The role of cytokines in septic myocardial dysfunction: a translational systematic review and meta-analysis

Background: Septic myocardial dysfunction is a frequent complication of sepsis, commonly defined by impaired cardiac contractility. Despite its clinical significance, its pathophysiology remains poorly understood and no targeted therapy is currently available. Pro-inflammatory cytokines have been implicated in experimental models, but their causal role and therapeutic relevance in septic myocardial dysfunction remain uncertain. We aimed to systematically review and meta-analyze the impact of cytokine addition or blockade on myocardial function in sepsis across in vitro, in vivo, and human studies. Methods: We performed a systematic search of MEDLINE, Embase, Cochrane, and PubMed databases up to December 2024. We included all cellular, animal, and human studies (descriptive or interventional) assessing the effect of cytokine modulation on myocardial contractility in sepsis. Studies lacking contractility assessment were excluded from the meta-analysis but retained in the systematic review. Standardized mean differences (SMDs) were pooled using a random-effects model. Risk of bias was assessed using dedicated tools adapted to each study design. Results: A total of 39 studies were included in the systematic review, and 21 in the meta-analysis. Eleven in vitro or ex vivo studies showed that cardiomyocyte contractility was significantly reduced after exposure to IL-1 (SMD 5.62 [5.01;6.23]), IL-6 (4.24 [1.49;6.99]) and TNF-α (4.45 [3.17;5.72]); all were included in the meta-analysis. Seventeen in vivo animal studies were reviewed, of which six were eligible for meta-analysis: TNF-α (5.06 [1.46;8.65]) and IL-18 (1.56 [0.77;2.36]) were associated with significant cardiac depression, whereas IL-1 showed a non-significant effect (2.58 [-0.90;6.07]). Among eleven human studies, four were included in the meta-analysis. Patients with septic myocardial dysfunction had higher circulating levels of IL-6 (SMD 0.51 [0.06;0.97]), IL-1 (0.67 [0.11;1.23]), IL-8 (0.59 [0.35;0.83]) and IL-10 (0.57 [0.34;0.80]) than controls, while the difference for TNF-α was not significant (0.63 [-0.02;1.28]). Two small interventional studies suggested potential benefits from cytokine-targeting therapies. Conclusions: This translational review supports a cytokine-mediated contribution to septic myocardial dysfunction. While mechanistic evidence is strong in preclinical models, clinical data remain observational. These findings justify further interventional studies targeting cytokines in septic myocardial dysfunction.