Lipoprotein(a) for Risk Assessment in Patients With Established Coronary Artery Disease

O’Donoghue, Michelle L.; Morrow, David A.; Tsimikas, Sotirios; Sloan, Sarah; Ren, Angela F.; Hoffman, Elaine; Desai, Nihar R.; Solomon, Scott D.; Domanski, Michael J.; Arai, Kiyohito; Chiuve, Stephanie E.; Cannon, Christopher P.; Sacks, Frank M.; Sabatine, Marc S.

doi:10.1016/j.jacc.2013.09.042

Cited by 165 publications

(125 citation statements)

References 46 publications

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“…11 On the other hand, statins, which cause an upregulation of the LDL-receptor markedly decrease levels of LDL-cholesterol but not Lp(a). Even the opposite might be the case as already suggested a long time ago by Kostner et al 12 and very recently by O'Donoghue et al 10 : both studies observed an increase in Lp(a) concentrations after successful lowering of LDL-cholesterol by statins. This is in line with the results of the JUPITER Study in the present issue of Circulation 8 : patients under rosuvastatin treatment showed even a statistically significant positive shift in the overall Lp(a) distribution that was not observed in the placebo group.…”

Section: February 11 2014mentioning

confidence: 80%

“…However, the findings of a similar association of Lp(a) with CVD events independently of the LDL-cholesterol values are in contrast to a very recently published meta-analysis of secondary prevention studies that observed an effect modification by LDL-cholesterol: the association between Lp(a) concentrations and CVD events was only observed in studies in which the average LDL-cholesterol was ≥130 mg/dL at baseline and not in those below this value. 10 A pronounced heterogeneity in the study populations, inclusion criteria, therapeutic regimens, and duration of observation periods might have contributed to the differences in results between the hitherto published studies.…”

Section: Article See P 635mentioning

confidence: 99%

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Lipoprotein(a)

Kronenberg

2014

Circulation

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When the first prospective studies on lipoprotein(a) [Lp(a)] were published in the early 1990s, the career of Lp(a) as a risk factor for cardiovascular disease (CVD) was almost stopped right at its beginning. A few of these prospective studies were negative 1 and resulted in a major discussion whether Lp(a) had its best times already behind it. However, numerous later studies and meta-analysis of the data strengthened the association between high Lp(a) concentrations and CVD.2 Finally, genetic research on Lp(a) became the basis for what revolutionized epidemiological research during the last decade in general. This is based on the observation that Lp(a) concentrations are largely determined by a copy number variation in the LPA gene, which results in an interindividually highly variable and large number of so-called kringle-IV repeats of the apolipoprotein(a) [apo(a)] protein. This polymorphism explains between 30% and 70% of the Lp(a) concentrations, which makes Lp(a) to the lipoprotein with the strongest genetic determination.3 Individuals with a low number of kringle-IV repeats (small isoform carriers) have on average markedly higher Lp(a) concentrations. 4 Because the number of kringle-IV repeats are subject of inheritance, it is already determined at the time of conception whether one inherits apo(a) isoforms associated with high or low Lp(a) concentrations. Consequently, those who inherit small isoforms are exposed life-long to high Lp(a) concentrations and are expected to have a high CVD risk. This was indeed the case when the first studies using this concept were published in the early 1990s. They demonstrated that individuals carrying small isoforms have indeed a high CVD risk.5 Studies using SNPs that tag a subfraction of the small apo(a) isoforms took the same line. 6 This concept using genetic variants that determine an important fraction of the risk factor under suspicion to demonstrate an association with the outcome of interest was later called Mendelian Randomization.7 It was a major step not only for Lp(a) research but for epidemiology in general because usually epidemiological studies can hardly prove causality. However, the Mendelian randomization concept can provide a very strong support of causality. With the help of this concept several risk factors have been reevaluated and some of them changed their status from a risk factor to a risk marker that is not necessarily involved in the causal chain of the disease. For Lp(a) it was even a starting point because all of a sudden it became an interesting object for intervention. Article see p 635In the past it was discussed controversially whether high Lp(a) concentrations are only a risk factor when also other well-known CVD risk factors are present in an individual. In this issue of Circulation, Khera et al 8 investigated whether Lp(a) is a significant determinant of residual CVD risk in the JUPITER trial that recruited individuals without a history of CVD at baseline, with low-density lipoprotein (LDL)-cholesterol <130 mg/dL and a high-sensitiv...

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Section: February 11 2014mentioning

confidence: 80%

Section: Article See P 635mentioning

confidence: 99%

Lipoprotein(a)

Kronenberg

2014

Circulation

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“…The most robust data to date regarding the interaction of Lp(a) and LDL‐C originate from the Women's Health Study (n=27 791 women with 899 incident cardiovascular events) in which a strong interaction between elevated Lp(a) levels (>44 mg/dL) and high LDL‐C levels (>3.1 mmol/L) was observed in women 24. Finally, although a recent observational study has suggested that patients with ACS and high Lp(a) have recurrent cardiovascular events despite low LDL‐C,25 a recent large meta‐analysis of statin trials in secondary prevention suggested that Lp(a) was only predictive of recurrent events in individuals with high LDL‐C >3.4 mmol/L 26. Although these studies have all demonstrated some evidence for interaction between elevated Lp(a) and LDL‐C levels, these analyses have been limited by small sample sizes, the lack of formal interaction tests, the inclusion of only women or the use of surrogate end points (ie, angina or vascular imaging).…”

Section: Discussionmentioning

confidence: 99%

Lipoprotein(a) Interactions With Low‐Density Lipoprotein Cholesterol and Other Cardiovascular Risk Factors in Premature Acute Coronary Syndrome (ACS)

Afshar

Pilote

Dufresne

et al. 2016

JAHA

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BackgroundCurrent recommendations for lipoprotein(a) (Lp[a]) focus on the control of other risk factors, including lowering low‐density lipoprotein cholesterol (LDL‐C), with little evidence to support this approach. Identifying interactions between Lp(a) and other risk factors could identify individuals at increased risk for Lp(a)‐mediated disease.Methods and ResultsWe used a case‐only study design and included 939 participants (median age=49 years, interquartile range 46–53, women=33.1%) from the GENdEr and Sex determInantS of cardiovascular disease: from bench to beyond‐Premature Acute Coronary Syndrome (GENESIS‐PRAXY) study, a multicenter prospective cohort study of premature acute coronary syndrome. There was a higher prevalence of elevated Lp(a) levels (>50 mg/dL; 80th percentile) in PRAXY participants as compared to the general population (31% versus 20%; P<0.001). Lp(a) was strongly associated with LDL‐C (adjusted β 0.17; P<0.001). Individuals with high Lp(a) were more likely to have LDL‐C >2.5 mmol/L, indicating a synergistic interaction (adjusted odds ratio 1.51; 95% CI 1.08–2.09; P=0.015). The interaction with high Lp(a) was stronger at increasing LDL‐C levels (LDL‐C >3.5, adjusted odds ratio 1.87; LDL‐C >4.5, adjusted odds ratio 2.72). In a polytomous logistic model comparing mutually exclusive LDL‐C categories, the interaction with high Lp(a) became attenuated at LDL‐C ≤3.5 mmol/L (odds ratio 1.16; 95% CI 0.80–1.68, P=0.447). Other risk factors were not associated with high Lp(a).ConclusionsIn young acute coronary syndrome patients, high Lp(a) is more prevalent than in the general population and is strongly associated with high LDL‐C, suggesting that Lp(a) confers greater risk for acute coronary syndrome when LDL‐C is elevated. Individuals with high Lp(a) and LDL‐C >3.5 mmol/L may warrant aggressive LDL‐C lowering.

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“…It is evident that common cut points and valid comparisons of Lp(a) levels among laboratories is not feasible at this point in time because of substantial differences in Lp(a) methods and calibrations and differences among both men and women (30)(31)(32)(33). Meta-analysis of long-term prospective studies were performed to assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes.…”

Section: Lp(a) Levels For Defi Nition Of Cvd Riskmentioning

confidence: 99%

Lipoprotein (a) measurements for clinical application

Marcovina

Albers

2016

Journal of Lipid Research

245

200

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This article is available online at http://www.jlr.org a unique hydrophilic, highly glycosylated protein referred to as apo(a), covalently attached to apoB-100 by a single disulfi de bridge, differentiates Lp(a) from LDL ( 1, 2 ). Apo(a) is part of the plasminogen gene superfamily, and its presence imparts distinctive synthetic and catabolic properties to Lp(a) along with a marked size heterogeneity ( 3 ).Treatment of purifi ed Lp(a) with a reducing agent dissociates apo(a) from the particle yielding a lipoprotein particle that is similar to LDL in physical and chemical properties. However, Lp(a) particles have been reported to associate noncovalently with triglyceride-rich lipoproteins in hypertriglyceridemic individuals or after a fatty meal ( 4 ). This association may result in overestimation of Lp(a) measured by ELISA methods based on the apo(a) capture/apoB detection approach.Apo(a), shares a high amino acid sequence homology to several regions of the serine protease zymogen plasminogen, including the protease domain, and the so-called kringle 4 (K4) and 5 domains, which are tri-loop polypeptides stabilized by three internal disulfi de bridges. Apo(a) is thus formed by an inactive carboxy-terminal proteaselike domain and by a kringle 5 domain, both of which exhibit ‫ف‬ 85% homology with plasminogen, and multiple copies of the plasminogen-like K4 domain ( Fig. 1 ). Based on amino acid sequence differences, the K4 domain of apo(a) is divided into 10 similar but distinct K4 types (1 through 10), having 75% to 85% amino acid homology with the K4 of plasminogen ( 5, 6 ). Each of the K4 types, except K4 type 2, is present as a single copy, whereas the identical K4 type 2 repeats vary from a minimum of 3 to as many as 40 ( 3, 7 ). As a consequence, apo(a) has the unique characteristic of being highly polymorphic in size, and the variable numbers of the K4 type 2 domains are primarily responsible for the size heterogeneity of Lp(a). Apo(a) is also heterogeneous in its glycosylation, which occurs both within the core of K4 motifs and within the linker sequences , is the most complex and polymorphic of the lipoprotein particles. Despite more than 50 years of intense research that has elucidated many aspects of Lp(a)'s structure and biochemistry, its physiological and pathological roles are still poorly understood. Lp(a) is composed of a lipoprotein particle quite similar in protein and lipid composition to LDL, containing one molecule of apoB wrapped around a particle that has primarily a core of cholesteryl ester and triglyceride with phospholipids and unesterifi ed cholesterol at its surface. The presence of

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Lipoprotein(a) for Risk Assessment in Patients With Established Coronary Artery Disease

Cited by 165 publications

References 46 publications

Lipoprotein(a)

Lipoprotein(a)

Lipoprotein(a) Interactions With Low‐Density Lipoprotein Cholesterol and Other Cardiovascular Risk Factors in Premature Acute Coronary Syndrome (ACS)

Lipoprotein (a) measurements for clinical application

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