European Society of Cardiology: Low-density lipoproteins cause atherosclerotic cardiovascular disease. Pathophysiological, genetic, and therapeutic insights.
A consensus statement from the European Atherosclerosis Society Consensus Panel
Implications for future prevention of atherosclerotic cardiovascular disease
Extensive evidence on the pathophysiology of ASCVD presented here supplements and extends our earlier review on the causality of LDL based on epidemiological, GWAS, and Mendelian randomization studies, as well as controlled intervention trials with pharmacological agents targeting the LDL receptor. Such evidence, together with the associated molecular mechanisms, has clear implications across the continuum of ASCVD prevention (i.e. primordial, primary, secondary, and tertiary) and is consistent with the central concept derived from genomics that the cumulative arterial burden of LDL-C drives the development and progression of ASCVD and its clinical sequelae.
Furthermore, the pathophysiological evidence supports therapeutic strategies aimed at maintaining very low levels of LDL-C . (e.g. <1 mmol/L or 40 mg/dL) in patients with established ASCVD at very high risk of recurrent events. Such low plasma LDL-C levels are now attainable with the combination of statins and PCSK9 inhibitors (with or without addition of ezetimibe), therapeutic regimens that have proven safety and tolerability. The unequivocal body of evidence for LDL causality in ASCVD will impact on future international recommendations for the management of atherogenic and ASCVD-promoting dyslipidaemias and will guide the rational use of both existing and new therapies. The success of modern programmes of ASCVD prevention will also rely on the practice of precision medicine and patient-centred approaches.
Finally, this thesis has highlighted emerging mechanistic features of atherosclerosis that can potentially lead to evaluation of new therapeutic targets integral to arterial wall biology and plaque stability. Prominent amongst these are endothelial transcytosis of atherogenic lipoproteins, monocyte/macrophage and SMC biology, efferocytosis, inflammation, innate and adaptive immune responses to the intimal retention of apoB-containing lipoproteins and calcification. The future holds great promise but will not be lacking in surprises.
Keywords
Atherosclerosis • Cardiovascular disease • Low-density lipoprotein • Mendelian randomization • Clinical trials • Statin • Ezetimibe • PCSK9 • Causality • Recommendations