Indoxyl-sulfate activation of the AhR- NF-κB pathway promotes interleukin-6 secretion and the subsequent osteogenic differentiation of human valvular interstitial cells from the aortic valve.

BACKGROUND: Calcific aortic stenosis (CAS) is more prevalent, occurs earlier, progresses faster and has worse outcomes in patients with chronic kidney disease (CKD). The uremic toxin indoxyl sulfate (IS) is powerful predictor of cardiovascular mortality in these patients and a strong promoter of ectopic calcification whose role in CAS remains poorly studied. The objective of this study was to evaluate whether IS influences the mineralization of primary human valvular interstitial cells (hVICs) from the aortic valve. METHODS: Primary hVICs were exposed to increasing concentrations of IS in osteogenic medium (OM). The hVICs' osteogenic transition was monitored by qRT-PCRs for BMP2 and RUNX2 mRNA. Cell mineralization was assayed using the o-cresolphthalein complexone method. Inflammation was assessed by monitoring NF-κB activation using Western blots as well as IL-1ß, IL-6 and TNF-α secretion by ELISAs. Small interfering RNA (siRNA) approaches enabled us to determine which signaling pathways were involved. RESULTS: Indoxyl-sulfate increased OM-induced hVICs osteogenic transition and calcification in a concentration-dependent manner. This effect was blocked by silencing the receptor for IS (the aryl hydrocarbon receptor, AhR). Exposure to IS promoted p65 phosphorylation, the blockade of which inhibited IS-induced mineralization. Exposure to IS promoted IL-6 secretion by hVICs, a phenomenon blocked by silencing AhR or p65. Incubation with an anti-IL-6 antibody neutralized IS's pro-calcific effects. CONCLUSION: IS promotes hVIC mineralization through AhR-dependent activation of the NF-κB pathway and the subsequent release of IL-6. Further research should seek to determine whether targeting inflammatory pathways can reduce the onset and progression of CKD-related CAS.

Anatomical and biometric study of the radial artery on human cadavers dissected in the anatomy laboratory.

OBJECTIVE: To study the anatomy and biometry of the radial artery and to report the implications of this study for daily practice in Cardiac Surgery. METHOD: Radial arteries from 45 human cadavers (28 males and 17 females, average age 79.2 (92) fixed in 10% formalin were dissected. The proximal and distal internal calibers and lengths of these radial arteries were measured. RESULTS: Our results showed the presence of a single radial artery variation in 2.3% of the entire sample (1.1% of the 90 dissected upper limbs). The distance between the epicondyle and the emergence of the radial artery was 32.4 (6.67) mm in men and 30.7 (9.00) mm in women, with an average of 31.8 (7.58) mm. For the right upper limb, the mean proximal internal caliber of the radial artery was 3.16 (0.56) mm and its mean distal internal caliber was 2.62 (0.66) mm. For the left upper limb, the mean proximal internal caliber of the radial artery was 3.17 (0.59) mm and its mean distal internal caliber was 2.64 (0.68) mm. The mean length of the left radial artery was 197.0 (17) mm. The mean length of the right radial artery was 201.0 (33) mm. CONCLUSION: It is very important to be aware of the possible anatomical variation of the radial artery. Despite its rarity, this knowledge may ensure a better safety and reliability of the harvesting technique for use as a graft.

Early hyperoxia and 28-day mortality in patients on venoarterial ECMO support for refractory cardiogenic shock: a bicenter retrospective propensity score-weighted analysis.

BACKGROUND: The mortality rate for a patient with a refractory cardiogenic shock on venoarterial (VA) extracorporeal membrane oxygenation (ECMO) remains high, and hyperoxia might worsen this prognosis. The objective of the present study was to evaluate the association between hyperoxia and 28-day mortality in this setting. METHODS: We conducted a retrospective bicenter study in two French academic centers. The study population comprised adult patients admitted for refractory cardiogenic shock. The following arterial partial pressure of oxygen (PaO2) variables were recorded for 48 h following admission: the absolute peak PaO2 (the single highest value measured during the 48 h), the mean daily peak PaO2 (the mean of each day's peak values), the overall mean PaO2 (the mean of all values over 48 h), and the severity of hyperoxia (mild: PaO2 < 200 mmHg, moderate: PaO2 = 200-299 mmHg, severe: PaO2 ≥ 300 mmHg). The main outcome was the 28-day all-cause mortality. Inverse probability weighting (IPW) derived from propensity scores was used to reduce imbalances in baseline characteristics. RESULTS: From January 2013 to January 2020, 430 patients were included and assessed. The 28-day mortality rate was 43%. The mean daily peak, absolute peak, and overall mean PaO2 values were significantly higher in non-survivors than in survivors. In a multivariate logistic regression analysis, the mean daily peak PaO2, absolute peak PaO2, and overall mean PaO2 were independent predictors of 28-day mortality (adjusted odds ratio [95% confidence interval per 10 mmHg increment: 2.65 [1.79-6.07], 2.36 [1.67-4.82], and 2.85 [1.12-7.37], respectively). After IPW, high level of oxygen remained significantly associated with 28-day mortality (OR = 1.41 [1.01-2.08]; P = 0.041). CONCLUSIONS: High oxygen levels were associated with 28-day mortality in patients on VA-ECMO support for refractory cardiogenic shock. Our results confirm the need for large randomized controlled trials on this topic.

Individualised or liberal red blood cell transfusion after cardiac surgery: a randomised controlled trial.

BACKGROUND: Current practice guidelines for red blood cell (RBC) transfusion in ICUs are based on haemoglobin threshold, without consideration of oxygen delivery or consumption. We aimed to evaluate an individual physiological threshold-guided by central venous oxygen saturation ScvO2. METHODS: In a randomised study in two French academic hospitals, 164 patients who were admitted to ICU after cardiac surgery with postoperative haemoglobin <9 g dl-1 were randomised to receive a transfusion with one unit of RBCs (haemoglobin group) or transfusion only if the ScvO2 was <70% (individualised group). The primary outcome was the number of subjects receiving at least one unit of RBCs. The secondary composite outcome was acute kidney injury, stroke, myocardial infarction, acute heart failure, mesenteric ischaemia, or in-hospital mortality. One- and 6-month mortality were evaluated during follow-up. RESULTS: The primary outcome was observed for 80 of 80 subjects (100%) in the haemoglobin group and in 61 of 77 patients (79%) in the individualised group (absolute risk -21% [-32.0; -14.0]; P<0.001). There was no significant difference in the secondary outcome between the two groups. Follow-up showed a non-significant difference in mortality at 1 and 6 months. CONCLUSIONS: An individualised strategy based on an central venous oxygen saturation threshold of 70% allows for a more restrictive red blood cell transfusion strategy with no incidence on postoperative morbidity or 6-month mortality. CLINICAL TRIAL REGISTRATION: NCT02963883.

Activation of the calcium-sensing receptor in human valvular interstitial cells promotes calcification.

INTRODUCTION AND AIMS: Calcific aortic valve disease (CAVD) is the most common heart valve disease in western countries. It has been reported that activation of the calcium-sensing receptor(CaSR) expressed by vascular smooth muscle cells prevents vascular calcification. However, to date, the CaSR's expression and function in cardiac valves have not been studied. The present study sought to evaluate the presence of the CaSR within human valvular interstitial cells (hVICs), assess the CaSR's functionality, and ascertain its involvement in hVIC calcification. METHODS AND RESULTS: Data from Western blot, flow cytometry and immunocytochemistry experiments demonstrated that primary hVICs express the CaSR. The receptor was functional, since the incubation of hVICs with the calcimimetic R-568 significantly increased Ca2+-induced ERK1/2 phosphorylation, and exposure to the calcilytic NPS2143 reduced ERK1/2 activation. A reduction in endogenous CaSR expression by hVICs (using siRNA) was associated with significantly lower levels of Ca2+-induced mineralization (quantified using Alizarin Red staining). Similar data were obtained after the pharmacological inhibition of CaSR activity by the calcilytic NPS2143. In contrast, overexpression of a functional CaSR amplified Ca2+-induced calcification. Pharmacological activation of the CaSR with the calcimimetic R-568 showed similar effects. CaSR's procalcific properties are associated with increased osteogenic transition (as characterized by elevated mRNA expression of bone morphogenetic protein 2 and osterix), and reduced the expression of the calcification inhibitor osteopontin. Histological analysis of 12 human aortic tricuspid valves showed that CaSR expression was greater in calcified areas than in non-calcified areas. These data were confirmed by Western blots. CONCLUSIONS: To the best of our knowledge, this study is the first to have demonstrated that hVICs express a functional CaSR. Taken as a whole, our data suggest that activation of the CaSR expressed by hVICs might be a key promoter of CAVD progression.

Endothelial cells exposed to phosphate and indoxyl sulphate promote vascular calcification through interleukin-8 secretion.

BACKGROUND: Vascular calcification (VC) is amplified during chronic kidney disease, partly due to uraemic toxins such as inorganic phosphate (Pi) and indoxyl sulphate (IS) that trigger osteogenic differentiation of vascular smooth muscle cells (VSMCs). These toxins also alter endothelial cell (EC) functions but whether this contributes to VC is unknown. Here, we hypothesized that ECs exposed to Pi and IS promote VSMC calcification. METHODS: Human umbilical vein ECs were treated with Pi, IS or both, and then the conditioned media [endothelial cell conditioned medium (EC-CM)] was collected. Human aortic SMCs (HASMCs) were exposed to the same toxins, with or without EC-CM, and then calcification and osteogenic differentiation were evaluated. Procalcifying factors secreted from ECs in response to Pi and IS were screened. Rat aortic rings were isolated to assess Pi+IS-induced calcification at the tissue level. RESULTS: Pi and Pi+IS induced HASMCs calcification, which was significantly exacerbated by EC-CM. Pi+IS induced the expression and secretion of interleukin-8 (IL-8) from ECs. While IL-8 treatment of HASMCs stimulated the Pi+IS-induced calcification in a concentration-dependent manner, IL-8 neutralizing antibody, IL-8 receptors antagonist or silencing IL-8 gene expression in ECs before collecting EC-CM significantly prevented the EC-CM procalcifying effect. IL-8 did not promote the Pi+IS-induced osteogenic differentiation of HASMCs but prevented the induction of osteopontin (OPN), a potent calcification inhibitor. In rat aortic rings, IS also promoted Pi-induced calcification and stimulated the expression of IL-8 homologues. Interestingly, in the Pi+IS condition, IL-8 receptor antagonist lifted the inhibition of OPN expression and partially prevented aortic calcification. CONCLUSION: These results highlight a novel role of IL-8, whose contribution to VC in the uraemic state results at least from interaction between ECs and VSMCs.

The Involvement of miRNA in Carotid-Related Stroke.

Cardiovascular disease is the leading cause of morbidity and mortality in developed countries. Stroke is associated with a marked disability burden and has a major economic impact; this is especially true for carotid artery stroke. Major advances in primary and secondary prevention during the last few decades have helped to tackle this public health problem. However, better knowledge of the physiopathology of stroke and its underlying genetic mechanisms is needed to improve diagnosis and therapy. miRNAs are an important, recently identified class of post-transcriptional regulators of gene expression and are known to be involved in cerebrovascular disease. These endogenous, small, noncoding RNAs may have applications as noninvasive biomarkers and therapeutic tools in practice. Here, we review the involvement of several miRNAs in cell-based and whole-animal models of stroke, with a focus on human miRNA profiling studies of carotid artery stroke. Lastly, we describe the miRNAs' potential role as a biomarker of stroke.

Postoperative Vasoplegic Syndrome Is Associated With Impaired Endothelial Vasomotor Response in Cardiac Surgery: A Prospective, Observational Study.

OBJECTIVES: Vasoplegic syndrome (VS) affects up to 30% of cardiac surgery patients. Onset of VS may be associated with overproduction of nitric oxide (NO). The response of the brachial artery to NO can be assessed using flow-mediated vasodilation (FMD). The aim of this study was to assess brachial artery diameter and FMD response immediately after cardiac surgery. DESIGN: Prospective, observational study. SETTING: Single-center study in a tertiary teaching hospital. PATIENTS: Patients older than 18 years undergoing elective cardiac surgery with cardiopulmonary bypass who provided informed consent. INTERVENTIONS: Brachial artery diameter and FMD response were measured before cardiac surgery and just after surgery on admission to the intensive care unit. Patients were screened for VS for the following 48 hours. RESULTS: Eleven (39%) of the 28 patients included in the study developed VS. Brachial artery diameter and FMD differed between VS and non-VS patients. On intensive care unit admission, mean (± standard deviation) brachial artery diameter was greater in VS patients than in non-VS patients (3.9 ± 0.7 mm v 3.0 ± 0.8 mm, respectively; p = 0.002). Similarly, the FMD response after surgery was greater in VS patients than in non-VS patients (42% ± 8% v 31% ± 1%, respectively; p = 0.014). Brachial artery diameter and FMD response after surgery were both predictive of VS, with an area under the curve (95% confidence interval) of 0.850 (0.705-0.995) (p = 0.002) and 0.755 (0.56-0.95) (p = 0.047), respectively. CONCLUSION: Cardiac surgery with cardiopulmonary bypass appears to alter the NO-mediated endothelial vasomotor response.

miR-92a: A Novel Potential Biomarker of Rapid Aortic Valve Calcification.

BACKGROUND AND AIM OF THE STUDY: The study aim was to compare the tissular expression of microRNAs (miRs) in bicuspid and tricuspid valves, and to evaluate their use as potential novel biomarkers of aortic valve calcification in bicuspid valves. METHODS: A prospective single-center observational study was conducted on stenotic bicuspid and tricuspid human aortic valves. According to their potential role in valve vascular and valvular calcification, a decision was taken to include miR- 92a, miR-141, and miR-223 in this analysis. A real-time quantitative polymerase chain reaction was used to measure the expression of each miR, using U6 and Cel-miR-39 as endogenous and exogenous gene controls, respectively. RESULTS: Among a total of 47 human calcified aortic valves collected, 30 (63.8%) were tricuspid valves. The mean preoperative transvalvular gradient was 50.8 mmHg (range: 37-89 mmHg), with no significant difference between bicuspid and tricuspid valves (50 mmHg versus 51.2 mmHg; p = 0.729). The mean aortic valve area was 0.79 cm2 (range: 0.33-1.3 cm2), again with no significant difference between the two groups (p = 0.34). The level of miR-92a expression was twofold higher in bicuspid valves compared to tricuspid valves (0.38 versus 0.17; p = 0.016), but no significant difference in miR-141 and miR-223 expression was observed between the two groups (p = 0.68 and p = 0.35, respectively). A positive correlation was observed between miR-92a expression and mean preoperative transvalvular gradient (r = 0.3257, p = 0.04). CONCLUSIONS: miR-92a is overexpressed in calcified bicuspid aortic valves, and may serve as a potential biomarker of rapid aortic valve calcification. Further studies based on these results may be designed to correlate the relative expression of miR-92a in the serum with its tissular expression in AS.

MicroRNA deregulation in symptomatic carotid plaque.

OBJECTIVE: Embolization of carotid stenotic plaques is the direct cause of stroke in nearly 20% of cases. Genetic mechanisms and especially the roles played by microRNAs in the regulation of plaque destabilization and rupture are mostly unknown. The aim of this pilot study was to compare the expression of seven microRNAs allegedly involved in plaque growth and instability (miR-100, 125a, 127, 133a, 145, 155, and 221), between symptomatic and asymptomatic human carotid plaques. METHODS: Thirty patients undergoing carotid endarterectomy in our department were prospectively included. Carotid plaques were subdivided into symptomatic (n = 15) and asymptomatic (n = 15) according to the presence or absence of stroke. After isolation of total RNA from atherosclerotic plaques, microRNAs were quantified by real-time polymerase chain reaction. RESULTS: The two groups of patients were comparable in terms of age, gender, risk factors for cerebral ischemia, medication, and stenosis severity. All seven microRNAs were quantified in extracted carotid plaques. miR-100, miR-125a, miR-127, miR-133a, miR-145, and miR-221 were significantly overexpressed in symptomatic vs asymptomatic plaques. miR-125a expression was significantly inversely correlated with the circulating level of low-density lipoprotein cholesterol in the symptomatic group. CONCLUSIONS: This pilot study evaluated the expression of seven selected miRNAs in human carotid plaques from a small group of patients and suggested a potential regulatory role for these miRNAs in evolution of the plaque towards growth, instability and rupture. Studies based on larger sample sizes are required to determine the potential use of miR-100, miR-125a, miR-127, miR-133a, miR-145, and miR-221 as biomarkers or therapeutic targets for stroke.

Optimizing coronary artery opacification and 3D reconstruction from human cadaver hearts in anatomy research.

OBJECTIVE: This study seeks to identify the ideal dilution rate of a radiopaque product to optimize the visualization of coronary arteries and their branches within human cadaver hearts. The process involves obtaining images in the anatomy laboratory and subsequently constructing a three-dimensional model. MATERIALS AND METHODS: We utilized 30 human hearts fixed in 10 % formalin (9 females and 21 males) with a mean age of 79 ± 5 years. The initial experiment, involving the first four hearts (referred to as "group 1"), encountered difficulties in opacifying coronary arteries. In this phase, a probabilistic injection of 20 % Visipaque and 80 % latex, with coronary sinus ostium closure, was performed. The optimal mixture ratio was then determined as 33 % Visipaque and 66 % latex. Recognizing the need for on-site injection at the CT Scan table, this protocol was applied to the subsequent 11 hearts in "group 2." Closure of the coronary sinus was deemed unnecessary. The final 15 hearts, constituting "group 3," revealed that the injection should be gradual, maintaining controlled pressure between 120 and 150 mm Hg. Post-injection, hearts were scanned with the injected coronary arteries using an Optima 660 CT scanner. Two-dimensional images were acquired with parameters set at 64 × 0.625 mm, 100 kV, 300-400 mA, and a rotation of 0.5 s. Subsequently, 3D reconstruction was conducted using Advantage Workstation 4.7 (GE Healthcare) and volume rendering with Volume Viewer software, version 15. RESULTS: Significant differences in the percentage of opacified coronaries were observed among the three groups (p < 0.005). This variation underscores the learning curve and comprehension required before establishing a reliable method. Group 1 (N = 4) demonstrated minimal opacification, group 2 (N = 11) displayed partial opacification, while group 3 (N = 15) achieved 100 % opacification of coronary arteries. CONCLUSION: The successive experiments culminated in the development of a protocol for CT imaging, enabling accurate three-dimensional reconstruction of the normal anatomy of the main and secondary coronary arteries. Our work is grounded in a series of progressively refined and successful experiments.

Influence of age and sex on the thickness of the radial artery wall.

OBJECTIVE: The aim of this study is to investigate whether there is a relationship between age or sex and the thickness of the radial artery wall. MATERIALS AND METHODS: We harvested human radial arteries from 48 cadavers (30 men and 18 women) in the anatomy laboratory. Histological sections of 3 µm thickness were prepared at the Laboratory of Anatomy and Pathological Cytology, mounted on slides, and stained with hematoxylin-phloxine-safran, Masson's trichrome, and orcein. The thickness of each radial artery wall (intima-media thickness) was measured using optical microscopy, and an average measurement was established among the three thicknesses (upper third, middle third, and lower third). STATISTICAL METHODS: Statistical analyses were performed using the R software. Means and standard deviations were utilized. A correlation analysis was also conducted to assess the relationship between radial artery wall thickness and subjects' age. RESULTS: On average, the thickness of the left radial artery wall and that of the right radial artery measured 282 (34) micrometers (µm). We found a correlation between radial artery wall thickness and age in both men (p < 0.001) and women (p < 0.001). CONCLUSIONS: In conclusion, this study elucidates that radial artery wall thickness is related to age and sex in its assessment.

Prevention by the CXCR2 antagonist SCH527123 of the calcification of porcine heart valve cusps implanted subcutaneously in rats.

Introduction: Calcification is a main cause of bioprosthetic heart valves failure. It may be promoted by the inflammation developed in the glutaraldehyde (GA)-fixed cusps of the bioprosthesis. We tested the hypothesis that antagonizing the C-X-C chemokines receptor 2 (CXCR2) may prevent the calcification of GA-fixed porcine aortic valves. Materiel and methods: Four-week-old Sprague Dawley males were transplanted with 2 aortic valve cusps isolated from independent pigs and implanted into the dorsal wall. Four groups of 6 rats were compared: rats transplanted with GA-free or GA-fixed cusps and rats transplanted with GA-fixed cusps and treated with 1 mg/kg/day SCH5217123 (a CXCR2 antagonist) intraperitoneally (IP) or subcutaneously (SC) around the xenograft, for 14 days. Then, rats underwent blood count before xenografts have been explanted for histology and biochemistry analyses. Results: A strong calcification of the xenografts was induced by GA pre-incubation. However, we observed a significant decrease in this effect in rats treated with SCH527123 IP or SC. Implantation of GA-fixed cusps was associated with a significant increase in the white blood cell count, an effect that was significantly prevented by SCH527123. In addition, the expression of the CD3, CD68 and CXCR2 markers was reduced in the GA-fixed cusps explanted from rats treated with SCH527123 as compared to those explanted from non-treated rats. Conclusion: The calcification of GA-fixed porcine aortic valve cusps implanted subcutaneously in rats was significantly prevented by antagonizing CXCR2 with SCH527123. This effect may partly result from an inhibition of the GA-induced infiltration of T-cells and macrophages into the xenograft.

Anatomical and biometric study of the mitral valve apparatus: application in valve repair surgery.

OBJECTIVE: Most mitral valve repair techniques provide excellent surgical results by removing regurgitation, but all of these techniques simultaneously reduce posterior valve mobility. A comprehensive biometric study of the mitral valve apparatus will provide landmarks that would help improve this posterior valve mobility. MATERIALS AND METHODS: Thirty one (31) human hearts have been studied, from 14 women and 17 men. The characteristics of the studied sample were analyzed descriptively. The difference in means of the variables between women and men were tested using a Student t test. Correlations between the different measures were determined by simple regression analysis. Mean values are shown with ± 1 standard deviation and the limit of significance was set at 0.05. RESULTS: The mean weight of the hearts was 275.3 ± 2.4 g. The anteroposterior diameter of the mitral annulus was 29.3 ± 1.22 mm, the intertrigonal distance was 25.2 ± 3.50 mm and the anterior leaflet to posterior leaflet ratio was 1.9 ± 0.10, the length of the chordae A2 = 19.4 ± 1.15 mm and P2 = 14.5 ± 0.85 mm. The length of the anterior papillary muscle averaged 30.9 ± 7.20 mm and that of the posterior one 30.0 ± 8.75 mm. The comparison of the different values measured between women and men showed no statistically significant difference (p > 0.05). There was no correlation between these different measured values (p > 0.05). CONCLUSION: A perfect knowledge of anatomy and biometry is therefore essential to offer alternative techniques that reproduce the real anatomy and physiology with a complete reconstruction of the mitral valve.

Trends in SAVR with biological vs. mechanical valves in middle-aged patients: results from a French large multi-centric survey.

Background/introduction: Currently, despite continued issues with durability ( 1), biological prosthetic valves are increasingly chosen over mechanical valves for surgical aortic valve replacement (SAVR) in adult patients of all ages, at least in Western countries. For younger patients, this choice means assuming the risks associated with a redo SAVR or valve-in-valve procedure. Purpose: To assess the use of mechanical vs. biological valve prostheses for SAVR relative to patient's age and implant time in a large population extracted from the French National Database EPICARD. Methods: Patients in EPICARD undergoing SAVR from 2007 to 2022 were included from 22 participating public or private centers chosen to represent a balanced representation of centre sizes and geographical discrepancies. Patients with associated pathology of the aorta (aneurysm or dissection) and requiring a vascular aortic prosthesis were excluded. Comparisons were made amongst centers, valve choice, implant date range, and patient age. Results: We considered 101,070 valvular heart disease patients and included 72,375 SAVR (mean age 71.4 ± 12.2 years). We observed a mechanical vs. biological prosthesis ratio (MBPR) of 0.14 for the overall population. Before 50 years old (y-o), MBPR was >1.3 (p < 0.001) while patients above 60 years-old received principally biological SAVR (p < 0.0001). Concerning patients between 50 and 60 years-old patients, MPVR was 1.04 (p = 0.03). Patients 50-60 years-old from the first and second study duration quartile (before August 2015) received preferentially mechanical SAVR (p < 0.001). We observed a shift towards more biological SAVR (p < 0.001) for patients from the third and fourth quartile to reach a MBPR at 0.43 during the last years of the series. Incidentally, simultaneous mitral valve replacement were more common in case of mechanical SAVR (p < 0.0001), while associated CABGs were more frequent in case of biological SAVR (p < 0.0001). Conclusion: In a large contemporary French patient population, real world practice showed a recent shift towards a lower age-threshold for biological SAVR as compared to what would suggest contemporary guidelines.

Aortic valve calcification is promoted by interleukin-8 and restricted through antagonizing CXC motif chemokine receptor 2.

AIMS: Inflammatory cytokines play a critical role in the progression of calcific aortic valve disease (CAVD), for which there is currently no pharmacological treatment. The aim of this study was to test the hypothesis that interleukin-8 (IL-8), known to be involved in arterial calcification, also promotes aortic valve calcification (AVC) and to evaluate whether pharmacologically blocking the IL-8 receptor, CXC motif chemokine receptor 2 (CXCR2), could be effective in preventing AVC progression. METHODS AND RESULTS: A cohort of 195 patients (median age 73, 74% men) diagnosed with aortic valve stenosis (severe in 16.9% of cases) were prospectively followed by CT for a median time of 2.6 years. A Cox proportional hazards regression analysis indicated that baseline IL-8 serum concentrations were associated with rapid progression of AVC, defined as an annualized change in the calcification score by CT ≥ 110 AU/year, after adjustment for age, gender, bicuspid anatomy, and baseline disease severity. In vitro, exposure of primary human aortic valvular interstitial cells (hVICs) to 15 pg/mL IL-8 induced a two-fold increase in inorganic phosphate (Pi)-induced calcification. IL-8 promoted NFκB pathway activation, MMP-12 expression, and elastin degradation in hVICs exposed to Pi. These effects were prevented by SCH527123, an antagonist of CXCR2. The expression of CXCR2 was confirmed in hVICs and samples of aortic valves isolated from patients with CAVD, in which the receptor was mainly found in calcified areas, along with MMP-12 and a degraded form of elastin. Finally, in a rat model of chronic kidney disease-associated CAVD, SCH527123 treatment (1 mg/kg/day given orally for 11 weeks) limited the decrease in aortic cusp separation, the increase in maximal velocity of the transaortic jet, and the increase in aortic mean pressure gradient measured by echocardiography, effects that were associated with a reduction in hydroxyapatite deposition and MMP-12 expression in the aortic valves. CONCLUSION: Overall, these results highlight, for the first time, a significant role for IL-8 in the progression of CAVD by promoting calcification via a CXCR2- and MMP-12-dependent mechanism that leads to elastin degradation, and identify CXCR2 as a promising therapeutic target for the treatment of CAVD.

Surgical Aortic Valve Replacement in the Elderly: It Is Worth It!

To evaluate survival and quality of life of octogenarians after surgical aortic valve replacement (SAVR), up to 10 year of follow-up. Retrospective observational study on octogenarians operated for an isolated or combined SAVR in 2 centers between 2005 and 2011. Preoperative data were collected for each patient and updated regularly with last follow-up on July 2018. Early postoperative course was assessed for all patients. The primary outcome was late survival after discharge. Health-related quality of life was evaluated in all surviving patients using the Short-Form 12 questionnaire. Nine hundred and nine patients were included. The median age was 82 ± 2.6 years, with 400/909 females (44%). Isolated AVR was performed in 452/909 patients (49.7%). Early in-hospital mortality occurred in 71/909 patients (7.8%). Mean follow-up was 5.9 ± 3.4 years. Survival at 2, 5, and 10 years in the overall cohort was 89%, 70%, and 28%, respectively, without significant difference between isolated or combined AVR. Survival was significantly higher in patients with a Euroscore <8% (P< 0.0001). Multivariate analysis found that older age at surgery, diabetes, history of myocardial infarction, atrial fibrillation and chronic renal failure were predictors of long-term mortality. Finally, the SF-12 physical score was 40.7 ± 10.4 and mental and emotional score was 52.7 ± 8.6 at last follow-up, which falls within the expected range for the general population (50 ± 10) with comparable age. SAVR remains an effective treatment for aortic valve disease in octogenarians, not only increasing life expectancy but also conferring a long-standing quality of life with excellent valve durability.

Interchangeability of right ventricular longitudinal shortening fraction assessed by transthoracic and transoesophageal echocardiography in the perioperative setting: A prospective study.

Background: Conventional transthoracic (TTE) and transoesophageal echocardiography (TEE) parameters assessing right ventricle (RV) systolic function are daily used assuming their clinical interchangeability. RV longitudinal shortening fraction (RV-LSF) is a two-dimensional speckle tracking parameter used to assess RV systolic function. RV-LSF is based on tricuspid annular displacement analysis and could be measured with TTE or TEE. Objective: The aim of the study was to determine if RV-LSFTTE and RV-LSFTEE measurements were interchangeable in the perioperative setting. Methods: Prospective perioperative TTE and TEE echocardiography were performed under general anesthesia during scheduled cardiac surgery in 90 patients. RV-LSF was measured by semi-automatic software. Comparisons were performed using Pearson correlation and Bland-Altman plots. RV-LSF clinical agreement was determined as a range of -5 to 5%. Results: Of the 114 patients who met the inclusion criteria, 90 were included. The mean preoperative RV-LSFTTE was 20.4 ± 4.3 and 21.1 ± 4.1% for RV-LSFTEE. The agreement between RV-LSF measurements was excellent, with a bias at -0.61 and limits of agreement of -4.18 to 2.97 %. All measurements fell within the determined clinical agreement interval in the Bland-Altman plot. Linear regression analysis showed a high correlation between RV-LSFTTE and RV-LSFTEE measurement (r = 0.9; confidence interval [CI] 95%: [0.87-0.94], p < 0.001). Conclusion: RV-LSFTTE and RV-LSFTEE measurements are interchangeable, allowing RV-LSF to be a helpful parameter for assessing perioperative changes in RV systolic function. NCT: NCT05404737. https://www.clinicaltrials.gov/ct2/show/NCT05404737.

Guidelines on enhanced recovery after cardiac surgery under cardiopulmonary bypass or off-pump.

OBJECTIVE: To provide recommendations for enhanced recovery after cardiac surgery (ERACS) based on a multimodal perioperative medicine approach in adult cardiac surgery patients with the aim of improving patient satisfaction, reducing postoperative mortality and morbidity, and reducing the length of hospital stay. DESIGN: A consensus committee of 20 experts from the French Society of Anaesthesia and Intensive Care Medicine (Société française d'anesthésie et de réanimation, SFAR) and the French Society of Thoracic and Cardiovascular Surgery (Société française de chirurgie thoracique et cardio-vasculaire, SFCTCV) was convened. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. The entire guideline process was conducted independently of any industry funding. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide the assessment of the quality of evidence. METHODS: Six fields were defined: (1) selection of the patient pathway and its information; (2) preoperative management and rehabilitation; (3) anaesthesia and analgesia for cardiac surgery; (4) surgical strategy for cardiac surgery and bypass management; (5) patient blood management; and (6) postoperative enhanced recovery. For each field, the objective of the recommendations was to answer questions formulated according to the PICO model (Population, Intervention, Comparison, Outcome). Based on these questions, an extensive bibliographic search was carried out and analyses were performed using the GRADE approach. The recommendations were formulated according to the GRADE methodology and then voted on by all the experts according to the GRADE grid method. RESULTS: The SFAR/SFCTCV guideline panel provided 33 recommendations on the management of patients undergoing cardiac surgery under cardiopulmonary bypass or off-pump. After three rounds of voting and several amendments, a strong agreement was reached for the 33 recommendations. Of these recommendations, 10 have a high level of evidence (7 GRADE 1+ and 3 GRADE 1-); 19 have a moderate level of evidence (15 GRADE 2+ and 4 GRADE 2-); and 4 are expert opinions. Finally, no recommendations were provided for 3 questions. CONCLUSIONS: Strong agreement existed among the experts to provide recommendations to optimise the complete perioperative management of patients undergoing cardiac surgery.