Endothelial ROS and Impaired Myocardial Oxygen Consumption in Sepsis-induced Cardiac Dysfunction

Abstract

Sepsis is known as the presence of a Systemic Inflammatory Response Syndrome (SIRS) in response to an infection. In the USA alone, 750,000 cases of severe sepsis are diagnosed annually. More than 70% of sepsis-related deaths occur due to organ failure and more than 50% of septic patients demonstrate cardiac dysfunction. Patients with sepsis who develop cardiac dysfunction have significantly higher mortality, and thus cardiac dysfunction serves as a predictor of survival in sepsis. We have very little understanding about the mechanisms that result in cardiac dysfunction in the setting of sepsis. At present, the factors involved in sepsis-related cardiac dysfunction are believed to include the following: persistent inflammatory changes in the vascular endothelium and endocardium leading to circulatory and micro vascular changes, increase in endothelial reactive oxygen species (ROS), abnormal endothelium-leukocyte interaction resulting in a feed-forward loop for inflammatory cytokines and ROS, contractile dysfunction of the heart due to autonomic dysregulation, metabolic changes in myocardium leading to impaired oxygen delivery and increased oxygen consumption, mitochondrial dysfunction, and persistent inflammatory signaling. In this review article, we will briefly discuss the clinical challenges and our current understanding of cardiac dysfunction in sepsis. Major focus will be on the pathological changes that occur in vascular endothelium, with an emphasis on endocardium, and how endothelial ROS, impaired endothelium-leukocyte interaction, and microcirculatory changes lead to cardiac dysfunction in sepsis. The importance of the ongoing quest for the clinical biomarkers for cardiac dysfunction will also be discussed.

Keywords: Biomarker; Cardiac dysfunction; Endothelium; Microvascular dysfunction; Reactive oxygen species (ROS); Sepsis.

Figure 1. Pathway leading from sepsis to cardiac dysfunction as a result of endothelial dysfunction

Systemic Inflammatory Response Syndrome (SIRS) in the presence of an infection constitutes sepsis. Initially, blood flow to the heart is preserved by autonomic regulation and tachycardia. At a later persistent inflammatory state of sepsis, there is an increase in endothelial ROS that leads to microvascular endothelial dysfunction. Altered endothelium-leukocyte interaction further exacerbates microvascular dysfunction and ROS production, which act as a feed-forward loop in sepsis. Together, these result in unequal oxygen delivery to and demand in the septic myocardial tissue. Increase in ROS (e.g. superoxide, peroxynitrite) generation in endocardium contributes to abnormal myocardial contractility and eventual cardiac dysfunction. Candidate biomarkers are indicated: soluble fms-like tyrosine kinase/sVEGFR1 (sFlt-1), plasminogen activator inhibitor-1 (PAI-1), sE-selectin, soluble intercellular adhesion molecule (sICAM-1), and soluble vascular cell adhesion molecule (sVCAM-1).

Figure 2. Effects of sepsis on endocardium

Cardiac dysfunction in the setting of sepsis is associated with abnormal oxygen delivery and consumption, initially preserved blood flow by increasing heart rate (HR), increased formation of reactive oxygen species, altered leukocyte-endothelium interactions, and microcirculatory dysfunction. HR, Heart Rate; O2•, Superoxide; ONOO, Peroxynitrite.