Niedrige Plasmaspiegel von HDL-Cholesterin (HDL-C) sind in epidemiologischen Studien
mit einem erhöhten Risiko für atherosklerotische kardiovaskuläre Erkrankungen (ASCVD)
assoziiert. In Zellkultur- und Tiermodellen üben HDL-Partikel potenziell antiatherogene
Wirkungen aus. Alle bisher getesteten Medikamente zur HDL-C-Erhöhung waren nicht in
der Lage, zusätzlich zu Statinen kardiovaskuläre Ereignisse zu verhüten. Auch Ergebnisse
genetischer Studien stellten die kausale Rolle von für ASCVD in Frage. Allerdings
reflektiert HDL-C nicht die Funktionalität von HDL-Partikeln.
Abstract
Many epidemiological studies found low plasma levels of high-density lipoprotein (HDL)
cholesterol (HDL-C) associated with an increased risk of atherosclerotic cardiovascular
disease (ASCVD). In cell culture and animal models, HDL particles show many anti-atherogenic
actions. However, until now, clinical trials did not find any prevention of ASCVD
events by drugs elevating HDL-C levels, at least not beyond statins. Also, genetic
studies show no associations of HDL-C levels altering variants with cardiovascular
risk. Therefore, the causal role and clinical benefit of HDL-C elevation in ASCVD
are questioned. However, the interpretation of previous data has important limitations:
First, the inverse relationship of HDL-C with the risk of ASCVD is limited to concentrations
< 60 mg/dl (< 1.5 mmol/l). Higher concentrations do not reduce the risk of ASCVD events
and are even associated with increased mortality. Therefore, neither the higher-the-better
strategies of earlier drug developments nor the assumption of linear cause-and-effect
relationships in Mendelian randomization trials are justified. Second, most of the
drugs tested so far do not act specifically on HDL metabolism. Therefore, the futile
endpoint studies question the clinical benefit of the investigated drugs, but not
the importance of HDL in ASCVD. Third, the vascular functions of HDL are not exerted
by its cholesterol content (i.e. HDL-C), but by a variety of other molecules. Comprehensive
knowledge of the structure-function-disease relationships of HDL particles and their
molecules is a prerequisite for testing their physiological and pathogenic relevance
and possibly for optimizing the diagnosis and treatment of persons with HDL-associated
risk of ASCVD, but also for other diseases, such as diabetes, chronic kidney disease,
infections, autoimmune and neurodegenerative diseases.
Schlüsselwörter
HDL - Atheroskerose - Risikofaktor - Biomarker - Lipoprotein
Keywords
HDL - atherosclerosis - risk factor - biomarker - lipoprotein
