Inflammatory mechanisms and intervention strategies for sepsis-induced myocardial dysfunction

Abstract

Sepsis-induced myocardial dysfunction (SIMD) is the leading cause of death in patients with sepsis in the intensive care units. The main manifestations of SIMD are systolic and diastolic dysfunctions of the myocardium. Despite our initial understanding of the SIMD over the past three decades, the incidence and mortality of SIMD remain high. This may be attributed to the large degree of heterogeneity among the initiating factors, disease processes, and host states involved in SIMD. Previously, organ dysfunction caused by sepsis was thought to be an impairment brought about by an excessive inflammatory response. However, many recent studies have shown that SIMD is a consequence of a combination of factors shaped by the inflammatory responses between the pathogen and the host. In this article, we review the mechanisms of the inflammatory responses and potential novel therapeutic strategies in SIMD.

Keywords: host-pathogen interactions; inflammation; myocardial dysfunction; sepsis; targeted therapy.

Figure 1

Immune response mediates sepsis‐induced myocardial dysfunction. Early microorganisms activate the immune cells to release immune mediators. Release of inflammatory mediators that target cardiomyocytes leads to cell death. Simultaneously, complement activation amplifies the inflammatory response and affects the myocardial action potential and coagulation system. After several days of infection, the body begins to enter the phase of immune suppression (immune cell failure), and the level of pathogen infection rises again. DC, dendritic cell; IL, interleukin; NE, neutrophil; NK, natural killer cell; M1/2, macrophage 1/2.

Figure 2

Mechanisms of mitochondrial dysfunction and local metabolic abnormalities. Under the action of inflammatory factors, electrons escape to form ROS, leading to a decrease in ATP production. ROS further attack nucleic acid structures and cause cell damage. The release of large amounts of mtDNA also activates inflammatory pathways. When aerobic respiration is impaired, the local glycolytic pathway gets switched to lactate metabolism, resulting in local metabolic and vasoconstriction disorders that affect the hemodynamic stability. mPTP, mitochondrial permeability transition pore; mtROS, mitochondrial reactive oxygen species; TLRs, toll‐like receptors.

Figure 3

Treatment strategies for septic shock. Based on traditional strategies, a new generation of monitoring and treatment approaches are being developed. Highly sensitive PCR and sequencing technologies allow for faster identification of pathogens. A variety of small molecule targeted drug development is expected to be the future solution. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ELISA, enzyme‐linked immunosorbent assay; GFR, glomerular filtration rate; GM‐CSF, granulocyte‐macrophage colony‐stimulating factor; IL, interleukin; MDT, multidisciplinary treatment; PCR, polymerase chain reaction; rhIFNγ, recombinant human interferon; ROS, reactive oxygen species; Scr, serum creatinine.