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Lipoprotein(a) and cardiovascular disease: Make use of the knowledge we have

      Keywords

      There is strong evidence that Lp(a) is a causal risk factor for cardiovascular disease [
      • Kronenberg F.
      • Mora S.
      • Stroes E.S.G.
      • et al.
      Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement.
      ]. This includes outcomes such as coronary artery disease, aortic valve stenosis, ischemic stroke, peripheral arterial disease, cardiovascular mortality and heart failure as recently reviewed by Arsenault and Kamstrup [
      • Arsenault B.J.
      • Kamstrup P.R.
      Lipoprotein(a) and cardiovascular and valvular diseases: a genetic epidemiological perspective.
      ]. The most recent European Atherosclerosis Society Lp(a) Consensus Statement provides data from the UK Biobank which clearly demonstrates that there is a continuous relationship between increasing Lp(a) concentrations and increasing risk for these outcomes [
      • Kronenberg F.
      • Mora S.
      • Stroes E.S.G.
      • et al.
      Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement.
      ].
      The literature is less consistent when it comes to the questions whether Lp(a) is also a risk factor for cardiovascular outcomes when LDL-cholesterol (LDL-C) or high-sensitivity C-reactive protein (hs-CRP) concentrations are low. In the current issue of Atherosclerosis, two publications add new evidence [
      • Yuan D.
      • Wang P.
      • Jia S.D.
      • et al.
      Lipoprotein(a), High-Sensitivity C-Reactive Protein, and Cardiovascular Risk in Patients Undergoing Percutaneous Coronary Intervention.
      ,
      • Rikhi R.
      • Hammoud A.
      • Ashburn N.
      • et al.
      Relationship of Low-Density Lipoprotein-Cholesterol and Lipoprotein(a) to Cardiovascular Risk: the Multi-Ethnic Study of Atherosclerosis (MESA).
      ].
      The first study by Rikhi et al. investigated whether elevated plasma Lp(a) concentrations were associated with increased coronary heart disease risk when LDL-C was 100 mg/dL or lower. The data are based on 4585 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of atherosclerotic cardiovascular disease and not on statin treatment at the baseline investigation. During the mean follow-up of 13.4 years a total of 315 coronary heart disease events occurred. The authors considered patients with LDL-C ≤100 mg/dL and Lp(a) < 50 mg/dL as reference group. Study participants with low LDL-C (≤100 mg/dL), but at the same time high Lp(a) ≥50 mg/dL, had an 1.83-fold increased risk for coronary heart disease, which was very similar compared to an 1.61-fold increased risk for the group with increased LDL-C (>100 mg/dL) and Lp(a) ≥50 mg/dL. In other words: when Lp(a) was elevated, risk for coronary heart disease events increased, regardless of baseline LDL-C [
      • Rikhi R.
      • Hammoud A.
      • Ashburn N.
      • et al.
      Relationship of Low-Density Lipoprotein-Cholesterol and Lipoprotein(a) to Cardiovascular Risk: the Multi-Ethnic Study of Atherosclerosis (MESA).
      ].
      These data are in contrast to the Women's Health study in which Lp(a) was no longer a risk factor when LDL-C was below 121.4 mg/dL [
      • Suk D.J.
      • Rifai N.
      • Buring J.E.
      • et al.
      Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women.
      ]. It is even more in contrast to the study by Verbeek and colleagues [
      • Verbeek R.
      • Hoogeveen R.M.
      • Langsted A.
      • et al.
      Cardiovascular disease risk associated with elevated lipoprotein(a) attenuates at low low-density lipoprotein cholesterol levels in a primary prevention setting.
      ] which found that in individuals with LDL-C below 100 mg/dL and an elevation of Lp(a) above the 80th percentile, Lp(a) was not associated with a significant increase in cardiovascular disease compared to individuals with an Lp(a) below the 80th percentile. They received similar results when they applied an Lp(a) threshold of 50 mg/dL. It is unclear whether this negative finding in that study for those patients with low LDL-C and high Lp(a) can be explained by the small number of individuals in the LDL-C <100 mg/dL and/or the fact that the LDL-C concentration was possibly (over-)corrected for Lp(a)-cholesterol by subtracting 30% of the Lp(a) mass from the LDL-C concentrations [
      • Verbeek R.
      • Hoogeveen R.M.
      • Langsted A.
      • et al.
      Cardiovascular disease risk associated with elevated lipoprotein(a) attenuates at low low-density lipoprotein cholesterol levels in a primary prevention setting.
      ]. This type of LDL-C correction is no longer recommended [
      • Kronenberg F.
      • Mora S.
      • Stroes E.S.G.
      • et al.
      Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement.
      ].
      On the other hand, the data by Rikhi et al. are in agreement with several other studies. In the JUPITER Trial, a primary prevention trial, the association between baseline Lp(a) and incident primary endpoints was very similar in individuals with LDL-C above and below the median of 110 mg/dL [
      • Khera A.V.
      • Everett B.M.
      • Caulfield M.P.
      • et al.
      Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin).
      ]. Also, Lp(a) remained significantly associated with incident CVD among JUPITER participants treated with an high-intensity statin achieving a median LDL-C of 54 mg/dL. This was even independent of LDL-C, hs-CRP, triglycerides, and other risk factors [
      • Khera A.V.
      • Everett B.M.
      • Caulfield M.P.
      • et al.
      Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin).
      ]. In the setting of secondary prevention there is also strong evidence that Lp(a) is predictive for risk at low LDL-C concentrations: in the Copenhagen General Population Study 2527 individuals with a history of CVD were followed for a median of 5 years for incident major adverse cardiovascular events. The adjusted incidence rate ratio was 1.65 (95%CI 1.31–2.06) when individuals with Lp(a) ≥50 mg/dL were compared against those with Lp(a) < 10 mg/dL. Very similar increased incidence rate ratios were observed when the analysis was restricted to Lp(a)-corrected LDL-C concentrations below 70 mg/dL or below 100 mg/dL [
      • Madsen C.M.
      • Kamstrup P.R.
      • Langsted A.
      • et al.
      Lp(a) (Lipoprotein[a])-Lowering by 50 mg/dL (105 nmol/L) may Be needed to reduce cardiovascular disease 20% in secondary prevention: a population-based study.
      ]. Patients in the AIM-HIGH trial had an almost 90% higher risk for major adverse cardiovascular events when baseline Lp(a) was above the 75th percentile (125 nmol/L) compared to those with low Lp(a) but in both groups having reached similar LDL-C concentrations of about 65 mg/dL [
      • Albers J.J.
      • Slee A.
      • O'Brien K.D.
      • et al.
      Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (atherothrombosis intervention in metabolic syndrome with low HDL/high triglyceride and impact on global Health outcomes).
      ]. In support, in secondary prevention patients with markedly elevated Lp(a) concentrations (median 203 nmol/L), potent LDL-C lowering using PCSK9-antibodies achieving LDL-C levels of 60 mg/dl did not result in a reduction of arterial wall inflammation which was likely attributable to the persistently elevated Lp(a) levels. In line, the Lp(a)-induced pro-inflammatory state of circulating monocytes in patients with elevated Lp(a) could also not be reversed following potent LDL-C lowering, reinforcing the concept that even potent LDL-C reduction is unable to reverse the pro-inflammatory impact of Lp(a) elevation [
      • Stiekema L.C.A.
      • Stroes E.S.G.
      • Verweij S.L.
      • et al.
      Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment.
      ]. However, a pronounced reduction of Lp(a) by anti-sense oligonucleotide therapy resulted in a reduction of arterial wall inflammation [
      • Stiekema L.C.A.
      • Prange K.H.M.
      • Hoogeveen R.M.
      • et al.
      Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a).
      ]. All the studies from primary and secondary prevention together including the new study from MESA with quite healthy participants at baseline [
      • Rikhi R.
      • Hammoud A.
      • Ashburn N.
      • et al.
      Relationship of Low-Density Lipoprotein-Cholesterol and Lipoprotein(a) to Cardiovascular Risk: the Multi-Ethnic Study of Atherosclerosis (MESA).
      ] suggest that Lp(a) is even a risk factor for cardiovascular disease independently of LDL-C concentrations and also in the stratum of patients with low LDL-C concentrations.
      The second study by Yuan et al. aimed to prospectively investigate the independent and combined association of Lp(a) and hs-CRP with adverse cardiac and cerebrovascular events (MACCE) in patients with coronary artery disease undergoing percutaneous coronary intervention [
      • Yuan D.
      • Wang P.
      • Jia S.D.
      • et al.
      Lipoprotein(a), High-Sensitivity C-Reactive Protein, and Cardiovascular Risk in Patients Undergoing Percutaneous Coronary Intervention.
      ]. During 5 years of follow-up, 2140 of the 10424 patients experienced a MACCE. Elevated Lp(a) and hs-CRP levels were both associated with increased risks of MACCE (p < 0.05). In patients with hs-CRP ≥2mg/L, a significantly and 20% higher risk of MACCE was observed in case of Lp(a) concentrations ≥30mg/dL compared to those with Lp(a) < 15 mg/dL. This association was with 12% less pronounced when hs-CRP was <2mg/L just missing statistical significance. When Lp(a) and hs-CRP were combined for risk stratification, patients with dual elevation of these two biomarkers had with 22% a significantly higher risk of MACCE compared to those with Lp(a) < 15mg/dL and hs-CRP <2mg/L. These data are in line with a post-hoc analysis of participants from the secondary prevention ACCELERATE trial, which observed that elevated Lp(a) was only associated with major adverse cardiovascular events when hs-CRP was ≥2 mg/L [
      • Puri R.
      • Nissen S.E.
      • Arsenault B.J.
      • et al.
      Effect of C-reactive protein on lipoprotein(a)-associated cardiovascular risk in optimally treated patients with high-risk vascular disease: a prespecified secondary analysis of the ACCELERATE trial.
      ]. Very similar data have been reported in the primary care setting in the MESA study [
      • Zhang W.
      • Speiser J.L.
      • Ye F.
      • et al.
      High-sensitivity C-reactive protein modifies the cardiovascular risk of lipoprotein(a): multi-ethnic study of atherosclerosis.
      ].
      There is a major difference between Lp(a) and hs-CRP. For Lp(a) we know for sure from Mendelian randomization studies that Lp(a) is a causal risk factor for cardiovascular disease: genetic variants which are associated with lifelong exposure to high Lp(a) concentrations are at the same time associated with an increased risk for cardiovascular disease [
      • Kronenberg F.
      • Mora S.
      • Stroes E.S.G.
      • et al.
      Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement.
      ,
      • Kronenberg F.
      • Mora S.
      • Stroes E.S.G.
      Consensus and guidelines on lipoprotein(a) - seeing the forest through the trees.
      ]. This is different for hs-CRP which can be considered as risk marker rather than a causal risk factor as discussed some time ago [
      • Kronenberg F.
      High-density lipoprotein cholesterol on a roller coaster: where will the ride end?.
      ]: genetic variants which are associated with lifelong elevated hs-CRP concentrations do not show any association with cardiovascular outcomes [
      • Zacho J.
      • Tybjaerg-Hansen A.
      • Jensen J.S.
      • et al.
      Genetically elevated C-reactive protein and ischemic vascular disease.
      ,
      • Wensley F.
      • Gao P.
      • Burgess S.
      • et al.
      Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data.
      ]. This is interpreted in the sense that an elevation of hs-CRP in case of patients with cardiovascular disease is rather a consequence of cardiovascular disease and a “read-out" of its related inflammatory processes than a cause (Fig. 1). Lp(a) as a carrier of oxidized phospholipids has been shown to stimulate monocytes resulting in an increased transendothelial migration followed by arterial wall inflammation, cytokine release and systemic inflammation [
      • Stiekema L.C.A.
      • Stroes E.S.G.
      • Verweij S.L.
      • et al.
      Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment.
      ,
      • Stiekema L.C.A.
      • Prange K.H.M.
      • Hoogeveen R.M.
      • et al.
      Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a).
      ,
      • Dzobo K.E.
      • Kraaijenhof J.M.
      • Stroes E.S.G.
      • et al.
      Lipoprotein(a): an underestimated inflammatory mastermind.
      ]. In the study by Yuan and colleagues [
      • Yuan D.
      • Wang P.
      • Jia S.D.
      • et al.
      Lipoprotein(a), High-Sensitivity C-Reactive Protein, and Cardiovascular Risk in Patients Undergoing Percutaneous Coronary Intervention.
      ], as well as the ACCELERATE [
      • Puri R.
      • Nissen S.E.
      • Arsenault B.J.
      • et al.
      Effect of C-reactive protein on lipoprotein(a)-associated cardiovascular risk in optimally treated patients with high-risk vascular disease: a prespecified secondary analysis of the ACCELERATE trial.
      ] and MESA study [
      • Zhang W.
      • Speiser J.L.
      • Ye F.
      • et al.
      High-sensitivity C-reactive protein modifies the cardiovascular risk of lipoprotein(a): multi-ethnic study of atherosclerosis.
      ], the less pronounced or non-existent association of high Lp(a) concentrations with MACCE in case of hs-CRP below 2 mg/L could be a sign of a less advanced or a less long-lasting cardiovascular disease with less inflammation of the arterial wall.
      Fig. 1
      Fig. 1Schematic illustration of the causal and independent contribution of LDL cholesterol and lipoprotein(a) [Lp(a)] concentrations as well as inflammation as causal contributors to the development of cardiovascular disease.
      Lp(a) carries oxidized phospholipids (oxPL) and contributes to the inflammation of the arterial wall. C-reactive protein as a consequence of inflammation is considered to be only a non-causally related predictor of cardiovascular disease.
      In population studies, the clinical impact of inflammation on Lp(a) concentrations is small. For example, among 34,829 individuals in the Copenhagen City Heart Study/Copenhagen General Population Study [
      • Langsted A.
      • Kamstrup P.R.
      • Nordestgaard B.G.
      Lipoprotein(a): fasting and nonfasting levels, inflammation, and cardiovascular risk.
      ], Lpa concentration was only slightly higher with higher CRP concentrations (3 mg/dL difference in Lp(a) concentration compared to individuals with CRP <1 vs >10 mg/L). Since there were no differences observed for the sum of KIV-2 repeat numbers with increasing CRP levels, the increase of Lp(a) might be rather a secondary effect of the inflammation. Furthermore, the association of baseline Lp(a) with atherosclerotic cardiovascular disease risk was not modified by baseline inflammation status [
      • Langsted A.
      • Kamstrup P.R.
      • Nordestgaard B.G.
      Lipoprotein(a): fasting and nonfasting levels, inflammation, and cardiovascular risk.
      ]. In the JUPITER study of individuals recruited on the basis of elevated C-reactive protein concentrations, Lp(a) concentrations were remarkably stable over a one-year period among individuals randomized to statin therapy or placebo [
      • Khera A.V.
      • Everett B.M.
      • Caulfield M.P.
      • et al.
      Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin).
      ]. Moreover, there is no evidence of differences in Lp(a) concentrations between coronary artery disease patients with or without inflammatory disease, or of a causal association with low-grade inflammation [
      • Holm S.
      • Oma I.
      • Hagve T.A.
      • et al.
      Levels of Lipoprotein (a) in patients with coronary artery disease with and without inflammatory rheumatic disease: a cross-sectional study.
      ].
      Ultimately, the prevention and treatment of cardiovascular disease will always be about looking not at one risk factor alone, but at the whole picture of as many risk factors as possible. The risk for cardiovascular disease is increasing cumulatively with the number of traditional risk factors as well as increased Lp(a) concentrations as has been demonstrated in the recent Lp(a) consensus statement [
      • Kronenberg F.
      • Mora S.
      • Stroes E.S.G.
      • et al.
      Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement.
      ]. Fighting against as many risk factors as possible and not only a single risk factor will be important and will result in less subclinical and clinical atherosclerosis development, followed by less inflammation in general and especially of the vascular wall. Therefore, looking at the global picture of risk factors is of utmost importance and for that purposes we have tools such as the “Lp(a) risk and benefit calculator" available which consider meanwhile also Lp(a) concentrations for global cardiovascular risk assessment (http://www.lpaclinicalguidance.com/). This type of tools have the advantage that they can much easier integrate the risk factors and risk markers we are aware of in a multivariate model for a better risk prediction. It is mandatory to take off the blinkers and to make use of the knowledge we have. It is pity enough that we have to disregard numerous other unmeasured and unknown risk factors we are not even aware of.

      Declaration of interest

      The author received honoraria from Novartis, Amgen and Kaneka for lectures and participation in advisory boards.

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