https://doi.org/10.1007/s00392-025-02737-x
1Universitätsklinikum Würzburg Medizinische Klinik und Poliklinik I, ZIM Kardiologie Würzburg, Deutschland; 2Universität Würzburg Institut für Virologie und Immunbiologie Würzburg, Deutschland; 3Universitätsklinikum Würzburg Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie Würzburg, Deutschland; 4Universitätsklinikum Würzburg Medizinische Klinik und Poliklinik I Würzburg, Deutschland; 5Universitätsklinikum Würzburg Deutsches Zentrum für Herzinsuffizienz/DZHI Würzburg, Deutschland; 6Universitätsklinikum Würzburg Neurologische Klinik und Poliklinik Würzburg, Deutschland
Background:
Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a cleaved fragment of the membrane-bound receptor TREM2, primarily studied in the context of neuroinflammation and Alzheimer’s disease (AD). TREM2 is expressed on myeloid cells such as macrophages and microglia, modulating inflammatory responses and lipid metabolism. Recent cardiovascular research has highlighted TREM2’s relevance in chronic heart failure (HF), particularly due to its role in regulating macrophage activity after myocardial infarction and in hypertensive HF. In both animal models of hypertensive HF and in patients with HF with preserved ejection fraction (HFpEF), elevated plasma sTREM2 levels were observed compared to controls, suggesting that sTREM2 may also serve as a biomarker for cardiac inflammation and hold prognostic value in HF. Since HF is also associated with a high prevalence of mild cognitive impairment (MCI), this study aimed to assess whether plasma sTREM2 levels in patients with chronic HF reflect cardiac function, cognitive performance, or predict long-term mortality.
Methods:
This post hoc analysis included 148 patients with chronic HF from the Cognition.Matters-HF cohort, who underwent comprehensive cardiac, laboratory, and neuropsychological evaluation. Plasma sTREM2 concentrations were measured using a bead-based immunoassay and stratified into high and low groups based on the median value (16.6 ng/mL). Neurocognitive domains assessed included working memory, verbal/visual memory, attention, and fluency. Cardiac parameters were derived from echocardiography and 6-minute walk tests. Univariate and multivariable linear regression identified independent predictors of sTREM2, while Cox regression models assessed associations with 10-year all-cause mortality.
Results:
Higher plasma sTREM2 levels were associated with significantly lower cognitive scores, particularly in working memory (T = –2.67, P = 0.009) and visual/verbal memory (T = –2.16, P = 0.032). In contrast, sTREM2 did not correlate independently with markers of cardiac dysfunction, including ejection fraction and NT-proBNP. Age and memory performance emerged as the only significant independent predictors of plasma sTREM2 concentrations. Kaplan–Meier analysis showed lower survival in the high sTREM2 group (log-rank P = 0.003), and univariable Cox regression linked elevated sTREM2 to increased mortality (HR = 1.28, P = 0.015). However, this association lost significance in multivariable analysis adjusted for age and HF severity (adjusted HR = 0.94, P = 0.713).
Discussion:
In this well-characterized chronic HF cohort, plasma sTREM2 levels were more strongly associated with cognitive dysfunction than with cardiac parameters or survival. While prior animal and human data suggest that sTREM2 reflects inflammatory macrophage activity and could indicate cardiac stress, our findings instead highlight its relevance as a potential biomarker of HF-associated cognitive decline. Further studies are needed to determine whether sTREM2 can aid in early identification of MCI in HF or serve as a prognostic marker in specific HF subtypes.