Apelin-13 in septic shock: effective in supporting hemodynamics in sheep but compromised by enzymatic breakdown in patients

Abstract

Sepsis is a prevalent life-threatening condition related to a systemic infection, and with unresolved issues including refractory septic shock and organ failures. Endogenously released catecholamines are often inefficient to maintain blood pressure, and low reactivity to exogenous catecholamines with risk of sympathetic overstimulation is well documented in septic shock. In this context, apelinergics are efficient and safe inotrope and vasoregulator in rodents. However, their utility in a larger animal model as well as the limitations with regards to the enzymatic breakdown during sepsis, need to be investigated. The therapeutic potential and degradation of apelinergics in sepsis were tested experimentally and in a cohort of patients. (1) 36 sheep with or without fecal peritonitis-induced septic shock (a large animal experimental design aimed to mimic the human septic shock paradigm) were evaluated for hemodynamic and renal responsiveness to incremental doses of two dominant apelinergics: apelin-13 (APLN-13) or Elabela (ELA), and (2) 52 subjects (33 patients with sepsis/septic shock and 19 healthy volunteers) were investigated for early levels of endogenous apelinergics in the blood, the related enzymatic degradation profile, and data regarding sepsis outcome. APLN-13 was the only one apelinergic which efficiently improved hemodynamics in both healthy and septic sheep. Endogenous apelinergic levels early rose, and specific enzymatic breakdown activities potentially threatened endogenous apelin system reactivity and negatively impacted the outcome in human sepsis. Short-term exogenous APLN-13 infusion is helpful in stabilizing cardiorenal functions in ovine septic shock; however, this ability might be impaired by specific enzymatic systems triggered during the early time course of human sepsis. Strategies to improve resistance of APLN-13 to degradation and/or to overcome sepsis-induced enzymatic breakdown environment should guide future works.

Apelin-13 as a Potential Biomarker in Critical Illness

“…The biological efficacy of the apelin system is compromised under some environmental pressure. For example, in human sepsis, endogenous apelinergic levels rise early, and specific enzymatic breakdown activities potentially threaten endogenous apelin system reactivity and negatively impact the outcome [35]. Furthermore, the short-term exogenous apelin-13 infusion helps stabilize cardiorenal functions in ovine septic shock; however, this ability might be impaired by specific enzymatic systems triggered during the early course of human sepsis [35].…”

Ventriculo-arterial (un)coupling in septic shock: Impact of current and upcoming hemodynamic drugs

“…VAC, as well as ventricular mechanical efficiency, are improved by more than 40% with APL-13 infusion in experimental ischemic failing hearts with an induced increase of the Ea/Ees ratio ( 61 ). APL-13 also clearly improves the left ventricular P/V relationship and reduces Ea in small and large animal models of septic shock ( 58 – 60 ). Essentially studied at the preclinical level, APL have been also assayed in humans (both healthy volunteers and patients with pulmonary arterial hypertension and heart failure).…”

“…AVP-specific V2 receptors (V2aR) in the heart can have a positive inotropic effect but needs gene transfer overexpression ( 57 ). APL are still molecules in development, but in the preclinical stage, they improve cardiac function, diuresis, and the cardiorenal axis, counteracting the AVP activities ( 58 – 60 ). However, the inotrope ability of APL is still a matter of debate (despite several demonstrations in vivo and in isolated hearts ex vivo ).…”

Multi-Omics Techniques Make it Possible to Analyze Sepsis-Associated Acute Kidney Injury Comprehensively

“…In all mammals (but most commonly used in large mammals (pigs and sheep) and zebrafish), direct bacterial delivery of live bacteria from Gram-negative and Gram-positive bacteria directly to the host (vein, peritoneal, subcutaneous, or directly into organs) is commonly used ( 20 ). In a recent prospective controlled study, the septic shock sheep model was widely used to study SA-AKI in vivo using Gram-negative bacteria and to assess renal function, histology, and glomerular ultrastructure in patients with septic shock ( 21 ). It overcomes the shortcomings of the endotoxin model and supports the view that early SA-AKI represents renal insufficiency.…”