The inflammatory fingerprint reveals immune cell populations associated with disease activity in cardiac sarcoidosis

Clinical Research in Cardiology https://doi.org/10.1007/s00392-026-02939-x ORIGINAL PAPER The inflammatory fingerprint reveals immune cell populations associated with disease activity in cardiac sarcoidosis Tobias Harm1 · Stella E. Autenrieth2 · Katharina Mezger1 · Anne‑Katrin Rohlfing1 · Helmut Dittman3 · Christian la Fougère3 · Konstantin Nikolaou4 · Patrick Krumm4 · Meinrad Gawaz1 · Karin Anne Lydia Müller1 · Simon Greulich1 Received: 10 September 2024 / Accepted: 3 May 2026 © The Author(s) 2026 Abstract Objective Sarcoidosis is a systemic granulomatous inflammatory disease and patients with cardiac involvement are at increased risk of adverse events. Pathophysiologic processes leading to myocardial inflammation and fibrosis are yet to be determined. Therefore, characterization of the immune response leading to enhanced disease activity and portending poor prognosis of patients with cardiac sarcoidosis (CS) is crucial. Methods Twenty-six patients with biopsy-proven sarcoidosis were prospectively enrolled for evaluation of suspected CS and disease activity was determined by hybrid cardiac PET/MR imaging. We then analyzed the peripheral blood of individuals with active CS (aCS), chronic CS (cCS), extracardiac sarcoidosis (noCS), and healthy controls using a 36-color spectral flow cytometry and immunoassay panel. Results Analysis of the inflammatory fingerprint in patients with CS uncovered 56 characteristic immune cell populations. Immunophenotyping of the inflammatory cells revealed distinctive differences between healthy individuals and patients with sarcoidosis. Further, the abundance of the cell populations was associated with cardiac manifestation and disease activity. A critical shift of lymphocytes, innate immune cells, and monocyte subsets occurred in patients with CS compared to extracardiac sarcoidosis and healthy individuals. In addition, cytokine/chemokine expression was aberrant in patients with CS and may contribute to the cardiac pathophysiology of sarcoidosis. Conclusions Comprehensive characterization of the inflammatory fingerprint reveals changes in frequency and phenotype of several immune cell populations associated with cardiac sarcoidosis. Our results may add further knowledge to the pathophysiology of cardiac sarcoidosis, allowing a better stratification of patients with high disease activity who seem to benefit most from immunosuppressive therapy. Karin Anne Lydia Müller and Simon Greulich contributed equally to this work. * Karin Anne Lydia Müller 1 Department of Cardiology and Angiology, University Hospital Tübingen, Otfried‑Müller‑Straße 10, 72076 Tübingen, Germany 2 German Cancer Research Centre, Research Group Dendritic Cells in Infection and Cancer, F171, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany 3 Department of Nuclear Medicine and Clinical Molecular Imaging, University Hospital Tübingen, Otfried‑Müller‑Straße 14, 72076 Tübingen, Germany 4 Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Hoppe‑Seyler‑Straße 3, 72076 Tübingen, Germany Vol.:(0123456789) Clinical Research in Cardiology Graphical Abstract Keywords Cardiac sarcoidosis · Immunophenotyping · Spectral flow cytometry · Inflammation · Immune cells Introduction Sarcoidosis is a systemic granulomatous disorder of idiopathic origin with a heterogenous variety of clinical symptoms [1]. The inflammatory disease commonly affects thoracic organs including the heart [2, 3]. In case of cardiac involvement, granuloma formation may lead to reversible inflammation with potential progression to irreversible fibrosis resulting in adverse events including heart failure or malignant arrhythmia [4–6] The prevalence of cardiac sarcoidosis (CS) has been widely described and cardiac involvement may lead to potentially life-threatening events [7, 8]. Especially in patients with a transition from acute (and potential reversible) towards persistent inflammation and fibrosis, anti-inflammatory treatment is a pivotal cornerstone for a successful therapy [3, 6, 9]. Therefore, early and accurate stratification of disease activity in patients with CS is an unmet need to attenuate disease progression and thus, to prevent potentially fatal outcome [8, 10]. Only recently, we were able to show that comprehensive simultaneous hybrid CMR/FDG-PET imaging leads to improved diagnosis of CS and classification of disease activity [11, 12]. Thus, detection of coexisting cardiac inflammation and fibrosis facilitates differentiation of active (aCS) from chronic (cCS) CS [11]. Inflammatory biomarkers including interleukin-2 receptor or angiotensin-converting enzyme are key players in the diagnosis of inflammatory diseases such as CS but reflect underlying pathophysiological pathways only partially [13–15]. Therefore, the assessment of distinct inflammatory signaling cascades and cell signatures in patients with CS might enlighten the expected course of the disease with either favorable or unfavorable outcome. Besides, CD4+ and CD8+ lymphocytes, innate immune cells and especially monocytes are pivotal in the formation of granulomatous diseases such as sarcoidosis [16, 17]. Nonetheless, the inflammatory fingerprint of patients with CS has yet to be determined and might provide striking diagnostic, therapeutic, and even prognostic perspectives. Clinical Research in Cardiology Methods Study population Twenty-six (n = 26) patients with biopsy-proven extracardiac sarcoidosis were enrolled in this prospective, consecutive study. All patients underwent cardiovascular magnetic resonance (CMR) coupled with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging for suspected CS as described previously [11]. Concisely, aCS was defined as abnormalities of cardiac tissue in CMR with concomitant focal or focal-on-diffuse myocardial FDG uptake in the presence of otherwise suppressed myocardial glucose uptake on PET imaging. Contrarily, cCS was defined as pathological CMR tissue and no myocardial FDG uptake (successful suppression). Ultimately, noCS was defined as the absence of myocardial tissue abnormalities on CMR imaging. Exclusion criteria of hybrid CMR/FDG-PET imaging were defined as homogeneous myocardial FDG uptake affecting the entire left ventricular tissue, as well as quantitative excess of cardiac FDG uptake compared to liver uptake. Peripheral blood samples were collected via venipuncture in an ambulatory setting during the morning hours, prior to cardiac MR/FDG-PET imaging, in order to minimize circadian variation. To reduce glucose levels, which could otherwise confound FDG uptake, all patients followed a strict low-carbohydrate diet the day before CMR/FDG-PET and blood sampling and fasted overnight for at least 12 h. Further, medication on admission was assessed prior to blood sampling and CMR/FDG-PET, and all patients completed a standardized questionnaire on medication history, comorbidities, and cardiovascular risk factors. Immunosuppre (...truncated)