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Originally Published 14 July 2016
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Lipoprotein Apheresis for Lipoprotein(a)-Associated Cardiovascular Disease: Prospective 5 Years of Follow-Up and Apolipoprotein(a) Characterization

Eberhard Roeseler, Ulrich Julius, Franz Heigl, Ralf Spitthoever, Dennis Heutling, Paul Breitenberger, Josef Leebmann, … Show All … , Walter Lehmacher, Pia R. Kamstrup, Børge G. Nordestgaard, Winfried Maerz, Asma Noureen, Konrad Schmidt, Florian Kronenberg, Andreas Heibges, and Reinhard Klingel for the Pro(a)LiFe-Study GroupAuthor Info & Affiliations
Arteriosclerosis, Thrombosis, and Vascular Biology
Volume 36, Number 9
https://doi.org/10.1161/ATVBAHA.116.307983
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Abstract

Objective—

Lipoprotein(a)-hyperlipoproteinemia (Lp(a)-HLP) along with progressive cardiovascular disease has been approved as indication for regular lipoprotein apheresis (LA) in Germany since 2008. We aimed to study the long-term preventive effect of LA and to assess hypothetical clinical correlations of apolipoprotein(a) (apo(a)) by analyzing genotypes and phenotypes.

Approach and Results—

This prospective observational multicenter study included 170 patients with Lp(a)-HLP and progressive cardiovascular disease (48.9 years median age at diagnosis) despite other cardiovascular risk factors, including low-density lipoprotein cholesterol had maximally been treated (mean baseline low-density lipoprotein cholesterol: measured, 2.56 mmol/L [98.9 mg/dL] and corrected, 1.72 mmol/L [66.3 mg/dL]). Patients were prospectively investigated during a 5-year period about annual incidence rates of cardiovascular events. In addition, apo(a) isoforms and polymorphisms at the apo(a) gene (LPA) were characterized. One hundred fifty-four patients (90.6%) completed 5 years of follow-up. Mean Lp(a) concentration before commencing regular LA was 108.1 mg/dL. This was reduced by a single LA treatment by 68.1% on average. Significant decline of the mean annual cardiovascular event rate was observed from 0.58±0.53 2 years before regular LA to 0.11±0.15 thereafter (P<0.0001); 95.3% of patients expressed at least 1 small apo(a) isoform. Small apo(a) isoform (35.2%) carrying phenotypes were not tagged by single-nucleotide polymorphisms rs10455872 or rs3798220.

Conclusions—

Results of 5 years of prospective follow-up confirm that LA has a lasting effect on prevention of cardiovascular events in patients with Lp(a)-HLP. Patients clinically selected by progressive cardiovascular disease were characterized by a highly frequent expression of small apo(a) isoforms. Only Lp(a) concentration seemed to comprehensively reflect Lp(a)-associated cardiovascular risk, however.

Introduction

Evidence from prospective epidemiological studies and Mendelian randomization studies has documented an independent and causal association of elevated lipoprotein(a) (Lp(a)) plasma concentrations with cardiovascular disease (CVD), including coronary artery disease, ischemic stroke, and peripheral arterial disease.1–4 Therefore, Lp(a) is regarded as a therapeutic target with the potential to lower cardiovascular risk and prevent clinical events.
Lp(a) is composed of a low-density lipoprotein (LDL)–like particle to which a single copy of apolipoprotein(a) (apo(a)) is covalently attached. Apo(a) is composed of a protease domain, and plasminogen-like kringle domains, namely, one kringle V and a variety of kringle IV (KIV) structures. Ten different KIV domains have evolved in the LPA gene with KIV type 1 and KIV types 3 to 10 being present in single copies only, whereas the KIV type 2 (KIV-2) domains show an extensive repeat copy number variation with 1 to >40 repeats. These are all translated and lead to a size polymorphism of apo(a), which is causally associated with Lp(a) concentrations in an inverse manner.4,5 Lp(a) isoforms have been categorized as small (≤22 KIV repeats) or large (>22 KIV repeats) with small isoforms, implying an ≈2-fold higher risk of CVD.6 Sequence variation in apo(a) other than the KIV-2 copy number variation is also associated with Lp(a) levels. Two common gene variants rs10455872 and rs3798220 have been found to be associated with CVD risk in whites.7
Lipoprotein apheresis (LA) is an effective option for lowering blood LDL-cholesterol (LDL-C) concentrations in patients with severe hypercholesterolemia, in whom lipid-lowering medicines are insufficient or poorly tolerated.8,9 In 2008, the German Federal Joint Committee (GBA) decided to accept Lp(a)-hyperlipoproteinemia (Lp(a)-HLP) associated with progressive CVD as an indication for regular LA with reimbursement.10 To become eligible for treatment, the Lp(a) concentration should exceed 60 mg/dL, LDL-C concentration should be at treatment targets with maximally tolerated lipid-lowering medication, and CVD should be progressive despite optimal treatment of all other cardiovascular risk factors. The current reimbursement regulation in Germany has no equivalent in any other country and offered the unique opportunity to characterize this clinically selected high-risk patient group in a prospective observational study comparing the incidence rates of cardiovascular events in patients with Lp(a)-HLP and progressive CVD retrospectively before and prospectively after commencing regular LA.10 Here we report the follow-up of these patients after 5 years of regular ongoing LA to assess prospectively long-term sustainability of the preventive effect of LA. In addition, apo(a) was analyzed to assess hypothetical clinical correlations of genotypes and phenotypes in this clinically selected cohort.

Materials and Methods

Materials and Methods are available in the online-only Data Supplement.

Results

Characteristics of Patients at the Time of the First LA and on y+5 of Follow-Up

A total of 170 patients all of white European ethnicity commenced regular LA at day 0, and 154 (90.6%) could be analyzed after completion of y+5 (Figure 1; Table 1). During a median period of 4.7 years of the pre-LA period, CVD was progressive, which finally led to the initiation of LA. It should be noted that approval for LA because of Lp(a)-HLP was not based on the occurrence of a recent cardiovascular event because it requires careful consideration of the entire clinical course after diagnosis of CVD.
Table 1. Patients’ Timeline of CVD and Characteristics at the Time of the First LA Treatment, and in y+5 of Follow-Up
 Time of the First LA (n=170)y+5 of Follow-Up (n=154)P Value
Male/female*123 (72.3)/47 (27.7)110 (71.4)/44 (28.6) 
Age, y†56.5 (48.0–65.8)60.0 (52.0–69.0) 
 Male, y†56.0 (47.8–65.0)59.0 (52.0–67.8) 
 Female, y†56.5 (51.0–68.0)61.0 (52.3–71.5) 
Age at diagnosis of CVD, y†48.9 (42.8–57.8)… 
Age at first CV event, y†49.5 (42.8–57.8)… 
Age at second CV event, y†51.8 (46.1–62.0)… 
Treatment intervals, 1.5× to twice per wk/weekly/biweekly/every 3 wk*3 (1.8)/157 (92.3)/9 (5.3)/1 (0.6)9 (5.8)/127 (82.5)/15 (9.7)/3 (2.0)0.323
Vascular access, peripheral veins/arteriovenous fistula134 (79.9)/36 (20.1)111 (72.1)/43 (27.9)0.101
Coronary artery disease*156 (91.8)143 (92.9)0.413
 1-/2-/3-vessel coronary disease*27 (15.9)/33 (19.4)/96 (56.5)23 (14.9)/27 (17.5)/93 (60.3)0.523
Cerebral atherosclerosis*77 (45.3)83 (53.9)0.109
Peripheral atherosclerosis*65 (38.2)62 (40.3)0.675
Renal artery stenosis*26 (15.3)14 (9.1)0.095
Diagnosis of diabetes mellitus*37 (21.8)32 (20.8)0.811
Antihypertensive medication*125 (73.5)141 (91.6)<0.0001
Vitamin-K antagonist*6 (3.5)10 (6.5)0.205
Antiplatelet medication*154 (90.6)142 (92.2)0.470
Creatinine, µmol/L (mg/dL)‡105.2±83.0 (1.19±0.95)104.3±68.1 (1.18±0.77)0.842
Hemoglobin, mmol/L (g/dL)‡8.5±1.9 (13.7±3.0)8.3±0.8 (13.3±1.3)0.242
LA indicates lipoprotein apheresis; CV cardiovascular; and CVD, cardiovascular disease.
*
Numbers (percentages).
†
Median (interquartile range).
‡
Mean±SD (conventional units).
Figure 1. Patient flow chart showing annual patient numbers during the entire 7 years of the study period. Reasons for terminating the study including deaths are listed in a table of the online Data Supplement.
Between the time of the first LA and y+5, prevalence rates of coronary artery disease, cerebral atherosclerosis, and peripheral atherosclerosis did not change significantly (Table 1). The proportion of patients with renal artery stenosis decreased until y+5 because of patients who had terminated the trial. There was no obvious explanation for this coincidence. A table listing all 17 patients with their reason for terminating the study together with their renal artery status can be found in the Table I in the online-only Data Supplement. The percentage of patients with diabetes mellitus remained stable throughout the study period with mean hemoglobin A1c at 6.3% to 6.5%.
The frequency of LA treatment was determined individually in the centers and showed only slight changes from the first LA to y+5 (Table 1). Peripheral veins were still used for vascular access in >70% of patients in y+5. Only 9 additional patients required an arteriovenous fistula (Table 1). The use of different LA methods and mean treatment volumes remained as previously described and are summarized in tabular format in the Table II in the online-only Data Supplement.10

Safety of LA Treatment

No serious adverse event related to LA treatment was observed during the entire prospective study period of 5 years. Also, no particular or sustaining clotting problems were reported. Minor adverse events typically associated with outpatient apheresis treatment, for example, transient hypotension, dizziness, hematoma at vascular access, or nausea, were not analyzed. Representative long-term safety analyses of 2 of the study sites have recently been published.11,12 Mean plasma concentrations of creatinine and fibrinogen remained stable throughout the entire study period. The patient group included 3 hemodialysis patients, 2 of whom died in y+2 or y+3 (see the analysis of events below) and 1 patient who successfully received a kidney transplant in y+4. Because iron deficiency can develop with chronic LA,13 the vast majority of patients received iron supplementation, mostly intravenously. Doses were determined individually according to monitoring of ferritin and transferrin saturation in intervals determined by local physicians. Hemoglobin levels of patients remained stable during regular ongoing LA treatment with a mean value of 13.7 g/dL at the time of the first LA and 13.3 g/dL in y+5.

Laboratory Parameters

Laboratory investigations are summarized in Table 2. Mean Lp(a) concentration before regular LA was 108.1 mg/dL and was reduced by a single LA treatment on average by 68.1% during 5 years of chronic LA. Mean Lp(a) concentration before LA treatments averaged during 5 years of follow-up was 91.1 mg/dL, that is, 16% lower compared with the mean baseline concentration before the first LA treatment (P<0.05). The mean LDL-C concentration before LA was 2.56 mmol/L (98.9 mg/dL). Mean LDL-C concentrations at baseline and before LA treatments averaged during 5 years of follow-up remained unchanged (Table 2). The mean LDL-C reduction was 66.3% per LA session. LDL-C as directly measured or calculated by the Friedewald formula includes the contribution of Lp(a) cholesterol, which is estimated as 30% to 45% of the total measured Lp(a) mass of a patient; thus, only corrected LDL-C reflects actually treatable LDL-C under the used lipid-lowering medication (Table 2).2,14,15
Table 2. Mean Plasma Concentrations of Lipoproteins and Fibrinogen of the Pre-LA Phase and in the 5-Year Lasting Phase of Regular LA
 Pre-LA Phase y-2, y-1, and Before First LAy+1–y+5, Before LALA Phase y+1–y+5, After LAReduction Rate, %
Lp(a), mg/dL108.1±46.191.1±36.528.5±13.568.1±9.7
 P<0.0001<0.0001 
LDL-C, measured, mmol/L/(mg/dL)2.56±0.99/(98.9±38.4)2.65±0.96/(102.2±37.2)0.90±0.47/(34.7±18.3)66.3±11.4
 P0.140<0.0001 
Corrected,* mmol/L/(mg/dL)1.72±0.66/(66.3±25.4)1.94±0.81/(75.0±31.2)0.68±0.31/(26.1±11.8) 
HDL-C,† mmol/L/(mg/dL)1.35±0.56/(52.3±21.8)1.29±0.37/(49.8±14.2)ND 
Total cholesterol,† mmol/L/(mg/dL)4.58±1.30/(176.8±50.2)4.68±1.18/(180.8±45.6)ND 
Triglycerides,† mmol/L/(mg/dL)1.92±1.31/(169.8±115.6)2.25±1.60/(199.1±141.2)ND 
Fibrinogen,† µmol/L/(mg/dL)10.33±3.99/(351.2±135.6)9.37±3.03/(318.7±103.2)ND 
Values indicate mean±SD (conventional units). On average, 4 measurements were available in the pre-LA phase, during the LA phase measurements were done every 6 months. HDL-C indicates high-density lipoprotein cholesterol; LA, lipoprotein apheresis; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); and ND, not done.
*
Correction of LDL-C for Lp(a)-derived cholesterol was done with the following formula: corrected LDL-C=measured LDL-C−0.3×(numeric value of Lp(a)).
†
Concentrations were measured only immediately before LA treatments.

Medication

More than 90% of patients received lipid-lowering drugs throughout the entire study, in the vast majority consisting of a statin or a combination of statins with ezetimibe. The number of patients taking lipid-lowering medication with statins as one component decreased from 90.5% at first LA to 86.2% in year +5. The subgroup of patients taking only a statin without other lipid-lowering drugs increased from 24.1% at first LA to 39.2% in y+5. Both changes reflect that LDL-C–lowering medication was reduced in complexity during the 5 years with regular LA. The only major change occurred with nicotinic acid because of the withdrawal of the drug from the German market in January 2013. Details of the lipid-lowering medication during all 7 study years are summarized in Table III in the online-only Data Supplement. The number of patients receiving antihypertensive medication significantly increased from the time of the first LA (73.5%) to y+5 (91.6%; Table 1).

Analysis of Events

Absolute numbers and mean annual rates of major adverse cardiac event (MACE) and adverse cardiac or vascular event (ACVE) in selected study periods of all 7 study years are depicted in Figure 2. The commencement of regular ongoing LA was associated with a rapid stabilization of progressive CVD that had developed in the median interval of 4.7 years since the second cardiovascular event. Mean annual rates of MACE in periods of y+1 and y+2 versus y+3 to y+5 revealed a significant decrease, indicating the sustaining effect of LA. Annual incidence rates for MACE and ACVE were 85% and 81% lower during chronic LA, respectively, in comparison to the progressive phase of CVD before commencing LA. Annual MACE or ACVE rates in patients with the diagnosis of diabetes mellitus (n=37, ie, 21.8% in y+1; n=32, ie, 20.8% in y+5) were statistically not different as compared with patients without diabetes mellitus. Mean annual rates for y+3 to y+5 for MACE and ACVE seemed similar to all LA methods used. Because of the sample size, only for the largest subgroup treated by temperature-optimized double filtration plasmapheresis (n=101 [61%] in y+2 and n=89 [58%] in y+5),10 a separate statistical analysis could be performed, and no difference to the entire cohort was found for MACE (ie, y+3: 0.06, y+4: 0.03, y+5: 0.07) and ACVE (ie, y+3: 0.14, y+4: 0.05, y+5: 0.14).
Figure 2. Seven-year course of the Pro(a)LiFe study with absolute numbers of events (A, major adverse cardiac event [MACE] or (B) adverse cardiac or vascular events [ACVEs] in all vascular beds) and comparative analysis of mean annual event rates in the select study periods.
In total, 12 deaths were recorded until y+5. Five cases were accounted for as death because of cardiovascular causes (Table I). In 7 cases, death had nonvascular causes (Table II). Two of 3 dialysis patients were among deaths, 1 patient with cardiovascular cause in y+2, and 1 patient with noncardiovascular cause in y+3. Accounting all deaths as cardiovascular deaths lead to mean annual rates for years y+3 to y+5 of MACE in y+3: 0.07, y+4: 0.03, and y+5: 0.08 and of ACVE in y+3: 0.16, y+4: 0.07, and y+5: 0.16. This did not change the significance levels of the comparative analysis of selected study periods (Figure 2A and 2B).

Genotype and Phenotype of Apo(a) Isoforms

For the analysis of apo(a) isoforms in genotypes and phenotypes, blood was collected at different times. Sample numbers differ from those of the clinical study because not all patients gave their consent for all genetic analyses.
One hundred thirty-six samples were available for analysis of genomic KIV domain copy numbers. The sum of KIV-2 repeats of both LPA alleles were determined by quantitative polymerase chain reaction. In comparison, 2550 participants of the Copenhagen General Population Study (CGPS) with a mean age of 59.5 years served as normal controls. Controls were all free of coronary artery disease or ischemic cerebrovascular disease according to the Danish patient registry. The distribution of Lp(a) concentrations differed significantly between both the cohorts: median of Pro(a)LiFe patients was 109.0 mg/dL (IQR, 77.0 mg/dL–132.0 mg/dL) and median of CGPS patients was 10.1 mg/dL (IQR, 5.2 mg/dL–32.4 mg/dL), P<0.0001. Pro(a)LiFe patients showed a significantly lower number of KIV-2 repeats in their genome (P<0.0001, Figure 3).
Figure 3. Comparison of Pro(a)LiFe patients (n=136) to a sample from the Copenhagen General Population Study (CGPS, n=2550). Total number (sum of both alleles resulting from polymerase chain reaction analysis) of genomic kringle IV domain copies (medians: Pro(a)LiFe 48.0 [interquartile range {IQR}, 44.3–50.9]; CGPS 58.2 [IQR, 53.3–63.3]; P<0.0001) is depicted.
For 134 patients, apo(a) isoform sizes for both of the 2 LPA alleles were assessed by pulsed-field gel electrophoresis (PFGE), and the apo(a) isoform expression pattern was available from immunoblots. Encoded isoforms ranged in size from 14 to 37 KIV domain copies (Figure 4A). On the DNA level, 59.0% of all alleles were small; 95.3% of the analyzed patients expressed at least 1 small isoform in plasma (Table 3). For 6 patients, it could not be determined whether they expressed only one or both of their alleles in plasma because they carried 2 alleles of the same or closely neighboring isoform sizes, resulting in a single band on the immunoblot. There were 5 homozygote patients (3.9%) detected by PFGE. For the sake of simplicity, their 10 alleles were accounted as 5 alleles expressing the total Lp(a) of patients and 5 null alleles. Thus, combined with the 59 heterozygotes with single-band phenotypes, we accounted 64 null alleles. Null alleles were in 90.6% encoding large isoforms (Figure 4A). Isoform-associated Lp(a) concentrations clearly showed that small isoforms carried the bulk of the Lp(a) in the vast majority of patients (Figure 4B). There was a striking difference in the Lp(a) concentrations associated with small (mean, 90.9±46.1 mg/dL) or with large isoforms (mean, 9.1±22.5 mg/dL), P<0.0001.
Table 3. Expression Pattern of Apo(a) Isoforms
Apo(a) expression patternn% of PatientsMean Total Lp(a)±SD, mg/dL (Before Commencing LA)
At least 1 small isoform expressed12295.3112.2±40.4
 2 Small alleles in genome2922.7126.1±52.4
 1 small and 1 large allele in genome9372.6107.8±35.1
Only large isoforms expressed64.788.8±29.5
 2 Large alleles in genome64.788.8±29.5
Isoforms were categorized as small (≤22 kringle IV [KIV] domain copies) or large (>22 KIV domain copies) according to the meta-analysis of Erqou et al,6 which showed increased cardiovascular disease risk associated with small size. apo(a) indicates apolipoprotein(a); LA, lipoprotein apheresis; and Lp(a), lipoprotein(a).
Figure 4. Expression of apolipoprotein(a) (apo(a)) isoforms in Pro(a)LiFe patients (n=128). Vertical lines separate small (≤22 kringle IV [KIV] domain copies) and large (>22 KIV domain copies) isoforms according to the categorization of6 (A) absolute numbers of expressed (black bars) and nonexpressed apo(a) alleles (gray bars) as detected by PFGE (pulsed-field gel electrophoresis) and Western blots. Expressed alleles had a median size of 20.0 KIV domain copies (interquartile range [IQR], 19.0–22.8), null alleles had a median size of 28.0 KIV domain copies (IQR, 26.0–32.0), P<0.0001. B, Isoform-associated lipoprotein(a) (Lp(a)) concentrations including null alleles depicted as means±SD.
For 121 patients with apo(a) phenotype data, information on their carrier status of variant alleles for the single-nucleotide polymorphisms (SNPs) rs10455872 and rs3798220 was available from previous genotyping.10 All of these 121 patients expressed at least 1 small apo(a) isoform, with 64.8% of them carrying also at least 1 SNP variant allele. Although all variant alleles were found in patients with such a small apo(a) phenotype, 35.2% of small apo(a) isoform carrying phenotypes were not tagged by either of the variant alleles.

Discussion

In this study, incidence rates of cardiovascular events were investigated prospectively during a period of 5 years in 170 consecutive patients who started regular LA to treat Lp(a)-HLP associated with progressive CVD. Patients had established early CVD with a median of 2 past cardiovascular events and experienced additional progression within a median time period of 4.7 years despite maximal treatment of all other cardiovascular risk factors, including LDL-C. As recently reported a marked, significant, and clinically relevant decrease of mean annual incidence rates for MACE or ACVE was observed comparing 2 years before commencing regular LA and 2 years during chronic LA. We now extend these findings by showing that the incidence rates of MACE or ACVE continued to be low during a total period of 5 years. The number of patients receiving antihypertensive medication significantly increased from the time of the first LA (73.5%) to y+5 (91.6%). There is no reason to think that this change in medication exerted a major therapeutic effect on the clinical course during the 5 years of LA treatment. Five deaths because of cardiovascular causes occurred during 5 years of follow-up with chronic LA, corresponding to a 5-year mortality rate of 3.0%. Thus, only 5 fatal cardiovascular events occurred during 804 patient-years. Regular LA seems to have reverted an accelerated progressive course of CVD to a stable course in terms of the incidence rates of cardiovascular events and mortality.
The most prominent finding of our characterization of apo(a) genotypes and phenotypes is the high frequency of patients with small apo(a) isoforms, which have been associated with increased cardiovascular risk6; 95.3% of patients expressed at least 1 small apo(a) isoform, which is 4× higher than 23.6% observed in a large sample of >6000 subjects from 2 population-based studies in Germany.1 The abundance of small KIV alleles could also propose that a subgroup of small apo(a) isoforms confer a particular risk by still unidentified sequence variations or particle compositions. Our study was not designed to investigate whether Lp(a) of small apo(a) isoforms has a higher atherogenic potential as suggested earlier.16
Likewise, the frequency of risk alleles of SNPs rs3798220 and rs10455872 was markedly increased in Pro(a)LiFe patients compared with other European patients with CVD.7 The variants have been reported to be associated with small apo(a) alleles in whites,7 and it had been suggested that they could be used as surrogate markers to identify small apo(a) isoforms associated with high Lp(a) and increased risk.17 However, 35.2% of the clinically recognized, highly selected Pro(a)LiFe patients with a small apo(a) phenotype would not be tagged by either of these SNPs, which suggests that these 2 SNPs would classify 35.2% of patients incorrectly to be at low Lp(a)-associated risk. A similar finding has been reported for the general German population in which 47% of the individuals carrying a small apo(a) isoform would not be identified by these 2 SNPs.18 Although in most patients analyzed for apo(a) isoform size and expression, small isoforms accounted for the high Lp(a) level, we also observed substantial variation of Lp(a) concentrations associated with isoforms of identical size. Furthermore, in a few cases (4.7% of patients), large isoforms were solely responsible for the elevated Lp(a), but patients were clinically indistinguishable. Consequently, our results in summary do not advise the addition of isoform-associated markers or SNPs as mandatory criteria to refine the definition of Lp(a)-HLP-associated progressive CVD in similar patient groups, but encourage further studies to better characterize high-risk LPA alleles and Lp(a) particles.
The immediate effect of regular LA is pulsed physical extracorporeal elimination of apoB-containing lipoproteins including Lp(a), the latter is loaded with oxidized phospholipids.19 Association of oxidized phospholipids with small apo(a) isoforms may be a key determinant of cardiovascular risk.20 High Lp(a) levels and small apo(a) sizes are associated with endothelial dysfunction.21 A single LA treatment improves endothelium-dependent vasodilation,22 and the elimination of oxidized Lp(a) might be more important to this effect than oxidized LDL.23 In particular about corrected LDL-C, Pro(a)LiFe patients achieved low levels at least 2 years before commencing chronic LA, suggesting that the cardiovascular benefit of LA substantially derived from the additional elimination of elevated concentrations of Lp(a) particles. There was no indication to suppose different clinical efficacy of one of the LA methods. For all patients included in this study, treatment volumes according to German reimbursement guidelines were adjusted for a 60% to 70% reduction of baseline Lp(a) concentration. Treatment frequency, treatment volume, or removed mass of the targeted plasma component can be regarded as general parameters of apheresis efficacy. A dose–response relationship for these parameters could not be investigated in this study.
Ruptured plaques tend to have large lipid cores. Improving plaque morphology could be one underlying mechanism of action for preventing clinical events by LA. It was hypothesized that LA quantitatively reduced the number of vulnerable plaques and qualitatively limited the propensity of plaques to rupture and their thrombogenicity.24,25 The resulting clinical benefit of all these mechanistic aspects of LA is the prevention of cardiovascular events.
PCSK9 inhibitors may play an indirect role in the management of Lp(a)-HLP because LDL-C needs to be brought to treatment targets before LA is considered. More than 90% of Pro(a)LiFe patients received LDL-C–lowering medication throughout the entire study period. PCSK9 inhibitors reduce Lp(a) levels; however, relative reductions decrease substantially with higher Lp(a) concentrations.26 Use of PCSK9 inhibitors with their potential to achieve ultralow LDL-C concentrations could facilitate the earlier clinical identification of patients with Lp(a)-HLP and associated progressive CVD.
Mortality data for patients with a risk profile identical to this study are not available. The cohort at baseline is necessarily biased by survival because it does not consider patients with the same characteristics who had already died because of CVD events. Only a randomized controlled trial could finally confirm the results of this 5-year follow-up. Although such a trial of LA has so far been considered unethical in Germany, it might become feasible with novel medicines specifically lowering Lp(a), for example, an antisense drug that has been successfully tested in a phase I clinical trial.27 Because LA eliminates LDL-C and Lp(a), it is not possible to disentangle whether the therapeutic effect derives from lowering Lp(a) or LDL-C or both or even from other compounds that could have an effect on CVD and are eliminated by LA, for example, fibrinogen.8 However, all patients received maximally tolerated LDL-C–lowering drug treatment before their progressive CVD was identified as associated with Lp(a)-HLP; thus, supporting the hypothesis that lowering Lp(a) levels further reduced cardiovascular risk. Finally, there are pronounced differences across ethnicities with regard to Lp(a) levels and pathophysiological relevance of Lp(a). Therefore, our conclusions are valid only for white Europeans.
In summary, results of the 5-year follow-up of the prospective Pro(a)LiFe study support that prevention of cardiovascular events is a rapid and lasting effect of LA in patients with progressive CVD associated with Lp(a)-HLP. Patients were characterized by abundant expression of small apo(a) isoforms, which have been associated with increased cardiovascular risk, although, besides elevated Lp(a) plasma concentration, selection of this patient cohort was based on clinical criteria. Measurement of Lp(a) concentration must be recommended to assess individual cardiovascular risk and to consider extracorporeal clearance of Lp(a) by chronic LA as treatment option for select high-risk patients.

Highlights

•
There is a subgroup of patients with lipoprotein(a)-hyperlipoproteinemia exhibiting a progressive course of cardiovascular disease, despite maximal treatment of all other cardiovascular risk factors, including low-density lipoprotein cholesterol.
•
Regular lipoprotein apheresis can rapidly revert progressive cardiovascular disease associated with lipoprotein(a)-hyperlipoproteinemia to a stable clinical course at least during a period of 5 years.
•
Patients were characterized by abundant expression of small apolipoprotein(a) isoforms, which have been associated with increased cardiovascular risk, although selection of this patient cohort was based on clinical criteria.

Footnote

Nonstandard Abbreviations and Acronyms

ACVE
adverse cardiac or vascular event
apo(a)
apolipoprotein(a)
CVD
cardiovascular disease
KIV
kringle IV
LA
lipoprotein apheresis
LDL-C
low-density lipoprotein cholesterol
Lp(a)
lipoprotein(a)
Lp(a)-HLP
lipoprotein(a)-hyperlipoproteinemia
MACE
major adverse cardiac event

Supplemental Material

File (atvb_atvb-2016-307983d_graphic_abstract.pdf)
File (atvb_atvb-2016-307983d_supp1.pdf)
File (atvb_atvb-2016-307983d_supp2.pdf)

Appendix

Pro(a)LiFe Study Group Coauthors

All coauthors are from Germany, unless otherwise specified. Writing Committee: Eberhard Roeseler, Hannover; Franz Heigl, Kempten; Ulrich Julius, Dresden; Konrad Schmidt and Florian Kronenberg, Innsbruck, Austria; Volker Schettler, Goettingen; and Andreas Heibges and Reinhard Klingel, Cologne. Principal Investigator: Reinhard Klingel, Cologne. Data Monitoring Committee: Thomas Benzing, Cologne and Hildegard Christ and Walter Lehmacher, Cologne. Clinical Investigators: Josef Leebmann, Passau; Eberhard Roeseler, Sabine Wehner, Hannover; Franz Heigl, Ines Schulz-Merkel, Kempten; Ulrich Julius, Dresden; Ralf Spitthoever, Essen; Ralf Kuehn, Dennis Heutling, Tangermuende; Paul Breitenberger, Germering; Albrecht Wagner, Trier; Wilfried Dschietzig, Claudia Ernst, Cottbus; Michael Koziolek, Goettingen; Johannes Bunia, Iserlohn; Peter Kulzer, Marktheidenfeld; Klaus-Dieter Kraenzle, Memmingen; Markus Toelle, Berlin; Gerhard Riechers, Christine Kuehnel, Braunschweig; Tobias Marsen, Cologne; Christina Saehn, Krefeld; Jens Ringel, Potsdam; Harald Messner, Wuppertal; Andreas Oehring, Suhl; Carsten Schuerfeld, Saarlouis; Michael Wintergalen, Olpe; Volker Schettler, Goettingen; Falko Neumann, Dresden; Harald Kaul, Deggendorf; Martin Haesner, Juergen Passfall, Berlin; and Andrea Benschneider, Berlin; Stefan Heidenreich, Aachen. Laboratory Investigators: Winfried März, Ruediger Klaes, and Priska Binner, Mannheim; Pia R. Kamstrup and Børge G. Nordestgaard, Copenhagen, Denmark; and Asma Noureen, Konrad Schmidt, Hans Dieplinger, Gertraud Erhart, and Florian Kronenberg, Innsbruck, Austria. Data Management and Statistical Analysis: Andreas Heibges, Cordula Fassbender, Cologne; Walter Lehmacher, Hildegard Christ, Cologne; and Konrad Schmidt, Innsbruck, Austria.

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Go to Arteriosclerosis, Thrombosis, and Vascular Biology
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The image shows lipid droplets accumulating in HIV-infected human monocyte-derived macrophages. Lipid droplets were stained with Oil Red O (red), HIV-1 p24 protein was stained with anti-p24 antibody conjugated with Alexa Fluor 488 (green), and nuclei were counterstained with DAPI (blue). (See pages 1758–1771.)

Arteriosclerosis, Thrombosis, and Vascular Biology
Volume 36 • Number 9 • September 2016
Pages: 2019 - 2027
PubMed: 27417585

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© 2016 American Heart Association, Inc.

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History

Received: 8 April 2016
Accepted: 24 June 2016
Published online: 14 July 2016
Published in print: September 2016

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Keywords

  1. cardiovascular disease
  2. coronary disease
  3. lipoprotein(a)
  4. lipoprotein apheresis
  5. risk factors

Subjects

  1. Cardiovascular Disease
  2. Clinical Studies
  3. Coronary Artery Disease
  4. Primary Prevention
  5. Treatment

Authors

Affiliations

Eberhard Roeseler
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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Ulrich Julius
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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Franz Heigl
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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Ralf Spitthoever
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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Dennis Heutling
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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Paul Breitenberger
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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Josef Leebmann
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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Walter Lehmacher
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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Pia R. Kamstrup
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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Børge G. Nordestgaard
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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Winfried Maerz
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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Asma Noureen
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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Konrad Schmidt
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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Florian Kronenberg
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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Andreas Heibges
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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Reinhard Klingel
From the Center for Nephrology, Hypertension, and Metabolic Diseases, Hannover, Germany (E.R.); 3rd Medical Clinic, University Hospital at the Technische Universität, Dresden, Germany (U.J.); Medical Health and Care Center Kempten-Allgäu, Kempten, Germany (F.H.); Dialysis and Lipid Center North Rhine, Essen, Germany (R.S.); Clinic for Nephrology and Dialysis, Tangermuende, Germany (D.H.); KfH-Kidney Center, Germering, Germany (P.B.); 1st Medical Clinic, General Hospital, Passau, Germany (J.L.); Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany (W.L.); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (P.R.K., B.G.N.); Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (W.M.); Synlab Academy, Mannheim, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (A.N., K.S., F.K.); and Apheresis Research Institute, Cologne, Germany (A.H., R.K.).
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for the Pro(a)LiFe-Study Group*
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Notes

*
A list of all Pro(a)LiFe Study Group (Prospective Documentation of Isolated Lipoprotein(a)-Elevation With Progressive Cardiovascular Disease and Lipoprotein Apheresis for Effective Treatment of Hyperlipoproteinemia) Coauthors is given in the Appendix.
The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/doi:10.1161/ATVBAHA.116.307983/-/DC1.
Correspondence to Reinhard Klingel, MD, Apheresis Research Institute, Stadtwaldguertel 77, 50935 Cologne, Germany. E-mail [email protected]

Disclosures

Dr Julius received honoraria from Fresenius Medical Care, Diamed, and Kaneka (all Germany). Dr Maerz is an employee with ownership interest of Synlab Holding, Germany, and he reports grants and personal fees from Aegerion, Amgen, Astrazeneca, Genzyme, Siemens Diagnostics, Sanofi, Hoffmann-Laroche, Alexion, MSD, Abbott Diagnostics, all outside the submitted work. Dr Klingel received research grants from Asahi Kasei Medical, Japan and Diamed, Germany. Dr Lehmacher received a research grant from Apheresis Research Institute, Germany. All other study group members had none declared. The other authors report no conflicts.

Sources of Funding

Financial funding of the study was provided by Diamed, Cologne, Germany. The financial sponsor had no role in the design and conduct of the study, the collection, management, analysis, and interpretation of data, or the preparation, review, and approval of the article.

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Lipoprotein Apheresis for Lipoprotein(a)-Associated Cardiovascular Disease
Arteriosclerosis, Thrombosis, and Vascular Biology
  • Vol. 36
  • No. 9

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Arteriosclerosis, Thrombosis, and Vascular Biology
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