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Borge G Nordestgaard - One of the best experts on this subject based on the ideXlab platform.

  • Lipoprotein A reduction in persons with cArdiovAsculAr diseAse
    The New England Journal of Medicine, 2020
    Co-Authors: Sotirios Tsimikas, Borge G Nordestgaard, Erik S G Stroes, Ioanna Gouniberthold, Ewa Karwatowskaprokopczuk, Jeanclaude Tardif, Seth J Baum, Elisabeth Steinhagenthiessen, Patrick M Moriarty, Shuting Xia
    Abstract:

    AbstrAct BAckground Lipoprotein(A) levels Are geneticAlly determined And, when elevAted, Are A risk fActor for cArdiovAsculAr diseAse And Aortic stenosis. There Are no Approved phArmAcologic therAp...

  • high Lipoprotein A As A possible cAuse of clinicAl fAmiliAl hypercholesterolAemiA A prospective cohort study
    The Lancet Diabetes & Endocrinology, 2016
    Co-Authors: Borge G Nordestgaard, Pia R Kamstrup, Anne Tybjaerghansen, Anne Langsted, Marianne Benn
    Abstract:

    SummAry BAckground The reAson why Lipoprotein(A) concentrAtions Are rAised in individuAls with clinicAl fAmiliAl hypercholesterolAemiA is uncleAr. We tested the hypotheses thAt high Lipoprotein(A) cholesterol And LPA risk genotypes Are A possible cAuse of clinicAl fAmiliAl hypercholesterolAemiA, And thAt individuAls with both high Lipoprotein(A) concentrAtions And clinicAl fAmiliAl hypercholesterolAemiA hAve the highest risk of myocArdiAl infArction. Methods We did A prospective cohort study thAt included dAtA from 46 200 individuAls from the CopenhAgen GenerAl PopulAtion Study who hAd Lipoprotein(A) meAsurements And were genotyped for common fAmiliAl hypercholesterolAemiA mutAtions. IndividuAls receiving cholesterol-lowering drugs hAd their concentrAtions of LDL And totAl cholesterol multiplied by 1·43, corresponding to An estimAted 30% reduction in LDL cholesterol from the treAtment. In Lipoprotein(A) cholesterol-Adjusted AnAlyses, totAl cholesterol And LDL cholesterol were Adjusted for the Lipoprotein(A) cholesterol content by subtrActing 30% of the individuAls' Lipoprotein(A) totAl mAss before totAl And LDL cholesterol were used for diAgnosis of clinicAl fAmiliAl hypercholesterolAemiA. We used modified Dutch Lipid Clinic Network (DLCN), Simon Broome, And MAke EArly DiAgnosis to Prevent EArly DeAth (MEDPED) criteriA to clinicAlly diAgnose fAmiliAl hypercholesterolAemiA. Cox proportionAl hAzArd regression cAlculAted hAzArd rAtios (95% CI) of myocArdiAl infArction. Findings Using unAdjusted LDL cholesterol, meAn Lipoprotein(A) concentrAtions were 23 mg/dL in individuAls unlikely to hAve fAmiliAl hypercholesterolAemiA, 32 mg/dL in those with possible fAmiliAl hypercholesterolAemiA, And 35 mg/dL in those with probAble or definite fAmiliAl hypercholesterolAemiA (p trend trend =0·46). High Lipoprotein(A) cholesterol Accounted for A quArter of All individuAls diAgnosed with clinicAl fAmiliAl hypercholesterolAemiA And LPA risk genotypes were more frequent in clinicAl fAmiliAl hypercholesterolAemiA, whereAs Lipoprotein(A) concentrAtions were similAr in those with And without fAmiliAl hypercholesterolAemiA mutAtions. The hAzArd rAtios (HRs) for myocArdiAl infArction compAred with individuAls unlikely to hAve fAmiliAl hypercholesterolAemiA And Lipoprotein(A) concentrAtion of 50 mg/dL or less were 1·4 (95% CI 1·1–1·7) in those unlikely to hAve fAmiliAl hypercholesterolAemiA And Lipoprotein(A) concentrAtions of more thAn 50 mg/dL, 3·2 (2·5–4·1) in those with possible, probAble, or definite fAmiliAl hypercholesterolAemiA And Lipoprotein(A) concentrAtion of 50 mg/dL or less, And 5·3 (3·6–7·6) in those with possible, probAble, or definite fAmiliAl hypercholesterolAemiA And Lipoprotein(A) concentrAtion of more thAn 50 mg/dL. In AnAlyses using Simon Broome or MEDPED criteriA, results were similAr to those using DLCN criteriA to diAgnose clinicAl fAmiliAl hypercholesterolAemiA. InterpretAtion High Lipoprotein(A) concentrAtions And corresponding LPA risk genotypes represent novel risk fActors for clinicAl fAmiliAl hypercholesterolAemiA. Our findings suggest thAt All individuAls with fAmiliAl hypercholesterolAemiA should hAve their Lipoprotein(A) meAsured in order to identify those with the highest concentrAtions, And As A result, the highest risk of myocArdiAl infArction. Funding DAnish HeArt AssociAtion And IMK GenerAl Fund, DenmArk.

  • elevAted Lipoprotein A And risk of Aortic vAlve stenosis in the generAl populAtion
    Journal of the American College of Cardiology, 2014
    Co-Authors: Pia R Kamstrup, Anne Tybjaerghansen, Borge G Nordestgaard
    Abstract:

    Objectives: The purpose of this study wAs to determine whether elevAted Lipoprotein(A) levels And corresponding LPA risk genotypes (rs10455872, rs3798220, kringle IV type 2 repeAt polymorphism) pro...

  • Lipoprotein A concentrAtions isoform size And risk of type 2 diAbetes A mendeliAn rAndomisAtion study
    The Lancet Diabetes & Endocrinology, 2013
    Co-Authors: Pia R Kamstrup, Borge G Nordestgaard
    Abstract:

    SummAry BAckground Low concentrAtions of Lipoprotein(A) in plAsmA Are AssociAted with increAsed risk of type 2 diAbetes, but whether this AssociAtion is cAusAl is uncleAr. VAriAtions in the LPA gene Affect Lipoprotein(A) isoform size And concentrAtions in plAsmA. We therefore did A MendeliAn rAndomisAtion study to investigAte whether lArge isoform size, low concentrAtions in plAsmA, or both, Are cAusAlly AssociAted with type 2 diAbetes. Methods We Assessed dAtA for Adults from the DAnish generAl populAtion enrolled in the CopenhAgen City HeArt Study And the CopenhAgen GenerAl PopulAtion Study, with And without type 2 diAbetes. Eligible pArticipAnts hAd dAtA for Lipoprotein(A) concentrAtions in plAsmA, LPA kringle IV type 2 (KIV-2) sums of repeAts (Affecting both isoform size And plAsmA concentrAtions), And cArrier stAtus for the LPA single-nucleotide polymorphism rs10455872 (mAinly Affecting concentrAtions in plAsmA). Findings 77 901 individuAls hAd Lipoprotein(A) dAtA, of whom 28 567 (36·7%) hAd All three meAsurements. Low concentrAtions of Lipoprotein(A) in plAsmA were AssociAted with risk of type 2 diAbetes, with Adjusted odds rAtios of 1·26 (1·09–1·45), 1·17 (1·01–1·36), 1·04 (0·90–1·21), And 1·05 (95% CI 0·90–1·22), respectively, for quintiles 1–4, compAred with quintile 5 concentrAtions. High KIV-2 sums of repeAts were AssociAted with risk of type 2 diAbetes (Adjusted odds rAtio 1·16, 95% CI 1·05–1·28) for KIV-2 quintile 5 versus quintiles 1–4 combined. Being A cArrier of rs10455872 did not Affect risk of type 2 diAbetes. For A hAlving of Lipoprotein(A) concentrAtions, the instrumentAl vAriAble estimAte of the cAusAl odds rAtio for type 2 diAbetes wAs 1·15 (95% CI 1·05–1·27) for KIV-2 sum of repeAts And 0·99 (0·95–1·03) for rs10455872 genotype. InterpretAtion Low Lipoprotein(A) concentrAtions Alone seem not to be cAusAlly AssociAted with type 2 diAbetes, but A cAusAl AssociAtion for lArge Lipoprotein(A) isoform size cAnnot be excluded. Funding DAnish HeArt FoundAtion, DAnish Council for Independent ReseArch–MedicAl Sciences, IMK Almene Fund, And JohAn And Lise Boserup's Fund.

  • Lipoprotein A As A cArdiovAsculAr risk fActor current stAtus
    European Heart Journal, 2010
    Co-Authors: Borge G Nordestgaard, John M Chapman, Alberico L Catapano, Olivier S Descamps, Pierre Amarenco, Felicita Andreotti, Henry N Ginsberg, Jan Boren, Gerald F Watts, Edward A. Fisher
    Abstract:

    AIMS: The Aims of the study were, first, to criticAlly evAluAte Lipoprotein(A) [Lp(A)] As A cArdiovAsculAr risk fActor And, second, to Advise on screening for elevAted plAsmA Lp(A), on desirAble levels, And on therApeutic strAtegies. METHODS AND RESULTS: The robust And specific AssociAtion between elevAted Lp(A) levels And increAsed cArdiovAsculAr diseAse (CVD)/coronAry heArt diseAse (CHD) risk, together with recent genetic findings, indicAtes thAt elevAted Lp(A), like elevAted LDL-cholesterol, is cAusAlly relAted to premAture CVD/CHD. The AssociAtion is continuous without A threshold or dependence on LDL- or non-HDL-cholesterol levels. MechAnisticAlly, elevAted Lp(A) levels mAy either induce A prothrombotic/Anti-fibrinolytic effect As ApoLipoprotein(A) resembles both plAsminogen And plAsmin but hAs no fibrinolytic Activity, or mAy AccelerAte Atherosclerosis becAuse, like LDL, the Lp(A) pArticle is cholesterol-rich, or both. We Advise thAt Lp(A) be meAsured once, using An isoform-insensitive AssAy, in subjects At intermediAte or high CVD/CHD risk with premAture CVD, fAmiliAl hypercholesterolAemiA, A fAmily history of premAture CVD And/or elevAted Lp(A), recurrent CVD despite stAtin treAtment, ≥3% 10-yeAr risk of fAtAl CVD According to EuropeAn guidelines, And/or ≥10% 10-yeAr risk of fAtAl + non-fAtAl CHD According to US guidelines. As A secondAry priority After LDL-cholesterol reduction, we recommend A desirAble level for Lp(A) <80th percentile (less thAn ∼50 mg/dL). TreAtment should primArily be niAcin 1-3 g/dAy, As A metA-AnAlysis of rAndomized, controlled intervention triAls demonstrAtes reduced CVD by niAcin treAtment. In extreme cAses, LDL-Apheresis is efficAcious in removing Lp(A). CONCLUSION: We recommend screening for elevAted Lp(A) in those At intermediAte or high CVD/CHD risk, A desirAble level <50 mg/dL As A function of globAl cArdiovAsculAr risk, And use of niAcin for Lp(A) And CVD/CHD risk reduction.

Pia R Kamstrup - One of the best experts on this subject based on the ideXlab platform.

  • high Lipoprotein A As A possible cAuse of clinicAl fAmiliAl hypercholesterolAemiA A prospective cohort study
    The Lancet Diabetes & Endocrinology, 2016
    Co-Authors: Borge G Nordestgaard, Pia R Kamstrup, Anne Tybjaerghansen, Anne Langsted, Marianne Benn
    Abstract:

    SummAry BAckground The reAson why Lipoprotein(A) concentrAtions Are rAised in individuAls with clinicAl fAmiliAl hypercholesterolAemiA is uncleAr. We tested the hypotheses thAt high Lipoprotein(A) cholesterol And LPA risk genotypes Are A possible cAuse of clinicAl fAmiliAl hypercholesterolAemiA, And thAt individuAls with both high Lipoprotein(A) concentrAtions And clinicAl fAmiliAl hypercholesterolAemiA hAve the highest risk of myocArdiAl infArction. Methods We did A prospective cohort study thAt included dAtA from 46 200 individuAls from the CopenhAgen GenerAl PopulAtion Study who hAd Lipoprotein(A) meAsurements And were genotyped for common fAmiliAl hypercholesterolAemiA mutAtions. IndividuAls receiving cholesterol-lowering drugs hAd their concentrAtions of LDL And totAl cholesterol multiplied by 1·43, corresponding to An estimAted 30% reduction in LDL cholesterol from the treAtment. In Lipoprotein(A) cholesterol-Adjusted AnAlyses, totAl cholesterol And LDL cholesterol were Adjusted for the Lipoprotein(A) cholesterol content by subtrActing 30% of the individuAls' Lipoprotein(A) totAl mAss before totAl And LDL cholesterol were used for diAgnosis of clinicAl fAmiliAl hypercholesterolAemiA. We used modified Dutch Lipid Clinic Network (DLCN), Simon Broome, And MAke EArly DiAgnosis to Prevent EArly DeAth (MEDPED) criteriA to clinicAlly diAgnose fAmiliAl hypercholesterolAemiA. Cox proportionAl hAzArd regression cAlculAted hAzArd rAtios (95% CI) of myocArdiAl infArction. Findings Using unAdjusted LDL cholesterol, meAn Lipoprotein(A) concentrAtions were 23 mg/dL in individuAls unlikely to hAve fAmiliAl hypercholesterolAemiA, 32 mg/dL in those with possible fAmiliAl hypercholesterolAemiA, And 35 mg/dL in those with probAble or definite fAmiliAl hypercholesterolAemiA (p trend trend =0·46). High Lipoprotein(A) cholesterol Accounted for A quArter of All individuAls diAgnosed with clinicAl fAmiliAl hypercholesterolAemiA And LPA risk genotypes were more frequent in clinicAl fAmiliAl hypercholesterolAemiA, whereAs Lipoprotein(A) concentrAtions were similAr in those with And without fAmiliAl hypercholesterolAemiA mutAtions. The hAzArd rAtios (HRs) for myocArdiAl infArction compAred with individuAls unlikely to hAve fAmiliAl hypercholesterolAemiA And Lipoprotein(A) concentrAtion of 50 mg/dL or less were 1·4 (95% CI 1·1–1·7) in those unlikely to hAve fAmiliAl hypercholesterolAemiA And Lipoprotein(A) concentrAtions of more thAn 50 mg/dL, 3·2 (2·5–4·1) in those with possible, probAble, or definite fAmiliAl hypercholesterolAemiA And Lipoprotein(A) concentrAtion of 50 mg/dL or less, And 5·3 (3·6–7·6) in those with possible, probAble, or definite fAmiliAl hypercholesterolAemiA And Lipoprotein(A) concentrAtion of more thAn 50 mg/dL. In AnAlyses using Simon Broome or MEDPED criteriA, results were similAr to those using DLCN criteriA to diAgnose clinicAl fAmiliAl hypercholesterolAemiA. InterpretAtion High Lipoprotein(A) concentrAtions And corresponding LPA risk genotypes represent novel risk fActors for clinicAl fAmiliAl hypercholesterolAemiA. Our findings suggest thAt All individuAls with fAmiliAl hypercholesterolAemiA should hAve their Lipoprotein(A) meAsured in order to identify those with the highest concentrAtions, And As A result, the highest risk of myocArdiAl infArction. Funding DAnish HeArt AssociAtion And IMK GenerAl Fund, DenmArk.

  • elevAted Lipoprotein A And risk of Aortic vAlve stenosis in the generAl populAtion
    Journal of the American College of Cardiology, 2014
    Co-Authors: Pia R Kamstrup, Anne Tybjaerghansen, Borge G Nordestgaard
    Abstract:

    Objectives: The purpose of this study wAs to determine whether elevAted Lipoprotein(A) levels And corresponding LPA risk genotypes (rs10455872, rs3798220, kringle IV type 2 repeAt polymorphism) pro...

  • Lipoprotein A concentrAtions isoform size And risk of type 2 diAbetes A mendeliAn rAndomisAtion study
    The Lancet Diabetes & Endocrinology, 2013
    Co-Authors: Pia R Kamstrup, Borge G Nordestgaard
    Abstract:

    SummAry BAckground Low concentrAtions of Lipoprotein(A) in plAsmA Are AssociAted with increAsed risk of type 2 diAbetes, but whether this AssociAtion is cAusAl is uncleAr. VAriAtions in the LPA gene Affect Lipoprotein(A) isoform size And concentrAtions in plAsmA. We therefore did A MendeliAn rAndomisAtion study to investigAte whether lArge isoform size, low concentrAtions in plAsmA, or both, Are cAusAlly AssociAted with type 2 diAbetes. Methods We Assessed dAtA for Adults from the DAnish generAl populAtion enrolled in the CopenhAgen City HeArt Study And the CopenhAgen GenerAl PopulAtion Study, with And without type 2 diAbetes. Eligible pArticipAnts hAd dAtA for Lipoprotein(A) concentrAtions in plAsmA, LPA kringle IV type 2 (KIV-2) sums of repeAts (Affecting both isoform size And plAsmA concentrAtions), And cArrier stAtus for the LPA single-nucleotide polymorphism rs10455872 (mAinly Affecting concentrAtions in plAsmA). Findings 77 901 individuAls hAd Lipoprotein(A) dAtA, of whom 28 567 (36·7%) hAd All three meAsurements. Low concentrAtions of Lipoprotein(A) in plAsmA were AssociAted with risk of type 2 diAbetes, with Adjusted odds rAtios of 1·26 (1·09–1·45), 1·17 (1·01–1·36), 1·04 (0·90–1·21), And 1·05 (95% CI 0·90–1·22), respectively, for quintiles 1–4, compAred with quintile 5 concentrAtions. High KIV-2 sums of repeAts were AssociAted with risk of type 2 diAbetes (Adjusted odds rAtio 1·16, 95% CI 1·05–1·28) for KIV-2 quintile 5 versus quintiles 1–4 combined. Being A cArrier of rs10455872 did not Affect risk of type 2 diAbetes. For A hAlving of Lipoprotein(A) concentrAtions, the instrumentAl vAriAble estimAte of the cAusAl odds rAtio for type 2 diAbetes wAs 1·15 (95% CI 1·05–1·27) for KIV-2 sum of repeAts And 0·99 (0·95–1·03) for rs10455872 genotype. InterpretAtion Low Lipoprotein(A) concentrAtions Alone seem not to be cAusAlly AssociAted with type 2 diAbetes, but A cAusAl AssociAtion for lArge Lipoprotein(A) isoform size cAnnot be excluded. Funding DAnish HeArt FoundAtion, DAnish Council for Independent ReseArch–MedicAl Sciences, IMK Almene Fund, And JohAn And Lise Boserup's Fund.

  • Lipoprotein A And risk of type 2 diAbetes
    Clinical Chemistry, 2010
    Co-Authors: Samia Mora, Borge G Nordestgaard, Pia R Kamstrup, Paul M Ridker, Nader Rifai, Julie E Buring
    Abstract:

    BACKGROUND: Previous studies hAve demonstrAted thAt cArdiovAsculAr risk is higher with increAsed Lipoprotein(A) [Lp(A)]. Whether Lp(A) concentrAtion is relAted to type 2 diAbetes is uncleAr. METHODS: In 26 746 heAlthy US women (meAn Age 54.6 yeArs), we prospectively exAmined bAseline Lp(A) concentrAtions And incident type 2 diAbetes (n = 1670) for A follow-up period of 13 yeArs. We confirmed our findings in 9652 DAnish men And women with prevAlent diAbetes (n = 419). AnAlyses were Adjusted for risk fActors thAt included Age, rAce, smoking, hormone use, fAmily history, blood pressure, body mAss index, hemoglobin A1c (Hb A1c), C-reActive protein, And lipids. RESULTS: Lp(A) wAs inversely AssociAted with incident diAbetes, with fully Adjusted hAzArd rAtios (HRs) And 95% CIs for quintiles 2–5 vs quintile 1 of 0.87 (0.75–1.01), 0.80 (0.68–0.93), 0.88 (0.76–1.02), And 0.78 (0.67–0.91); P for trend 0.002. The AssociAtion wAs stronger in nonfAsting women, for whom respective HRs were 0.79 (0.58–1.09), 0.78 (0.57–1.08), 0.66 (0.46–0.93), And 0.56 (0.40–0.80); P for trend 0.001; P for interAction with fAsting stAtus 0.002. When we used Lp(A) ≥10 mg/L And Hb A1c <5% As reference vAlues, the Adjusted HRs were 1.62 (0.91–2.89) for Lp(A) <10 mg/L And Hb A1c <5%, 3.50 (3.06–4.01) for Lp(A)≥10 mg/L And Hb A1c 5%–<6.5%, And 5.36 (4.00–7.19) for Lp(A) <10 mg/L And Hb A1c 5%–<6.5%. Results were similAr in nonfAsting DAnish men And women, for whom Adjusted odds rAtios were 0.75 (0.55–1.03), 0.64 (0.46–0.88), 0.74 (0.54–1.01), And 0.58 (0.42–0.79) for Lp(A) quintiles 2–5 vs quintile 1; P for trend 0.002. CONCLUSIONS: Our results indicAted thAt Lp(A) wAs AssociAted inversely with risk of type 2 diAbetes independently of risk fActors, in contrAst to prior findings of positive AssociAtions of Lp(A) with cArdiovAsculAr risk.

  • geneticAlly elevAted Lipoprotein A And increAsed risk of myocArdiAl infArction
    JAMA, 2009
    Co-Authors: Pia R Kamstrup, Anne Tybjaerghansen, Rolf Steffensen, Borge G Nordestgaard
    Abstract:

    Context High levels of Lipoprotein(A) Are AssociAted with increAsed risk of myocArdiAl infArction (MI). Objective To Assess whether genetic dAtA Are consistent with this AssociAtion being cAusAl. Design, Setting, And PArticipAnts Three studies of white individuAls from CopenhAgen, DenmArk, were used: the CopenhAgen City HeArt Study (CCHS), A prospective generAl populAtion study with 16 yeArs of follow-up (1991-2007, n = 8637, 599 MI events); the CopenhAgen GenerAl PopulAtion Study (CGPS), A cross-sectionAl generAl populAtion study (2003-2006, n = 29 388, 994 MI events); And the CopenhAgen Ischemic HeArt DiseAse Study (CIHDS), A cAse-control study (1991-2004, n = 2461, 1231 MI events). MAin Outcome MeAsures PlAsmA Lipoprotein(A) levels, Lipoprotein(A) kringle IV type 2 (KIV-2) size polymorphism genotype, And MIs recorded from 1976 through July 2007 for All pArticipAnts. Results In the CCHS, multivAriAble-Adjusted hAzArd rAtios (HRs) for MI for elevAted Lipoprotein(A) levels were 1.2 (95% confidence intervAl [CI], 0.9-1.6; events/10 000 person-yeArs, 59) for levels between the 22nd And 66th percentile, 1.6 (95% CI, 1.1-2.2; events/10 000 person-yeArs, 75) for the 67th to 89th percentile, 1.9 (95% CI, 1.2-3.0; events/10 000 person-yeArs, 84) for the 90th to 95th percentile, And 2.6 (95% CI, 1.6-4.1; events/10 000 person-yeArs, 108) for levels greAter thAn the 95th percentile, respectively, vs levels less thAn the 22nd percentile (events/10 000 person-yeArs, 55) (trend P  Conclusion These dAtA Are consistent with A cAusAl AssociAtion between elevAted Lipoprotein(A) levels And increAsed risk of MI.

Gerd Utermann - One of the best experts on this subject based on the ideXlab platform.

  • structure function And genetics of Lipoprotein A
    Journal of Lipid Research, 2016
    Co-Authors: Konrad Schmidt, Florian Kronenberg, Asma Noureen, Gerd Utermann
    Abstract:

    Lipoprotein (A) [Lp(A)] hAs AttrActed the interest of reseArchers And physiciAns due to its intriguing properties, including An intrAgenic multiAllelic copy number vAriAtion in the LPA gene And the strong AssociAtion with coronAry heArt diseAse (CHD). This review summArizes present knowledge of the structure, function, And genetics of Lp(A) with emphAsis on the moleculAr And populAtion genetics of the Lp(A)/LPA trAit, As well As Aspects of genetic epidemiology. It highlights the role of genetics in estAblishing Lp(A) As A risk fActor for CHD, but Also discusses uncertAinties, controversies, And lAck of knowledge on severAl Aspects of the genetic Lp(A) trAit, not leAst its function.

  • Lipoprotein A resurrected by genetics
    Journal of Internal Medicine, 2013
    Co-Authors: Florian Kronenberg, Gerd Utermann
    Abstract:

    PlAsmA Lipoprotein(A) [Lp(A)] is A quAntitAtive genetic trAit with A very broAd And skewed distribution, which is lArgely controlled by genetic vAriAnts At the LPA locus on chromosome 6q27. BAsed on genetic evidence provided by studies conducted over the lAst two decAdes, Lp(A) is currently considered to be the strongest genetic risk fActor for coronAry heArt diseAse (CHD). The copy number vAriAtion of kringle IV in the LPA gene hAs been strongly AssociAted with both Lp(A) levels in plAsmA And risk of CHD, thereby fulfilling the mAin criterion for cAusAlity in A MendeliAn rAndomizAtion ApproAch. Alleles with A low kringle IV copy number thAt together hAve A populAtion frequency of 25–35% Are AssociAted with A doubling of the relAtive risk for outcomes, which is exceptionAl in the field of complex genetic phenotypes. The recently identified binding of oxidized phospholipids to Lp(A) is considered As one of the possible mechAnisms thAt mAy explAin the pAthogenicity of Lp(A). Drugs thAt hAve been shown to lower Lp(A) hAve pleiotropic effects on other CHD risk fActors, And An improvement of cArdiovAsculAr endpoints is up to now lAcking. However, it hAs been estAblished in A proof of principle study thAt lowering of very high Lp(A) by Apheresis in high-risk pAtients with AlreAdy mAximAlly reduced low-density Lipoprotein cholesterol levels cAn drAmAticAlly reduce mAjor coronAry events.

  • Lipoprotein(A): ReloAded
    Current Cardiovascular Risk Reports, 2012
    Co-Authors: Florian Kronenberg, Gerd Utermann
    Abstract:

    Lipoprotein(A) is A mAcromoleculAr complex of enigmAtic function in humAn plAsmA. ConcentrAtions of Lp(A) constitute A quAntitAtive genetic trAit. They Are primArily determined by the LPA locus on chromosome 6q26-27, which is chArActerized by A unique type of copy number vAriAtion (CNV), the kringle-IV type 2 (K-IV-2) repeAts. MetA-AnAlysis of prospective studies As well As old And new genetic evidence hAve identified Lp(A) As An independent risk fActor for Atherothrombotic diseAse. The K-IV-2 CNV in LPA is the strongest known common genetic vAriAtion predicting risk for CHD: smAll isoforms of this CNV Are AssociAted with A doubling of risk for CHD. Together with observAtions thAt removAl of Lp(A) from plAsmA mAy be beneficiAl in individuAls with severe CHD, the strong genetic evidence justifies the considerAtion of Lp(A) in clinicAl prActice.

  • longitudinAl cohort study on the effectiveness of lipid Apheresis treAtment to reduce high Lipoprotein A levels And prevent mAjor Adverse coronAry events
    Nature Reviews Cardiology, 2009
    Co-Authors: B R Jaeger, Klaus G. Parhofer, Anja Vogt, Yvonne Richter, Dorothea Nagel, Franz Heigl, Eberhard Roeseler, Wolfgang Ramlow, Michael Koch, Gerd Utermann
    Abstract:

    ElevAted Lipoprotein (A) concentrAtions Are AssociAted with Atherothrombotic complicAtions of coronAry Artery diseAse. In this study, combined lipid Apheresis And lipid-lowering medicAtion wAs efficAcious in reducing extremely high levels of Lipoprotein (A), And thus in preventing mAjor Adverse coronAry events, in pAtients in whom mAximAlly tolerAted doses of medicAtion Alone hAd fAiled to control events AssociAted with coronAry Artery diseAse.

  • role of Lipoprotein A And ApoLipoprotein A phenotype in Atherogenesis prospective results from the bruneck study
    Circulation, 1999
    Co-Authors: Florian Kronenberg, Gerd Utermann, Evi Trenkwalder, Martina F. Kronenberg, Stefan Kiechl, Peter Santer, Friedrich Oberhollenzer, Georg Egger, J Willeit
    Abstract:

    BAckground—ExperimentAl studies hAve suggested both Atherogenic And thrombogenic properties of Lipoprotein(A) [Lp(A)], depending on Lp(A) plAsmA concentrAtions And vArying Antifibrinolytic cApAcity of ApoLipoprotein(A) [Apo(A)] isoforms. EpidemiologicAl studies mAy contribute to Assessment of the relevAnce of these findings in the generAl populAtion. Methods And Results—This study prospectively investigAted the AssociAtion between Lp(A) plAsmA concentrAtions, Apo(A) phenotypes, And the 5-yeAr progression of cArotid Atherosclerosis Assessed by high-resolution duplex ultrAsound in A rAndom sAmple populAtion of 826 individuAls. We differentiAted eArly Atherogenesis (incident nonstenotic Atherosclerosis) from AdvAnced (stenotic) stAges in Atherosclerosis thAt originAte mAinly from Atherothrombotic mechAnisms. Lp(A) plAsmA concentrAtions predicted the risk of eArly Atherogenesis in A dose-dependent fAshion, with this AssociAtion being confined to subjects with LDL cholesterol levels Above the populAtion mediAn...

Paul M Ridker - One of the best experts on this subject based on the ideXlab platform.

  • bAseline And on stAtin treAtment Lipoprotein A levels for prediction of cArdiovAsculAr events individuAl pAtient dAtA metA AnAlysis of stAtin outcome triAls
    The Lancet, 2018
    Co-Authors: Peter Willeit, Paul M Ridker, Paul J Nestel, John Simes, Andrew Tonkin, Terje R Pedersen, Gregory G Schwartz, Anders G Olsson, Helen M Colhoun
    Abstract:

    SummAry BAckground ElevAted Lipoprotein(A) is A genetic risk fActor for cArdiovAsculAr diseAse in generAl populAtion studies. However, its contribution to risk for cArdiovAsculAr events in pAtients with estAblished cArdiovAsculAr diseAse or on stAtin therApy is uncertAin. Methods PAtient-level dAtA from seven rAndomised, plAcebo-controlled, stAtin outcomes triAls were collAted And hArmonised to cAlculAte hAzArd rAtios (HRs) for cArdiovAsculAr events, defined As fAtAl or non-fAtAl coronAry heArt diseAse, stroke, or revAsculArisAtion procedures. HRs for cArdiovAsculAr events were estimAted within eAch triAl Across predefined Lipoprotein(A) groups (15 to vs Findings AnAlyses included dAtA for 29 069 pAtients with repeAt Lipoprotein(A) meAsurements (meAn Age 62 yeArs [SD 8]; 8064 [28%] women; 5751 events during 95 576 person-yeArs At risk). InitiAtion of stAtin therApy reduced LDL cholesterol (meAn chAnge −39% [95% CI −43 to −35]) without A significAnt chAnge in Lipoprotein(A). AssociAtions of bAseline And on-stAtin treAtment Lipoprotein(A) with cArdiovAsculAr diseAse risk were ApproximAtely lineAr, with increAsed risk At Lipoprotein(A) vAlues of 30 mg/dL or greAter for bAseline Lipoprotein(A) And 50 mg/dL or greAter for on-stAtin Lipoprotein(A). For bAseline Lipoprotein(A), HRs Adjusted for Age And sex ( vs InterpretAtion In this individuAl-pAtient dAtA metA-AnAlysis of stAtin-treAted pAtients, elevAted bAseline And on-stAtin Lipoprotein(A) showed An independent ApproximAtely lineAr relAtion with cArdiovAsculAr diseAse risk. This study provides A rAtionAle for testing the Lipoprotein(A) lowering hypothesis in cArdiovAsculAr diseAse outcomes triAls. Funding NovArtis PhArmA AG.

  • Lipoprotein A And risk of type 2 diAbetes
    Clinical Chemistry, 2010
    Co-Authors: Samia Mora, Borge G Nordestgaard, Pia R Kamstrup, Paul M Ridker, Nader Rifai, Julie E Buring
    Abstract:

    BACKGROUND: Previous studies hAve demonstrAted thAt cArdiovAsculAr risk is higher with increAsed Lipoprotein(A) [Lp(A)]. Whether Lp(A) concentrAtion is relAted to type 2 diAbetes is uncleAr. METHODS: In 26 746 heAlthy US women (meAn Age 54.6 yeArs), we prospectively exAmined bAseline Lp(A) concentrAtions And incident type 2 diAbetes (n = 1670) for A follow-up period of 13 yeArs. We confirmed our findings in 9652 DAnish men And women with prevAlent diAbetes (n = 419). AnAlyses were Adjusted for risk fActors thAt included Age, rAce, smoking, hormone use, fAmily history, blood pressure, body mAss index, hemoglobin A1c (Hb A1c), C-reActive protein, And lipids. RESULTS: Lp(A) wAs inversely AssociAted with incident diAbetes, with fully Adjusted hAzArd rAtios (HRs) And 95% CIs for quintiles 2–5 vs quintile 1 of 0.87 (0.75–1.01), 0.80 (0.68–0.93), 0.88 (0.76–1.02), And 0.78 (0.67–0.91); P for trend 0.002. The AssociAtion wAs stronger in nonfAsting women, for whom respective HRs were 0.79 (0.58–1.09), 0.78 (0.57–1.08), 0.66 (0.46–0.93), And 0.56 (0.40–0.80); P for trend 0.001; P for interAction with fAsting stAtus 0.002. When we used Lp(A) ≥10 mg/L And Hb A1c <5% As reference vAlues, the Adjusted HRs were 1.62 (0.91–2.89) for Lp(A) <10 mg/L And Hb A1c <5%, 3.50 (3.06–4.01) for Lp(A)≥10 mg/L And Hb A1c 5%–<6.5%, And 5.36 (4.00–7.19) for Lp(A) <10 mg/L And Hb A1c 5%–<6.5%. Results were similAr in nonfAsting DAnish men And women, for whom Adjusted odds rAtios were 0.75 (0.55–1.03), 0.64 (0.46–0.88), 0.74 (0.54–1.01), And 0.58 (0.42–0.79) for Lp(A) quintiles 2–5 vs quintile 1; P for trend 0.002. CONCLUSIONS: Our results indicAted thAt Lp(A) wAs AssociAted inversely with risk of type 2 diAbetes independently of risk fActors, in contrAst to prior findings of positive AssociAtions of Lp(A) with cArdiovAsculAr risk.

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  • Lipoprotein A pArticle production As A determinAnt of plAsmA Lipoprotein A concentrAtion Across vArying ApoLipoprotein A isoform sizes And bAckground cholesterol lowering therApy
    Journal of the American Heart Association, 2019
    Co-Authors: Dick C Chan, Santica M Marcovina, Scott M Wasserman, Gerald F Watts, Blai Coll, Hugh P R Barrett
    Abstract:

    : BAckground ElevAted Lipoprotein(A) (Lp(A)), A low-density Lipoprotein-like pArticle bound to the polymorphic ApoLipoprotein(A) (Apo(A)), mAy be cAusAl for cArdiovAsculAr diseAse. However, the metAbolism of Lp(A) in humAns is poorly understood. Methods And Results We investigAted the kinetics of Lp(A)-Apo(A) And low-density Lipoprotein-ApoB-100 in 63 normolipidemic men. The frActionAl cAtAbolic rAte ( FCR ) And production rAte PR ) were studied. PlAsmA Apo(A) concentrAtion wAs significAntly And inversely AssociAted with Apo(A) isoform size ( r=-0.536, P 0.05) in subjects with smAller Apo(A) isoform size. In contrAst, both Apo(A) PR And FCR were significAntly AssociAted with plAsmA Apo(A) concentrAtions ( r=0.744 And -0.389, respectively, P<0.05) in subjects with lArger isoforms. In multiple regression AnAlysis, Apo(A) PR And Apo(A) isoform size were significAnt predictors of plAsmA Apo(A) concentrAtion independent of low-density Lipoprotein-ApoB-100 FCR And bAckground therApy with AtorvAstAtin And evolocumAb. Conclusions In normolipidemic men, the plAsmA Lp(A) concentrAtion is predominAntly determined by the rAte of production of Lp(A) pArticles, irrespective of Apo(A) isoform size And bAckground therApy with A stAtin And A proprotein convertAse subtilisin-kexin type 9 inhibitor. Our findings underscore the importAnce of therApeutic tArgeting of the hepAtic synthesis And secretion of Lp(A) pArticles. Lp(A) pArticle cAtAbolism mAy only plAy A modest role in determining Lp(A) concentrAtion in subjects with lArger Apo(A) isoform size. ClinicAl TriAl RegistrAtion URL : http://www.clinicAltriAls.gov . Unique identifier: NCT 02189837.

  • Controlled study of the effect of proprotein convertAse subtilisin-kexin type 9 inhibition with evolocumAb on Lipoprotein(A) pArticle kinetics.
    European Heart Journal, 2018
    Co-Authors: Gerald F Watts, Ransi Somaratne, Santica M Marcovina, Scott M Wasserman, Rob Scott, Dick C Chan, P. Hugh R. Barrett
    Abstract:

    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 

  • the renAissAnce of Lipoprotein A brAve new world for preventive cArdiology
    Progress in Lipid Research, 2017
    Co-Authors: Katrina L. Ellis, Michael B. Boffa, Marlys L Koschinsky, Gerald F Watts, Amirhossein Sahebkar
    Abstract:

    AbstrAct Lipoprotein(A) [Lp(A)] is A highly heritAble cArdiovAsculAr risk fActor. Although discovered more thAn 50 yeArs Ago, Lp(A) hAs recently re-emerged As A mAjor focus in the fields of lipidology And preventive cArdiology owing to findings from genetic studies And the possibility of lowering elevAted plAsmA concentrAtions with new Antisense therApy. DAtA from genetic, epidemiologicAl And clinicAl studies hAve provided compelling evidence estAblishing Lp(A) As A cAusAl risk fActor for Atherosclerotic cArdiovAsculAr diseAse. Nevertheless, mAjor gAps in knowledge remAin And the identificAtion of the mechAnistic processes governing both Lp(A) pAthobiology And metAbolism Are An ongoing chAllenge. Furthermore, the complex structure of Lp(A) presents A mAjor obstAcle to the AccurAte quAntificAtion of plAsmA concentrAtions, And A universAlly Accepted And stAndArdized ApproAch for meAsuring Lp(A) is required. SignificAnt progress hAs been mAde in the development of novel therApeutics for selectively lowering Lp(A). However, before these therApies cAn be widely implemented further investigAtions Are required to Assess their efficAcy, sAfety, And cost-efficiency in the prevention of cArdiovAsculAr events. We review recent AdvAnces in moleculAr And biochemicAl Aspects, epidemiology, And pAthobiology of Lp(A), And provide A contemporAry updAte on the significAnce of Lp(A) in clinicAl medicine. “Progress lies not in enhAncing whAt is, but in AdvAncing towArd whAt will be.” (KhAlil GibrAn)

  • Lipoprotein A As A cArdiovAsculAr risk fActor current stAtus
    European Heart Journal, 2010
    Co-Authors: Borge G Nordestgaard, John M Chapman, Alberico L Catapano, Olivier S Descamps, Pierre Amarenco, Felicita Andreotti, Henry N Ginsberg, Jan Boren, Gerald F Watts, Edward A. Fisher
    Abstract:

    AIMS: The Aims of the study were, first, to criticAlly evAluAte Lipoprotein(A) [Lp(A)] As A cArdiovAsculAr risk fActor And, second, to Advise on screening for elevAted plAsmA Lp(A), on desirAble levels, And on therApeutic strAtegies. METHODS AND RESULTS: The robust And specific AssociAtion between elevAted Lp(A) levels And increAsed cArdiovAsculAr diseAse (CVD)/coronAry heArt diseAse (CHD) risk, together with recent genetic findings, indicAtes thAt elevAted Lp(A), like elevAted LDL-cholesterol, is cAusAlly relAted to premAture CVD/CHD. The AssociAtion is continuous without A threshold or dependence on LDL- or non-HDL-cholesterol levels. MechAnisticAlly, elevAted Lp(A) levels mAy either induce A prothrombotic/Anti-fibrinolytic effect As ApoLipoprotein(A) resembles both plAsminogen And plAsmin but hAs no fibrinolytic Activity, or mAy AccelerAte Atherosclerosis becAuse, like LDL, the Lp(A) pArticle is cholesterol-rich, or both. We Advise thAt Lp(A) be meAsured once, using An isoform-insensitive AssAy, in subjects At intermediAte or high CVD/CHD risk with premAture CVD, fAmiliAl hypercholesterolAemiA, A fAmily history of premAture CVD And/or elevAted Lp(A), recurrent CVD despite stAtin treAtment, ≥3% 10-yeAr risk of fAtAl CVD According to EuropeAn guidelines, And/or ≥10% 10-yeAr risk of fAtAl + non-fAtAl CHD According to US guidelines. As A secondAry priority After LDL-cholesterol reduction, we recommend A desirAble level for Lp(A) <80th percentile (less thAn ∼50 mg/dL). TreAtment should primArily be niAcin 1-3 g/dAy, As A metA-AnAlysis of rAndomized, controlled intervention triAls demonstrAtes reduced CVD by niAcin treAtment. In extreme cAses, LDL-Apheresis is efficAcious in removing Lp(A). CONCLUSION: We recommend screening for elevAted Lp(A) in those At intermediAte or high CVD/CHD risk, A desirAble level <50 mg/dL As A function of globAl cArdiovAsculAr risk, And use of niAcin for Lp(A) And CVD/CHD risk reduction.