Cardioimmunology: the new frontier!

Immunology has made it into the hearts of cardiologists. Just recently immunological questions concerning the heart were still considered inter-disciplinary. Now ‘cardioimmunology’ is on the best way of maturing into a distinct discipline bridging previously disparate fields. With the benefit of hindsight, it appears surprising that cardioimmunology is only now making its deserved appearance in the limelight. Yet, there was little to no notable communication between cardiology and immunology up until very recently, despite longstanding recognition of inflammatory cardiac conditions, including rheumatic heart disease and infectious myocarditis. Cardiology and immunology/rheumatology are historically distinct fields. Any overlap in research and training is still sparse. Clinically, the aspiring rheumatologist and cardiologist are barely exposed to each other’s field beyond undergraduate studies. At the pre-clinical level, many standard techniques are shared among research fields. Yet, only the cardiovascular scientist deals with cardiomyocytes too large for flow cytometry and too sensitive to survive tissue culture for more than a couple of days. Instead, contractility assays, optical mapping of calcium cycling, and Langendorff perfusion are the bread and butter of the cardiovascular scientist; technologies others have often never even heard of. Even finding a common language is challenging; just ask people in either field what MHC means to them! The initial appreciation that the immune system may be a target in heart disease dates back to a time when our understanding of cardioimmunology was still rather rudimentary. Early studies showing an increase in inflammatory markers after a myocardial infarction (MI) were misinterpreted as a sign that the post-infarction immune response was detrimental. This started a time of misguided thus unsuccessful trials using potent immunosuppression immediately after MI.1 The cumulative failure of these trials, understandably, caused concern that the immune system was not a suitable target after all. However, several decades after, we now understand that they never stood a chance of succeeding, because they were performed before we had had a chance to gather enough meaningful mechanistic insight. Up until the 1990s, ‘myocardial inflammation’ was a vague term mainly assessed by histological analyses not able to capture the complexity of myocardial immune cell subsets (Figure 1A). A range of technical and conceptual advances over the past years have made it clear though that inflammation associated with acute MI is a necessary part of the wound healing response that will ensure that scar tissue quickly stabilizes the myocardium to prevent fatal ventricular rupture. Suppressing this early response too much or too soon has detrimental effects. Yet, for reasons that are now being investigated by cardioimmunologists around the world, this early wound healing response can trigger autoimmunity and ongoing inflammatory damage to the myocardium.2,3 After MI, the therapeutic target therefore needs to be this persistent in inflammatory condition rather than the beneficial early healing cascade. Importantly, several such studies are ongoing (e.g. LILCAS and RITA-MI24), and the cardioimmunology community awaits their outcomes with bated breath. The raising field of cardioimmunology. (A) Major technological advances have paved the way to a deeper and far more comprehensive understanding of myocardial immune processes and inflammation. Heart-directed immunological phenomena formerly interpreted as a simple detrimental pathophysiological mechanism to be suppressed, are now recognized as sophisticated time- and context-dependent modulators of disease progression. (B) We now need to establish ways to assess individual inflammatory burden and immunophenotypes and stratify patients accordingly before immunomodulatory strategies can be administered safely. Patient phenotypes are simplistically represented as two main categories for practical reasons. A far more complex clinical scenario should be anticipated. The realization that the myocardium after infarction is a bona fide sterile wound and as such an immunological site, together with the appreciation that antigens released from necrotic cardiomyocytes cause an adaptive autoimmune response against the heart5,6,7 has super-charged the merger between cardiology and immunology. Methods such as flow cytometry and single-cell RNA sequencing are increasingly used on heart tissue,8 and now common consensus leaves little room to doubt the importance of the immune system in and for the heart. These modern molecular biology techniques also allow a deep dive into the spatial and temporal heterogeneity and dynamics of the interaction between the heart and the immune system (Figure 1A). While the results of such studies sometimes seem to add more confusion to an already complicated system, this is in fact the reality of immune responses, and we do need to keep going until we have a full picture. This is critical for safe immunomodulation, because it cannot be stressed enough that targeting the immune system can be a double-edged sword, and we still need to find tools to stratify heart disease patients according to their inflammatory burden versus infectious risk (Figure 1B). The recent development of PET tracers able to non-invasively monitor myocardial leucocyte influx and mediastinal lymph node cellularity9 are an exciting step towards helping cardiologists to define, on an individual basis, when inflammation has gone astray, and when it should be targeted. Importantly, while we focus here on ischaemic heart disease, the relevance of cardioimmunology goes way beyond that and includes cardiovascular disease in autoimmune and systemic inflammatory conditions and cardiomyopathies with or without apparent immunological trigger. While we have a good cardioimmunology literature base for some of them (e.g. heart failure with reduced ejection fraction, HFrEF), others are still mostly immunological black boxes (e.g. heart failure with preserved ejection fraction, HFpEF, or rare congenital heart diseases). Most prominently the recent emergence of immune-checkpoint inhibitor myocarditis, a potentially fatal complication of cancer immunotherapy,10 is a very clear example of the critical importance of understanding the effect of immune perturbances on the heart. To ensure the field of cardioimmunology can continue to grow and develop from these exciting early days, we still need to intensify communication between the parental fields. We need structured training programs and joint conferences. We need people who understand either field’s language and are comfortable with either field’s technologies. 2022 saw the first dedicated cardioimmunology conference in Europe, and international consortia are being established to build a collaborative community driven by a shared goal. We believe that understanding both benefits and detrimental effects of the immune-heart crosstalk, will one day soon, allow us to have significant clinical impact in cardiology. We might finally be able to predict who is at risk of developing heart failure, add immunomodulatory medication to standard pharmacotherapy for ischaemic heart disease. A cardioimmunology community, living by the principles of open science, will ensure that mistakes of the past are not repeated, and new clinical trials will be based on a solid understanding of the heterogeneous und dynamic nature of the immune response. S.S. was supported by a grant from the Leducq Foundation (ImmunFib-HF). G.C.R. is funded by the German Research foundation (Collaborative Research Centre1525 ‘Cardio-Immune interfaces’, grant number 453989101). G.C.R. and P.P.R. are funded by the European Research Area Network—Cardiovascular Diseases [ERANET-CVD JCT2018, AIR-MI Consortium grants 01KL1902 to G.C.R. and I 4168-B to P.P.R. (via the Austrian Science Fund)]. The figure was prepared with the help of the Servier Medical Art.