Abstract
The CD40–CD40 ligand (CD40L) dyad represents a scientific and clinical field that has raised many controversies in the past and cannot be clearly defined as being an either beneficial or harmful pathway. Being crucially involved in physiological immunological processes as well as pathological inflammatory reactions, the signaling pathway has been recognized as a key player in the development of both autoimmune and cardiovascular disease. Even though the possibilities of a therapeutic approach to the dyad were recognized decades ago, due to unfortunate events, detailed in this review, pharmacological treatment targeting the dyad, especially in patients suffering from atherosclerosis, is not available. Despite the recent advances in the treatment of classical cardiovascular risk factors, such as arterial hypertension and diabetes mellitus, the treatment of the associated low-grade inflammation that accounts for the progression of atherosclerosis is still challenging. Low-grade inflammation can be detected in a significant portion of patients that suffer from cardiovascular disease and it is therefore imperative to develop new therapeutic strategies in order to combat this driver of atherosclerosis. Of note, established cardiovascular drugs such as angiotensin-converting enzyme inhibitors or statins have proven beneficial cardiovascular effects that are also related to their pleiotropic immunomodulatory properties. In this review, we will discuss the setbacks encountered as well as new avenues discovered on the path to a different, inflammation-centered approach for the treatment of cardiovascular disease with the CD40–CD40L axis as a central therapeutic target.
Highlights
Cardiovascular disease (CVD) and its main driver, atherosclerosis, have been recognized as inflammatory-driven entities [1,2]
The majority of the population still suffers from atherosclerotic complications while showing signs of systemic low-grade inflammation [5] indicated by elevated plasma levels of high-sensitive C-reactive protein [6]
The usefulness of soluble CD40 ligand (sCD40L) as a marker of vascular inflammation is subject to vital scientific discussions. Besides this key role for inflammatory processes, CD40–CD40 ligand (CD40L) signaling plays a key role for thrombosis [42,50] and contributes to the coagulation process [51], where the activation of the endothelium and smooth muscle cells plays an important role [52]
Summary
Cardiovascular disease (CVD) and its main driver, atherosclerosis, have been recognized as inflammatory-driven entities [1,2]. Within the last 50 years, clinical efforts have focused on treating risk factors associated with CVD such as smoking, lifestyle changes, hypertension and dyslipidemia This approach, including the use of lipid-lowering drugs, such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase-inhibitors (statins) and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, has reduced the risk of CVD by 30% [4]. Despite this therapeutic success, the majority of the population still suffers from atherosclerotic complications while showing signs of systemic low-grade inflammation [5] indicated by elevated plasma levels of high-sensitive C-reactive protein (hsCRP) [6]. One should note that the classical cardiovascular risk markers obviously have a more powerful predictive value in comparison with inflammatory markers and may provide better risk assessment in the clinical situation
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