Combatting sepsis-induced myocardial dysfunction: emerging mechanisms and immunomodulatory breakthroughs

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  Figure 1. Inflammatory mechanisms in septic cardiac injury. Cardiac injury in sepsis is driven by inflammatory cascades initiated through Gram-negative bacterial LPS. LPS directly activates pro-inflammatory cells or binds to TLR4, triggering pathways such as NF-κB to upregulate the expression of TNF-α, IL-1β, and IL-6. TNF-α mediates primary inflammatory manifestations, while IL-6 selectively activates the p38 MAPK signaling pathway. Elevated IL-6 levels promote coagulation cascade activation and vascular endothelial dysfunction, thereby suppressing myocardial contractility. IL-40 drives sepsis progression. CD38high monocytes predict 28-day mortality in sepsis; their CD38-NAD+-HIF-1α axis drives glycolysis.Concurrently, LPS activates the NLRP3 inflammasome, accelerating multiorgan dysfunction.Central to myocardial injury regulation is m6A RNA methylation. The methyltransferase METTL3 coordinates multiple pathological processes through distinct downstream pathways, collectively exacerbating myocardial dysfunction in SIMD. This figure was created using BioRender (biorender.com).

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  Figure 2. Immunosuppressive mechanisms in septic cardiac injury.The early phase of sepsis is characterized by a hyperinflammatory response marked by a surge in pro-inflammatory cytokines, concurrent with functional exhaustion of CD4+/CD8+ T cells, B cells, and follicular DCs, which compromises anti-inflammatory capacity. Monocyte dysfunction (evidenced by impaired pro-inflammatory cytokine production) and lymphocyte abnormalities (including reduced proliferative activity and aberrant anti-inflammatory cytokine elevation, such as IL-10) collectively drive a pro-/anti-inflammatory imbalance. This immunosuppressive state predisposes to secondary infections, further amplifying systemic inflammatory responses and exacerbating myocardial injury. This figure was created using BioRender (biorender.com).

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  Figure 3. Oxidative stress mechanisms in septic cardiac injury. Cardiac tissue from non-surviving septic patients exhibits marked upregulation of iNOS, NOX2, nitrotyrosine, and 8-OHdG, highlighting the central role of OS/NS in myocardial injury.Golgi stress (inflammation/apoptosis) exacerbates sepsis-induced myocardial dysfunction (SIMD) characterized by LVEF reduction, LVEDD elevation, and cTnI/CK-MB elevation. Infiltrating leukocytes excessively release free radicals, directly damaging cardiomyocytes.LPS-induced overproduction of ROS activates the NLRP3 inflammasome, mediating cardiomyocyte death and exacerbating injury. Concurrently, ROS disrupt mitochondrial membrane potential, triggering mtDNA release as DAMPs that further amplifies inflammatory cascades. This sustained ROS generation activates the IL-6/STAT3/NF-κB signaling pathway, propagating inflammatory responses.The endogenous antioxidant defense system is compromised via reduced expression of SOD,CAT, and GPx. Conversely, mitochondrial ALDH2 mitigates LPS-induced cardiac dysfunction, inflammation, and apoptosis by suppressing the cGAS/STING pathway. SIMD is driven by ischemia/reperfusion injury, involving oxidative stress,…

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  Figure 4. Pathological mechanisms of ANS dysregulation in septic cardiac injury. The ANS maintains systemic homeostasis by regulating cardiac output, vascular tone, inflammatory responses, immune equilibrium, and energy metabolism. During sepsis, infection or tissue injury activates the central nervous system, triggering the HPA axis, hypothalamic-pituitary-thyroid axis, and hypothalamic-neurohypophysial axis to orchestrate stress responses. ANS dysregulation, coupled with elevated inflammatory mediators (e.g., cytokine storm), synergistically promotes microcirculatory disturbances, culminating in multiorgan failure, including cardiac dysfunction. In septic shock, desensitization of adrenergic receptors leads to myocardial depression and vascular paralysis, exacerbating the vicious cycle and increasing mortality. This figure was created using BioRender (biorender.com). ANS, The autonomic nervous system.

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  Figure 5. Molecular mechanisms of complement system hyperactivation in septic cardiac injury. The complement system exerts dual roles in sepsis. During early stages, activation via the classical, alternative, or lectin pathways cleaves C3 into C3a/C3b, facilitating pathogen clearance and immune regulation. However, excessive late-phase activation drives systemic inflammation and tissue injury.In early sepsis, the complement activation product C5a binds to the C5a receptor (C5aR), Myocardial pyroptosis and dysfunction:C5a activates the reactive oxygen species/NOD-like receptor protein 3 (ROS/NLRP3) inflammasome pathway, inducing cardiomyocyte pyroptosis;Disrupted intracellular calcium homeostasis impairs myocardial contraction/relaxation.Immune dysregulation:C5a activates natural killer (NK) and NKT cells, amplifying cytokine storms (e.g., TNF-γ release) and recruiting immune cells to infection sites.These synergistic mechanisms culminate in irreversible myocardial damage and cardiac failure. This figure was created using BioRender (biorender.com).

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  Figure 6. Roles of extracellular vesicles in sepsis-induced myocardial dysfunction.This figure illustrates the pathophysiological role of extracellular vesicles in sepsis-associated cardiac injury: Circulating EVs derived from immune cells (e.g., neutrophils, macrophages) propagate systemic inflammation by delivering pro-inflammatory cargo (miRNAs, cytokines, DAMPs) to cardiomyocytes and endothelial cells.Key pathways include miR-885-5p/HMBOX1/NF-κB-mediated pyroptosis, TLR4/NF-κB activation in macrophages via MIR17HG, and miR-1262/SLC2A1-driven metabolic dysregulation.Platelet-derived EVs exacerbate endothelial dysfunction through NO and superoxide overproduction.Note: This figure was created using BioRender (biorender.com).

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  Figure 7. Multidimensional therapeutic strategies for sepsis-induced myocardial injury. 1. Anti-inflammatory therapeutics (e.g., NLRP3 inflammasome inhibitors, IL-6 receptor antibodies); 2. Immunomodulatory interventions (PD-1/PD-L1 checkpoint inhibitors); 3. Oxidative stress-targeted therapies (mitochondrial-targeted antioxidants, Nrf2/HO-1 pathway activation); BFA exacerbates injury, GSH rescues this effect, suggesting Golgi integrity as a therapeutic target;4. Autonomic regulation (electroacupuncture via vagal-splenic-immune reflex to suppress inflammation); Oral BTO@Cap particles combined with low-intensity US activate local vagus nerve electrical stimulation; via α7nAChR, this inhibits macrophage pro-inflammatory cytokines (TNF-α/IL-6), reducing inflammation and increasing survival by 67% in septic mice. The particles enhance gastric adhesion via TRPV1 targeting and avoid systemic absorption due to their micro-sized structure; a portable US device enables home-based therapy; 5. Complement system modulation (C5a receptor antagonists);Microcirculatory optimization (fluid resuscitation and vasoactive agents); 6. Extracellular vesicle-based therapies (stem cell-derived EVs delivering…