Promotion of vascular integrity in sepsis through modulation of bioactive adrenomedullin and dipeptidyl peptidase 3

Lier, Dirk van; Kox, Matthijs; Pickkers, Peter

doi:10.1111/joim.13220

Cited by 29 publications

(25 citation statements)

References 151 publications

(256 reference statements)

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“…As cDPP3 has a half-life of only 20 to 70 min, 13,19 high levels induced by surgery should quickly normalise, provided tissue perfusion is adequate and no additional cellular necrosis occurs. By analogy, if cDPP3 levels remain high despite treatment, this signals that tissue perfusion is persistently impaired through factors not directly related to surgery-induced tissue injury, indicating an increased risk for the development of organ failure and impaired outcomes 7 . In line with the above, the vast majority of patients in our cohort showed normalised cDPP3 levels (below the upper normal range of 40 ng ml −1 ) on day 2 of ICU admission, with only emergency surgery patients being the notable exception.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Adrenomedullin (ADM) is a key hormone involved in the regulation of endothelial barrier function and vascular tone 6,7 . Dipeptidyl peptidase 3 (DPP3) is a ubiquitous cytosolic enzyme involved in the degradation of several important regulators of vascular tone, most notably angiotensin II 7,8 . Whenever cell injury occurs, intracellular DPP3 is released into the circulation (cDPP3), 7 and the subsequent degradation of angiotensin II may contribute to haemodynamic instability.…”

Section: Introductionmentioning

confidence: 99%

“…Dipeptidyl peptidase 3 (DPP3) is a ubiquitous cytosolic enzyme involved in the degradation of several important regulators of vascular tone, most notably angiotensin II 7,8 . Whenever cell injury occurs, intracellular DPP3 is released into the circulation (cDPP3), 7 and the subsequent degradation of angiotensin II may contribute to haemodynamic instability. Increased levels of both bioactive ADM (bio-ADM) and cDPP3 are associated with the development of organ failure and increased mortality in cardiogenic shock and sepsis patients 9–11 .…”

Section: Introductionmentioning

confidence: 99%

“…Increased levels of both bioactive ADM (bio-ADM) and cDPP3 are associated with the development of organ failure and increased mortality in cardiogenic shock and sepsis patients 9–11 . Thus, ADM and DPP3 represent two distinct molecular pathways, which could be involved in the development of circulatory shock 7 . Furthermore, both biomarkers represent promising targets for drug therapy, as ADM-modulating and DPP3-modulating treatments have shown beneficial effects in animal models of cardiogenic and septic shock 12–14 …”

Section: Introductionmentioning

confidence: 99%

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The value of bioactive adrenomedullin and dipeptidyl peptidase 3 to predict short-term unfavourable outcomes after cardiac surgery

Lier

Beunders

Kox

et al. 2022

European Journal of Anaesthesiology

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BACKGROUND Adrenomedullin (ADM) is a key regulator of endothelial barrier function and vascular tone. Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of several cardiovascular mediators. Increased levels of bioactive ADM (bio-ADM) and circulating DPP3 (cDPP3) were found to predict short-term outcome in cardiogenic shock patients.OBJECTIVES To investigate the unknown temporal profiles of bio-ADM and cDPP3 and their association with short-term outcome following cardiac surgery.DESIGN Prospective observational study of 203 adult cardiac surgery patients admitted to the intensive care unit (ICU) postoperatively. Plasma bio-ADM and cDPP3 levels were measured at ICU admission (day 1) and on days 2 and 3.MAIN OUTCOME MEASURES Biomarker prediction of prolonged vasopressor dependency (>3 days), acute kidney injury (AKI) and prolonged ICU length of stay (ICU-LOS) (>3 days).RESULTS bio-ADM and cDPP3 levels displayed distinct temporal profiles following cardiac surgery. cDPP3 levels were highest on day 1 and strongly correlated with surgical complexity and duration but subsequently normalised on day 2 in most patients. In contrast, bio-ADM levels on day 1 were within the normal range but subsequently increased. Day 2 bio-ADM levels were strongly associated with study outcomes: the area under the receiver-operating curves (AUROC) were 0.82 (95% CI, 0.72 to 0.92) for prolonged vasopressor dependency, 0.87 (0.81 to 0.92) for AKI and 0.82 (0.75 to 0.90) for prolonged ICU-LOS (all P < 0.0001). cDPP3 levels on day 2 also predicted these outcomes, albeit to a lesser extent, with AUROCs of 0.73 (95% CI, 0.64 to 0.81) for prolonged vasopressor dependency, 0.69 (0.61 to 0.77) for AKI and 0.70 (0.62 to 0.79) for prolonged ICU-LOS (all P < 0.0001).CONCLUSION Following cardiac surgery, increased bio-ADM levels are strongly associated with unfavourable short-term outcomes, whereas cDPP3 levels are mainly related to surgery complexity and duration. On the basis of these findings, ADM-modulating therapies may have beneficial effects in cardiac surgery patients whereas DPP3targeted therapies should be reserved for patient categories with higher baseline disease severity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%