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

Sepsis is an archetype of distributive shock and combines different levels of alterations in preload, afterload, and often cardiac contractility. The use of hemodynamic drugs has evolved over the past few years, along with the invasive and non-invasive tools used to measure these components in real time. However, none of them is impeccable, which is why the mortality of septic shock remains too high. The concept of ventriculo-arterial coupling (VAC) allows for the integration of these three fundamental macroscopic hemodynamic components. In this mini review, we discuss the knowledge, tools, and limitations of VAC measurement, along with the evidence supporting ventriculo-arterial uncoupling in septic shock. Finally, the impact of recommended hemodynamic drugs and molecules on VAC is detailed.

Hemodynamic impacts of apelin-13 in a neonatal lamb model of septic peritonitis.

BACKGROUND: Apelins are potential candidate therapeutic molecules for hemodynamic support. The objective of this study was to assess the hemodynamic impacts of apelin-13 in a neonatal lamb model of septic shock. METHODS: Lambs were randomized to receive apelin-13 or normal saline. Septic shock was induced by injecting a fecal slurry into the peritoneal cavity. Lambs underwent volume repletion (30 mL/kg over 1 h) followed by intravenous administration of 5 incremental doses (D) of apelin-13 (D1 = 0.039 to D5 = 19.5 µg/kg/h) or normal saline. RESULTS: Following fecal injection, mean arterial pressure (MAP) and cardiac index (CI) dropped in both groups (p < 0.05). The MAP decreased non-significantly from D1 to D5 (p = 0.12) in the saline group, while increasing significantly (p = 0.02) in the apelin group (-12 (-17; 12) vs. +15 (6; 23) % (p = 0.012)). Systemic vascular resistances were higher in the apelin-13 group at D5 compared to the saline group (4337 (3239, 5144) vs. 2532 (2286, 3966) mmHg/min/mL, respectively, p = 0.046). The CI increased non-significantly in the apelin-13 group. CONCLUSION: Apelin-13 increased MAP in a neonatal lamb septic shock model. IMPACT: Administration of apelin-13 stabilized hemodynamics during the progression of the sepsis induced in this neonatal lamb model. Systemic vascular resistances were higher in the apelin-13 group than in the placebo group. This suggests ontogenic differences in vascular response to apelin-13 and warrants further investigation. This study suggests that apelin-13 could eventually become a candidate for the treatment of neonatal septic shock.

Size-Reduced Macrocyclic Analogues of [Pyr1]-apelin-13 Showing Negative Gα12 Bias Still Produce Prolonged Cardiac Effects.

We previously reported a series of macrocyclic analogues of [Pyr1]-apelin-13 (Ape13) with increased plasma stability and potent APJ agonist properties. Based on the most promising compound in this series, we synthesized and then evaluated novel macrocyclic compounds of Ape13 to identify agonists with specific pharmacological profiles. These efforts led to the development of analogues 39 and 40, which possess reduced molecular weight (MW 1020 Da vs Ape13, 1534 Da). Interestingly, compound 39 (Ki 0.6 nM), which does not activate the Gα12 signaling pathway while maintaining potency and efficacy similar to Ape13 to activate Gαi1 (EC50 0.8 nM) and ß-arrestin2 recruitment (EC50 31 nM), still exerts cardiac actions. In addition, analogue 40 (Ki 5.6 nM), exhibiting a favorable Gα12-biased signaling and an increased in vivo half-life (t1/2 3.7 h vs <1 min of Ape13), produces a sustained cardiac response up to 6 h after a single subcutaneous bolus injection.

Relationship Between the Degree of Carotid Stenosis and the Risk of Stroke in Patients Undergoing Cardiac Surgery.

BACKGROUND: The impact of carotid stenosis (CS) in patients undergoing cardiac surgery remains controversial. The aim of this study was to evaluate the association between carotid stenosis and stroke and/or transient ischemic attack (TIA) in patients undergoing cardiac surgery on cardiopulmonary bypass. METHODS: This was a retrospective cohort study including patients undergoing cardiac surgery on cardiopulmonary bypass from January 2006 to March 2018 at the Québec Heart and Lung Institute. Data of patients' preoperative demographic characteristics, operative and postoperative variables were taken from a computerised database and patients' charts. Univariate and multivariate analyses were performed. RESULTS: A total of 20,241 patients were included in the study. Among those who had received preoperative carotid ultrasound, 516 (2.6% of the total population) had unilateral or bilateral CS ≥ 50%. Categorised levels of CS severity were identified as independent risk factors for postoperative stroke and/or TIA. There was an almost 3-fold increased risk of postoperative neurologic events in 80%-99% CS vs less severe 50%-79% CS (odds ratio 2.91, 95% confidence interval 1.30-6.54), suggesting that the degree of severity of CS is potentially a strong independent predictor of postoperative neurologic events. CONCLUSIONS: CS is an independent risk factor of postoperative stroke and/or TIA. This study suggests for the first time that the risk of stroke increases with the degree of severity of CS, with the greatest risk being for CS of 80%-99%. The strength of this relationship and potential causality effect should be further explored in a prospective study focusing on this population most at risk.

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

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.

Elabela Protects Spontaneously Hypertensive Rats From Hypertension and Cardiorenal Dysfunctions Exacerbated by Dietary High-Salt Intake.

Objectives: Arterial hypertension, when exacerbated by excessive dietary salt intake, worsens the morbidity and mortality rates associated with cardiovascular and renal diseases. Stimulation of the apelinergic system appears to protect against several circulatory system diseases, but it remains unknown if such beneficial effects are conserved in severe hypertension. Therefore, we aimed at determining whether continuous infusion of apelinergic ligands (i.e., Apelin-13 and Elabela) exerted cardiorenal protective effects in spontaneously hypertensive (SHR) rats receiving high-salt diet. Methods: A combination of echocardiography, binding assay, histology, and biochemical approaches were used to investigate the cardiovascular and renal effects of Apelin-13 or Elabela infusion over 6 weeks in SHR fed with normal-salt or high-salt chow. Results: High-salt intake upregulated the cardiac and renal expression of APJ receptor in SHR. Importantly, Elabela was more effective than Apelin-13 in reducing high blood pressure, cardiovascular and renal dysfunctions, fibrosis and hypertrophy in high-salt fed SHR. Unlike Apelin-13, the beneficial effects of Elabela were associated with a counter-regulatory role of the ACE/ACE2/neprilysin axis of the renin-angiotensin-aldosterone system (RAAS) in heart and kidneys of salt-loaded SHR. Interestingly, Elabela also displayed higher affinity for APJ in the presence of high salt concentration and better resistance to RAAS enzymes known to cleave Apelin-13. Conclusion: These findings highlight the protective action of the apelinergic system against salt-induced severe hypertension and cardiorenal failure. As compared with Apelin-13, Elabela displays superior pharmacodynamic and pharmacokinetic properties that warrant further investigation of its therapeutic use in cardiovascular and kidney diseases.

Constraining the Side Chain of C-Terminal Amino Acids in Apelin-13 Greatly Increases Affinity, Modulates Signaling, and Improves the Pharmacokinetic Profile.

Side-chain-constrained amino acids are useful tools to modulate the biological properties of peptides. In this study, we applied side-chain constraints to apelin-13 (Ape13) by substituting the Pro12 and Phe13 positions, affecting the binding affinity and signaling profile on the apelin receptor (APJ). The residues 1Nal, Trp, and Aia were found to be beneficial substitutions for Pro12, and the resulting analogues displayed high affinity for APJ (Ki 0.08-0.18 nM vs Ape13 Ki 0.7 nM). Besides, constrained (d-Tic) or α,α-disubstituted residues (Dbzg; d-α-Me-Tyr(OBn)) were favorable for the Phe13 position. Compounds 47 (Pro12-Phe13 replaced by Aia-Phe, Ki 0.08 nM) and 53 (Pro12-Phe13 replaced by 1Nal-Dbzg, Ki 0.08 nM) are the most potent Ape13 analogues activating the Gα12 pathways (53, EC50 Gα12 2.8 nM vs Ape13, EC50 43 nM) known to date, displaying high affinity, resistance to ACE2 cleavage as well as improved pharmacokinetics in vitro (t1/2 5.8-7.3 h in rat plasma) and in vivo.

Gαi-biased apelin analog protects against isoproterenol-induced myocardial dysfunction in rats.

Apelin receptor (APJ) activation by apelin-13 (APLN-13) engages both Gαi proteins and ß-arrestins, stimulating distinct intracellular pathways and triggering physiological responses like enhanced cardiac contractility. Substituting the C-terminal phenylalanine of APLN-13 with α-methyl-l-phenylalanine [(l-α-Me)Phe] or p-benzoyl-l-phenylalanine (Bpa) generates biased analogs inducing APJ functional selectivity toward Gαi proteins. Using these original analogs, we proposed to investigate how the canonical Gαi signaling of APJ regulates the cardiac function and to assess their therapeutic impact in a rat model of isoproterenol-induced myocardial dysfunction. In vivo and ex vivo infusions of either Bpa or (l-α-Me)Phe analogs failed to enhance rats' left ventricular (LV) contractility compared with APLN-13. Inhibition of Gαi with pertussis toxin injection optimized the cardiotropic effect of APLN-13 and revealed the inotropic impact of Bpa. Moreover, both APLN-13 and Bpa efficiently limited the forskolin-induced and PKA-dependent phosphorylation of phospholamban at the Ser16 in neonatal rat ventricular myocytes. However, only Bpa significantly reduced the inotropic effect of forskolin infusion in isolated-perfused heart, highlighting its efficient bias toward Gαi. Compared with APLN-13, Bpa also markedly improved isoproterenol-induced myocardial systolic and diastolic dysfunctions. Bpa prevented cardiac weight increase, normalized both ANP and BNP mRNA expressions, and decreased LV fibrosis in isoproterenol-treated rats. Our results show that APJ-driven Gαi/adenylyl cyclase signaling is functional in cardiomyocytes and acts as negative feedback of the APLN-APJ-dependent inotropic response. Biased APJ signaling toward Gαi over the ß-arrestin pathway offers a promising strategy in the treatment of cardiovascular diseases related to myocardial hypertrophy and high catecholamine levels.NEW & NOTEWORTHY By using more potent Gαi-biased APJ agonists that strongly inhibit cAMP production, these data point to the negative inotropic effect of APJ-mediated Gαi signaling in the heart and highlight the potential protective impact of APJ-dependent Gαi signaling in cardiovascular diseases associated with left ventricular hypertrophy.

Structure-Activity Relationship and Bioactivity of Short Analogues of ELABELA as Agonists of the Apelin Receptor.

ELABELA (ELA) is the second endogenous ligand of the apelin receptor (APJ). Although apelin-13 and ELA both target APJ, there is limited information on structure-activity relationship (SAR) of ELA. In the present work, we identified the shortest bioactive C-terminal fragment ELA23-32, which possesses high affinity for APJ (Ki 4.6 nM) and produces cardiorenal effects in vivo similar to those of ELA. SAR studies on conserved residues (Leu25, His26, Val29, Pro30, Phe31, Pro32) show that ELA and apelin-13 may interact differently with APJ. His26 and Val29 emerge as important for ELA binding. Docking and binding experiments suggest that Phe31 of ELA may bind to a tight groove distinct from that of Phe13 of Ape13, while the Phe13 pocket may be occupied by Pro32 of ELA. Further characterization of signaling profiles on the Gαi1, Gα12, and ß-arrestin2 pathways reveals the importance of aromatic residue at the Phe31 or Pro32 position for receptor activation.

Hypertonic sodium lactate improves microcirculation, cardiac function, and inflammation in a rat model of sepsis.

BACKGROUND: Hypertonic sodium lactate (HSL) may be of interest during inflammation. We aimed to evaluate its effects during experimental sepsis in rats (cecal ligation and puncture (CLP)). METHODS: Three groups were analyzed (n = 10/group): sham, CLP-NaCl 0.9%, and CLP-HSL (2.5 mL/kg/h of fluids for 18 h after CLP). Mesenteric microcirculation, echocardiography, cytokines, and biochemical parameters were evaluated. Two additional experiments were performed for capillary leakage (Evans blue, n = 5/group) and cardiac hemodynamics (n = 7/group). RESULTS: HSL improved mesenteric microcirculation (CLP-HSL 736 [407-879] vs. CLP-NaCl 241 [209-391] UI/pixel, p = 0.0006), cardiac output (0.34 [0.28-0.43] vs. 0.14 [0.10-0.18] mL/min/g, p < 0.0001), and left ventricular fractional shortening (55 [46-73] vs. 39 [33-52] %, p = 0.009). HSL also raised dP/dtmax slope (6.3 [3.3-12.1] vs. 2.7 [2.0-3.9] 103 mmHg/s, p = 0.04), lowered left ventricular end-diastolic pressure-volume relation (1.9 [1.1-2.3] vs. 3.0 [2.2-3.7] RVU/mmHg, p = 0.005), and reduced Evans blue diffusion in the gut (37 [31-43] vs. 113 [63-142], p = 0.03), the lung (108 [82-174] vs. 273 [222-445], p = 0.006), and the liver (24 [14-37] vs. 70 [50-89] ng EB/mg, p = 0.04). Lactate and 3-hydroxybutyrate were higher in CLP-HSL (6.03 [3.08-10.30] vs. 3.19 [2.42-5.11] mmol/L, p = 0.04; 400 [174-626] vs. 189 [130-301] µmol/L, p = 0.03). Plasma cytokines were reduced in HSL (IL-1ß, 172 [119-446] vs. 928 [245-1470] pg/mL, p = 0.004; TNFα, 17.9 [12.5-50.3] vs. 53.9 [30.8-85.6] pg/mL, p = 0.005; IL-10, 352 [267-912] vs. 905 [723-1243] pg/mL) as well as plasma VEGF-A (198 [185-250] vs. 261 [250-269] pg/mL, p = 0.009). CONCLUSIONS: Hypertonic sodium lactate fluid protects against cardiac dysfunction, mesenteric microcirculation alteration, and capillary leakage during sepsis and simultaneously reduces inflammation and enhances ketone bodies.

Apelin-13 Regulates Vasopressin-Induced Aquaporin-2 Expression and Trafficking in Kidney Collecting Duct Cells.

BACKGROUND/AIMS: Apelin and its G protein-coupled receptor APJ (gene symbol Aplnr) are strongly expressed in magnocellular vasopressinergic neurons suggesting that the apelin/APJ system plays a key role at the central level in regulating salt and water balance by counteracting the antiduretic action of vasopressin (AVP). Likewise, recent studies revealed that apelin exerts opposite effects to those of vasopressin induced on water reabsorption via a direct action on the kidney collecting duct. However, the underlying mechanisms of the peripheral action of apelin are not clearly understood. Here, we thus investigated the role of the apelin/APJ system in the regulation of water balance in the kidney, and more specifically its involvement in modulating the function of aquaporin-2 (AQP2) in the collecting duct. METHODS: Mouse cortical collecting duct cells (mpkCCD) were incubated in the presence of dDAVP and treated with or without apelin-13. Changes in AQP2 expression and localization were determined by immunoblotting and confocal immunofluorescence staining. RESULTS: Herein, we showed that the APJ was present in mpkCCD cells. Treatment of mpkCCD with apelin-13 reduced the cAMP production and antagonized the AVP-induced increase in AQP2 mRNA and protein expressions. Immunofluorescent experiments also revealed that the AVP-induced apical cell surface expression of AQP2, and notably its phosphorylated isoform AQP2-pS269, was considerably reduced following apelin-13 application to mpkCCD cells. CONCLUSION: Our data reinforce the aquaretic role of the apelin/APJ system in the fine regulation of body fluid homeostasis at the kidney level and its physiological opposite action to the antiduretic activity of AVP.

In Vivo Endomicroscopy of Lung Injury and Repair in ARDS: Potential Added Value to Current Imaging.

BACKGROUND: Standard clinical imaging of the acute respiratory distress syndrome (ARDS) lung lacks resolution and offers limited possibilities in the exploration of the structure-function relationship, and therefore cannot provide an early and clear discrimination of patients with unexpected diagnosis and unrepair profile. The current gold standard is open lung biopsy (OLB). However, despite being able to reveal precise information about the tissue collected, OLB cannot provide real-time information on treatment response and is accompanied with a complication risk rate up to 25%, making longitudinal monitoring a dangerous endeavor. Intravital probe-based confocal laser endomicroscopy (pCLE) is a developing and innovative high-resolution imaging technology. pCLE offers the possibility to leverage multiple and specific imaging probes to enable multiplex screening of several proteases and pathogenic microorganisms, simultaneously and longitudinally, in the lung. This bedside method will ultimately enable physicians to rapidly, noninvasively, and accurately diagnose degrading lung and/or fibrosis without the need of OLBs. OBJECTIVES AND METHODS: To extend the information provided by standard imaging of the ARDS lung with a bedside, high-resolution, miniaturized pCLE through the detailed molecular imaging of a carefully selected region-of-interest (ROI). To validate and quantify real-time imaging to validate pCLE against OLB. RESULTS: Developments in lung pCLE using fluorescent affinity- or activity-based probes at both preclinical and clinical (first-in-man) stages are ongoing-the results are promising, revealing correlations with OLBs in problematic ARDS. CONCLUSION: It can be envisaged that safe, high-resolution, noninvasive pCLE with activatable fluorescence probes will provide a "virtual optical biopsy" and will provide decisive information in selected ARDS patients at the bedside.

The apelinergic system: a perspective on challenges and opportunities in cardiovascular and metabolic disorders.

The apelinergic pathway has been generating increasing interest in the past few years for its potential as a therapeutic target in several conditions associated with the cardiovascular and metabolic systems. Indeed, preclinical and, more recently, clinical evidence both point to this G protein-coupled receptor as a target of interest in the treatment of not only cardiovascular disorders such as heart failure, pulmonary arterial hypertension, atherosclerosis, or septic shock, but also of additional conditions such as water retention/hyponatremic disorders, type 2 diabetes, and preeclampsia. While it is a peculiar system with its two classes of endogenous ligand, the apelins and Elabela, its intricacies are a matter of continuing investigation to finely pinpoint its potential and how it enables crosstalk between the vasculature and organ systems of interest. In this perspective article, we first review the current knowledge on the role of the apelinergic pathway in the above systems, as well as the associated therapeutic indications and existing pharmacological tools. We also offer a perspective on the challenges and potential ahead to advance the apelinergic system as a target for therapeutic intervention in several key areas.

Hemodynamic support in the early phase of septic shock: a review of challenges and unanswered questions.

BACKGROUND: Improving sepsis support is one of the three pillars of a 2017 resolution according to the World Health Organization (WHO). Septic shock is indeed a burden issue in the intensive care units. Hemodynamic stabilization is a cornerstone element in the bundle of supportive treatments recommended in the Surviving Sepsis Campaign (SSC) consecutive biannual reports. MAIN BODY: The "Pandera's box" of septic shock hemodynamics is an eternal debate, however, with permanent contentious issues. Fluid resuscitation is a prerequisite intervention for sepsis rescue, but selection, modalities, dosage as well as duration are subject to discussion while too much fluid is associated with worsen outcome, vasopressors often need to be early introduced in addition, and catecholamines have long been recommended first in the management of septic shock. However, not all patients respond positively and controversy surrounding the efficacy-to-safety profile of catecholamines has come out. Preservation of the macrocirculation through a "best" mean arterial pressure target is the actual priority but is still contentious. Microcirculation recruitment is a novel goal to be achieved but is claiming more knowledge and monitoring standardization. Protection of the cardio-renal axis, which is prevalently injured during septic shock, is also an unavoidable objective. Several promising alternative or additive drug supporting avenues are emerging, trending toward catecholamine's sparing or even "decatecholaminization." Topics to be specifically addressed in this review are: (1) mean arterial pressure targeting, (2) fluid resuscitation, and (3) hemodynamic drug support. CONCLUSION: Improving assessment and means for rescuing hemodynamics in early septic shock is still a work in progress. Indeed, the bigger the unresolved questions, the lower the quality of evidence.

Fluorescence Endomicroscopy Imaging of Mesenchymal Stem Cells in the Rat Lung.

Stem cell therapy has shown great promise for organ repair and regeneration. In the context of lung disease, such as radiation-induced lung damage (RILD) in cancer radiotherapy, mesenchymal stem cells (MSCs) have shown the ability to reduce damage possibly due to their immunomodulatory properties and other unknown mechanisms. However, once MSCs are transplanted into the body, little is known as to their localization or their mechanisms of action. In this work, we proposed, implemented, and validated a fluorescence endomicroscopy (FE) imaging technique that allows for the real-time detection and quantification of transplanted pre-labeled MSCs in vivo and tracking in a rat model. This protocol covers aspects related to MSCs extraction, labeling, FE imaging, and image analysis developed in a RILD rat model but applicable to other biological systems. © 2018 by John Wiley & Sons, Inc.

The hypotensive effect of activated apelin receptor is correlated with ß-arrestin recruitment.

The apelinergic system is an important player in the regulation of both vascular tone and cardiovascular function, making this physiological system an attractive target for drug development for hypertension, heart failure and ischemic heart disease. Indeed, apelin exerts a positive inotropic effect in humans whilst reducing peripheral vascular resistance. In this study, we investigated the signaling pathways through which apelin exerts its hypotensive action. We synthesized a series of apelin-13 analogs whereby the C-terminal Phe13 residue was replaced by natural or unnatural amino acids. In HEK293 cells expressing APJ, we evaluated the relative efficacy of these compounds to activate Gαi1 and GαoA G-proteins, recruit ß-arrestins 1 and 2 (ßarrs), and inhibit cAMP production. Calculating the transduction ratio for each pathway allowed us to identify several analogs with distinct signaling profiles. Furthermore, we found that these analogs delivered i.v. to Sprague-Dawley rats exerted a wide range of hypotensive responses. Indeed, two compounds lost their ability to lower blood pressure, while other analogs significantly reduced blood pressure as apelin-13. Interestingly, analogs that did not lower blood pressure were less effective at recruiting ßarrs. Finally, using Spearman correlations, we established that the hypotensive response was significantly correlated with ßarr recruitment but not with G protein-dependent signaling. In conclusion, our results demonstrated that the ßarr recruitment potency is involved in the hypotensive efficacy of activated APJ.

A Systematic Exploration of Macrocyclization in Apelin-13: Impact on Binding, Signaling, Stability, and Cardiovascular Effects.

The apelin receptor generates increasing interest as a potential target across several cardiovascular indications. However, the short half-life of its cognate ligands, the apelin peptides, is a limiting factor for pharmacological use. In this study, we systematically explored each position of apelin-13 to find the best position to cyclize the peptide, with the goal to improve its stability while optimizing its binding affinity and signaling profile. Macrocyclic analogues showed a remarkably higher stability in rat plasma (half-life >3 h versus 24 min for Pyr-apelin-13), accompanied by improved affinity (analogue 15, Ki 0.15 nM and t1/2 6.8 h). Several compounds displayed higher inotropic effects ex vivo in the Langendorff isolated heart model in rats (analogues 13 and 15, maximum response at 0.003 nM versus 0.03 nM of apelin-13). In conclusion, this study provides stable and active compounds to better characterize the pharmacology of the apelinergic system.

The apelinergic system as an alternative to catecholamines in low-output septic shock.

Catecholamines, in concert with fluid resuscitation, have long been recommended in the management of septic shock. However, not all patients respond positively and controversy surrounding the efficacy-to-safety profile of catecholamines has emerged, trending toward decatecholaminization. Contextually, it is time to re-examine the "maintaining blood pressure" paradigm by identifying safer and life-saving alternatives. We put in perspective the emerging and growing knowledge on a promising alternative avenue: the apelinergic system. This target exhibits invaluable pleiotropic properties, including inodilator activity, cardio-renal protection, and control of fluid homeostasis. Taken together, its effects are expected to be greatly beneficial for patients in septic shock.

Image-Guided Fluorescence Endomicroscopy: From Macro- to Micro-Imaging of Radiation-Induced Pulmonary Fibrosis.

Radiation-induced pulmonary fibrosis (RIPF) is a debilitating side effect of radiation therapy (RT) of several cancers including lung and breast cancers. Current clinical methods to assess and monitor RIPF involve diagnostic computed tomography (CT) imaging, which is restricted to anatomical macroscopic changes. Confocal laser endomicroscopy (CLE) or fluorescence endomicroscopy (FE) in combination with a fibrosis-targeted fluorescent probe allows to visualize RIPF in real-time at the microscopic level. However, a major limitation of FE imaging is the lack of anatomical localization of the endomicroscope within the lung. In this work, we proposed and validated the use of x-ray fluoroscopy-guidance in a rat model of RIPF to pinpoint the location of the endomicroscope during FE imaging and map it back to its anatomical location in the corresponding CT image. For varying endomicroscope positions, we observed a positive correlation between CT and FE imaging as indicated by the significant association between increased lung density on CT and the presence of fluorescent fiber structures with FE in RT cases compared to Control. Combining multimodality imaging allows visualization and quantification of molecular processes at specific locations within the injured lung. The proposed image-guided FE method can be extended to other disease models and is amenable to clinical translation for assessing and monitoring fibrotic damage.

Improving the evaluation of cardiac function in rats at 7T with denoising filters: a comparison study.

BACKGROUND: We investigate the use of different denoising filters on low signal-to-noise ratio cardiac images of the rat heart acquired with a birdcage volume coil at 7T. Accuracy and variability of cardiac function parameters were measured from manual segmentation of rat heart images with and without filtering. METHODS: Ten rats were studied using a 7T Varian system. End-diastolic and end-systolic volumes, ejection fraction and left ventricle mass (LVM) were calculated from manual segmentation by two experts on cine-FLASH short-axis slices covering the left ventricle. Series were denoised with an anisotropic diffusion filter, a whole variation regularization or an optimized Rician non-local means (ORNLM) filtering technique. The effect of the different filters was evaluated by the calculation of signal-to-noise (SNR) and contrast-to-noise (CNR) ratios, followed by a study of intra- and inter-expert variability of the measurement of physiological parameters. The calculated LVM was compared to the LVM obtained by weighing the heart ex vivo. RESULTS: The SNR and the CNR increased after application of the different filters. The performance of the ORNLM filter was superior for all the parameters of the cardiac function, as judged from the inter- and intra-observer variabilities. Moreover, this filtering technique resulted in the lowest variability in the LVM evaluation. CONCLUSIONS: In cardiac MRI of rats, filtering is an interesting alternative that yields better contrast between myocardium and surrounding tissues and the ORNLM filter provided the largest improvements.