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; Walter Lehmacher; Pia R Kamstrup; Børge G Nordestgaard; Winfried Maerz; Asma Noureen; Konrad Schmidt; Florian Kronenberg; Andreas Heibges; Reinhard Klingel; Pro(a)LiFe-Study Group

doi:10.1161/ATVBAHA.116.307983

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

Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):2019-27. doi: 10.1161/ATVBAHA.116.307983. Epub 2016 Jul 14.

Authors

Eberhard Roeseler¹, Ulrich Julius¹, Franz Heigl¹, Ralf Spitthoever¹, Dennis Heutling¹, Paul Breitenberger¹, Josef Leebmann¹, Walter Lehmacher¹, Pia R Kamstrup¹, Børge G Nordestgaard¹, Winfried Maerz¹, Asma Noureen¹, Konrad Schmidt¹, Florian Kronenberg¹, Andreas Heibges¹, Reinhard Klingel²; Pro(a)LiFe-Study Group

Collaborators

Pro(a)LiFe-Study Group:
Volker Schettler, Thomas Benzing, Hildegard Christ, Sabine Wehner, Ines Schulz-Merkel, Ralf Kuehn, Albrecht Wagner, Wilfried Dschietzig, Claudia Ernst, Michael Koziolek, Johannes Bunia, Peter Kulzer, Klaus-Dieter Kraenzle, Markus Toelle, Gerhard Riechers, Christine Kuehnel, Tobias Marsen, Christina Saehn, Jens Ringel, Harald Messner, Andreas Oehring, Carsten Schuerfeld, Michael Wintergalen, Volker Schettler, Falko Neumann, Harald Kaul, Martin Haesner, Juergen Passfall, Andrea Benschneider, Stefan Heidenreich, Winfried März, Ruediger Klaes, Priska Binner, Hans Dieplinger, Gertraud Erhart, Cordula Fassbender, Hildegard Christ

Affiliations

¹ 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.).
² 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.). klingel@apheresis-research.org.

PMID: 27417585
DOI: 10.1161/ATVBAHA.116.307983

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.

Keywords: cardiovascular disease; coronary disease; lipoprotein apheresis; lipoprotein(a); risk factors.

Publication types

Multicenter Study
Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Apoprotein(a) / blood*
Biomarkers / blood
Blood Component Removal / adverse effects
Blood Component Removal / methods*
Cardiovascular Diseases / blood
Cardiovascular Diseases / epidemiology
Cardiovascular Diseases / prevention & control*
Female
Follow-Up Studies
Genetic Predisposition to Disease
Germany
Humans
Hyperlipoproteinemias / blood
Hyperlipoproteinemias / epidemiology
Hyperlipoproteinemias / genetics
Hyperlipoproteinemias / therapy*
Incidence
Lipoprotein(a) / blood*
Lipoprotein(a) / genetics
Male
Middle Aged
Phenotype
Polymorphism, Single Nucleotide
Prospective Studies
Risk Assessment
Risk Factors
Time Factors
Treatment Outcome

Substances

Biomarkers
Lipoprotein(a)
Apoprotein(a)