For decades, longitudinal studies have supported the multifactorial nature of atherosclerosis. Indeed, unless in exceptional cases, there is no single cause that is fundamental or sufficient by itself for the development of atherosclerotic disease. Overall, a variable combination of the so-called risk factors initiates the atherosclerosis process, and may contribute to its evolution, and ultimately to its complications. Interestingly, since the use of the medical term “risk factor” by Kannel et al.1 who led the way for the widely recognized Framingham Heart Study, the list of potential risk factors for cardiovascular disease has dramatically increased. In addition to traditional risk factors such as hypercholesterolemia, for which the pivotal influence on the development of coronary heart disease has been established since the 1960s, several different plasma “markers”, causal or not, emerged several years ago with the promise to help identifying those persons who are prone to premature atherothrombosis.2–4 Among the distinct biomarkers, those reflecting a low-grade inflammatory status gathered most of the attention of scientific community, not only because of their power of prediction of cardiovascular events observed in large-scale epidemiologic studies (high-sensitivity C-reactive protein (hsCRP) being the best example),2 but also due to a well-recognized role of inflammation in atherosclerosis from experimental studies in the last three decades.5 In this issue of European Journal of Preventive Cardiology, a Working Group of Atherosclerosis and Vascular Biology of the European Society of Cardiology addresses the close connections between these two risk factors, hypercholesterolemia and inflammation, concerning their synergistic biological contributions to atherosclerosis, and also their specific therapies, which now seem complementary approaches to reduce cardiovascular risk (Table 1).6

Table 1. Common effects of hypercholesterolemia and inflammation on atherothrombosis.

Cholesterol and inflammation – “partners in crime” As described in this Consensus paper, cholesterol and inflammation are biologically interrelated in their impact on atherosclerosis.6 The entry and retention of low-density lipoprotein (LDL) particles within the arterial wall trigger several inflammatory signals, culminating in the expression of adhesion molecules by the endothelium and the local secretion of cytokines and chemokines, which ultimately contribute to accumulation of macrophages and other inflammatory cells in the subendothelial space.5,7 This lipid-inflammation interface reunites enough elements for setting up a proper soil for atherosclerosis initiation and often times, atherosclerosis progression. Beyond the well-known biological plausibility behind cholesterol’s role in atherogenesis, the causal relationship between low-density lipoprotein cholesterol (LDL-C) and atherosclerotic coronary heart disease is currently unequivocal, with consistent and robust evidence from prospective epidemiologic cohort studies,8 Mendelian randomization studies,9,10 and randomized trials of different LDL-lowering therapies10–12 that act by enhancing the LDL receptor-mediated apolipoprotein B containing lipoprotein clearance pathway. Cumulative data, including over 20 m person-years of follow-up, have supported a dose-dependent, log-linear association between the magnitude of exposure to LDL-C and risk of atherosclerotic cardiovascular disease (ASCVD).10 The recent studies of outcomes of a new class of potent LDL-C-lowering agents, the monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9), reinforced this causal association. The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial,13 the combined Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) trials,14 and the recently presented Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab (ODYSSEY Outcomes) trial, demonstrated a significant reduction of cardiovascular events under use of PCSK9 inhibitors, in addition to intensive statin treatment and already low baseline LDL-C levels. In a prespecified secondary analysis of the FOURIER trial, the monotonic relationship between attained LDL-C and major cardiovascular outcomes continued down to LDL-C levels below 0.2 mmol/l (mere 7.5 mg/dl).15 While the association between LDL-C and ASCVD clearly fulfills the criteria for causality, the analysis of a causal relationship between inflammation and ASCVD can be much more complex. Inflammation is represented by an immense network of cells and their mediators, including chemokines, cytokines, and acute-phase reactants. Inhibiting one single molecule from this multi-branched network may not alter its equilibrium, considering that there is some degree of redundancy in the system, which may limit the clinical application of this approach. Besides, interfering with the immune system could also unbalance protection against infections, another potential obstacle in the use of anti-inflammatory strategies to reduce cardiovascular risk. Choosing the right target in this system is therefore a challenging task. Yet, the recently published Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) demonstrated successfully the causal relationship between inflammation and atherothrombosis.16 In this study, anti-inflammatory therapy targeting the interleukin-1β (IL-1β) innate immunity pathway in patients on statin therapy but with elevated hsCRP resulted in a significant reduction of cardiovascular events, without further interference with lipid levels. Despite extensive experimental evidence demonstrating the role of inflammation in the process of atherothrombosis, the CANTOS trial was the first large-scale trial finally fulfilling one of the most decisive Koch’s criteria of causality on the relationship between inflammation and ASCVD. Choosing a successful target was certainly not a matter of chance. While hsCRP, the most extensively studied of the circulating inflammatory biomarkers, is clinically useful for risk prediction, CRP was unlikely to represent an appropriate target for intervention. So, clinical investigation moved to other potential targets in the same axis, first to interleukin-6 (IL-6)17,18 and then to interleukin-1 (IL-1), based on pathophysiologic, genetic, and also phase II trial data.19

LDL-C-lowering and anti-inflammatory effects – a successful dynamic duo against atherothrombosis This Consensus paper also addresses the LDL-C-lowering and anti-inflammatory interface of current therapies for atherothrombosis. The anti-inflammatory effects of statins, whether mediated by removal of pro-inflammatory modified LDL from the artery wall or by intrinsic non-LDL anti-inflammatory properties through reduction of isoprenoids, are well known. A decade ago a meta-analysis by Kinlay20 assessed the contribution of LDL-dependent and LDL-independent effects of LDL-lowering therapies to changes in hsCRP, and concluded that most of their anti-inflammatory effect related to the magnitude of LDL-C change. Nonetheless, PCSK9 inhibitors, despite promoting a dramatic 50–60% LDL-C fall21 and significant reduction of ASCVD risk,13,14 do not change plasma levels of hsCRP and other blood inflammatory markers, raising doubts on the systemic anti-inflammatory effect of LDL-C reduction per se. Interestingly, as discussed by the Consensus paper, potential anti-inflammatory effects occurring at the level of the artery wall rather than systemically may represent an anti-inflammatory hint in the use of PCSK9 inhibitors, but the evidence around it is still incipient.6 Although questions on the anti-inflammatory properties of non-statin LDL-C-lowering agents still remain, there is robust evidence showing that reducing both LDL-C and hsCRP is better than reducing only one of these markers. In an analysis of Pravastatin or Atorvastatin Evaluation and Infection Therapy– Thrombolysis in Myocardial Infarction (PROVE-IT) trial, those who not only attained LDL-C below 70 mg/dl but also hsCRP below 2 mg/dl derived greatest clinical benefits.22 Analysis from the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial also strengthens the relevance of both on-treatment hsCRP and LDL-C levels.23 A recent analysis from FOURIER just demonstrated that even in patients with very low levels of LDL-C, hsCRP is still a risk predictor.24 Besides, those with higher hsCRP presented greater absolute benefit with use of evolocumab, the PCSK9 inhibitor tested in FOURIER. Thus, the previously controversial25 evidence that a “dual target” for maximized atheroprotection is indeed beneficial is building up. Obviously, before turning to expensive pharmacological therapies (particularly biological drugs), healthy lifestyle measures, including exercise, weight control, and smoking cessation should be the first options to reduce inflammation.26–28 Whether it is still not known if canakinumab will be incorporated in the arsenal to reduce ASCVD, CANTOS can be considered a milestone in cardiovascular medicine, paving the way for new targets and anti-inflammatory approaches. In summary, after decades of studies, it is now safe to say that LDL-C and inflammation represent important causal cardiovascular risk factors, with a rich interplay between them present in the pathophysiology of atherosclerosis, and in the mechanisms of their directed therapies. Considering the current evidence, both must be reduced to prevent ASCVD and its ominous consequences.

Declaration of conflicting interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: VZR has received honoraria from Amgen and Sanofi related to speaker activities; RDS has received honoraria from Amgen, Akcea, Astra Zeneca, Biolab, Esperion, Kowa, Pfizer, Merck, and Sanofi/Regeneron related to consulting, speaker, and or research activities.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.