Author + information
- Daniele Pastori, MD,
- Cristina Nocella, MSc,
- Alessio Farcomeni, PhD,
- Simona Bartimoccia, MSc,
- Roberto Carnevale, PhD,
- Francesco Violi, MD,
- Pasquale Pignatelli, PhD∗ (, )
- for the ATHERO-AF Study Group
- ↵∗I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
We read with interest the letter by Dr. Egom regarding our research paper, recently published in the Journal (1), showing a direct association between levels of proprotein convertase subtilisin kexin type 9 (PCSK9) and cardiovascular events in patients with atrial fibrillation.
The introduction of the PCSK9 inhibitors opened a new era in the treatment of atherosclerosis, providing new evidence for the mechanisms of atherosclerosis.
The causal relationship between low-density lipoprotein cholesterol (LDL-C) and atherosclerosis has been reaffirmed by the GLAGOV (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound) trial, in which the PCSK9 inhibitor evolocumab dose-dependently reduced LDL-C and, when a very low level of LDL-C was achieved (i.e., <40 mg/dl), a regression of coronary plaque was observed (2).
On the other hand, the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) showed that an anti-inflammatory antibody against interleukin-1β reduced the incidence of cardiovascular events independently from LDL-C (3), raising concerns about whether LDL-C is the most appropriate target to slow atherosclerosis progression, as also reported by Dr. Egom.
Our belief is that findings from these 2 trials are not mutually exclusive and may represent 2 steps of the same process. Thus, according to the sterile inflammation theory, the deposition of LDL-C within subendothelial space induces the recruitment of inflammatory cells, such as macrophages, at the site of atherosclerotic lesions, triggering interleukin-1β production (4).
In addition, LDL-C is oxidized by reactive oxidant species produced by Nox2 from macrophages and platelets, forming oxidized LDL that is then taken by macrophages, thus forming foam cells (4). This process leads to accumulation of necroinflammatory material within atherosclerotic lesion and favors platelet activation. Oxidative modifications of LDL-C may therefore be another mechanism contributing to atherogenesis independently from LDL-C levels (4).
Hence, so far, the highly effective LDL-C-lowering action is to be considered the main mechanism underlying the cardiovascular beneficial effect of PSCK9 inhibitors, as recently confirmed by the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial (5). Pleiotropic effects of PCSK9 inhibitors, such as platelet inhibition, are intriguing but deserve more research.
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Violi and Pignatelli contributed equally to this work and are joint senior authors. The ATHERO-AF Study Group includes: Mirella Saliola, Marco Antonio Casciaro, Domenico Ferro, Tommasa Vicario, Danilo Menichelli, Fabiana Albanese, Francesco Cribari, Alberto Paladino, Francesco Del Sole, Marta Novo, Vittoria Cammisotto, Paola Andreozzi, Maria Santulli, Fortunata Vasaturo, Tiziana Di Stefano, Patrizia Iannucci, and Elio Sabbatini.
- 2018 American College of Cardiology Foundation
- Pastori D.,
- Nocella C.,
- Farcomeni A.,
- et al.
- Nicholls S.J.,
- Puri R.,
- Anderson T.,
- et al.
- Violi F.,
- Loffredo L.,
- Carnevale R.,
- Pignatelli P.,
- Pastori D.