ESC William Harvey Lecture in Basic Science: Prof. Christian Weber
Novel mechanisms and therapeutic targets in atherosclerosis
27 Aug 2022
The presenter of this year’s ESC William Harvey Lecture in Basic Science, Professor Christian Weber (Institute for Cardiovascular Prevention [IPEK-LMU] - Munich, Germany), has made significant steps in unravelling the complexity of atherosclerosis and identifying innovative disruptive strategies.
What first made you interested in CV research?
I was fascinated very early on in my medical training by the fact that CVD was the most prevalent cause of disease and death worldwide. The challenge to find new therapies that would improve the CVD burden led to me pursuing a MD thesis under the supervision of the man who subsequently became my mentor, Peter C. Weber – no relation! That was in 1989. It is astonishing to reflect that, more than 30 years later, I have returned to work in the very same building and in the post (Chair of Vascular Medicine) previously held by my mentor!
What are the key themes of your lecture?
Thanks to studies evaluating the effects of anti-inflammatory therapies, namely the anti-interleukin (IL)-1β antibody, canakinumab, reducing levels of high-sensitivity C-reactive protein, IL-6 and IL-1β, there is proof of principle that atherosclerosis is an inflammatory disease. Even if you optimally treat hyperlipidaemia and other metabolic conditions, a residual inflammatory risk remains. In addition, work has implicated inappropriate activation of the NLRP3 inflammasome in a variety of inflammatory disorders, including atherosclerosis. However, there is considerable pleiotropy within the inflammatory cascade and inhibiting individual elements can have wide-ranging effects that can ultimately lead to the blockade of beneficial actions. For this reason, we need to devise more specific targets, and my lecture discusses a variety of promising approaches my group has investigated. One example involves employing TRAF-STOPs to specifically disrupt signalling of the costimulatory molecule dyad CD40-CD40 ligand, which can prevent the immune suppression associated with long-term CD40 inhibition in atherosclerosis.1 Another approach is to use a more targeted method for interfering with chemokines. For example, binding to only selected sites of receptors for macrophage migration-inhibitory factor (MIF) has been shown to block the atherosclerosis-promoting effects of MIF but not to interfere with its atheroprotective activity.2
What do you see as the current challenges in your field?
The overwhelming challenge is to select the optimal target from the huge variety of potential candidates. It’s like working your way through an inverted triangle of options, all of which have to be investigated. So it is not surprising that it can be frustrating. We can learn lessons from other therapeutic areas that are investigating new approaches, such as RNA-based therapies. And genome-wide association studies (GWAS) are instructive in helping to find relevant targets. However, an integrated approach is required to make sure that promising candidates are not overlooked: if GWAS alone had been used when aspirin was discovered, it would not have been developed further.
Where do you think research in your field is heading in the future?
We are currently working on something that has opened the door to a whole new approach to the management of atherosclerosis. Our research has identified the presence of neuroimmune cardiovascular interfaces in mice, involving an artery-brain circuit that can regulate and promote the development of atherosclerosis.3 Efferent-associated denervation was demonstrated to reduce the atherosclerotic burden and to improve plaque stability. In the future, it may be possible to map the neuronal pathways in the brain and to specifically inhibit peripheral activity by targeting these central circuits, for example, with the use of bioelectronics.
1. Seijkens TTP, et al. J Am Coll Cardiol. 2018;71:527–542.
2. Kontos C, et al. Nat Commun. 2020;11:5981.
3. Mohanta SK, et al. Nature. 2022;605:152–159.