Sepsis-Induced Cardiac Dysfunction Mechanisms

Sepsis-induced cardiac dysfunction encompasses a spectrum of reversible alterations in myocardial performance triggered by the host response to infection. Pathogenic components such as pathogen-associated molecular patterns activate inflammatory cascades, leading to excessive cytokine release, nitric oxide overproduction and endothelial barrier disruption. Concurrent damage-associated molecular patterns released from injured cells amplify inflammation in a feed-forward loop. At the cellular level, cardiomyocytes suffer mitochondrial injury and oxidative stress that compromise ATP generation, calcium handling and excitation–contraction coupling. Innate immune cells infiltrate cardiac tissue, where dysregulated subsets may either clear debris or fuel further injury. Emerging evidence implicates dysregulated autophagy, impaired mitophagy and programmed cell death pathways—including apoptosis and pyroptosis—in the progression of myocardial depression. Clinically, this manifests as reduced ejection fraction, ventricular dilatation and altered diastolic relaxation. Although often transient, sepsis-induced cardiac dysfunction correlates with worsened outcomes and remains without targeted therapy beyond optimisation of haemodynamics and infection control.

Research from Nature Portfolio

Recent studies have delineated the role of specialised cardiac-resident macrophages in preserving myocardial homeostasis during sepsis. A distinct subset of TREM2-high resident macrophages demonstrates enhanced endocytic capacity, selectively scavenging dysfunctional mitochondria ejected by stressed cardiomyocytes. Maintenance of this population attenuates local inflammation and limits ventricular dysfunction in experimental models. Loss of the TREM2-high phenotype impairs mitochondrial clearance, exacerbates cytokine release and precipitates more profound cardiac depression. Importantly, adoptive transfer of these protective macrophages into the pericardial space restores contractile function and improves survival, highlighting a potential cell-based therapeutic avenue.

Research from all publishers

Investigations into intracellular signalling have identified the STING–IRF3 axis as a central driver of lipopolysaccharide-induced cardiomyocyte injury. Activation of STING promotes IRF3 phosphorylation, nuclear translocation and upregulation of the NLRP3 inflammasome, culminating in caspase-1–dependent pyroptosis and interleukin-1β release. Genetic or pharmacological inhibition of this pathway preserves cardiac contractility and reduces inflammatory cell death in preclinical models. Parallel advances in echocardiographic assessment have demonstrated the superior sensitivity of global longitudinal strain measured by speckle-tracking over conventional ejection fraction. Meta-analytic data reveal that less negative strain values correlate with higher mortality in severe sepsis or septic shock, offering a refined prognostic tool and underscoring the prevalence of subtle systolic impairment in this population.

Sepsis-Induced Cardiac Dysfunction Mechanisms publication trend

The graph below shows the total number of articles in sepsis-induced cardiac dysfunction mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

DAMP (Damage-Associated Molecular Pattern): Endogenous molecules released from injured cells that trigger inflammation.

Pyroptosis: A form of programmed cell death driven by inflammasome activation and inflammatory cytokine release.

Inflammasome: A multiprotein complex that activates caspase-1, leading to processing of interleukin-1β and pyroptosis.

Speckle-Tracking Echocardiography: An imaging technique that analyses myocardial deformation by tracking acoustic markers in ultrasound images.

Global Longitudinal Strain: A quantitative measure of myocardial fibre shortening during systole, expressed as a negative percentage value.

References

1. TREM2hi resident macrophages protect the septic heart by maintaining cardiomyocyte homeostasis. Nature Metabolism (2023).
2. Sepsis-induced myocardial dysfunction: pathophysiology and management. Journal of Intensive Care (2016).
3. STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3. Redox Biology (2019).
4. Left ventricular systolic function evaluated by strain echocardiography and relationship with mortality in patients with severe sepsis or septic shock: a systematic review and meta-analysis. Critical Care (2018).