Cytokines as Potential Novel Therapeutic Targets in Severe Inflammatory Cardiomyopathy

Background Despite currently available state-of-the art therapies, a substantial proportion of patients with inflammatory cardiomyopathy progresses to advanced heart failure. There is an urgent need for novel therapies to improve outcomes. We hypothesized that elevated cyto-kine levels in inflammatory cardiomyopathy may lead to cardiac injury and that specific cyto-kines are associated with severely decreased left ventricular function consequently, thereby suggesting their potential as therapeutic targets. Methods and Results Blood samples collected from 529 patients at 2 registries were inves-tigated. First, in a derivation cohort of inflammatory cardiomyopathy from our medical center (n=63), we discovered cytokines that correlate inversely with severely decreased left ventricu-lar ejection fraction (LVEF). We confirmed reproducibility of our results in an independent cohort from a national registry (n=425) and to some degree generalizability in a small cohort of idiopathic dilated cardiomyopathy (IDCM, n=41). In total, we identified 82 cytokines asso-ciated with severely decreased LVEF (FDR < 0.05); a small portion had been previously pro-posed as therapeutic targets, while others emerged as novel discoveries. Finally, real-world data from electronic medical records further indicated the potential of inhibitors targeting cy-tokines of interest to confer a cardioprotective effect. Conclusions We identified 82 cytokines associated with severe inflammatory cardiomyopa-thy. Our data were highly significant, reproducible, and generalizable to IDCM. The fact that some of the cytokines had been suggested as potential targets in prior literature supports va-lidity and plausibility of our data. Given that inhibition of cytokines is technically feasible, the identified proteins are compelling potential novel therapeutic targets. Trial registration number: [ClinicalTrials.gov][1] Identifier: [NCT04265040][2], [NCT02187263][3] ![Figure][4] ### Competing Interest Statement DISCLOSURES BH is inventor on patents that use RNA for diagnosis of myocarditis. Patent protection is in process for MCG for diagnosis and measurement of therapy response in inflammatory cardio-myopathy. BH, JW, DB, UL: Patent protection is in process for cytokines for targeted therapy in inflammatory cardiomyopathy and heart failure. ACKNOWLEDGEMENTS We thank all TORCH investigators and staff, Andrea Heuberger, Michele Violano, and Xia-omin Wang for their help with sample collection and sample processing. ### Funding Statement This study was funded by a project grant from the Swiss National Science Foundation issued to Bettina Heidecker, MD (money follows researcher grant). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was reviewed and approved by the ethics committee of DHZC Universitatsmedizin Berlin (EA4/056/20, EA1/187/22) and the Ethikkommission Medizinische Fakultat Heidelberg (S-344/2014). All patients provided their written informed consent. In the TORCH registry, all participants provided written informed consent, and the study received approval from the ethics committees of the participating study centers. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes An anonymized dataset can be made available upon request. Access is only granted to aca-demic staff and after signing a data sharing agreement. The code of the statistical evaluation for the statistics program R is published on GitHub. [1]: https://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04265040&atom=%2Fmedrxiv%2Fearly%2F2023%2F08%2F04%2F2023.07.27.23293253.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02187263&atom=%2Fmedrxiv%2Fearly%2F2023%2F08%2F04%2F2023.07.27.23293253.atom [4]: pending:yes