIVES: To quantify the relationship between Lp(a) molar concentration and Lp(a) mass in the context of various Lp(a) level thresholds and apo(a) isoform size. METHODS: In all samples, Lp(a) levels in molar concentration and apo(a) isoform size were determined at the Northwest Lipid Metabolism and Diabetes Research Laboratories (NLMDRL). Lp(a) mass levels were determined at the University of California, San Diego (UCSD) (1635 samples), by 5 commercially available assays: Denka 1 and Denka 2 (each 80 samples), 2 turbidimetric assays (2545 and 2673 samples, respectively), and an enzyme-linked immunosorbent assay (2605 samples). The ratios between Lp(a) molar concentration and mass (eg, nmol/L/mg/dL) were calculated and related to apo(a) isoform size. RESULTS: The mean (SD) ratios for NLMDRL/UCSD, NLMDRL/Denka1, and NLMDRL/Denka2 were 2.42 (1.25), 1.64 (0.18), and 2.02 (0.22), respectively. The ratios for NLMDRL/UCSD, NLMDRL/Denka1, and NLMDRL/Denka2 increased by Lp(a) cutoffs, with ratios of 1.82, 1.52, and 1.87, respectively, for Lp(a) < 75 nmol/L and 2.80, 1.89, and 2.24, respectively, for Lp(a) > 125 nmol/L. For the commercial turbidimetric assays and enzyme-linked immunosorbent assay, the ratios ranged from <1 to >5. CONCLUSIONS: Lp(a) molar/mass ratios are threshold, method, and isoform dependent. A single conversion factor between assays is not appropriate. These data support the transition of Lp(a) mass assays to molar concentration to improve diagnostic and clinical interpretation of Lp(a)-mediated risk.


Assuntos
Apoproteína(a)/química , Lipoproteína(a)/química , Lipoproteína(a)/metabolismo , Apoproteína(a)/metabolismo , Humanos , Lipoproteína(a)/genética , Peso Molecular , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo
15.
Transfus Apher Sci ; 57(5): 661-664, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30087087

RESUMO

BACKGROUND: Lipoprotein apheresis (LA) is the elective therapy for homozygous and other forms of Familial Hypercholesterolemia, Familial Combined Hypercholesterolemia, resistant/intolerant to lipid lowering drugs, and hyper-lipoproteinemia(a). Lipoprotein(a) [Lp(a)] has been classified as the most prevalent genetic risk factor for coronary artery disease and aortic valve stenosis. AIM: Our multicenter retrospective study has the aim to analyze the incidence of adverse cardiovascular events (ACVE) before and during the LA treatment, in subjects with elevated level of Lp(a) (>60 mg/dL) [hyper-Lp(a)] and chronic ischemic heart disease. METHODS: We collected data of 23 patients (mean age 63 ± 9 years, male 77%; from hospital of Pisa 11/23, Pistoia 7/23, Verona 2/23, Padova 2/23 and Ferrara 1/23), with hyper-Lp(a), pre-apheresis LDL-cholesterol <100 mg/dL, cardiovascular disease, on maximally tolerated lipid lowering therapy and LA treatment (median 7 years, interquartile range 3-9 years). The LA treatment was performed by heparin-induced LDL precipitation apheresis (16/23), dextran-sulphate (4/23), cascade filtration (2/23) and immunoadsorption (1/23). The time lapse between first cardiovascular event and beginning of apheresis was 6 years (interquartile range 1-12 years). RESULTS: The recorded ACVE, before and after the LA treatment inception, were 40 and 10 respectively (p < 0.05), notably, the AVCE rates/year were 0.43 and 0.11 respectively (p < 0.05) with a 74% reduction of event occurrence. CONCLUSIONS: Our data confirm long-term efficacy and positive impact of LA on morbidity in patients with hyper-Lp(a) and chronic ischemic heart disease on maximally tolerated lipid lowering therapy.


Assuntos
Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Lipoproteína(a)/metabolismo , Idoso , Humanos , Incidência , Pessoa de Meia-Idade , Projetos Piloto , Estudos Retrospectivos
16.
Diabetes Obes Metab ; 20(7): 1632-1641, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29493859

RESUMO

AIMS: This analysis assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in patients with or without metabolic syndrome (MetS) using pooled data from 10 phase 3 ODYSSEY trials. MATERIALS AND METHODS: Data from 4983 randomized patients (1940 with MetS; 1642 with diabetes excluded) were assessed in subgroups by MetS status. Efficacy data were analysed in 4 pools per study design: 2 placebo-controlled pools (1 using alirocumab 150 mg every 2 weeks [Q2W], 1 using 75/150 mg Q2W) with background statin, and 2 ezetimibe-controlled pools (both alirocumab 75/150 mg Q2W), 1 with and 1 without background statin. Alirocumab 75/150 mg indicates possible dose increase from 75 to 150 mg at Week 12 based on Week 8 LDL-C. RESULTS: LDL-C percentage reduction from baseline at Week 24 with alirocumab was 63.9% (MetS) and 56.8% (non-MetS) in the pool of alirocumab 150 mg Q2W, and 42.2% to 52.2% (MetS) and 45.0% to 52.6% (non-MetS) in 3 pools using 75/150 mg Q2W. Levels of other lipid and lipoprotein parameters were also improved with alirocumab treatment, including apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a) and HDL-C. Overall, the percentage change at Week 24 in LDL-C and other lipids and lipoproteins did not vary by MetS status. Adverse event rates were generally similar between treatment groups, regardless of MetS status; injection-site reactions occurred more frequently in alirocumab vs control groups. CONCLUSIONS: Across study pools, alirocumab-associated reductions in LDL-C, apolipoprotein B, and non-HDL-C were significant vs control, and did not vary by MetS status.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Apolipoproteínas B/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Dislipidemias/tratamento farmacológico , Lipoproteína(a)/metabolismo , Síndrome Metabólica/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Quimioterapia Combinada , Dislipidemias/metabolismo , Ezetimiba/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Curr Opin Lipidol ; 29(3): 259-267, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29528858

RESUMO

PURPOSE OF REVIEW: Evidence continues to mount for an important role for elevated plasma concentrations of lipoprotein(a) [Lp(a)] in mediating risk of atherothrombotic and calcific aortic valve diseases. However, there continues to be great uncertainty regarding some basic aspects of Lp(a) biology including its biosynthesis and catabolism, its mechanisms of action in health and disease, and the significance of its isoform size heterogeneity. Moreover, the precise utility of Lp(a) in the clinic remains undefined. RECENT FINDINGS: The contribution of elevated Lp(a) to cardiovascular risk continues to be more precisely defined by larger studies. In particular, the emerging role of Lp(a) as a potent risk factor for calcific aortic valve disease has received much scrutiny. Mechanistic studies have identified commonalities underlying the impact of Lp(a) on atherosclerosis and aortic valve disease, most notably related to Lp(a)-associated oxidized phospholipids. The mechanisms governing Lp(a) concentrations remain a source of considerable dispute. SUMMARY: This article highlights some key remaining challenges in understanding Lp(a) actions and clinical significance. Most important in this regard is demonstration of a beneficial effect of lowering Lp(a), a development that is on the horizon as effective Lp(a)-lowering therapies are being tested in the clinic.


Assuntos
Estenose da Valva Aórtica/metabolismo , Valva Aórtica/patologia , Aterosclerose/metabolismo , Calcinose/metabolismo , Lipoproteína(a)/metabolismo , Trombose/metabolismo , Animais , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Aterosclerose/patologia , Calcinose/patologia , Humanos , Fatores de Risco , Trombose/patologia
18.
J Clin Lipidol ; 12(3): 597-603.e1, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29550494

RESUMO

BACKGROUND: Elevated lipoprotein(a) (Lp(a)) levels are associated with increased risk for atherosclerotic cardiovascular disease (ASCVD). Individuals with a family history of premature ASCVD are at increased cardiovascular risk with concomitantly a higher burden of (subclinical) atherosclerosis. However, whether Lp(a) contributes to the increased atherosclerotic burden in these individuals remains to be established. OBJECTIVE: In this study, we evaluated the association between Lp(a) levels and coronary atherosclerotic burden, assessed by coronary arterty calcium (CAC) scores, in asymptomatic individuals with a family history of premature ASCVD. METHODS: Lp(a) levels and other ASCVD risk factors were assessed in 432 individuals with premature ASCVD and in 937 healthy asymptomatic family members. CAC scores were only measured in asymptomatic family members. RESULTS: In this cohort, 16% had elevated Lp(a) levels, defined as ≥ 50 mg/dL. Among healthy family members, elevated Lp(a) levels were associated with both absolute CAC scores of ≥ 100 (odds ratio [OR] 1.79 [95% confidence interval {CI} 1.13-2.83]) as well as with age- and gender-corrected CAC scores ≥ 80th percentile (OR 1.69 [95% CI 1.14-2.50]). This coincides with a higher prevalence of cardiovascular events (OR 1.48 [95% CI 1.11-2.01]) in the whole cohort. CONCLUSION: Elevated Lp(a) levels were associated with higher CAC scores, both absolute as well as age- and gender-corrected percentiles, in individuals with a family history of premature ASCVD. These data imply that Lp(a) accelerates progression of atherosclerosis in these individuals, thereby contributing to their increased ASCVD risk.


Assuntos
Doenças Assintomáticas , Aterosclerose/metabolismo , Cálcio/metabolismo , Vasos Coronários/metabolismo , Lipoproteína(a)/metabolismo , Linhagem , Adulto , Aterosclerose/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
19.
Eur Heart J ; 39(27): 2577-2585, 2018 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-29566128

RESUMO

Aims: Lipoprotein(a) [Lp(a)], a low-density lipoprotein (LDL) particle covalently bound to apolipoprotein(a) [apo(a)], is a potentially potent heritable risk factor for cardiovascular disease. We investigated the mechanism whereby evolocumab, a monoclonal antibody against proprotein convertase subtilisin-kexin type 9 (PCSK9), lowers Lp(a). Methods and results: We studied the kinetics of Lp(a) particles in 63 healthy men, with plasma apo(a) concentration >5 nmol/L, participating in an 8-week factorial trial of the effects of evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on lipoprotein metabolism. Lipoprotein(a)-apo(a) kinetics were studied using intravenous D3-leucine administration, mass spectrometry, and compartmental modelling; Lp(a)-apoB kinetics were also determined in 16 subjects randomly selected from the treatment groups. Evolocumab, but not atorvastatin, significantly decreased the plasma pool size of Lp(a)-apo(a) (-36%, P < 0.001 for main effect). As monotherapy, evolocumab significantly decreased the production of Lp(a)-apo(a) (-36%, P < 0.001). In contrast, in combination with atorvastatin, evolocumab significantly increased the fractional catabolism of Lp(a)-apo(a) (+59%, P < 0.001), but had no effect on the production of Lp(a)-apo(a). There was a highly significant association between the changes in the fractional catabolism of Lp(a)-apo(a) and Lp(a)-apoB in the substudy of 16 subjects (r = 0.966, P < 0.001). Conclusions: Evolocumab monotherapy lowered the plasma Lp(a) pool size by decreasing the production of Lp(a) particles. In combination with atorvastatin, evolocumab lowered the plasma Lp(a) pool size by accelerating the catabolism of Lp(a) particles. This dual mechanism may relate to an effect of PCSK9 inhibition on Lp(a)-apo(a) production and to marked up-regulation of LDL receptor activity on Lp(a) holoparticle clearance. Clinical Trial Registration Information: NCT02189837.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticolesterolemiantes/farmacologia , Atorvastatina/farmacologia , Lipoproteína(a)/efeitos dos fármacos , Lipoproteína(a)/metabolismo , Pró-Proteína Convertase 9/antagonistas & inibidores , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Humanos , Cinética , Lipoproteína(a)/sangue , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Eur J Clin Invest ; 48(3)2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29327345

RESUMO

BACKGROUND: Different cut-off values of serum lipoprotein (a) [Lp (a)] were recently identified to better stratify cardiovascular risk categories. Both pathophysiological and prognostic values of Lp (a) remain unclear. MATERIALS AND METHODS: Here, the prognostic value of Lp (a) and its correlation with intraplaque features were assessed in patients with severe carotid artery stenosis undergoing endarterectomy (n = 180). The cut-off value of 10 mg/dL for serum Lp (a) was selected to predict 24-month follow-up acute coronary syndrome (ACS). In addition, the association between serum Lp (a) and intraplaque lipids, collagen, inflammatory and vascular cells was assessed. Serum Lp (a) levels were measured by nephelometric assay. RESULTS: Patients with high Lp (a) had similar comorbidities, medications and laboratory parameters as compared to low Lp (a) levels. At 24-month follow-up, patients with high Lp (a) had more ACS as compared to low levels. Histological parameters within plaques were comparable in the study groups. No significant correlation between Lp (a) serum levels and intraplaque parameters was found, except for a weak positive association with smooth muscle cells in upstream plaque portions. When adjusted for gender, the presence of dyslipidaemia and chronic coronary artery disease, Lp (a) ≥10 mg/dL remained predictive for ACS. CONCLUSIONS: Lp (a) determination could be a useful tool to predict ACS in patients with severe carotid stenosis.


Assuntos
Síndrome Coronariana Aguda/diagnóstico , Estenose das Carótidas/complicações , Lipoproteína(a)/metabolismo , Síndrome Coronariana Aguda/sangue , Assistência ao Convalescente , Idoso , Biomarcadores/metabolismo , Estenose das Carótidas/sangue , Feminino , Humanos , Masculino , Projetos Piloto , Placa Aterosclerótica/sangue , Placa Aterosclerótica/diagnóstico
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