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In this preliminary uncontrolled case series of terminally critically ill patients with refractory shock due to septic shock and septic cardiomyopathy, the administration of the specific inhibitory anti-DPP3 antibody was well tolerated and followed by improvements in clinical parameters. It is important to note that the non-controlled design and the small sample size preclude any definitive statements about the safety and potential efficacy of the anti-DPP3 antibody in refractory shock patients, and that no causality can be claimed between the application of the anti-DPP3 antibody and the shock reversal observed in the three patients. Still, the results of this case series are encouraging for the ongoing clinical development programme.

Early recognition and timely treatment of sepsis and septic shock is vital. Despite appropriate management, mortality and morbidity rates remain high. In recent years, many of the research efforts have been directed towards finding novel biomarkers that would rapidly identify, classify and risk-stratify the severity of sepsis in order to achieve prompt and targeted treatment of patients with sepsis and septic shock. Among these biomarkers, adrenomedullin (ADM) in the form of the biologically active fragment (bioADM) and dipeptidyl peptidase 3 (DPP3) have recently been in the spotlight. The aim of this narrative review is to summarize current evidence on these two novel biomarkers regarding their clinical utility in diagnosis, prognosis, treatment monitoring and therapy guidance of sepsis and septic shock in the emergency department (ED) and in the intensive care unit (ICU) setting. Bio-ADM seems to be a promising biomarker with respect to the overall management of sepsis (diagnosis, severity prediction, prognosis and treatment monitoring and guidance). On the other hand, DPP3 appears to be useful mainly for sepsis prognosis and for predicting sepsis-induced acute kidney injury. Given their potential clinical utility in sepsis management, the use of these two novel biomarkers, in conjunction with established biomarkers and clinical scores, could lead to the application of refined integrated protocols in the ED and the ICU, which could promptly and effectively inform clinical decision-making in patients presenting with sepsis or septic shock.

"Methods: Using plasma samples collected from participants enrolled in the fourth Accelerating COVID-19 Therapeutic Interventions and Vaccines Host Tissue platform trial, we measured DPP3 and renin in 184 subjects hospitalized with acute hypoxemia from COVID-19 without baseline vasopressor requirement. We calculated the odds ratio of development of shock (defined as the initiation of vasopressor therapy) by Day 28 based on Day 0 DPP3 and renin levels. Results: Subjects with DPP3 above the median had a significantly higher incidence of vasopressor initiation within 28 days (28.4 % vs. 16.7 %, p = 0.031) and higher 28-day mortality (25.0 % vs. 6.7 %, p < 0.001). After adjusting for covariables, DPP3 above the median was associated with shorter time to vasopressor initiation, greater 28-day mortality, fewer vasopressor-free days, and greater odds of a hypotensive event over 7 days. Significant associations were not observed for renin. Conclusions: In patients hospitalized with COVID-19 and hypoxemia without baseline hypotension, higher baseline plasma levels of DPP3 but not renin were associated with increased risk of subsequent shock and death."

Cardiogenic shock (CS) carries a 30–50% in-hospital mortality rate, with little improvement in outcomes in the last decade. Challenges in improving outcomes are closely linked to the frequent late presentation or diagnosis of CS where the ‘point of no return’ has often passed, leading to haemodynamic dysregulation, progressive myocardial depression, hypotension, and a downward spiral of hypoperfusion, organ dysfunction and decreasing myocardial function, driven by inflammation and metabolic derangements. Novel therapeutic interventions may have varying efficacy depending on the type and stage of shock in which they are applied. Biomarkers that aid prediction and early detection of CS, provide early signs of organ dysfunction and define prognosis could help optimize management. Temporal change in such biomarkers, particularly in response to pharmacological interventions and/or mechanical circulatory support, can guide management and predict outcome. Several novel biomarkers enhance the prediction of mortality in CS, compared to conventional parameters such as lactate, with some, such as adrenomedullin and circulating dipeptidyl peptidase 3, also able to predict the development of CS. Some biomarkers reflect systemic inflammation (e.g. interleukin-6, angiopoietin 2, fibroblast growth factor 23 and suppressor of tumorigenicity 2) and are not specific to CS, yet inform on the activation of important pathways involved in the downward shock spiral. Other biomarkers signal end-organ hypoperfusion and could guide targeted interventions, while some may serve as novel therapeutic targets. We critically review current and novel biomarkers that guide prediction, detection, and prognostication in CS. Future use of biomarkers may help improve management in these high-risk patients.

"Cardiogenic shock is a complex syndrome defined by systemic hypoperfusion and inadequate cardiac output arising from a wide array of underlying causes. Although the understanding of cardiogenic shock epidemiology, specific subphenotypes, haemodynamics, and cardiogenic shock severity staging has evolved, few therapeutic interventions have shown survival benefit. Results from seminal randomised controlled trials support early revascularisation of the culprit vessel in infarct-related cardiogenic shock and provide evidence of improved survival with the use of temporary circulatory support in selected patients. However, numerous questions remain unanswered, including optimal pharmacotherapy regimens, the role of mechanical circulatory support devices, management of secondary organ dysfunction, and best supportive care. This Review summarises current definitions, pathophysiological principles, and management approaches in cardiogenic shock, and highlights key knowledge gaps to advance individualised shock therapy and the evidence-based ethical use of modern technology and resources in cardiogenic shock."

"The classification of cardiogenic shock (CS) has evolved from a singular cold-and wet-hemodynamic profile. Data from registries and clinical trials have contributed to a broader recognition that although all patients with CS have insufficient cardiac output leading to end organ hypoperfusion, there is considerable variability in CS acuity, underlying etiologies, volume status, and systemic vascular resistance. Mixed CS can be broadly categorized as CS with at least 1 additional shock state. Mixed CS states are now the second leading cause of shock in contemporary coronary intensive care units, but there is little high-quality evidence to guide routine care, and there are no standardized classification frameworks or well-established hemodynamic definitions. This primer summarizes the current epidemiology and proposes a classification framework and invasive hemodynamic parameters to guide categorization that could be applied to help better phenotype patients captured in registries and trials, as well as guide management of mixed CS states."

"In cardiogenic shock, biomarkers should ideally help make the diagnosis, choose the right therapeutic options and monitor the patient in addition to clinical and echocardiographic indices. Among “old” biomarkers that have been used for decades, lactate detects, quantifies, and follows anaerobic metabolism, despite its lack of specificity. Renal and liver biomarkers are indispensable for detecting the effect of shock on organ function and are highly predictive of poor outcomes. Direct biomarkers of cardiac damage such as cardiac troponins, B-type natriuretic and N-terminal pro-B-type natriuretic peptides have a good prognostic value, but they lack specificity to detect a cardiogenic cause of shock, as many factors influence their plasma concentrations in critically ill patients. Among the biomarkers that have been more recently described, dipeptidyl peptidase-3 is one of the most interesting. In addition to its prognostic value, it could represent a therapeutic target in cardiogenic shock in the future as a specific antibody inhibits its activity. Adrenomedullin is a small peptide hormone secreted by various tissues, including vascular smooth muscle cells and endothelium, particularly under pathological conditions. It has a vasodilator effect and has prognostic value during cardiogenic shock. An antibody inhibits its activity and so adrenomedullin could represent a therapeutic target in cardiogenic shock. An increasing number of inflammatory biomarkers are also of proven prognostic value in cardiogenic shock, reflecting the inflammatory reaction associated with the syndrome. Some of them are combined to form prognostic proteomic scores. Alongside clinical variables, biomarkers can be used to establish biological “signatures” characteristic of the pathophysiological pathways involved in cardiogenic shock. This helps describe patient subphenotypes, which could in the future be used in clinical trials to define patient populations responding specifically to a treatment."

"The management of cardiogenic shock is an ongoing challenge. Despite all efforts and tremendous use of resources, mortality remains high. Whilst reversing the underlying cause, restoring/maintaining organ perfusion and function are cornerstones of management. The presence of comorbidities and preexisting organ dysfunction increases management complexity, aiming to integrate the needs of vital organs in each individual patient. This review provides a comprehensive overview of contemporary literature regarding the definition and classification of cardiogenic shock, its pathophysiology, diagnosis, laboratory evaluation, and monitoring. Further, we distill the latest evidence in pharmacologic therapy and the use of mechanical circulatory support including recently published randomized-controlled trials as well as future directions of research, integrating this within an international group of authors to provide a global perspective. Finally, we explore the need for individualization, especially in the face of neutral randomized trials which may be related to a dilution of a potential benefit of an intervention (i.e., average effect) in this heterogeneous clinical syndrome, including the use of novel biomarkers, artificial intelligence, and machine learning approaches to identify specific endotypes of cardiogenic shock (i.e., subclasses with distinct underlying biological/molecular mechanisms) to support a more personalized medicine beyond the syndromic approach of cardiogenic shock"

Recent years have seen a resurgence of interest for the renin–angiotensin–aldosterone system in critically ill patients. Emerging data suggest that this vital homeostatic system, which plays a crucial role in maintaining systemic and renal hemodynamics during stressful conditions, is altered in septic shock, ultimately leading to impaired angiotensin II angiotensin II type 1 receptor signaling. Indeed, available evidence from both experimental models and human studies indicates that alterations in the renin–angiotensin–aldosterone system during septic shock can occur at three distinct levels: 1. Impaired generation of angiotensin II, possibly attributable to defects in angiotensin-converting enzyme activity; 2. Enhanced degradation of angiotensin II by peptidases; and/or 3. Unavailability of angiotensin II type 1 receptor due to internalization or reduced synthesis. These alterations can occur either independently or in combination, ultimately leading to an uncoupling between the renin angiotensin–aldosterone system input and downstream angiotensin II type 1 receptor signaling. It remains unclear whether exogenous angiotensin II infusion can adequately address all these mechanisms, and additional interventions may be required. These observations open a new avenue of research and offer the potential for novel therapeutic strategies to improve patient prognosis. In the near future, a deeper understanding of renin angiotensin–aldosterone system alterations in septic shock should help to decipher patients’ phenotypes and to implement targeted interventions.

Background Dipeptidyl peptidase 3 (DPP3) is a ubiquitous cytosolic enzyme released into the bloodstream after tissue injury, that can degrade angiotensin II. High concentrations of circulating DPP3 (cDPP3) have been associated with worse outcomes during sepsis. The aim of this study was to assess the effect of Procizumab (PCZ), a monoclonal antibody that neutralizes cDPP3, in an experimental model of septic shock. Methods In this randomized, open-label, controlled study, 16 anesthetized and mechanically ventilated pigs with peritonitis were randomized to receive PCZ or standard treatment when the mean arterial pressure (MAP) dropped below 50 mmHg. Resuscitation with fluids, antimicrobial therapy, peritoneal lavage, and norepinephrine was initiated one hour later to maintain MAP between 65–75 mmHg for 12 h. Hemodynamic variables, tissue oxygenation indices, and measures of organ failure and myocardial injury were collected. Organ blood flow was assessed using isotopic assessment (99mtechnetium albumin). cDPP3 activity, equilibrium analysis of the renin–angiotensin system and circulating catecholamines were measured. Tissue mRNA expression of interleukin-6 and downregulation of adrenergic and angiotensin receptors were assessed on vascular and myocardial samples. Results PCZ-treated animals had reduced cDPP3 levels and required less norepinephrine and fluid than septic control animals for similar organ perfusion and regional blood flow. PCZ-treated animals had less myocardial injury, and higher PaO2/FiO2 ratios. PCZ was associated with lower circulating catecholamine levels; higher circulating angiotensin II and higher angiotensin II receptor type 1 myocardial protein expression, and with lower myocardial and radial artery mRNA interleukin-6 expression. Conclusions In an experimental model of septic shock, PCZ administration was associated with reduced fluid and catecholamine requirements, less myocardial injury and cardiovascular inflammation, along with preserved angiotensin II signaling.

Background: High circulating DPP3 (dipeptidyl peptidase 3) has been associated with poor prognosis in critically ill patients with circulatory failure. In such situation, DPP3 could play a pathological role, putatively via an excessive angiotensin peptides cleavage. Our objective was to investigate the hemodynamics changes induced by DPP3 in mice and the relation between the observed effects and renin-angiotensin system modulation. Methods: Ten-week-old male C57Bl/6J mice were subjected to intravenous injection of purified human DPP3 or an anti-DPP3 antibody (procizumab). Invasive blood pressure and renal blood flow were monitored throughout the experiments. Circulating angiotensin peptides and catecholamines were measured and receptor blocking experiment performed to investigate the underlying mechanisms. Results: DPP3 administration significantly increased renal blood flow, while blood pressure was minimally affected. Conversely, procizumab led to significantly decreased renal blood flow. Angiotensin peptides measurement and an AT1R (angiotensin II receptor type 1) blockade experiment using valsartan demonstrated that the renovascular effect induced by DPP3 is due to reduced AT1R activation via decreased concentrations of circulating angiotensin II, III, and IV. Measurements of circulating catecholamines and an adrenergic receptor blockade by labetalol demonstrated a concomitant catecholamines release that explains blood pressure maintenance upon DPP3 administration. Conclusions: High circulating DPP3 increases renal blood flow due to reduced AT1R activation via decreased concentrations of circulating angiotensin peptides while blood pressure is maintained by concomitant endogenous catecholamines release.

Purpose: Biomarkers independently associated with outcome of intensive care unit (ICU) patients can improve risk assessment. The cytosolic protease dipeptidyl-peptidase 3 (DPP3) is released into the circulation upon cell necrosis. We aimed to investigate the prognostic properties of cDPP3 in a mixed-admission ICU cohort. Materials and methods: Prospective observational study in 650 adult ICU patients. cDPP3 concentrations were measured at ICU admission (day 1), and on days 2 and 3. Results: cDPP3 concentrations on days 1 and 2, but not on day 3 were associated with 28-day mortality; HR 1.36 (95%CI 1.01-1.83, p = 0.043) and HR 1.49 (95%CI 1.16-1.93, p = 0.002) for days 1 and 2, respectively. cDPP3 was also associated with acute kidney injury (AKI), with OR's of 1.31 (95%CI 1.05-1.64, p = 0.016), 1.87 (95%CI 1.51-2.34, p < 0.001) and 1.49 (95%CI 1.16-1.92, p = 0.002) for measurements performed on days 1, 2, and 3, respectively. In multivariate analyses including SOFA or APACHE-II scores, cDPP3 assessed at day 2 of admission remained an independent predictor of mortality and all-stage AKI. Conclusions: In a mixed-ICU cohort, cDPP3 concentrations after start of initial treatment were independently associated with both mortality and development of AKI. Therefore, measurement of cDPP3 can improve risk-stratification provided by established disease severity scores.

Background and Aims Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of angiotensin II which disturbs peripheral blood pressure regulation and compromises left ventricular function. This study examined the relationship of circulating DPP3 (cDPP3) with cardiogenic shock (CS) and mortality in patients presenting with acute coronary syndromes (ACS). Methods Plasma cDPP3 levels were assessed at baseline and 12–24 h after presentation in patients with ACS prospectively enrolled into the multi-centre SPUM-ACS study (n = 4787). Results Circulating DPP3 levels were associated with in-hospital CS when accounting for established risk factors including the ORBI risk score [per log-2 increase, hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.05–1.82, P = .021]. High cDPP3 was an independent predictor of mortality at 30 days (HR 1.87, 95% CI 1.36–2.58, P < .001) and at one year (HR 1.61, 95% CI 1.28–2.02, P < .001) after adjustment for established risk factors and the GRACE 2.0 score. Compared to values within the normal range, persistently elevated cDPP3 levels at 12–24 h were associated with 13.4-fold increased 30-day mortality risk (HR 13.42, 95% CI 4.86–37.09, P < .001) and 5.8-fold increased 1-year mortality risk (HR 5.79, 95% CI 2.70–12.42, P < .001). Results were consistent across various patient subgroups. Conclusions This study identifies cDPP3 as a novel marker of CS and increased mortality in patients with ACS. Circulating DPP3 offers prognostic information beyond established risk factors and improves early risk assessment.

Biomarkers as Prognostic Predictors and Guide in Critically Ill Patients

Dipeptidyl peptidase 3 (DPP3), a zinc-dependent aminopeptidase, is a highly conserved enzyme among higher animals. The enzyme cleaves dipeptides from the N-terminus of tetra- to decapeptides, thereby taking part in activation as well as degradation of signalling peptides critical in physiological and pathological processes such as blood pressure regulation, nociception, inflammation and cancer. Besides its catalytic activity, DPP3 moonlights as a regulator of the cellular oxidative stress response pathway, e.g., the Keap1-Nrf2 mediated antioxidative response. The enzyme is also recognized as a key modulator of the renin-angiotensin system. Recently, DPP3 has been attracting growing attention within the scientific community, which has significantly augmented our knowledge of its physiological relevance. Herein, we review recent advances in our understanding of the structure and catalytic activity of DPP3, with a focus on attributing its molecular architecture and catalytic mechanism to its wide-ranging biological functions. We further highlight recent intriguing reports that implicate a broader role for DPP3 as a valuable biomarker in cardiovascular and renal pathologies and furthermore discuss its potential as a promising drug target.

Dipeptidyl amino-peptidase 3 (DPP3) is an aminopeptidase that is released into circulation upon cell death. DPP3 is involved in the degradation of angiotensins, enkephalines, and endomorphines. It has been shown that circulating DPP3 (cDPP3) plasma concentration increases in cardiogenic shock (CS) patients and correlates with high mortality risk. Cardiogenic shock is a life threatening syndrome associated with organ hypoperfusion. One of the common causes of CS is acute myocardial infarction (AMI). This study aimed to investigate if cDPP3 levels are associated with CS severity and the need for ventilation in patients suffering from CS. Fifteen patients with CS were included in this study. Six patients were invasively ventilated. The values of cDPP3 were higher in ventilated patients than in non-ventilated patients at admission, 3 h, and 24 h after admission in the intensive care unit. Patients with pulmonary hypertension at admission also showed high cDPP3 values at all time points. Furthermore, high cDPP3 levels were associated with reduced stroke volume. Our results suggest that cDPP3 could predict CS progression and guide therapy escalation.

A biomarker is a molecule that can be measured in a biological sample in an objective, systematic, and precise way, whose levels indicate whether a process is normal or pathological. Knowing the most important biomarkers and their characteristics is the key to precision medicine in intensive and perioperative care. Biomarkers can be used to diagnose, in assessment of disease severity, to stratify risk, to predict and guide clinical decisions, and to guide treatments and response to them. In this review, we will analyze what characteristics a biomarker should have and how to ensure its usefulness, and we will review the biomarkers that in our opinion can make their knowledge more useful to the reader in their clinical practice, with a future perspective. These biomarkers, in our opinion, are lactate, C-Reactive Protein, Troponins T and I, Brain Natriuretic Peptides, Procalcitonin, MR-ProAdrenomedullin and BioAdrenomedullin, Neutrophil/lymphocyte ratio and lymphopenia, Proenkephalin, NefroCheck, Neutrophil gelatinase-associated lipocalin (NGAL), Interleukin 6, Urokinase-type soluble plasminogen activator receptor (suPAR), Presepsin, Pancreatic Stone Protein (PSP), and Dipeptidyl peptidase 3 (DPP3). Finally, we propose an approach to the perioperative evaluation of high-risk patients and critically ill patients in the Intensive Care Unit (ICU) based on biomarkers.

Background: High circulating DPP3 (dipeptidyl peptidase 3) has been associated with poor prognosis in critically ill patients with circulatory failure. In such situation, DPP3 could play a pathological role, putatively via an excessive angiotensin peptides cleavage. Our objective was to investigate the hemodynamics changes induced by DPP3 in mice and the relation between the observed effects and renin-angiotensin system modulation. Methods: Ten-week-old male C57Bl/6J mice were subjected to intravenous injection of purified human DPP3 or an anti-DPP3 antibody (procizumab). Invasive blood pressure and renal blood flow were monitored throughout the experiments. Circulating angiotensin peptides and catecholamines were measured and receptor blocking experiment performed to investigate the underlying mechanisms. Results: DPP3 administration significantly increased renal blood flow, while blood pressure was minimally affected. Conversely, procizumab led to significantly decreased renal blood flow. Angiotensin peptides measurement and an AT1R (angiotensin II receptor type 1) blockade experiment using valsartan demonstrated that the renovascular effect induced by DPP3 is due to reduced AT1R activation via decreased concentrations of circulating angiotensin II, III, and IV. Measurements of circulating catecholamines and an adrenergic receptor blockade by labetalol demonstrated a concomitant catecholamines release that explains blood pressure maintenance upon DPP3 administration. Conclusions: High circulating DPP3 increases renal blood flow due to reduced AT1R activation via decreased concentrations of circulating angiotensin peptides while blood pressure is maintained by concomitant endogenous catecholamines release.

Introduction: Dipeptidyl peptidase-3 (DPP3) is a protease involved in the degradation of several cardiovascular mediators. Adrenomedullin (bio-ADM) is a peptide essential for regulation of endothelial barrier function. In different shock-pathologies, both biomarkers are associated with disease severity, organ dysfunction and mortality. Associations with outcome in critically ill COVID-19 patients are unknown. The objectives of the present study were to investigate associations of bio-ADM and "circulating DPP3" (cDPP3) with short-term outcome in critically ill COVID-19 patients (n=80). Methods: A multicentre prospective cohort study was performed. The primary end-point was 28-day mortality. Secondary end-points included different severities of acute kidney injury (AKI). Results: cDPP3 levels were mainly associated with 28-day mortality; Area under the receiver operating characteristics (AUROCs) of 0.69 (0.56-0.82, p=0.023), 0.77 (0.64-0.90, p<0.001) and 0.81 (0.65-0.96, p<0.001) at admission, day 3 and day 7, respectively. In contrast, bio-ADM levels were mainly associated with AKI, with AUROCs of 0.64 (0.51-0.77, p=0.048), 0.75 (0.64-0.86, p<0.001) and 0.83 (0.74-0.93, p<0.001) for day 1, 3 and 7, respectively. Interestingly, patients with high levels of both cDPP3 and bio-ADM at day 7 had an additionally increased risk of 28-day mortality (hazard ratio 11.8; 95% CI 2.5-55.3, p<0.001). Conclusions: cDPP3 and bio-ADM responses were associated with short-term mortality and AKI in critically ill COVID-19 patients, respectively. These findings suggest that treatment with specific antibodies modulating cDPP3 or bio-ADM-related pathways may improve outcome of COVID-19.

Background: Dipeptidyl peptidase 3 (DPP-3) is an intracellular enzyme that causes hemodynamic instability and cardiac depression in several cases such as cardiogenic shock, sepsis and burns where DPP-3 is released into the blood due to cell death. Data on the effect of higher DPP-3 levels on acute coronary syndrome (ACS) patients are currently lacking. The aim of this study was to evaluate the effect of DPP-3 levels on ACS patients. Methods: In this prospective study, we included ACS patients including STEMI and non-STEMI groups and a control group to compare various demographic, echocardiographic and laboratory parameters including DPP-3. DPP-3 levels were measured at 24th, 48th, and 72nd h from the onset of symptoms in ACS patients and then compared with left ventricle ejection fraction (LVEF) for the assessment of left ventricle systolic function. Results: A total of 70 ACS patients (age 62.5 ± 11 years, 68.6% male) were recruited and 48 normal individuals were included as control group (age 61.1 ± 10 years, 66.7% male). It has been demonstrated that DPP-3 levels are significantly higher in the ACS group than the control group like troponin I levels. DPP-3 levels were found to be one of the independent predictors of LVEF similar to NT-proBNP and troponin I. Conclusions: This study suggests that DPP-3 could be an important indicator of myocardial depression predicting left ventricle systolic function in ACS.

Cardiovascular disease is the leading cause of death globally among non-communicable diseases, which imposes a serious socioeconomic burden on patients and the healthcare system. Therefore, finding new strategies for preventing and treating cardiovascular diseases is of great significance in reducing the number of deaths and disabilities worldwide. Dipeptidyl peptidase 3 (DPP3) is the first zinc-dependent peptidase found among DPPs, mainly distributes within the cytoplasm. With the unique HEXXGH catalytic sequence, it is associated with the degradation of oligopeptides with 4 to 10 amino acids residues. Accumulating evidences have demonstrated that DPP3 plays a significant role in almost all cellular activities and pathophysiological mechanisms. Regarding the role of DPP3 in cardiovascular diseases, it is currently mainly used as a biomarker for poor prognosis in patients with cardiovascular diseases, suggesting that the level of DPP3 concentration in plasma is closely linked to the mortality of diseases such as cardiogenic shock and heart failure. Interestingly, it has been reported recently that DPP3 regulates blood pressure by interacting with the renin-angiotensin system. In addition, DPP3 also participates in the processes of pain signaling, inflammation, and oxidative stress. But the exact mechanism by which DPP3 affects cardiovascular function is not clear. Hence, this review summarizes the recent advances in the structure and catalytic activity of DPP3 and its extensive biological functions, especially its role as a therapeutic target in cardiovascular diseases. It will provide a theoretical basis for exploring the potential value of DPP3 as a therapeutic target for cardiovascular diseases.

Dipeptidyl peptidase 3 (DPP3), a zinc-dependent aminopeptidase, is a highly conserved enzyme among higher animals. The enzyme cleaves dipeptides from the N-terminus of tetra- to decapeptides, thereby taking part in activation as well as degradation of signalling peptides critical in physiological and pathological processes such as blood pressure regulation, nociception, inflammation and cancer. Besides its catalytic activity, DPP3 moonlights as a regulator of the cellular oxidative stress response pathway, e.g., the Keap1-Nrf2 mediated antioxidative response. The enzyme is also recognized as a key modulator of the renin-angiotensin system. Recently, DPP3 has been attracting growing attention within the scientific community, which has significantly augmented our knowledge of its physiological relevance. Herein, we review recent advances in our understanding of the structure and catalytic activity of DPP3, with a focus on attributing its molecular architecture and catalytic mechanism to its wide-ranging biological functions. We further highlight recent intriguing reports that implicate a broader role for DPP3 as a valuable biomarker in cardiovascular and renal pathologies and furthermore discuss its potential as a promising drug target.

Background: Patients with cirrhosis suffer from a complex multiorgan disturbance and their prognosis is influenced by the development of portal hypertension and systemic circulatory dysfunction. Although non-invasive techniques such as transient elastography aid in early detection, there is an unmet need for reliable markers of these clinically significant complications. Methods: We conducted an exploratory single-center study investigating dipeptidyl peptidase-3 (DPP3) concentrations in various vascular beds in a cohort of 48 patients with cirrhosis and 16 healthy controls. Liver vein catheterisation with sampling from femoral artery and femoral, renal and hepatic veins as well as measurement of hepatic pressure and liver function via indocyanine green and galactose elimination tests were performed. Results: DPP3 concentrations were higher in cirrhotic patients compared to controls (12.6 vs. 7.4 ng/mL, p = 0.006) and increased according to the severity of cirrhosis. DPP3 associated with MELD-Na score, Child class, indocyanine green clearance, increased DPP3 with the increased hepatic venous pressure gradient (p = 0.015) as well as increased heart rate and reduced systemic vascular resistance. DPP3 concentrations predicted the presence of clinically significant portal hypertension in cirrhotic patients (AUROC 0.78, 95% CI 0.65-0.9). Conclusion: DPP3 is a promising marker for portal hypertension and systemic hemodynamic changes in cirrhosis.

Background Our aim was to investigate the prognostic potential of circulating dipeptidyl peptidase 3 (cDPP3) to predict mortality and development of organ dysfunction in a mixed intensive care unit (ICU) population, and for this reason, we analysed prospectively collected admission blood samples from adult ICU patients at four Swedish hospitals. Blood samples were stored in a biobank for later batch analysis. The association of cDPP3 levels with 30-day mortality and Sequential Organ Failure Assessment (SOFA) scores on day two was investigated before and after adjustment for the simplified acute physiology score III (SAPS-3), using multivariable (ordinal) logistic regression. The predictive power of cDPP3 was assessed using the area under the receiver operating characteristic curve (AUROC). Results Of 1978 included consecutive patients in 1 year (2016), 632 fulfilled the sepsis 3-criteria, 190 were admitted after cardiac arrest, and 157 because of trauma. Admission cDPP3 was independently (of SAPS-3) associated with 30-day mortality with odds ratios of 1.45 (95% confidence interval (CI) 1.28–1.64) in the entire ICU population, 1.30 (95% CI 1.08–1.57) in the sepsis subgroup and 2.28 (95% CI 1.50–3.62) in cardiac arrest. For trauma, there was no clear association. Circulating DPP3 alone was a moderate predictor of 30-day mortality with AUROCs of 0.68, 0.62, and 0.72 in the entire group, the sepsis subgroup, and the cardiac arrest subgroup, respectively. By adding cDPP3 to SAPS-3, AUROC improved for the entire group, the sepsis subgroup, and the cardiac arrest subgroup (p = 0.023). Conclusion Circulating DPP3 on admission is a SAPS-3 independent prognostic factor of day-two organ dysfunction and 30-day mortality in a mixed ICU population and needs further evaluation.

Background: A large proportion of adult survivors of cardiac arrest have a poor neurological outcome. Guidelines recommend multimodal neuro-prognostication no earlier than 72-96 h after cardiac arrest. There is great interest in earlier prognostic markers, including very early markers at admission. The novel blood biomarkers proenkephalin A 119-159 (penKid), bioactive adrenomedullin (bio-ADM) and circulating dipeptidyl peptidase 3 (cDPP3) have not been previously investigated for the early prognosis of cardiac arrest survivors. Methods: This multicentre observational study included adult survivors of cardiac arrest admitted to intensive care at four Swedish intensive care units (ICUs) during 2016. Blood samples were collected at ICU admission and batch analysed. The association between admission plasma penKid, bio-ADM and cDPP3 and poor long-term neurological outcome, according to the Cerebral Performance Category (CPC) scale, was assessed by binary logistic regression. Their prognostic performance was assessed using the area under the receiver operating characteristic curve (AUC). Results: A total of 190 patients were included, of which 136 patients had suffered out-of-hospital and 54 patients in-hospital cardiac arrest. Poor long-term neurological outcome was associated with elevated admission plasma concentrations of penKid and cDPP3, but not with bio-ADM. The association for penKid, but not for cDPP3, remained after adjusting for clinical cardiac arrest variables with prognostic value (time to return of spontaneous circulation (ROSC), initial rhythm, admission Glasgow coma scale (GCS) motor score and absence of pupillary reflexes). The prognostic performance of above mentioned clinical cardiac arrest variables alone was very good with an AUC of 0.90 (95% confidence interval, CI, 0.86-0.95), but improved further with the addition of penKid resulting in an AUC of 0.93 (95% CI 0.89-0.97, p < 0.026). Plasma penKid and cDPP3 alone provided moderate long-term prognostic information with AUCs of 0.70 and 0.71, respectively. Conclusion: After cardiac arrest, admission plasma levels of penKid and cDPP3, but not bio-ADM, predicted long-term neurological outcome. When added to clinical cardiac arrest variables, penKid further improved prognostic performance.

Purpose of review: Circulatory shock is one of the most common reasons for ICU admission. Mortality rates in excess of 40% necessitate the rapid identification of high-risk patients, as well as the early assessment of effects of initiated treatments. There is an unmet medical need for circulating biomarkers that may improve patient stratification, predict responses to treatment interventions and may even be a target for novel therapies, enabling a better biological rationale to personalize therapy. Recent findings: Apart from established biomarkers such as lactate, ScvO2 or NT-pro-BNP, novel biomarkers, including adrenomedullin, angiopoietins, angiotensin I/II ratios, renin and DPP3 show promise, as they are all associated with well defined, therapeutically addressable molecular pathways that are dysregulated during circulatory shock. Although some of the therapies related to these biomarkers are still in preclinical stages of development, they may represent personalized treatment opportunities for patients in circulatory shock. Summary: From a molecular perspective, shock represents a highly heterologous syndrome, in which multiple unique pathways are dysregulated. Assessment of the status of these pathways with circulating biomarkers may provide a unique opportunity to detect specific phenotypes and implement personalized medicine in the treatment of circulatory shock.

Purpose of review: Circulatory shock is one of the most common reasons for ICU admission. Mortality rates in excess of 40% necessitate the rapid identification of high-risk patients, as well as the early assessment of effects of initiated treatments. There is an unmet medical need for circulating biomarkers that may improve patient stratification, predict responses to treatment interventions and may even be a target for novel therapies, enabling a better biological rationale to personalize therapy. Recent findings: Apart from established biomarkers such as lactate, ScvO2 or NT-pro-BNP, novel biomarkers, including adrenomedullin, angiopoietins, angiotensin I/II ratios, renin and DPP3 show promise, as they are all associated with well defined, therapeutically addressable molecular pathways that are dysregulated during circulatory shock. Although some of the therapies related to these biomarkers are still in preclinical stages of development, they may represent personalized treatment opportunities for patients in circulatory shock. Summary: From a molecular perspective, shock represents a highly heterologous syndrome, in which multiple unique pathways are dysregulated. Assessment of the status of these pathways with circulating biomarkers may provide a unique opportunity to detect specific phenotypes and implement personalized medicine in the treatment of circulatory shock.

Introduction Delayed cerebral ischemia (DCI) is a common complication after aneurysmal subarachnoid hemorrhage (aSAH) that can culminate in secondary brain damage. Although it remains one of the main preventable causes of aSAH-related morbidity, there is still a lack of prognostic criteria for identification of patients at risk of developing DCI. Because elevated circulatory levels of the enzyme dipeptidyl peptidase 3 (cDPP3) were recently identified as a potential biomarker for outcome prediction in critically ill patients, we evaluated the time-course of changes in cDPP3 levels after aSAH. Materials and methods cDPP3 levels were quantified in serum obtained from 96 confirmed aSAH patients during the early (EP: d1–4), critical (CP: d5–8, d9–12, d13–15) and late (LP: d16–21) phase after aSAH onset. Associations between cDPP3 levels and demographic or clinical parameters were evaluated. The relations between cDPP3 levels and DCI, DCI-related infarctions and long-term clinical outcomes were examined by receiver operating characteristics (ROC) curve analysis and multivariate logistic regression. Results Significantly higher cDPP3 levels during CP (d5–8, d9–12, d13–15) were observed in patients with poor clinical (p < 0.001 to p = 0.033) or radiological (p = 0.012 to p = 0.039) status on admission, DCI (p < 0.001 to p = 0.001), DCI-related infarctions (p = 0.002 to p = 0.007), and poorer long-term outcome (p = 0.007 to p = 0.019). ROC curve analysis indicated that higher cDPP3 levels on d5–8 are predictive for a poor clinical outcome (area under the curve = 0.677, p = 0.007). In multivariate analysis, there was an independent association between cDPP3 levels on d5–8 and development of DCI-related infarctions (p = 0.038). Conclusion Our results provide first evidence that cDPP3 could serve as a promising biomarker for early diagnosis of DCI-related infarctions in poor grade aSAH patients.

Background Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in the degradation of various cardiovascular and endorphin mediators. High levels of circulating DPP3 (cDPP3) indicate a high risk of organ dysfunction and mortality in cardiogenic shock patients. Methods The aim was to assess relationships between cDPP3 during the initial intensive care unit (ICU) stay and short-term outcome in the AdrenOSS-1, a prospective observational multinational study in twenty-four ICU centers in five countries. AdrenOSS-1 included 585 patients admitted to the ICU with severe sepsis or septic shock. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by the Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use and need for renal replacement therapy. cDPP3 levels were measured upon admission and 24 h later. Results Median [IQR] cDPP3 concentration upon admission was 26.5 [16.2–40.4] ng/mL. Initial SOFA score was 7 [5–10], and 28-day mortality was 22%. We found marked associations between cDPP3 upon ICU admission and 28-day mortality (unadjusted standardized HR 1.8 [CI 1.6–2.1]; adjusted HR 1.5 [CI 1.3–1.8]) and between cDPP3 levels and change in renal and liver SOFA score (p = 0.0077 and 0.0009, respectively). The higher the initial cDPP3 was, the greater the need for organ support and vasopressors upon admission; the longer the need for vasopressor(s), mechanical ventilation or RRT and the higher the need for fluid load (all p < 0.005). In patients with cDPP3 > 40.4 ng/mL upon admission, a decrease in cDPP3 below 40.4 ng/mL after 24 h was associated with an improvement of organ function at 48 h and better 28-day outcome. By contrast, persistently elevated cDPP3 at 24 h was associated with worsening organ function and high 28-day mortality. Conclusions Admission levels and rapid changes in cDPP3 predict outcome during sepsis.

Objectives: Endovascular and open thoraco-abdominal aortic aneurysm (TAAA) repair is associated with specific complications. Circulating dipeptidyl peptidase 3 (cDPP3) is a novel biomarker that shows a strong association with organ failure which has not been assessed in surgical settings. Therefore, the objective of this study was to assess the prognostic capabilities of cDPP3 for predicting patient survival and organ failure following open and endovascular TAAA repair. Methods: Thirty-three patients undergoing TAAA repair were assessed in this prospective observational single-centre study. cDPP3 levels were serially measured perioperatively until 72 h after admission to the intensive care unit (ICU). In-hospital mortality and any organ failure were the clinical end points. Results: Postoperative organ failure was detected in 17 patients (51.5%), and 6 patients died after surgery (18.2%). At 12 h after admission to the ICU, cDPP3 levels were significantly increased in patients who died or developed organ failure (P < 0.001). cDPP3 levels after surgery demonstrated a remarkable predictive accuracy for in-hospital mortality [12 h area under the receiver operating characteristic curve (AUC): 0.907 (P < 0.001), 24 h AUC: 0.815 (P = 0.016), 48 h AUC: 0.914 (P = 0.003)] and the development of organ failure [12 h AUC: 0.882 (P < 0.001), 24 h AUC: 0.850 (P < 0.001), 48 h AUC: 0.846 (P < 0.001)]. Additionally, a significant correlation between cDPP3, the sequential organ failure assessment score and procalcitonin, C-reactive protein and interleukin-6 levels (P < 0.001, P < 0.001, P = 0.011, P = 0.007, respectively) based on all available measurements and time points was observed. Conclusions: The present findings highlight the role of cDPP3 as an early, highly specific postoperative biomarker for prediction of in-hospital mortality and organ failure after TAAA repair.

Purpose of review: Cardiogenic shock is a severe complication with mortality rates of ∼50% that requires a rapid and complex management to aid and identify the highest and lowest risk patients. To that end, novel cardiogenic shock biomarkers are needed to improve risk stratification and to personalize therapy. Recent findings: Established biomarkers such as BNP, NT-proBNP, ST2, and troponins provide insufficient predictive value in cardiogenic shock. More recent biomarkers, including DPP3, adrenomedullin, angiopoietin 2, and the CS4P score are gaining momentum. DPP3 showed early prediction of refractory status and survival in cardiogenic shock. The CS4P score is based on the levels of liver fatty acid-binding protein (L-FABP), beta-2-microglobulin (B2M), fructose-bisphosphate aldolase B (ALDOB), and SerpinG1 (IC1). These proteins are not cardiac-specific but reflect multiorgan dysfunction, systemic inflammation, and immune activation. The CS4P improved reclassification of 32% of patients compared with the CardShock risk score. Summary: A new wave of research focused on novel proteomic and molecular techniques, is providing new candidates that promise to aid clinical decision-making and patient stratification in cardiogenic shock. The CS4P score is emerging as the most robust, yet it requires prospective validation in cardiogenic shock patients managed with circulatory and ventricular assist devices.